COMPOUND, PHARMACEUTICAL COMPOSITION, METHODS TO INHIBIT PD-1, PD-L1 AND / OR THE INTERACTION OF PD-

专利摘要:
there are described compounds of formula (i), methods of using said compounds individually or in combination with additional agents and compositions of said compounds for the treatment of cancer.
公开号:BR112020016466A2
申请号:R112020016466-6
申请日:2019-02-12
公开日:2020-12-15
发明作者:Evangelos Aktoudianakis；Devan Naduthambi；Eric Q. Parkhill；Barton W. Phillips (Falecido)；Scott Preston Simonovich；Neil H. Squires；Peiyuan Wang；Jie Xu；William J. Watkins；Christopher Allen Ziebenhaus；Kin Shing Yang；Aesop Cho；Zhimin Du；Michael Graupe；Lateshkumar Thakorlal Lad；Paulo A. Machicao Tello；Jonathan William Medley；Samuel E. Metobo；Prasenjit Kumar Mukherjee
申请人:Gilead Sciences, Inc.；
IPC主号:

专利说明:

[001] [001] This application claims the benefit under 35 USC § 119 (e) of United States Provisional Applications No. 62 / 630,187, filed on February 13, 2018, 62 / 640,534, filed on March 8, 2018, 62 / 763,116 , filed on April 19, 2018, and 62 / 747,029, filed on October 17, 2018, each of which is hereby incorporated herein in its entirety as a reference. FIELD
[002] [002] The present description generally refers to compounds useful as inhibitors of PD-1, PD-L1 or the interaction of PD-1 / PD-L1. Compounds, compositions comprising such compounds, and method for using them are provided. FUNDAMENTALS
[003] [003] Programmed Death-1 (Programmed Death-1, PD-1) (CD279) is a T-cell receptor that has been shown to suppress T-cell receptor activation signals when bound by any one of its ligands, Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) or PD-L2 (CD273, B7-DC). When T-cells that express PD-1 contact cells that express their ligands, functional activities in response to antigenic stimuli are reduced, including proliferation, cytokine secretion, and cytotoxicity. The interactions of PD-1 / PD ligand infragulate immune responses during the resolution of an infection or tumor, or during the development of self-tolerance. Chronic antigenic stimulation,
[004] [004] Blocking the binding of PD-1 / PD-L1 using antibodies to PD-L1 has been shown to restore and increase T-cell activation in many systems. Advanced cancer patients benefit from therapy with a monoclonal antibody to PD-L1. Pre-clinical animal models of tumors and chronic infections have shown that blocking the PD-1 / PD-L1 pathway by monoclonal antibodies can enhance the immune response and result in tumor rejection or infection control. Antitumor immunotherapy via PD-1 / PD-L1 blockade can increase the therapeutic immune response to numerous histologically different tumors.
[005] [005] Interference with the PD-1 / PD-L1 interaction has also shown enhanced T-cell activity in chronic infection systems. Chronic infection by the mouse lymphocytic choriomeningitis virus also shows improved viral clearance and restored immunity with PD-L1 blockade. Humanized mice infected with HIV-1 show enhanced protection against viremia and viral depletion of CD4 + T-cells. Blocking PD-1 / PD-L1 by monoclonal antibodies to PD-L1 can restore antigen-specific functionality in vitro for T-cells of HIV patients, HCV patients or HBV patients.
[006] [006] Consequently, agents that block PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1 are desired. Small molecular agents that block or inhibit PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1 are particularly desired. Applicants have discovered small molecular compounds that have activity as PD-1, PD-L1 inhibitors
[007] [007] The present description provides a compound of formula (I): (Z1) n N Q-RE W
[008] [008] The present description additionally provides a compound of formula (I): (I) where: each n is independently 0, 1, 2, 3 or 4; each Z1 is independently halo, -ORa, -NO2, -CN, -NRaRb, -N3, -S (O) 2Ra, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -O2 alkynyl - C1-6 alkyl, -O-C1-6 haloalkyl, -C3-8 cycloalkyl or -C1-6 alkyl- C3-8 cycloalkyl; each group being alkyl, alkenyl, alkynyl, and
[009] [009] Also provided here are compounds from Table 1, or a salt
[0010] [0010] The present description provides a method of inhibiting PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1 comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, to a patient who needs it.
[0011] [0011] The present description provides a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, to a patient in need of same.
[0012] [0012] One embodiment provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, for the treatment of cancer or a condition in a patient who is responsive to treatment by inhibiting PD-1, PD-L1, or the interaction of PD-1 / PD-L1 comprising administering said compound of formula (I) to said patient who needs it.
[0013] [0013] In one embodiment, a method is provided to treat a cancer and the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer , cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS (Central Nervous System) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, comprising administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt,
[0014] [0014] In one embodiment, a method is provided to treat a cancer or condition in a patient who is responsive to treatment by inhibiting PD-1, PD-L1 or the interaction of PD-1 / PD- L1 selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head cancer and neck, melanoma, neuroendocrine cancer, CNS (Central Nervous System) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer and colon cancer comprising administering an amount therapeutically effective use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof to a patient who needs it, additionally comprising administering at least one anti-cancer agent r additional or additional anti-cancer therapy to a patient who needs it. In certain modalities, the additional anti-cancer agent or additional anti-cancer therapy is selected from among nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiotherapy, and resection therapy, to a patient who needs it.
[0015] [0015] In one embodiment, a method is provided for treating hepatitis B virus (HBV), comprising administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof to a patient who needs it.
[0016] [0016] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, is provided for the treatment of cancer or
[0017] [0017] In one embodiment, the present description provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, in combination with at least one additional anticancer agent selected from rituxan, doxorubicin, gemcitabine , nivolumab, pembrolizumab, and ipilimumab.
[0018] [0018] In one embodiment, the present description provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, in combination with at least one additional checkpoint inhibitor selected from nivolumab, pembrolizumab, atezolizumab, and ipilimumab.
[0019] [0019] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
[0020] [0020] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, and at least one additional anticancer agent and at least one carrier or pharmaceutically acceptable excipient.
[0021] [0021] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, at least one additional therapeutic agent suitable for treating an infection by HBV, and at least one pharmaceutically acceptable carrier or excipient.
[0022] [0022] In one embodiment, the present description provides a kit that includes a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, a label and / or instructions for using the compound in treatment cancer or a disease or condition mediated by the activity of PD-1, PD-L1 or the interaction of PD-1 / PD-L1.
[0023] [0023] In one embodiment, the present description provides a kit that includes a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, at least one additional anticancer agent, a label (s) and / or instructions for using the compound (s) in the treatment of a disease or condition mediated by the activity of PD-1, PD-L1 or the interaction of PD-1 / PD-L1.
[0024] [0024] In one embodiment, the present description provides articles of manufacture that include a compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof; and a container. In one embodiment, the container can be a vial, a pot, an ampoule, a pre-filled syringe, or an intravenous bag.
[0025] [0025] In one embodiment, the present description provides a compound
[0026] [0026] In another embodiment, the present description provides a compound of formula (I) for use in the manufacture of a drug to treat cancer. DESCRIPTION OF THE FIGURES
[0027] [0027] Figure 1, panels A (Figure 1A) and B (Figure 1B), show that compound 139 intensifies the production of IFN-γ and Granzyme B in CD8 + T-cells of chronic hepatitis B (CHB, Chronic Hepatitis B ).
[0028] [0028] Figure 2, panels A (Figure 2A) and B (Figure 2B), show that compound 139 intensifies the production of IFN-γ and Granzyme B in CD4 + T-cells of chronic hepatitis B (CHB).
[0029] [0029] Figure 3 shows the experimental design for inactivating mouse PD-L1 and replacing it with human PD-L1 in a MC38 colorectal tumor cell line in mouse.
[0030] [0030] Figure 4 shows the relationship between HR (Pharmacokinetics) (Figure 4A) and OA (Target Occupation) (Figure 4B) for compound 139 on Day 6 in a tumor model MC38, in mouse C57BL / 6, which expresses PD-L1 from human.
[0031] [0031] Figure 5 shows the antitumor activity of compound 139 in a mouse model MC38, which expresses human PD-L1.
[0032] [0032] As used in the present description, the following words and phrases are generally intended to have the meanings as presented below unless otherwise expressly indicated or the context in which they are used indicates otherwise.
[0033] [0033] The following description presents exemplifying methods, exemplifying parameters and the like. It should be recognized, however,
[0034] [0034] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set out below, except as the context in which they are used indicates otherwise.
[0035] [0035] A hyphen ("-") that is not between two letters or two symbols is used to indicate a point of attachment for a substituent. For example, - C (O) NH2 is bonded via the carbon atom. A hyphen in front of or at the end of a chemical group is a matter of convenience; chemical groups can be represented with or without one or more hyphens without losing their common meaning. Unless it is chemically or structurally required, no directionality is indicated or implied in the order in which a chemical group is written or named.
[0036] [0036] A wavy line in a chemical group, as shown below, for example, indicates a connection point, that is, it shows the broken connection by which the group is connected to another described group.
[0037] [0037] The suffix “Cu-v” indicates that the group before it has from u to v carbon atoms. For example, "C1-6alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.
[0038] [0038] Reference to "about" a value or parameter here includes (and describes) modalities that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other modalities, the term “about” includes the indicated amount ± 5%. In certain other modalities, the term “about” includes the indicated amount ± 1%. Also, the term "about X" includes the description of "X". Also, the forms in the singular “one”, “one”, “o” and
[0039] [0039] The term "substituted" means that one or more (for example, one to three, or one to five) hydrogen atoms in the designated atom or group is replaced by one or more (for example, one to three, or one to five) different hydrogen substituents, provided that the normal valence of the designated atom is not exceeded. The one or more (e.g., one to three, or one to five) substituents, include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, starch, amidino, aryl, azido, carbamoyl, carboxyl , carboxylic ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar undefined structures obtained by the substituents defined with additional substituents attached ad infinitum (for example, a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is additionally substituted with a heteroaryl group substituted, etc.) are not intended for inclusion here, whether the same or different substituents. Unless otherwise indicated, the maximum number of serial substitutions for compounds described herein is three. For example, serial substitutions of aryl groups substituted with two other substituted aryl groups are limited to substituted aryl - ((substituted aryl) (substituted aryl). Similarly, the above definitions are not intended to include non-permissible substitution patterns (for example, methyl substituent with 5 fluorines or heteroaryl groups having two adjacent oxygen atoms in the ring. Such non-permissible substitution patterns are well
[0040] [0040] A "substituted" group also includes modalities in which a monoradical substituent is attached to a single atom of the substituted group (for example, forming a branch), and also includes modalities in which the substituent can be a diradical bridge-forming group attached to two adjacent atoms of the substituted group, thus forming a fused ring in the substituted group.
[0041] [0041] "Alkyl" refers to a branched or unbranched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20alkyl), 1 to 8 carbon atoms (i.e., C1-8alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl) ), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by the chemical name or identified by the molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., - (CH2) 3CH3), sec-butyl (i.e., -CH (CH3) CH2CH3), isobutyl (i.e., -CH2CH (CH3) 2 ) and tert-butyl (i.e., -C (CH3) 3); and "propyl" includes n-propyl (i.e., - (CH2) 2CH3) and isopropyl (i.e., -CH (CH3) 2).
[0042] [0042] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (ie, C2-20 alkenyl), 2 to 8 carbon atoms (ie , C2- alkenyl
[0043] [0043] "Alquinyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (ie, C2-20 alkynyl), 2 to 8 carbon atoms (ie , C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes those groups having a triple bond and a double bond.
[0044] [0044] "Alkoxyl" refers to the group "alkyl-O-" or "-O-alkyl". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxyl, sec-butoxy, n-pentoxyl, n-hexoxy, and 1,2-dimethylbutoxy.
[0045] [0045] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (for example, one to three, or one to five) hydrogen atoms are replaced by a halogen.
[0046] [0046] "Amino" refers to a group -NRyRz in which Ry and Rz are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each of which can be optionally replaced.
[0047] [0047] "Aryl" refers to a monoradical or diradical aromatic carbocyclic group having a single ring (for example, monocyclic) or multiple rings (for example, bicyclic or tricyclic) including fused ring systems in which one or more (for example) example, one, two, or three) fused rings are / are completely or partially unsaturated (s). As used herein, aryl has 6 to 20 carbon atoms in the ring (ie, arylC6-20), 6 to 12 carbon atoms in the ring (ie, arylC6-12), or 6 to 10 carbon atoms in the ring (ie is, arilaC6-10). Non-limiting examples of aryl groups as used herein include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanyl, and
[0048] [0048] The term "alkylsulfinyl" refers to the group -S (O) -alkyl, where alkyl is as defined above, and includes optionally substituted alkyl groups as also defined above.
[0049] [0049] The term "alkylsulfonyl" refers to the group -S (O) 2alkyl, where alkyl is as defined above, and includes optionally substituted alkyl groups as also defined above.
[0050] [0050] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (ie, C3-12 cycloalkyl), 3 to 10 ring carbon atoms ( i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term "cycloalkenyl" refers to the non-aromatic carbocyclic group (partially saturated cyclic alkyl) having at least one double bond.
[0051] [0051] "Cyanoalkyl" refers to an alkyl group substituted with cyano (CN).
[0052] [0052] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.
[0053] [0053] The term "haloalkyl" refers to a monoradical or diradical having the indicated carbon atoms of the alkyl group in which one or more (for example, one to three, or one to five) hydrogen atoms are replaced by a halogen. Examples of haloalkyl groups include - CH2F, -CHF2, -CF3, -CH2CF3, -CHFCH2F, -CF2-, -CHF-, and the like. Similarly, the term "haloalkoxy", for example, –O-haloalkylC1-3, refers to an alkoxyl group in which one or more (for example, one to three, or one to five) hydrogen atoms of the alkyl group are replaced by a halogen. Examples of haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCHFCH2F, and the like. A person skilled in the art is aware that similar definitions apply to alkenyl and alkynyl analogues (for example, C2-4 haloalkenyl, -O-haloalkylyl2-4).
[0054] [0054] "Heteroalkyl" refers to an alkyl group in which one or more (for example, one to three, or one to five) of the carbon atoms (and any associated hydrogen atoms) are each independently substituted with the same or different heteroaromatic groups. The term "heteroalkyl" includes branched or unbranched saturated chains having carbon and heteroatoms. As an example, 1, 2 or 3 carbon atoms can be independently substituted with the same or different heteroaromatic group. Heteroaromatic groups include, but are not limited to, -NR-, -O-, -S-, -S (O) -, -S (O) 2-, and the like, where R is H, alkyl, aryl, cycloalkyl , heteroalkyl, heteroaryl, or heterocycloalkyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, - NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which can be optionally substituted . As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 hetero atoms, 1 to 2 hetero atoms, or 1 hetero atom.
[0055] [0055] "Heteroaryl" refers to a monoradical or diradical aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more hetero atoms in the ring independently selected from nitrogen, oxygen, and sulfur. The term includes fused ring systems in which one or more (for example, one, two, or three) fused rings is / are completely or partially unsaturated (s). As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 ring carbon atoms ( i.e., C3-8 heteroaryl); and 1 to 5 hetero atoms, 1 to 4 hetero atoms, 1 to 3 ring hetero atoms, 1 to 2 ring hetero atoms, or 1 ring hetero atoms independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, benzodioxanyl, indolinyl, and pyrazolyl. The classification of monoradical or diradical indicates whether the heteroaryl group ends the chain (monoradical) or is within a chain (diradical). The above definition does not exclude additional substituents in the heteroaryl group. For example, the heteroaryl group in "A-heteroaryl-B" is a diradical while the heteroaryl group in "A-B-heteroaryl" is monoradical, although additional substituents may be present in the heteroaryl group. Heteroaryl does not cover or coincide with aryl as defined above.
[0056] [0056] "Heterocycloalkyl" refers to a saturated or unsaturated cyclic alkyl group, with one or more hetero atoms in the ring independently selected from nitrogen, oxygen and sulfur. The heterocycloalkyl can be a single ring or multiple rings with the multiple rings being fused, bridged, or spiro. As used herein, heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocycloalkyl), 2 to 10 ring carbon atoms (ie It's,
[0057] [0057] The term "heterocyclyl", "heterocycle", or "heterocyclic" refers to a saturated or unsaturated monoradical or diradical group having a single ring or multiple condensed rings, having 3 to 12 carbon atoms, from 1 to 6 heteroatoms, or 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and / or oxygen within the ring. If the group does not
[0058] [0058] The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), heterocyclyl-bridging groups, heterocyclyl-fused groups, and spiro-heterocyclyl groups. A heterocyclyl can be a single ring or multiple rings with multiple rings being fused, bridged, or spiro. Any non-aromatic ring containing at least one hetero atom is considered a heterocyclyl, regardless of the bond (that is, it can be linked by means of a carbon atom or a hetero atom). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, whose ring may be fused to an aryl or heteroaryl ring, regardless of binding to the rest of the molecule. A heterocyclyl can contain one or more (for example, one or two) oxo and / or thioxo groups.
[0059] [0059] Exemplifying heterocyclic groups include, but are not limited to, 2,5-diazaspiro [3.4] octan-6-one (eg compound 1), azetidine (eg compound 2), 2,6-diazospiro [ 3.3] heptane (for example, compound 4), pyrrolidin-2-one (for example, compound 6), tetrahydrofuran (for example, compound 11), pyrrolidine (for example, compound 17), piperidin-2-one ( eg compound 36), piperazin-2-one (eg compound 41), 5-oxa-2,7-diazaspiro [3.4] octan-6-one (eg compound 50), 3-azabicyclo [3.1 .0] hexane (for example, compound 52), 2-azabicyclo [2.1.1] hexane (for example, compound 53), tetrahydro-2H-pyran (for example, compound 55), 2,6-diazospiro [ 3.4] octan-7-one (for example, compound 61), 4,5-dihydro-1H-imidazole (for example, compound 114), 1,4,5,6-tetrahydropyrimidine (for example, compound 119), piperidine (eg compound 158), 1,2,4-oxadiazole-5 (2H) -one (eg compound 161), 2,5,7-triazaspiro [3.4] octan-6-one ( for example, compound 168), 2.7-
[0060] [0060] "Acyl" refers to a group -C (= O) R, in which R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.
[0061] [0061] The term "N-alkylated" means that an alkyl group replaces one of the hydrogen atoms of a monosubstituted amine, or of a disubstituted amine group or of a tri-substituted amine group. When the alkylation is in a tri-substituted amine group, an alkali salt is generated, that is, a positive charge is generated on the nitrogen atom. N-alkylation is commonly associated with alkyl substitution on a nitrogen atom in the ring.
[0062] [0062] The term "cyan" refers to the group -CN.
[0063] [0063] The term "oxo" refers to a group = O.
[0064] [0064] The term "carboxyl" refers to a -C (O) OH group.
[0065] [0065] The term "ester" or "carboxylic ester" refers to the group - C (O) OR, where R is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which can be optionally additionally substituted, for example, with alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyan or - S (O) yRz, in which Rz is alkyl, aryl, or heteroaryl, and y is 0, 1 or 2.
[0066] [0066] The term "substituted amino" refers to the group -NRR, where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which may be optionally substituted, or a group as described herein or exemplified, or where both R groups are joined to form a heterocyclic group (e.g., morpholino) as described or exemplified herein, which may also be optionally substituted.
[0067] [0067] The term "starch" refers to the group -C (O) NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or
[0068] [0068] The term "sulfoxide" refers to a group -S (O) R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted.
[0069] [0069] The term "sulfone" refers to a group -S (O) 2R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted.
[0070] [0070] As used herein, the terms "alkylcycloalkyl", "alkylaryl", "alkylheteroaryl" and "alkylheterocyclyl" are intended to refer to a cycloalkyl, aryl, heteroaryl or heterocyclyl group that is attached to the rest of the molecule via an alkyl portion, where the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl" and "heterocyclyl" are as defined herein. Exemplary alkylaryl groups include benzyl, phenethyl, and the like.
[0071] [0071] "Optional" or "optionally" means that the subsequently described event or the subsequently described circumstance may or may not occur, and that the description includes cases in which said event or said circumstance occurs and cases in which it does not occur.
[0072] [0072] Certain commonly used alternative chemical names can be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be called an "alkylene" group or an "alkenyl" group, an "arylene" group or an " arylenyl ”, respectively. Also, unless explicitly stated otherwise, where combinations of groups are here referred to as a moiety, for example, arylalkyl, the last group
[0073] [0073] Where a group is represented by a link, multiple adjacent groups, both the same and different, when represented by the links, constitute a simple link. For example, the group "-L1-V1-L2-" constitutes a simple bond if each of L1, V1 and L2 is a bond.
[0074] [0074] Where a given group (a given portion) is described as being linked to a second group and the binding site is not explicit, the given group can be linked anywhere available in the given group or anywhere available in the second group. For example, an "alkyl substituted phenyl", where the binding sites are not explicit, can have any available alkyl group site linked to any available phenyl group site. In this respect, an "available site" is a site in the group where the hydrogen in the group may be replaced by a substituent.
[0075] [0075] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers.
[0076] [0076] "Stereoisomers" are isomers that differ only in the way in which the atoms are arranged in space.
[0077] [0077] "Enantiomers" are a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1: 1 mixture of a pair of enantiomers is a “racemic” mixture. The term "(±)" is used to designate a racemic mixture where appropriate.
[0078] [0078] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but that are not mirror images of each other.
[0079] [0079] The compounds of the description can have one or more asymmetric centers and can be produced as a racemic mixture or as individual enantiomers or individual diastereomers. The number of stereoisomers present in a given compound of a given formula
[0080] [0080] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R and S system. When the compound is a pure enantiomer the stereochemistry in each chiral carbon can be specified either by R or S. A solved compound whose absolute configuration is unknown can be designated by (+) or (-) depending on the direction (dextrorotatory or levorotatory) that it rotates the plane of polarized light on the wavelength of the sodium D line.
[0081] [0081] Some of the compounds exist as tautomeric isomers. Tautomeric isomers are in balance with each other. For example, compounds containing the amide group may exist in equilibrium with the imidic acid tautomers. Regardless of whose tautomer is shown, and regardless of the nature of the balance between the tautomers, the compounds are understood by a person commonly versed in the art as comprising both the amide and imidic acid tautomers. Thus, the amide group containing compounds are intended to include their imidic acid tautomers. Also, compounds containing imidic acid group are understood to include their amide tautomers.
[0082] [0082] The term "solvate" refers to a complex formed by combining a compound of formula (I), or any other formula
[0083] [0083] The term "hydrate" refers to the complex formed by the combination of a compound of formula (I), or any other formula described herein, and water.
[0084] [0084] The term "prodrug" refers to the compounds of formula (I), or derivatives of formula (I) described herein, which include chemical groups that, in vivo, can be converted and / or can be separated from the remainder of the molecule to provide the active drug. Pharmaceutically acceptable or biologically active metabolic salts thereof of the prodrug of a compound of formula (I) are also within the scope of the present description.
[0085] [0085] Any formula or structure presented herein, including formula (I), or any formula described herein, is intended to represent unlabeled forms and also isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the shapes presented here except that one or more (for example, one to three, or one to five) atoms are replaced by an isotope having a selected atomic mass or a selected mass number. Examples of isotopes that can be incorporated into the compounds of the description include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C , 14C, 15 N, 18F, 31P, 32P, 35S, 36Cl, and 125 I. Various isotopically labeled compounds of the present description, for example those in which radioactive isotopes such as 3H, 13 C and 14 C are incorporated, are within the scope of this description. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques, such as positron emission tomography (PET, Positron Emission Tomography) or single photon emission tomography (SPECT, Single -Photon Emission Computed Tomography) including
[0086] [0086] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and biological properties of the given compound, and that are not biologically or otherwise undesirable. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di (alkyl-substituted) amines, tri (alkyl-substituted) amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di (alkenyl-substituted) amines, tri (alkenyl-substituted) amines, cycloalkylamines, di (cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkylamines, di (cycloalkyl-substituted) amines, tri (substituted) cycloalkyl-substituted) amines, cycloalkenylamines, di (cycloalkenyl) amines, tri (cycloalkenyl) amines, substituted cycloalkenylamines, di (cycloalkenyl-substituted) amines, tri (cycloalkenyl-substituted) amines, arylamines, diarylamines, triarylamines, heteroamine
[0087] [0087] Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (n-propyl) amine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglycines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
[0088] [0088] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glyconic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, formic acid, tartaric acid, citric acid, benzoic acid,
[0089] [0089] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial agents, and antifungal agents, isotonic agents and absorption retarding agents and the like. The use of such means and agents for pharmaceutically active substances is well known in the art. Except to the extent that any conventional medium or agent is incompatible with the active ingredient, or unless otherwise indicated here, its use in therapeutic compositions is considered. Supplementary active ingredients can also be incorporated into the compositions.
[0090] [0090] The term "anticancer agent" is any drug that is effective in treating a malignant or cancerous disease. Effectiveness can mean inhibition, partial or complete remission, prolongation of life, improvement in quality of life, or healing. There are several major classes of anticancer drugs including chemical compositions as described or known to a person skilled in the art for example, PD-1, PD-L1 inhibitors, PD-1 / PD-L1 interaction, alkylating agents, antimetabolites , natural products, and hormones.
[0091] [0091] The term "additional anticancer agent", as used herein, means the use or combination of a second, third, fourth, fifth, etc., anticancer agent (s) in addition to a compound according to formula (I) described here.
[0092] [0092] The term "anticancer therapy" means any of the currently known therapeutic methods for treating cancer.
[0093] [0093] The term "blocking agent" or "checkpoint inhibitors" are classes of immune cancer agents that inhibit PD-1, PD-L1, or the interaction of PD-1 / PD-L1.
[0094] [0094] The term "treatment or" treating "means any administration of a compound or compounds, according to the present description, to a subject (for example, a human) having or susceptible to a condition or disease described herein for the purpose of: 1) preventing or protecting against the disease or condition, that is, causing the non-development of clinical symptoms; 2) inhibit the disease or condition, that is, interrupt or suppress the development of clinical symptoms; or 3) relieving the disease or condition, that is, causing the regression of clinical symptoms. In some modalities, the term "treatment" or "treating" refers to the alleviation of the disease or condition or cause of regression of clinical symptoms.
[0095] [0095] As used here, the term "prevent" refers to the prophylactic treatment of a patient who needs it. Prophylactic treatment can be performed by providing an appropriate dose of a therapeutic agent to a subject at risk for suffering from an illness, thereby substantially preventing the onset of the illness. The presence of a genetic mutation or the predisposition to have a mutation may not be alterable. However, prophylactic treatment (prevention), as used here, has the potential to prevent / lessen the symptoms or the clinical consequences of having the disease caused by such a genetic mutation or predisposition.
[0096] [0096] It will be understood by those people commonly versed in the technique that in human medicine, it is not always possible to differentiate between “prevent” and “suppress” because the final inductive event or the final inductive events may be unknown, latent (s), or the patient is not checked until long after the event or events have occurred. Therefore, as used herein, the term "prophylaxis" is intended as an element of "treatment" to cover both "prevent" and "suppress" as defined herein. The term "protection", as used herein, means that it includes "prophylaxis".
[0097] [0097] The term "patient" typically refers to a "mammal" that
[0098] [0098] Here are provided compounds which function as PD-1 inhibitors, PD-L1 inhibitors, and / or inhibitors of the interaction of PD-1 / PD-L1, methods of using such compounds and compositions comprising such compounds optionally in combination with one or more additional anti-cancer agents or additional anti-cancer therapies. In all the modalities discussed here, there is more than one occurrence of a group or variable, it is intended that the group or variable be independently selected from the list below. It is further considered that all modalities directed to the compounds include any pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, prodrug or tautomer thereof.
[0099] [0099] In one embodiment, a compound of formula (I) is provided: (Z1) n N Q-RE W
[00100] [00100] The present description additionally provides a compound of formula (I): (I) where: each n is independently 0, 1, 2, 3 or 4; each Z1 is independently halo, -ORa, -NO2, -CN, -NRaRb, -N3, -S (O) 2Ra, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -O2 alkynyl - C1-6 alkyl, -O-C1-6 haloalkyl, -C3-8 cycloalkyl or -C1-6 alkyl- C3-8 cycloalkyl; each alkyl, alkenyl, alkynyl, and cycloalkyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, -N3, - ORa, halo, and cyano; Q is aryl, heteroaryl or heterocyclyl, with each aryl, heteroaryl and heterocyclyl group optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, oxo, - ORa, N3, NO2, -CN, -NR1R2, -S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, - NRaC (O) Ra, -C (O) Ra, -C (O) ORa, -C (O) NRaRb, -NRaC ( O) ORa, - NRaC (O) NR1R2, -OC (O) NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, - C1-6alkyl, -AlkenylC2-6, -alquinylC2-6 , -O-C 1-6 alkyl, -C 3-8 cycloalkyl, - C 1-6 alkyl-C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and RN; the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyano, -NRaRb, - C (O) Ra, -C (O) ORa, -O-C1-6-alkyl-CN, - C (O) NRaRb, NRaC (O) Ra, -NRaC (O) ORa, -S (O) 2Ra, - NRaS (O) 2Rb, -
[00101] [00101] In certain embodiments, a compound of Formula (I) is provided: (I) where: each n is independently 0, 1, 2, 3 or 4; each Z1 is independently halo, -ORa, -NO2, -CN, -NRaRb, -N3, -S (O) 2Ra, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -O2 alkynyl - C1-6 alkyl, -O-C1-6 haloalkyl, monocyclic-C3-8 cycloalkyl or -C1-6-cycloalkylC3-8 cycloalkyl; each alkyl, alkenyl, alkynyl, and cycloalkyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, -N3, - ORa, halo, and cyano; Q is monocyclic aryl, monocyclic heteroaryl or heterocyclyl
[00102] [00102] Also provided are compounds of Formula (Ia): (Ia) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, whereby: each X is independently CH, CZ3 or N;
[00103] [00103] Also provided are compounds of Formula (Ib): (Ib) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined herein.
[00104] [00104] Also provided are compounds of Formula (Ic): (Ic) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, whereby: each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined herein.
[00105] [00105] Compounds of Formula (Id) are also provided: (Id) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, whereby: each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined herein.
[00106] [00106] Formula (II) compounds are also provided:
[00107] [00107] Also provided are compounds of formula (III): (III) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: each X is independently CH, CZ3 or N; each n is independently 0, 1, 2, 3 or 4; each m is independently 0, 1 or 2; each R5 is independently selected from the group consisting of NRaRb, halo, cyano, -ORa, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 cyanoalkyl, -C1-6 alkyl-NRaRb, -C1-6 alkyl-OH, -cycloalkylC3- E - C1-3alkyl-C3-8-cycloalkyl; and R1, R2, Z1, Z3, RE and RW are as defined herein.
[00108] [00108] The present description provides a compound of formula (III): (III) where: each X is independently CH, CZ3 or N; each n is independently 0, 1, 2, 3 or 4;
[00109] [00109] The present description provides a compound of formula (IIIa): (IIIa) where: each X is independently CH, CZ3 or N; each Z1 is independently halo or -C1-6alkyl; each Z3 is independently halo or -O-C1-6alkyl; each R1 is independently selected from the group consisting of H, -C1-8 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-aryl, -C1-6alkyl-heteroaryl , - C1-6 alkyl-heterocyclyl, -C1-6 alkyl (O) ORa, -C2-6-C alkenyl (O) ORa, - S (O) 2Ra, -S (O) 2ORa, -S (O) 2NRaRb , -C (O) NRaS (O) 2Ra, and C1-6alkylC3-8-cycloalkyl; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, -NO2, halo, C1-6alkyl, -C1-6alkyl-ORa , -C1-6-cyanoalkyl, -C1-6-haloalkyl, C3-8-cycloalkyl, heteroaryl, heterocyclyl, -C1-3-cycloalkylC3-8, - C (O) Ra, -C1-6-alkyl (O) Ra, -C (O ) ORa, -C1-6-C (O) ORa, -NRaRb, - OC (O) NRaRb, -NRaC (O) ORb, -NRaC (O) Rb, -C1-6-NRaRb, -C (O) NRaRb, -C1-6-alkyl (C) NRaRb, -S (O) 2Ra, -S (O) 2ORa, -C1-6alkyl (O) 2Ra, - S (O) 2NRaRb, -C1-6alkyl S (O) 2NRaRb, -C (O) NRaS (O) 2Rb, -NRaC (O) NRb, -
[00110] [00110] The present description provides a compound of formula (IIIb): (IIIb) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where:
[00111] [00111] The present description provides a compound of formula (IIIc): (IIIc) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: Z1, Z3, R1 and R2 are as defined herein.
[00112] [00112] The present description provides a compound of formula (IIId): (IIId) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: Z1, Z3, R1 and R2 are as defined herein.
[00113] [00113] In one embodiment, Q is selected from the group consisting of phenyl, pyridinyl, indazolyl, and thienyl, each optionally substituted with 1 to 2 groups independently selected from the group consisting of halo, - ORa, N3, NO2, -CN, - NRaRb, -S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, - NRaC (O) Ra, -C (O) NRaRb, -C1-6alkyl, -O-C1-6alkyl, cycloalkylC3 -8, and - C1-6alkyl-C3-8-cycloalkyl.
[00114] [00114] In another embodiment, Q is selected from the group consisting of phenyl, pyridinyl and indanyl, each optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, -ORa, N3, NO2, -CN, -NRaRb, - S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, -NRaC (O) Ra, - C (O) NRaRb, -C1-6 alkyl, -O-C1-6 alkyl, C3-8 cycloalkyl, and -C1-6alkyl- C3-8 cycloalkyl.
[00115] [00115] In one embodiment, Q is optionally substituted aryl. In one embodiment, Q is optionally substituted phenyl.
[00116] [00116] In one embodiment, Q is optionally substituted heteroaryl. In one embodiment, Q is optionally substituted monocyclic heteroaryl. In one embodiment, Q is an optionally substituted 5- or 6-membered heteroaryl. In one embodiment, Q is an optionally substituted 5-membered heteroaryl. In one embodiment, Q is an optionally substituted 6-membered heteroaryl. In one embodiment, Q is optionally substituted pyridyl. In one embodiment, Q is optionally substituted pyrazinyl.
[00117] [00117] In certain modalities, Q is,,,,,,,,,, or, and m and Z3 are as defined herein.
[00118] [00118] In certain modalities, Q is,,,,,, or, and m and Z3 are as defined here.
[00119] [00119] In one embodiment, the substituents on Q are independently selected from the group consisting of OH, halo, CN, -C1-6alkyl, -C1-6haloalkyl -O-C1-6alkyl, -O-haloC1-6alkyl, -
[00120] [00120] In one embodiment, Q is optionally substituted with 1 to 3 groups independently selected from the group consisting of OH, halo, CN, S (O) 2Ra, -C1-6alkyl, and -O-C1-6alkyl.
[00121] [00121] In one embodiment, Q is optionally substituted with 1 to 3 groups independently selected from the group consisting of OH, halo, CN, S (O) 2Ra, -C1-6alkyl, and -O-C1-6alkyl.
[00122] [00122] In one embodiment, RE and RW are each independently - NR1R2, -C1-6alkyl-NR1R2, -O-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl- NR1R2, -NRa- C1-6alkyl-NR1R2, -C1-6alkyl-N + R1R2R3, -S-C1-6alkyl- NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - (CH2) uNRaS (O) 2NRaRb , -S (O) 2NRa- C1-6-NR1R2alkyl, -NRaS (O) 2C1-6-NR1R2alkyl, - (CH2) uC (O) NRaS (O) 2NRaRb, - (CH2) uN + R1R2O-, - ( CH2) uP + RbRcRd, - (CH2) uP + RcRdO-, - (CH2) uP + O [NRaRb] [NRcRd], - (CH2) uNRcP (O) (ORc) 2, - (CH2) uCH2OP (O) (ORc) (ORd), - (CH2) uOP (O) (ORc) (ORd), - (CH2) uOP (O) NRaRb) (ORa), or; where: V2 is independently a bond, O, NRa, S, S (O), S (O) 2, S (O) 2NR1, or NRaS (O) 2; L3 is independently a bond, O, NRa, S, S (O), S (O) 2,
[00123] [00123] In one embodiment, RE and RW are independently selected from -NR1R2, -C1-6-NR1R2, -O-C1-6-alkyl1, R2 -C1-6-O-alkylC1-6-NR1R2, -NRa-alkylC1 -6-NR1R2, -C1-6alkyl- N + R1R2R3, -S-C1-6-NR1R2, -C (O) NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - (CH2 ) uNRaS (O) 2NRaRb, -S (O) 2NRa-C1-6-NR1R2 alkyl, - NRaS (O) 2C1-6alkyl-NR1R2, - (CH2) uC (O) NRaS (O) 2NRaRb, - (CH2) uN + R1R2O-, - (CH2) uP + RbRcRd, - (CH2) uP + RcRdO-, - (CH2) uP + O [NRaRb] [NRcRd], - (CH2) uNRcP (O) (ORc) 2, - ( CH2) uCH2OP (O) (ORc) (ORd), - (CH2) uOP (O) (ORc) (ORd), and - (CH2) uOP (O) NRaRb) (ORa); each R1 being independently selected from H, -C1-6 alkyl, -C3-6 cycloalkyl, heterocyclyl, -C2-6-alkyl-ORa, or -C1-6-C (O) ORa; each alkyl, cycloalkyl, or heterocyclyl being
[00124] [00124] In one embodiment, RE and RW are independently selected from -C (O) NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - (CH2) uNRaS (O) 2NRaRb, -S (O) 2NRa-C1-6-alkyl1R2, -NRaS (O) 2C1-6alkyl-
[00125] [00125] In one embodiment, RE and RW are independently selected from - (CH2) uN + R1R2O-, - (CH2) uP + RbRcRd, - (CH2) uP + RcRdO-, - (CH2) uP + O [NRaRb] [NRcRd], - (CH2) uNRcP (O) (ORc) 2, - (CH2) uCH2OP (O) (ORc) (ORd), - (CH2) uOP (O) (ORc) (ORd), and - ( CH2) uOP (O) NRaRb) (ORa); being that
[00126] [00126] In one embodiment, RE and RW are each independently - NR1R2, -C1-6alkyl-NR1R2, -O-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl-
[00127] [00127] In one embodiment, RE and RW are each independently - NR1R2, -C1-6alkyl-NR1R2, -O-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl- NR1R2, -NRa- C1-6alkyl-NR1R2, or; where: V2 is independently a bond, O, NRa, S, S (O) or S (O) 2;
[00128] [00128] In one modality, RE and RW are each; where: V2 is independently a bond, O, NRa, S, S (O) or S (O) 2; Rc is independently selected from H, OH, -C1-6 alkyl, and -C3-8 cycloalkyl;
[00129] [00129] In one embodiment, RE and RW are each, independently - NR1R2, -C1-6 alkyl-NR1R2, or -O-C1-6 alkyl-NR1R2;
[00130] [00130] In one embodiment, RE and RW are each -C1-6alkyl-O-C1-6alkyl-NR1R2; each R1 is selected from H, -C1-6 alkyl, -C3-6 cycloalkyl, heterocyclyl, -C2-6 alkyl-ORa, and -C1-6-C alkyl (O) ORa; each alkyl, cycloalkyl, or heterocyclyl being optionally substituted with 1 to 2 groups independently selected from –ORa, -CN, halo, -C1-6-alkyl, -cyanoalkylC1-6, -haloalkylC1-3, -
[00131] [00131] In one embodiment, a compound of formula (I) is provided, with RE and RW each being -O-C1-6-NR1R2-alkyl; R1 is selected from H, -C1-6 alkyl, -C3-6 cycloalkyl, heterocyclyl, -C2-6-alkyl-ORa, and -C1-6-C (O) ORa; each alkyl, cycloalkyl, or heterocyclyl being optionally substituted with 1 to 2 groups independently selected from –ORa, -CN, halo, -C1-6-alkyl, -cyanoalkylC1-6, -haloalkylC1-3, - C (O) Ra, -C1-6-C-O (O) Ra, -C (O) ORa, -C1-6-C (O) ORa, -C (O) NRaRb, and -C1-6-C (O) NRaRb; R2 is selected from -C1-6alkyl, -C3-6cycloalkyl, heterocyclyl, -C2-6-alkyl-ORa, and -C1-6-C (O) ORa; each alkyl, cycloalkyl, or heterocyclyl being
[00132] [00132] In one modality, RE and RW are each –NR1R2; R1 is selected from H, -C1-6 alkyl, -C3-6 cycloalkyl, heterocyclyl, -C2-6-alkyl-ORa, and -C1-6-C (O) ORa; each alkyl, cycloalkyl, or heterocyclyl being optionally substituted with 1 to 2 groups independently selected from –ORa, -CN, halo, -C1-6-alkyl, -cyanoalkylC1-6, -haloalkylC1-3, - C (O) Ra, -C1-6-C-O (O) Ra, -C (O) ORa, -C1-6-C (O) ORa, -C (O) NRaRb, and -C1-6-C (O) NRaRb; R2 is selected from -C1-6alkyl, -C3-6cycloalkyl, heterocyclyl, -C2-6-alkyl-ORa, and -C1-6-C (O) ORa; each alkyl, cycloalkyl, or heterocyclyl group being optionally substituted with 1 to 2 groups independently selected from -ORa, -CN, -C1-6alkyl-ORa, -cyanoalkylC1-6, - haloalkylC1-3, -cycloalkylC3-8, - C1-3alkyl-C3-8alkyl, -C (O) Ra, --C1-6-alkyl (O) Ra, -C (O) ORa, -C1-6alkyl-C (O) ORa, -C (O) NRaRb , and C1-6-C-C (O) NRaRb; or R1 and R2 combine to form a heterocyclyl group
[00133] [00133] In one embodiment, RE and RW do not contain an amide group (ie, -NC (O) - or -C (O) N-). In one embodiment, at least one of RE and RW contains a heterocyclyl portion that optionally comprises an oxo.
[00134] [00134] In one embodiment, RE and RW are each independently - NR1R2, -C1-6alkyl-NR1R2, -O-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl- NR1R2, -NRa- C1-6alkyl-NR1R2, -C1-6alkyl-N + R1R2R3, -S-C1-6alkyl, NR1R2, -C (O) NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - ( CH2) uNRaS (O) 2NRaRb, -S (O) 2NRa-C1-6-NR1R2 alkyl, -NRaS (O) 2C1-6-NR1R2 alkyl; each R1 is independently -C1-6alkyl-heterocyclyl; each heterocyclyl being independently 2,5-diazaspiro [3.4] octan-6-one, azetidine, 2,6-diazaspiro [3.3] heptane, pyrrolidin-2-one, tetrahydrofuran, pyrrolidine, piperidin-2-one ( 36), piperazin-2-one, 5-oxa-2,7-diazaspiro [3.4] octan-6-one, 3-azabicyclo [3.1.0] hexane, 2-azabicyclo [2.1.1] hexane, tetrahydro -2H-pyran, 2,6-diazaspiro [3.4] octan-7-one, 4,5-dihydro-1H-imidazole, 1,4,5,6-tetrahydropyrimidine, piperidine, 1,2,4 -oxadiazole-5 (2H) -one, 2,5,7- triazaspiro [3.4] octan-6-one, 2,7-diazaspiro [4.4] nonan-3-one, 1,7-diazaspiro [4.4] nonan- 2-one, 2-azospiro [4.4] nonan-3-one, 1,8-diazaspiro [4.5] decan-2-one, 2-azospiro [3.3] heptane, oxazolidin-2-one, octahydrocyclopenta [b] pyrrole, octahydrocyclopenta [c] pyrrole, 2-oxa-7-azaospiro [4.4] nonan-1-one, 6-oxa-2-azaespiro [3.4] octane, piperazine, 1,1-dioxotetrahydrothiophene, hexa- hydropyrrolo [3,4-b] pyrrole-6 (1H) -one, 1,3,8-
[00135] [00135] In one mode, RW and RE are each independently selected from:,,,,,,,,,,,,,,,,,,,,,,
[00136] [00136] In one mode, each RW and RE is independently selected from:,,,, N N N N H
[00137] [00137] In one mode, each RW and RE is independently selected from:,,,,,,,,,,,,,,,,,,,,,, N
[00138] [00138] In one modality, each RW and RE is independently
[00139] [00139] In one mode, each RW and RE is independently selected from:,,,,
[00140] [00140] In certain modalities, each Z1 is independently halo or -C1-6alkyl. In certain embodiments, each Z1 is fluoro, chloro, or methyl.
[00141] [00141] In certain modalities, each Z1 is independently halo. In certain modalities, each Z1 is chlorine.
[00142] [00142] In certain embodiments, each Z3 is independently - C1-6alkyl, -O-C1-6alkyl, or -O-C3-8-cycloalkyl. In certain embodiments, each Z3 is methyl, methoxy, or cyclopropoxy.
[00143] [00143] In certain embodiments, each Z3 is independently C1-6 alkoxy. In certain modalities, each Z3 is methoxy.
[00144] [00144] In certain embodiments, none of RE or RW is an optionally substituted fused 5,6-aromatic or 5,6-heteroaromatic ring. In certain embodiments, none of Z1, Z3, RN, RE or RW is an optionally substituted fused 5,6-aromatic or 5,6-heteroaromatic ring.
[00145] [00145] In certain embodiments, a compound as shown in Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, is provided.
[00146] [00146] In certain embodiments, the compound, as provided herein, has a molecular weight of less than about 850 g / mol, or less than about 800 g / mol, or less than about 750 g / mol, or less than about 700 g / mol, or between about 500 and about 850 g / mol, or between about 500 and about 600 g / mol, or between about 550 and about 650 g / mol, or between about from about 600 to about 700 g / mol, or between about 650 and about 750 g / mol, or between about 700 and about 800 g / mol, or between about 750 and about 850 g / mol.
[00147] [00147] A person skilled in the art is aware that each
[00148] [00148] PD-1 and its ligand, PD-L1, are monomeric type I transmembrane proteins that perform critical functions in the inhibition and exhaustion of T-cells. PD-L1 is composed of two immunoglobulin-like (Ig) extracellular domains, while PD-1 is composed of a single Ig-type extracellular domain and an intracellular tail. The crystal structure of the PD-1 / PD-L1 complex reveals that PD-1 binds PD-L1 with a 1: 1 stoichiometry to form a monomeric complex (see, for example, Cheng et al. J Biol Chem, 2013; 288 (17); 11771-85, Lin et al. Proc Natl Acad Sci USA, 2008; 105 (8); 3011-6, Zak et al. Structure, 2015; 23 (12); 2341-8). This arrangement represents a different mode of ligand binding and signaling mechanism that differs from other co-stimulatory receptor / ligand interactions such as CTLA-4 / B7, where oligomerization plays an important role in signaling (see, for example, Schwartz et al. Nature , 2001; 410 (6828); 604-8). The interaction of PD-1 with PD-L1, along with TCR (T-Cell Receptor, T-cell receptor) signaling, results in phosphorylation of cytoplasmic domain tyrosines in PD-1 and recruitment of tyrosine phosphatases containing domain of homology-Src-2 (Src-homology 2- containing tyrosine phosphatases, SHP-1 and SHP-2). These phosphatases dephosphorylate TCR-associated proteins, resulting in the alteration of downstream signaling including phosphoinositide-3-kinase blocking (PI3K, PhosphoInositide 3 Kinase) and activation of kinase-Akt, interruption of glucose metabolism, and inhibition of glucose secretion of IL-2 and IFN-γ (see, for example, Hofmeyer et al. J. Biomed. Biotechnol., 2011; 2011;
[00149] [00149] Monoclonal antibodies developed for cancer immunotherapy, which bind to either PD-1 or PD-L1, have demonstrated significant response rates in patients, particularly for melanoma, non-small cell lung cancer (NSCLC, Non-Small Cell Lung Cancer), renal cell carcinoma (RCC, Renal Cell Carcinoma) and bladder cancer. Many of these studies have shown that blocking the PD-1 / PD-L1 axis results in an intensification of T-cell cytotoxic activity at the tumor site (see, for example, Wherry EJ. Nat. Immunol, 2011; 12 (6 ); 492-9). In addition to cancer, inhibition of this pathway has also shown promise for the control or elimination of chronic viral infections, such as HBV (see, for example, Bengsch et al. J. Hepatol, 2014; 61 (6); 1212-9 , Fisicaro et al. Gastroenterology, 2010; 138 (2), 682-93, 93 e1-4, Fisicaro et al. Gastroenterology, 2012; 143 (6), 1576-85 e4). Methods
[00150] [00150] In one embodiment, the present description provides a compound of formula (I) useful as an inhibitor of PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1. In some embodiments, the compounds, described herein, inhibit the interaction of PD-1 / PD-L1 by dimerizing PD-L1, or by inducing or stabilizing the formation of PD-L dimer.
[00151] [00151] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
[00152] [00152] The present description provides a compound of formula (I) for use in therapy.
[00153] [00153] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, is provided, useful for treating an HBV infection or a condition in a patient that is responsive to treatment through the
[00154] [00154] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, at least one additional therapeutic agent suitable for treating an infection by HBV, and at least one pharmaceutically acceptable carrier or excipient. In another embodiment, the present description provides a compound of formula (I) for use in the manufacture of a drug to treat or eliminate HBV. The elimination of HBV during acute infection is associated with the appearance of HBV-specific functional CD8 + T-cells. In contrast, chronic infection is marked by the presence of dysfunctional CD8 + T-cells for HBV that are unable to control viral infection (see, for example, Boni et al. J. Virol, 2007; 81 (8); 4215- 4225, Ferrari, Liver Int, 2015; 35; Suppl 1: 121-8, Fisicaro et al., Gastroenterology, 2010; 138 (2); 682-693, 93 e1-4, Guidotti et al. Cell, 2015; 161 (3); 486-500). Mechanisms that can contribute to HBV-specific T-cell dysfunction in CHB (Chronic Hepatitis B, chronic hepatitis B) include suppression of inhibitory T-cell receptors (for example, PD-1, CTLA-4 and TIM-3 ), due to persistent high viral load and persistent high levels of antigen (see, for example, Boni et al. J Virol, 2007; 81 (8); 4215-4225, Franzese et al. J. Virol, 2005; 79 (6); 3322-3328, Peppa et al. J. Exp. Me.d, 2013; 210 (1); 99-114, Wherry EJ. Nature Immunology 2011; 12 (6); 492-499). Among all immune inhibitory receptors, PD-1 is the most frequently overloaded on HBV-specific T-cells. In addition, multiple studies have confirmed that the majority of circulating and intrahepatic CDV + T-cells in patients with CHB are depleted and express high levels of PD-1 (see, for example, Bengsch et al. J. Hepatol , 2014; 61 (6); 1212-1219, Fisicaro et al., Gastroenterology, 2010;
[00155] [00155] In one embodiment, the present description provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, and at least one additional anticancer agent and at least one excipient pharmaceutically acceptable.
[00156] [00156] In one embodiment, the present description provides a method
[00157] [00157] In another embodiment, the present description provides a compound of formula (I) for use in the manufacture of a drug to treat cancer.
[00158] [00158] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, useful for treating cancer or a condition in a patient who is responsive, is provided treatment by inhibiting PD-1, PD-L1, or the interaction of PD-1 / PD-L1. The cancers that can be treated with the compounds of formula (I), described herein, include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS (Central Nervous System) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, cancer cell lung cancer and colon cancer.
[00159] [00159] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, useful for treating cancer or a condition in a patient who is responsive, is provided treatment by inhibiting PD-1, PD-L1, or the interaction of PD-1 / PD-L1 including, but not limited to, lymphoma, multiple myeloma, and leukemia. Additional diseases or conditions that can be treated include, but are not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), syndrome
[00160] [00160] "Administer" or "administration" refers to the distribution of one or more therapeutic agents to a patient. In one embodiment, administration is a monotherapy in which a compound of formula (I) is the only active ingredient administered to the patient in need of therapy. In another embodiment, administration is co-administration such that two or more therapeutic agents are distributed together during the course of treatment. In one embodiment, two or more therapeutic agents can be co-formulated into a single dosage form or "combined dosage unit", or formulated separately and subsequently combined into a combined dosage unit, as is typically for intravenous or oral administration as a monolayer or bilayer tablet or capsule.
[00161] [00161] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a human patient who needs it in an effective amount, such as, from about 0.1 mg to about 1,000 mg per day of said compound. In one embodiment, the effective amount is about 0.1 mg to about 200 mg per day. In one embodiment, the effective amount is about 1 mg to about 100 mg per day. In other embodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, or about 100 mg per day.
[00162] [00162] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one anticancer agent
[00163] [00163] In one embodiment, the compound of formula (I) and / or a combination of the compound of formula (I) and an additional anticancer agent or a pharmaceutically acceptable salt thereof is administered (a) once a day. In yet another embodiment, the compound of formula (I) and / or an additional anti-cancer agent or a pharmaceutically acceptable salt thereof is administered as a loading dose of about 10 mg to about 500 mg per compound on the first day and at each day or every other day or weekly for up to one month followed by a regular regimen of a compound of formula (I) and / or one or more additional anti-cancer agents or additional anti-cancer therapies. The maintenance dose can be 1-500 mg daily or weekly for each component of a multi-component drug regimen. A qualified healthcare professional or treating physician is aware of which dose regimen is best for a specific patient or specific current conditions and will make regimen decisions.
[00164] [00164] Co-administration may also include the administration of pharmaceutical components, for example, one or more compounds of formula (I) and one or more (for example, a second, third, fourth or fifth) additional or other anti-cancer agents ) additional therapeutic agent (s). Such a combination of one or more compounds of formula (I) and one or more additional anticancer agent (s) or other additional therapeutic agent (s) may be administered simultaneously or in sequence (one after the other) within a reasonable period of time for each administration (for example, about 1 minute to 24 hours) depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination. Co-administration may also involve treatment with a fixed combination in which the agents of the treatment regimen are combinable in a fixed dosage or combined dosage medium, for example, solid, liquid or aerosol. In one embodiment, a kit can be used to administer the drug or pharmaceutical components.
[00165] [00165] Thus, one embodiment of the present description is a method of treating a disease responsive to treatment with an inhibitor of
[00166] [00166] "Intravenous administration" is the administration of a substance directly into a vein, or "intravenously". Compared to other routes of administration, the intravenous (IV) route is a faster way to distribute fluids and medications throughout the body. An infusion pump can allow precise control of the flow rate and the total amount of medication delivered. However, in cases where a change in flow rate would have serious consequences, or if pumps are not available, drip is often allowed to flow simply by positioning the bag above the level of the patient and using the clamp to regulate the rate. . Alternatively, a rapid infusion device can be used if the patient requires a high flow rate and the IV access device is large enough to accommodate him. This is either an inflatable sleeve positioned around the fluid bag to force the fluid into the patient or a similar electrical device that can also heat up the fluid being infused. When a patient requires medication only at certain times, an intermittent infusion is used that does not require additional fluid. You can use the same techniques as an intravenous drip (drip or gravity drip), but after the full dose of medication has been administered, the tubing is disconnected from the IV access device. Some medications are also administered by bolus or IV boost, meaning that a syringe is connected to the
[00167] [00167] "Oral administration" is an administration route in which a substance is ingested through the mouth, and includes buccal, sublabial, and sublingual administration, as well as enteral administration and that through the respiratory tract, unless it is performed through for example, tubing so that the medication does not come into direct contact with any portion of the oral mucosa. The typical form for oral administration of therapeutic agents includes the use of pills or capsules. Thus, in one embodiment, compound (s) or combination of compounds, described herein, can be administered by the oral route only or in combination with administration of certain components of the treatment regime by IV or parenteral routes. Pharmaceutical Formulations
[00168] [00168] The compound (s) of formula (I) or a pharmaceutically acceptable salt of the same (s) can be administered in a pharmaceutical formulation. Pharmaceutical formulations / compositions considered by the present description comprise, in addition to a carrier, the compound of
[00169] [00169] The pharmaceutical formulations / compositions considered by the present description can also be intended for administration by injection and include aqueous solutions, oily suspensions, oily emulsions (such as sesame oil, corn oil, cotton seed oil, or peanut oil) ) and also elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical carriers. Aqueous saline solutions are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid poly (ethylene glycol), and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion and / or by using surfactants. The prevention of the action of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
[00170] [00170] Sterile injectable solutions are prepared by incorporating the component compound (s) in the required amount in the appropriate solvent with various other ingredients as listed above or as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the sterile active ingredients into a sterile vehicle that contains the basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying or
[00171] [00171] In the preparation of pharmaceutical compositions comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, optionally in combination with an additional agent / an additional useful therapy for the purpose or pharmaceutically acceptable salt thereof, the ingredient active is usually diluted by an excipient or carrier and / or terminated or mixed with such a carrier that it may be in the form of a capsule, sachet, paper bag or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets (flat capsules), elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 20% by weight of the active compounds, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
[00172] [00172] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.
[00173] [00173] The compositions of the description can be formulated so as to
[00174] [00174] Certain compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" or "combined dosage unit" refers to physically individual units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of one or more of the active materials (for example, compound (I), optionally in combination with an additional agent calculated to produce the desired effect, in combination with a suitable pharmaceutical excipient in, for example, a tablet, capsule, ampoule or vial for injection. that the amount of each active ingredient actually administered will be determined by a doctor, considering the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compounds administered and their relative activity, age, weight, and the response of the individual patient, the severity of the patient's symptoms, and the like.
[00175] [00175] For the preparation of solid compositions such as tablets, the main active ingredient (s) is / are mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present description. When these preformulation compositions are referred to as homogeneous, it means that the active ingredient (s) is (are) uniformly dispersed (s) throughout the composition so that the
[00176] [00176] Tablets or pills comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present description optionally in combination with the second agent can be coated or differently combined to provide a form of dosage that provides the advantage of prolonged action, or to protect against acidic stomach conditions. For example, the tablet or pill may comprise an internal dosage element and an external dosage element, the latter being in the form of an envelope over the former. In one embodiment, the internal dosing element can comprise compound (I) and the external dosing element can comprise the second or additional agent or vice versa. Alternatively, the combined dosage unit can be configured side by side as in a capsule or tablet where one portion or half of the tablet or capsule is filled into a formulation of the compound of formula (I) while the other portion or half of the tablet or capsule comprises the additional agent.
[00177] [00177] A variety of materials can be used for such enteric layers or enteric coatings, as materials including numerous polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. A person commonly versed in the art is aware of the techniques and materials in the manufacture of dosage formulations described herein.
[00178] [00178] An "extended release formulation or" extended release formulation "is a formulation that is designed to slowly release a therapeutic agent into the body over an extended period of time, while an" immediate release formulation "is an formulation that is designed to quickly release a therapeutic agent
[00179] [00179] A lyophilized formulation can also be used to administer a compound of formula (I) individually or in combination with an additional anti-cancer agent. A person skilled in the art is aware of how to prepare and use lyophilized formulations of pharmaceutical substances susceptible to lyophilization.
[00180] [00180] Spray dried formulations can also be used to administer a compound of formula (I) individually or in combination with an additional anti-cancer agent. A person skilled in the art is aware of how to prepare and use spray dried formulations of pharmaceutical substances susceptible to spray drying. Other known formulation techniques can also be used to formulate a compound or a combination of compounds described herein. Manufacturing Articles
[00181] [00181] Articles of manufacture comprising a container in which are contained a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier are provided. The article of manufacture can be a bottle, vial, ampoule, disposable single-use applicator, or the like,
[00182] [00182] It should be understood that the active ingredient can be packaged by any material capable of providing reasonable chemical and physical stability, such as a foil pouch.
[00183] [00183] Unit dosage forms of the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier are also provided.
[00184] [00184] Any pharmaceutical composition provided in the present description can be used in articles of manufacture, the same as if each individual composition were specifically and individually listed for use in a article of manufacture.
[00185] [00185] A kit is also provided which includes a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof; a label, and / or instructions for using the compound to treat a disease or condition mediated by PD-1, PD-L1 activity or PD-1 / PD-L1 interaction.
[00186] [00186] In one embodiment, the instructions are directed to use the pharmaceutical composition for the treatment of cancer, including for example, leukemia or lymphoma. In specific modalities, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL, indolent Non-Hodgkin's Lymphoma), refractory iNHL, non-lymphoma
[00187] [00187] In a specific variation, the instructions are directed to use the pharmaceutical composition for the treatment of an autoimmune disease. Specific modalities of an autoimmune disease include asthma, rheumatoid arthritis, multiple sclerosis, and lupus.
[00188] [00188] An article of manufacture is also provided which includes a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or solvate thereof; and a container. In one embodiment, the container can be a vial, a pot, an ampoule, a pre-filled syringe, or an intravenous bag.
[00189] [00189] The formulations of compound (s) of the present description i.e. a compound of formula (I) or the combination of a compound of formula (I) and an additional agent can be prepared by mixing said compounds or salts thereof with one or more vehicles, carriers and / or diluents and / or pharmaceutically acceptable, non-toxic adjuvants, collectively referred to herein as excipients or carrier materials. The compounds of the description can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for that purpose.
[00190] [00190] In one embodiment, the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional agent useful for the treatment of cancer can be formulated in a fixed dose formulation or a formulation combined dose in a tablet, capsule or premixed IV solution. In another embodiment, the fixed dose combination preferably comprises the compound of formula (I), and an additional anti-cancer agent. Other fixed dose formulations may include pre-mixed liquids, suspensions, elixirs, aerosolized sprays or plaster presentations. As used herein, fixed dose formulations or combined dose formulations are synonymous with simultaneous co-administration of the active ingredients of compound (I) and at least one additional agent. Combination Therapy
[00191] [00191] Treatment methods are also provided in which a compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered to a patient in combination with one or more additional active agents or additional therapy. The compound, described herein, can be used or combined with one or more of the additional therapeutic agents. The one or more therapeutic agents include, but are not limited to, an inhibitor, an agonist, an antagonist, a ligand, a modulator, a stimulator, a blocker, an activator or a suppressor of a gene, a ligand, a repressor, a protein, a factor like, gene homologous to the Abelson murine leukemia viral oncogene (ABL, like ABL1), Acetyl-CoA-carboxylase
[00192] [00192] Thus, in one embodiment, a method of treating cancer and / or diseases or symptoms that coexist or are exacerbated or triggered by cancer, for example, an allergic disorder and / or an autoimmune disease and / or an inflammatory disease, and / or an acute inflammatory reaction, comprises administering to a patient, who needs it, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with an additional agent (for example, a second, third, fourth or fifth active agent) that may be useful to treat cancer, an allergic disorder and / or an autoimmune disease and / or an inflammatory disease, and / or an acute inflammatory reaction related to or present with a cancer. Treatment with the second, third, fourth or fifth active agent can be before, simultaneously with, or after treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with another active agent in a single dosage form. Suitable therapeutic or anti-tumor agents that can be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, chemotherapeutic agents, for example mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or a combination comprising at least one of the aforementioned chemotherapeutic agents. Radiotherapy antitumor agents can also be used, alone or in combination with chemotherapeutic agents.
[00193] [00193] A compound of formula (I) or a pharmaceutically acceptable salt thereof can be useful as chemosensitizing agents, and thus, it can be useful in combination with other chemotherapeutic drugs, in particular drugs that induce apoptosis. Thus, in one embodiment, the present description provides a method for
[00194] [00194] The compounds described herein can be used or combined with one or more of a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a bispecific antibody and a therapeutic protein of the "type" antibody ”(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drug conjugate (CAF), a radiotherapeutic agent, an antineoplastic agent, an antiproliferation agent, an oncolytic virus, a gene editor or modifier (such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, TALENs), a T-cell immunotherapeutic agent (chimeric antigenic receptor), a T-cell receptor (TCR-T ) modified, or any combination thereof. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, or polynucleotides. In one embodiment, the application provides a product comprising a compound described herein and an additional therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy.
[00195] [00195] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to encompass any non-protein (i.e., non-peptide) chemical compound useful in the treatment cancer. Examples of chemotherapeutic agents include, but are not limited to: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); sulfonates
[00196] [00196] The compound described herein can be used or combined with one or more of the additional therapeutic agents. Therapeutic agents can be categorized by their mechanism of action, for example, in the following groups: antimetabolite / anticancer agents, such as pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118; purine analogs, folate antagonists (such as pralatrexate), and related inhibitors; antiproliferative / antimitotic agents including natural products, such as Vinca alkaloids (vinblastine, vincristine) and microtubule-disrupting agents such as taxane (paclitaxel, docetaxel), vimblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotines; DNA damaging agents, such as actinomycin, ansacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin, mithromycin, taxon, nitroquinone, taxon, nitroquinone , teniposide, etoposide, and triethylene thiophosphoramide; hypomethylating DNA agents, such as guadecitabine (SGI-110), ASTX727; antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin);
[00197] [00197] Examples of other chemotherapeutic drugs that can be used in combination with compounds of formula (I), or a pharmaceutically acceptable salt thereof include topoisomerase I inhibitors (camptotesin or topotecan), topoisomerase II inhibitors (eg daunomycin and etoposide), alkylating agents (eg, cyclophosphamide, melphalan and BCNU), agents targeting tubulin (eg, taxol and vinblastine), and biological agents (eg, antibodies such as anti-CD20 antibody, IDEC 8, immunotoxins, and cytokines ).
[00198] [00198] In some embodiments, the compound (s) of formula (I), or a pharmaceutically acceptable salt of the same (s) is (are) used in combination with Rituxan® (Rituximabe) and / or other agents that function by selective depletion of CD20 + B cells.
[00199] [00199] Included here are methods of treatment in which a compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, specific and non-specific inhibitors of the COX-2 cyclooxygenase enzyme, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) receptor antagonists, immunosuppressants and methotrexate.
[00200] [00200] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of sodium diclofenac and misoprostol, sulindac, oxaprozine, diflunisal, piroxicam, indomethacin, methomethacin, methomethacin, methomethacin, methidolone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include specific COX-2 inhibitors (i.e., a compound that inhibits COX-2 with an IC50
[00201] [00201] In another embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
[00202] [00202] The anti-inflammatory agent can also from a corticosteroid. For example, corticosteroids can be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone and sodium phosphate, and prednisone.
[00203] [00203] In some modalities, the anti-inflammatory therapeutic agent is a gold compound such as gold and sodium thiomalate or auranofin.
[00204] [00204] In some embodiments, the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, like methotrexate or a dihydro-orotate dehydrogenase inhibitor, like leflunomide.
[00205] [00205] In one embodiment, the compound (s) of formula (I), or a pharmaceutically acceptable salt of the same (s) is (are) used in combination with at least one anti-compound -inflammatory which is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF-alpha monoclonal antibody.
[00206] [00206] In one embodiment, the compound (s) of formula (I), or a pharmaceutically acceptable salt of the same (s) is (are) used in combination with at least one active agent which is an immunosuppressive compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.
[00207] [00207] In other embodiments, the compound (s) of formula (I), or
[00208] [00208] Compounds A, B and C are described in WO2015 / 017460 and WO2015 / 100217. PI3K inhibitors include PI3Kγ, PI3Kδ, PI3Kβ, PI3Kα, and / or pan-PI3K inhibitors. Additional examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisibe), CH5132799, copanlisibe (BAY 80-6946), duvelisib, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111, OXY111 -866, RG7604, rigosertib, RP5090, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmanina, ZSTK474, and compounds described in WO 2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences). Other examples of PI3K inhibitors include, but are not limited to, GDC-0032, GDC-0077, INCB50465, RP6530, and SRX3177.
[00209] [00209] In yet another embodiment, the compound (s) of formula (I) can be used in combination with Splenic Tyrosine Kinase Inhibitors (SYK). Examples of SYK inhibitors include, but are not
[00210] [00210] In yet another embodiment, the compounds of formula (I) can be used in combination with tyrosine kinase inhibitors (TKIs). TKIs can recognize epidermal growth factor receptors (EGFRs) and fibroblast growth factor receptors (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087, asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinibe, gititef (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, midostaurine, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, radizinib, quizartinib, quizartinib, rociletinib, sulfatinib (HMPL-012), sunitinib, and TH-4000. In certain embodiments, TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinibe, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinibe, dovitinib, E-6201, erfit erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurine, nintedanib, ODM-203, osimertatinib (AZD), 9 , poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody).
[00211] [00211] In still other embodiments, the compound (s) of formula (I), or a pharmaceutically acceptable salt of the same (s) is (are) used in combination with one or more Inhibitors Lysyl-Oxidase-like 2 (LOXL) or
[00212] [00212] In yet another embodiment, the compounds of formula (I) can be used in combination with Toll 8-type receptor inhibitors (TLR8). Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463, and VTX-763.
[00213] [00213] In yet another embodiment, the compounds of formula (I) can be used in combination with Toll 9-type receptor inhibitors (TLR9). Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.
[00214] [00214] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with a BTK inhibitor (Bruton Tyrosine Kinase). An example of such a BTK inhibitor is a compound described in U.S. Patent No. 7,405,295. Additional examples of BTK inhibitors include, but are not limited to, (S) -6-amino-9- (1- (but-2-inoyl) pyrrolidin-3-yl) -7- (4-phenoxyphenyl) -7H -purin-8 (9H) -one, acalabrutinib (ACP-196), BGB-3111, HM71224, ibrutinib, M-2951 (evobrutinib), tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), and TAK-020. Other examples of BTK inhibitors include, but are not limited to, CB988, M7583, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, and
[00215] [00215] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with a BET inhibitor. An example of such a BET inhibitor is a compound described in WO2014 / 182929, the entire contents of which are incorporated herein by reference.
[00216] [00216] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with a TBK inhibitor (Tank Binding Kinase). An example of such a TBK inhibitor is a compound described in WO2016 / 049211.
[00217] [00217] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with an MMP inhibitor. Exemplary MMP inhibitors include MMP1 inhibitors up to 10. Additional examples of MMP9 inhibitors include, but are not limited to, marimastate (BB-2516), cipemastate (Ro 32-3555), GS-5745 (andecaliximab) and those described in WO 2012/027721 (Gilead Biologics).
[00218] [00218] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with an OX40 inhibitor. An example of such an OX40 inhibitor is a compound described in U.S. 8,450,460, the entire contents of which are incorporated herein by reference.
[00219] [00219] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with a JAK-1 inhibitor. An example of such a JAK-1 inhibitor is a compound described in WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinibe), lestaurtinibe, NSYT-7 018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.
[00220] [00220] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with Indolamine-Pyrrol-2,3-Dioxigenase Inhibitors (IDO). An example of such an IDO inhibitor is a compound described in WO2016 / 186967. In one embodiment, the compounds of formula (I) are useful for the treatment of cancer in combination with IDO1 inhibitors including, but not limited to, BLV-0801, epacadostate, F-001287, GBV-1012, GBV-1028, GDC -0919, indoximode, NKTR-218, vaccine based on NLG-919, PF-06840003, pyranonephtoquinone derivatives (SN-35837), resminostate, SBLK-200802, and shIDO-ST. Other examples of IDO1 inhibitors include, but are not limited to, BMS-986205, EOS-200271, KHK-2455, LY-3381916.
[00221] [00221] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with Mitogen Activated Protein Kinase Inhibitors (MEK). MEK inhibitors useful for combination treatment with a compound (s) of formula (I) include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212) , uprosertibe and trametinib. Other exemplary MEK inhibitors include PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.
[00222] [00222] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with Apoptosis Signal Regulatory Kinase Inhibitors (ASK): ASK inhibitors include, but are not limited to those described in WO 2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead Sciences) including, for example, selonsertib.
[00223] [00223] In one embodiment, the compounds of formula (I) can be combined with Differentiation Cluster Inhibitors 47 (CD47).
[00224] [00224] Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAbs (Vx-1004), anti-CD47-human mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody
[00225] [00225] In one embodiment, the compounds of formula (I) can be combined with Cycline Dependent Kinase Inhibitors (CDK). CDK inhibitors include CDK inhibitors 1, 2, 3, 4, 6 and 9, such as abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, FLX-925, LEE001, palbocyclib, ribocyclib, rigosertib, selinexor, UCN-01, and TG-02. Other exemplary CDK inhibitors include dinacyclib, ibrance, SY1365, CT-7001, SY-1365, G1T38, milciclib, and trilacyclib.
[00226] [00226] In one embodiment, the compounds of formula (I) can be combined with Discoidin Domain Receptor Inhibitors (DDR) for the treatment of cancer. DDR inhibitors include DDR1 and / or DDR2 inhibitors. Examples of DDR inhibitors include, but are not limited to, those described in WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO 2013/034933 (Imperial Innovations).
[00227] [00227] In one embodiment, the compounds of formula (I) can be combined with Histone Deacetylase Inhibitors (HDAC) such as those described in U.S. Patent 8,575,353 and equivalents thereof. Additional examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostate), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat. Other examples of HDAC inhibitors include, but are not limited to, tinostamustine, remetinostat, entinostat.
[00228] [00228] In one embodiment, the compounds of formula (I) can be combined with a Hematopoietic Progenitor Cell Kinase Inhibitor 1 (HPK1). Examples of Cell Kinase Inhibitors
[00229] [00229] Anti-hormonal Agents: Anti-hormonal agents also included in the definition of “chemotherapeutic agent” such as anti-estrogens and selective estrogen receptor modulators (SERMs), aromatase enzyme inhibitors, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act to regulate or inhibit the hormonal action on tumors.
[00230] [00230] Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene, ceoxifene, LY117018, onapristone, and toremifene (FARESTON®).
[00231] [00231] Aromatase enzyme inhibitors regulate the production of estrogen in the adrenal glands. Examples include 4 (5) -imidazoles, aminoglutetimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).
[00232] [00232] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204.
[00233] [00233] Examples of progesterone receptor antagonist include onapristone.
[00234] [00234] Antiangiogenic Agents: Antiangiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuparanib, suramin, squalamine, tissue inhibitor of tissue methoproteinase-1, 1 metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, inhibitor derived from
[00235] [00235] Antifibrotic Agents: Antifibrotic agents include but are not limited to compounds such as beta-aminoproprionitrile (BAPN), and also to the compounds described in US 4965288 related to lysyl oxidase inhibitors and their use in the treatment of diseases and associated conditions with abnormal collagen deposition and in US 4997854 related to compounds that inhibit LOX for the treatment of various pathological fibrotic states, which are incorporated herein by reference. Other exemplifying inhibitors are described in US 4943593 related to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, in US 5021456, US 5059714, US 5120764, US 5182297, US 5252608 related to 2- (1-naphthyloxymethyl) -3-
[00236] Exemplary antifibrotic agents also include primary amines that react with the carbonyl group at the active site of lysyl oxidases, and more particularly those that produce, after binding with carbonyl, a resonance stabilized product, such as the following primary amines: ethylenomamin, hydrazine, phenylhydrazine, and derivatives thereof; semicarbazide and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and selene-homocysteine-lactone.
[00237] [00237] Other antifibrotic agents are copper chelating agents that penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that block aldehyde derivatives originating from oxidative deamination of lysyl and hydroxylisyl residues by lysyl oxidases. Examples include thiolamines, particularly D-penicillamine, and their analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3 - ((2-acetamidoethyl) dithio acid) butanoic, p-2-amino-3-methyl-3 - ((2-aminoethyl) dithio) butanoic acid, 4 - ((p-1-dimethyl-2-amino-2-carboxyethyl) dithio) butane sulfurate [sic ] sodium, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate [sic], and sodium 4-mercaptobutanesulfinate trihydrate.
[00238] [00238] Immunotherapeutic Agents: Immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alentuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatuxumab, cintatima, cintu,
[00239] [00239] Exemplary therapeutic antibodies can be additionally labeled or combined with a radioisotope particle such as indium-111, yttrium-90 (90Y-clivatuzumab), or iodine-131.
[00240] [00240] Cancer Gene Therapy and Cell Therapy: Cancer Gene Therapy and Cell Therapy including the insertion of a normal gene into
[00241] [00241] Gene editors: The genome editing system is selected from the group consisting of: a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system ), and a meganuclease system.
[00242] [00242] T-Cell Therapy and T-Cell Therapy-TCR: A population of immune effector cells modified to express a chimeric antigen receptor (CAR, Chimeric Antigen Receptor), in which the CAR comprises an antigen-binding domain tumor. The immune effector cell is a T-cell or an NK cell. T-TCR-cells are modified to recognize tumor-derived peptides present on the surface of tumor cells. The cells can be autologous or allogeneic.
[00243] [00243] In some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain for one or more proteins selected from the
[00244] [00244] In some embodiments, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, antigen-1 associated with lymphocyte function (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE , CD103, ITGAL, CD 1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 ( CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.
[00245] [00245] In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, on CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9 , CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD1 la, CD18), ICOS (CD278), 4-1BB (CD137) , GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2R beta, IL2R gamma, IL7R u, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ld, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226) , SLAMF4 (CD244, 2B4),
[00246] [00246] In some embodiments, the antigen-binding domain binds to a tumor antigen. In some modalities, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also called CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); type-C lectin-type molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor (EGFRvIII) variant III; ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc (2-8) aNeuSAc (2-3) bDGaip (1-4) bDGIcp (1-1) Cer); member of the family of TNF receptors, B-cell maturation protein (BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate specific membrane antigen (PSMA); Receptor 1 orphan receptor tyrosine kinase (RORI); Tyrosine kinase 3 Fms-Like (FLT3); Tumor-associated glycoprotein-72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor alpha-2 subunit (IL-13Ra2 or CD213A2); Mesothelin; Alpha interleukin-11 receptor (IL-11Ra); prostate stem cell antigen (PSCA); Serine-Protease-21 (Testisin or PRSS21); vascular endothelial growth factor receptor-2 (VEGFR2); Lewis antigen (Y); CD24; platelet-derived growth factor beta-receptor (PDGFR-beta); embryonic specific stage 4 antigen (SSEA-4); CD20; delta-like 3 (DLL3); Alpha-folate receptor; Receptor tyrosine kinase protein, ERBB2 (Her2 / neu); Mucine 1 associated with the cell surface (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostasis; prostatic acid phosphatase (PAP); mutated elongation factor-2 (ELF2M); Efrina
[00247] [00247] In some embodiments, the tumor antigen is selected from among CD150, 5T4, ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, fibronectin ED-B, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 in combination , HER2-HER3 in combination, HERV-K, HIV-1 envelope gp120 glycoprotein, HIV1 envelope gp41 glycoprotein, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL - 11Ralfa, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, II, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligands, NKG2D ligands, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-Rl ( DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor, alpha-fetoprotein (AFP), an angiogenesis factor, an exogenous cognate ligand molecule (ExoCBM), oncogene product, folate anti-receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2 , epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor and acetate, folate-binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, double minute homologous mouse 2 (MDM2), mucin 16 (MUC16), mutated p53, mutated ras,
[00248] [00248] Non-limiting examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX-501) rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, allogeneic natural killer cells activated CNDO-109-AANK, MG-4101 , AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190 , CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z T-cells / 4- 1BBL CAR, autologous T-cells 4H11-28z / fIL-12 / EFGRt, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.
[00249] [00249] Additional agents include those in which the tumor recognizing antigen is: Alpha-fetoprotein, such as ET-1402, and AFP-TCR; Anthrax toxin receptor-1, as anti-TEM8 T-cell therapy CAR; B-cell mutation antigens (BCMA), such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101, and AUTO-2 (APRIL-CAR); Anti-CLL-1 antibodies, such as KITE-796; Homologous B7 6, such as CAR-NKp30 and CAR-B7H6; B-lymphocyte CD19 antigen, such as TBI-1501, T-cells CTL-119 huCART-19, JCAR-015 US7446190, JCAR-014, JCAR-017,
[00250] [00250] Any of the treatment methods provided can be used to treat a subject (eg, human) who has been diagnosed with or is suspected of having cancer. As used herein, a subject refers to a mammal, including, for example, a human.
[00251] [00251] In some modalities, the subject may be a human who presents one or more symptoms associated with cancer or hyperproliferative disease. In some embodiments, the subject may be a human who has one or more symptoms associated with cancer. In some modalities, the subject is in an early stage of cancer. In other modalities, the subject is in an advanced stage of cancer.
[00252] [00252] In certain modalities, the subject may be a human who is at risk, or genetically or differently predisposed (for example, risk factor) to develop cancer or hyperproliferative disease that has or has not been diagnosed. As used herein, a subject "at risk" is a subject who is at risk for developing cancer. The subject may or may not have detectable disease, and may or may not have had detectable disease before the treatment methods described herein. A subject at risk may have one or more of the so-called risk factors, which are measurable parameters that correlate with the development of cancer, which are described here. A subject having one or more of these risk factors is more likely to develop cancer than an individual without these risk factor (s). These risk factors may include, for example, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic considerations (eg, heredity), and environmental exposure. In some modalities, subjects at risk for cancer include, for example, those having relatives who have experienced the disease, and those whose risk is determined by analyzing genetic or biochemical markers.
[00253] [00253] In addition, the subject may be a human being subjected to one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof. Consequently, one or more kinase inhibitors can be administered before, during, or after the administration of chemotherapy, radiation therapy, immunotherapy, surgery or a combination thereof.
[00254] [00254] In certain modalities, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) is relapsing after treatment with chemotherapy, or both (i) and (ii) . In some embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
[00255] [00255] As used herein, a "therapeutically effective amount" means an amount sufficient to modulate a specific route, and thus treat a subject (such as a human) suffering from an indication, or to alleviate the existing symptoms of the indication. The determination of a therapeutically effective amount is within the capacity of those skilled in the art, especially considering the detailed description provided herein. In some embodiments, a therapeutically effective amount of a JAK inhibitor, such as Compound A or ruxolitinib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of PI3K inhibitor, such as Compound B, Compound C, Compound D, or Compound and salt pharmaceutically acceptable product, can (i) reduce the number of diseased cells; (ii) reducing the size of the tumor; (iii) inhibit, delay, slow down to some extent, and preferably interrupt the infiltration of diseased cells into peripheral organs; (iv) inhibiting (for example, slowing to some extent and preferably interrupting) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and / or recurrence of a
[00256] [00256] In some modalities, cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, multiple myeloma (MM), chronic myeloid leukemia (CML) , acute lymphocytic leukemia (ALL), B-cell ALL, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), cell lymphoma mantle (MCL), follicular lymphoma (FL), Waldenstrom macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or marginal zone lymphoma (MZL). In one embodiment, cancer is a minimal residual disease (MRD, Minimal Residual Disease). In an additional modality, the cancer is selected among Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL. In a given modality, the cancer is indolent non-Hodgkin's lymphoma (iNHL). In some modality, cancer is refractory iNHL. In
[00257] [00257] In certain modalities, cancer is a solid tumor that is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer or kidney cancer, including, for example, metastatic kidney cell carcinoma; hepatocellular cancer; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC, Bronchioloalveolar Carcinoma), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendodrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytone; bone cancer; and soft tissue sarcoma, liver carcinoma, rectal cancer, penile carcinoma, vulvar cancer, thyroid cancer, salivary gland carcinoma, endometrial carcinoma or uterine carcinoma, hepatoma, hepatocellular cancer, liver cancer, gastric cancer or stomach cancer including cancer gastrointestinal cancer, peritoneum cancer, squamous carcinoma of the lung, gastroesophageal cancer, biliary tract cancer, gallbladder cancer, colorectal / appendix cancer, squamous cell cancer (eg, squamous epithelial cell cancer).
[00258] [00258] Any of the treatment methods can be used to treat cancer at various stages. As an example, the cancer stage includes, but is not limited to, early stage, advanced stage, locally advanced stage, remission stage, refractory stage, stadium
[00259] [00259] Combination Therapy Against Lymphoma or Leukemia: Some chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplastone A10, antineoplastone AS2-1, thymocyte antiglobulin, arsenic trioxide, ABT-263 protein inhibitor from the Bcl-2 family, beta-aletine, BMS- 345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), briostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclo , doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileucine diftitox, dexamethasone, docetaxel, chlorethaxine, doletaxel, 10 -PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurine, alfaepoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarfamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and citar, and citar, etoposide), ifosfamide, irinotecan hydrochloride, interferon-alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, chlorine, methotrexate of mitoxantrone, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersene, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel03, palbocy1 pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, perifosine,
[00260] [00260] A modified approach is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle, such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131-asitumomab (BEXXAR®), yttrium-90-ibritumomab-tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.
[00261] [00261] The aforementioned therapies can be supplemented or combined with stem cell treatment or transplantation. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion , bone marrow ablation with stem cell support, transplantation of peripheral blood stem cells treated in vitro, umbilical cord blood transplantation, immunoenzyme technique, cobalt-60 gamma-ray therapy with low-TEL (Transfer Linear Energy), bleomycin, conventional surgery, radiotherapy, and transplantation of non-myeloablative allogeneic hematopoietic stem cells.
[00262] [00262] Combination Therapy Against Non-Hodgkin's Lymphomas: Treatment of non-Hodgkin's lymphomas (NHL), especially those of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy approaches (for example, CHOP, CVP, FCM, MCP, and the like), radioimmunotherapy, and combinations thereof, especially integration of antibody therapy with chemotherapy.
[00263] [00263] Examples of unconjugated monoclonal antibodies for the treatment of NHL / B-cell cancers include rituximab, alentuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-apoptosis-related-ligand-inducing-antibody TNF (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74 antibody.
[00264] [00264] Examples of exemplifying antibody agents used in the treatment of NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alentuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.
[00265] [00265] Examples of standard chemotherapy regimens for NHL / B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.
[00266] [00266] Examples of radioimmunotherapy for NHL / B-cell cancers include yttrium-90-ibritumomab-tiuxetan (ZEVALIN®) and iodine-131- asitumomab (BEXXAR®).
[00267] [00267] Combination Therapy Against Mantle Cell Lymphoma: Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the aforementioned therapies can be combined with stem cell transplantation or ICE for the purpose of treating MCL.
[00268] [00268] An alternative approach to treat MCL is immunotherapy.
[00269] [00269] A modified approach to treating MCL is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle, such as iodine-131-asitumomab (BEXXAR®) and yttrium-90-ibritumomab-tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.
[00270] [00270] Other approaches to treating MCL include transplantation of autologous stem cells coupled with high dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of antiangiogenesis agents such as thalidomide, especially in combination with rituximab.
[00271] [00271] Another treatment approach is the administration of drugs that result in the degradation of Bcl-2 protein and in the increased sensitivity of cancer cells to chemotherapy, such as oblimersene, in combination with other chemotherapeutic agents.
[00272] [00272] Another treatment approach includes administration of mTOR inhibitors, which can result in cell growth inhibition and even cell death. Non-limiting examples are sirolimus, tensirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and tensirolimus in combination with RITUXAN®, VELCADE ®, or other chemotherapeutic agents.
[00273] [00273] Other recent therapies for MCL have been described. Such examples include flavopyridol, palbocyclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, anti-TRAIL-death-receptors-DR4-and-DR5 antibodies, tensirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin
[00274] [00274] Combination Therapy Against Waldenstrom's Macroglobulinemia: Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM) include aldesleukin, alentuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplastone A10, antineoplastin A10, antineoplastone A10, antineoplastone, antineoplastone A10, antineoplastone, antineoplastone A10, antineoplastone, antineoplastone A10, antineoplastone, antineoplastone A10, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone, antineoplastone. arsenic trioxide, HSPPC-96 derived from autologous human tumor, ABT-263 inhibitor of Bcl-2 family protein, beta-alethine, bortezomib (VELCADE®), briostatin 1, busulfan, campath-1H, carboplatin, carmustine, acetate caspofungin, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileucine diphthitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurine, alfaepoetine, epratuzbe, epratuzbe , everolimus, fenretinide, filgrastim, fludarabine, ifosfamide, monoclonal antibody-indium-111 MN-14, iodo-131-asitumomab, irinotecan hydrochloride, ixabepilone, killer cells activated by lymphokines, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal anti-CD19 antibody (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal anti-CD20 antibody, motexafin gadolinium, mycophenolate mofetil, nellabine, nellabine octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon-recombinant, interleukin 11 , rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimicina, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristine sulfate, ditartarate1 Peptide Vaccine ”(amino acid peptide vaccine 126-to-136 of human Wilms tumor protein-1),“ WT-1
[00275] [00275] Examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total irradiation of the body, stem cell infusion, bone marrow ablation with stem cell support, transplantation of peripheral blood stem cells treated in vitro, umbilical cord blood transplantation, immunoenzyme technique, cobalt gamma ray therapy -60 with low-TEL (Linear Energy Transfer), bleomycin, conventional surgery, radiotherapy, and transplantation of non-myeloablative allogeneic hematopoietic stem cells.
[00276] [00276] Combination Therapy Against Diffuse Large B-Cell Lymphoma: Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many listed agents for WM, and any combination thereof, such as ICE and R-ICE.
[00277] [00277] Combination Therapy Against Chronic Lymphocytic Leukemia: Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, many of the agents listed for many of the listed agents. WM, and comminution chemotherapy and combination chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.
[00278] [00278] Combination Therapy Against Myelofibrosis: Myelofibrosis inhibiting agents include, but are not limited to, myelofibrosis inhibitors
[00279] [00279] Combination Therapy Against Hyperproliferative Disorder: Gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel can be used with a JAK inhibitor and / or PI3Kδ inhibitor to treat hyperproliferative disorders.
[00280] [00280] Bladder Cancer Combination Therapy: Therapeutic agents used to treat bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, 5-fluorouracil (5-FU), gemcitabine, elderfamide, Interferon-alpha-2b, methotrexate , mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.
[00281] [00281] Combination Therapy Against Breast Cancer: Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, fluorouritine, gulorinea, gulpoururine, fulcourantine, gulpoururine, fulcourantine, gulpourine, fulcourantine, fluorouracine, fulcourantine, fluorouracine, fulcourantine, fulcourantine, fluorouracine, fulcourantine, fulcourantine, gulpourine. , ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, liposomal pegylated doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combinations thereof.
[00282] [00282] Triple Negative Breast Cancer Combination Therapy: Therapeutic agents used to treat triple negative breast cancer include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.
[00283] [00283] Combination Therapy Against Colorectal Cancer: Agents
[00284] [00284] Combination Therapy Against Castration-Resistant Prostate Cancer: Therapeutic agents used to treat castration-resistant prostate cancer include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, sipuleucel-T, and any combinations thereof.
[00285] [00285] Combination Therapy Against Esophageal Cancer and Esophagogastric Junction: Therapeutic agents used to treat esophageal cancer and esophagogastric junction include capecitabine, carboplatin, cisplatin, docetaxel, epirububicin, fluoropyrimidine, fluorouracil, irinucleotide, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine, fluorine. trastuzumab, and any combinations thereof.
[00286] [00286] Gastric Cancer Combination Therapy: Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxine, paclitaxine, paclitaxine, paclitaxine, paclitaxin, paclitaxine, paclitaxine and any other compound. themselves.
[00287] [00287] Head & Neck Cancer Combination Therapy: Therapeutic agents used to treat head & neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumaelb, paclita pembrolizumab, vinorelbine, and any combinations thereof.
[00288] [00288] Combination Therapy Against Hepatobiliary Cancer: Therapeutic agents used to treat hepatobiliary cancer include capecitabine, cisplatin, fluoropyrimidine, 5-fluorouracil, gemecitabine, oxaliplatin,
[00289] [00289] Combination Therapy Against Hepatocellular Carcinoma: Therapeutic agents used to treat hepatocellular carcinoma include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combinations thereof.
[00290] [00290] Non-Small Cell Lung Cancer Combination Therapy: Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexede, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vimblastine, vimblastine and vinobastine.
[00291] [00291] Small Cell Lung Cancer Combination Therapy: Therapeutic agents used to treat small cell lung cancer (SCLC) include bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, irinotecan, nirinotecan, irinotecan, nivinotechan , paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combinations thereof.
[00292] [00292] Combination Therapy Against Melanoma: Therapeutic agents used to treat melanoma cancer include albumin-linked paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon-alpha-2b, ipilimumab, nitrosourea, nivou , paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vimblastine, and any combinations thereof.
[00293] [00293] Ovarian Cancer Combination Therapy: Therapeutic agents used to treat ovarian cancer include 5-flourouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab,
[00294] [00294] Combination Therapy Against Pancreatic Cancer: Therapeutic agents used to treat pancreatic cancer include 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxalin, and oxalin, oxalin, and oxalin, oxalin, oxalin, and oxalin, oxalin, and oxalin. of the same.
[00295] [00295] Combination Therapy Against Renal Cell Carcinoma: Therapeutic agents used to treat renal cell carcinoma include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus ,uscinib, nivolumab, pazopanib, sorafenib, sunitinib, same combinations, and any combinations.
[00296] [00296] In one embodiment, the compound of formula (I) is useful for the treatment of cancer in combination with a standard of care in the treatment of the respective cancer. A person skilled in the art is aware of the standard of care as from a given date in the specific field of cancer therapy or with respect to a given cancer.
[00297] [00297] Certain embodiments of the present application include or use one or more additional therapeutic agents. The one or more additional therapeutic agents can be useful agents for the treatment of cancer, inflammation, autoimmune disease and / or related conditions. The one or more additional therapeutic agents can be a chemotherapeutic agent, an antiangiogenic agent, an antifibrotic agent, an anti-inflammatory agent, an immunomodulatory agent, an immunotherapeutic agent, a therapeutic antibody, a radiotherapeutic agent, an antineoplastic agent, an agent
[00298] [00298] In one embodiment, the compound (s) of formula (I) optionally in combination with an additional anticancer agent described herein, can be used or combined with an antineoplastic agent or an anti-cancer agent, an anti-fibrotic agent, an anti-inflammatory agent, or an immunomodulatory agent.
[00299] [00299] In one embodiment, kits are provided comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, or a compound of formula (I) and at least one additional anticancer agent, or a pharmaceutically acceptable salt of the same, and at least one pharmaceutically acceptable carrier. In one embodiment, the kit comprises instructions for use in the treatment of cancer or inflammatory conditions. In one embodiment, the instructions in the kit are directed to use the pharmaceutical composition for the treatment of cancer selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS (Central Nervous System) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-cell lung cancer small cell lung cancer and colon cancer.
[00300] [00300] The application also provides a method for treating a subject who
[00301] [00301] In one embodiment, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) relapse after treatment with chemotherapy, or both (i) and (ii). In some embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies). In one embodiment, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alentuzumab and other treatments chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; tensirolimus and rituximab; tensirolimus and Velcade®; Iodine-131- asitumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (ifosfamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
[00302] [00302] Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, the treatment of certain lymphomas is reviewed in Cheson, B.D., Leonard, J.P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin’s Lymphoma” The New England Journal of Medicine 2008, 359 (6), p. 613-626; and Wierda, W.G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. The patterns of lymphoma incidence in the United States are profiled in Morton, L.M., et al. "Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001" Blood 2006, 107 (1), p. 265-276.
[00303] [00303] Examples of immunotherapeutic agents for treating lymphoma or leukemia include, but are not limited to, rituximab (like Rituxan), alentuzumab (like Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN- antibodies 14, anti-TRAIL, anti-TRAIL-DR4-and-DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2 - humanized anti-CD22 antibody), galiximab, ha20, ibritumomabe tiuxetana, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, “WT-1 Analog Peptide Vaccine” (peptide vaccine comprised of an epitope of Wilms tumor human protein-1), “WT1 126-134 Peptide Vaccine” (peptide vaccine from amino acids 126-to-136 of Wilms tumor human protein-1), tositumomab, HSPPC-96 derived from autologous human tumor, and veltuzumab. Additional immunotherapeutic agents include the use of cancer vaccines based on the genetic makeup of an individual patient's tumor, as an example of a lymphoma vaccine is GTOP-99 (MyVax®).
[00304] [00304] Examples of chemotherapeutic agents to treat lymphoma or leukemia include aldesleukin, alvocidib, antineoplastone AS2-1, antineoplastone A10, antiglobulin-thymocyte, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta-alethine 26, inhibitor 26 in
[00305] [00305] In some modalities, cancer is melanoma. Suitable agents for use in combination with the compounds described herein include, without limitation, dacarbazine (DTIC), optionally, along with other chemotherapeutic drugs such as carmustine (BCNU) and cisplatin; The “Dartmouth regime”, which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY ™. The compounds described herein can also be combined with immunotherapeutic drugs, including cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF) in the treatment of melanoma.
[00306] [00306] The compounds described herein can also be used in combination with vaccine therapy in the treatment of melanoma. Antimelanoma vaccines are, in some ways, similar to antiviral vaccines that are used to prevent diseases caused by viruses such as polio viruses, measles viruses, and mumps viruses. Weakened melanoma cells or parts of melanoma cells called antigens can be injected into a patient to stimulate the patient's immune system to destroy the melanoma cells.
[00307] [00307] Melanomas that are confined to the arms or legs can also be treated with a combination of agents including one or more compounds described herein, using for example, an isolated hyperthermic limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapeutic agent into the artery that feeds the limb, thus providing high doses to the tumor area without exposing the internal organs to these high doses. that could otherwise cause
[00308] [00308] Therapeutic treatments can be supplemented or combined with any of the aforementioned therapies with treatment or transplantation of stem cells. An example of a modified approach is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle, such as indium (In-111), yttrium (Y-90), iodine (I-131). Examples of combination therapies include, but are not limited to, Iodo-131-asitumomab (Bexxar®), Yttrium-90-ibritumomab-tiuxetan (Zevalin®), Bexxar® with CHOP.
[00309] [00309] Other useful therapeutic procedures in combination with treatment with a compound of formula (I) include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy , enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow ablation with stem cell support, transplantation of peripheral blood stem cells treated in vitro, umbilical cord blood transplantation, immunoenzyme, pharmacological study, cobalt-60 gamma-ray therapy with low-TEL (Linear Energy Transfer), bleomycin, conventional surgery, radiotherapy, and transplantation of allogeneic non-myeloablative hematopoietic stem cells.
[00310] [00310] In some embodiments, the application provides pharmaceutical compositions comprising a compound of formula (I) in combination with an MMP9 binding protein and / or one or more additional therapeutic agents, and a pharmaceutically diluent, carrier or excipient
[00311] [00311] In one embodiment, the pharmaceutical compositions comprise the compound of formula (I), anti-MMP9 antibody AB0045, at least one additional therapeutic agent which is an immunomodulatory agent, and a pharmaceutically acceptable diluent, carrier or excipient. In certain other embodiments, the pharmaceutical compositions comprise the AB0045 anti-MMP9 antibody, at least one additional therapeutic agent which is an anti-inflammatory agent, and a pharmaceutically acceptable diluent, carrier or excipient. In certain other embodiments, the pharmaceutical compositions comprise the compound of formula (I), the AB0045 anti-MMP9 antibody, at least one additional therapeutic agent which is an antineoplastic agent or an anti-cancer agent, and a pharmaceutically acceptable diluent, carrier or excipient. In one embodiment, MMP9 compounds useful for combination treatment with a compound of formula (I) include but are not limited to marimastate (BB-2516), cipemastate (Ro 32-3555) and those described in WO 2012/027721 (Gilead Biologics ).
[00312] [00312] In one embodiment, the one or more additional therapeutic agent (s) is (are) an immunomodulatory agent, for example, an immunostimulant or an immunosuppressant. In certain other embodiments, an immunomodulating agent is an agent capable of altering the function of immune checkpoints, including CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200 pathways and / or PD-1. In other embodiments, the immunomodulating agent is a modulating agent (s) of immune checkpoints. Immune checkpoint modulating agents
[00313] [00313] In some embodiments, the one or more therapy or anticancer agent (s) is (are) cancer gene therapy or cell therapy. Gene cancer and cell therapy include inserting a normal gene into cancer cells to replace a mutated or altered gene; genetic modification to silence a mutated gene; genetic approaches to directly kill cancer cells; including the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to cancer cells, or to activate the patient's own immune system (T-cells or Natural Killer Cells) to kill cancer cells, or find and kill cancer cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness to cancer. Non-limiting examples are Algenpantucel-L (2 pancreatic cell lines),
[00314] [00314] In one embodiment, the one or more additional therapeutic agent (s) is (are) an immune checkpoint inhibitor. Tumors subvert the immune system by benefiting from a mechanism known as T-cell exhaustion, which results from chronic exposure to antigens and is characterized by the overloading of inhibitory receptors. These inhibitory receptors serve as immune checkpoints for the purpose of preventing uncontrolled immune reactions.
[00315] [00315] PD-1 and co-inhibitory receptors such as Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), B-and-T Lymphocyte Attenuator (BTLA; CD272), Mucin Domain and T-Cell Immunoglobulin Domain - 3 ( Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as checkpoint regulators. They act as molecular determinants to influence whether cell cycle progression and other intracellular signaling processes should proceed based on extracellular information.
[00316] [00316] In addition to the recognition of specific antigen by means of the T-cell receptor (TCR), T-cell activation is regulated by a balance of positive and negative signals provided by the co-stimulatory receptors. These surface proteins are typically members of both the TNF receptor superfamily and the B7 superfamily.
[00317] [00317] Programmed Cell Death Protein 1, (PD-1 or CD279), a 55-kD type 1 transmembrane protein, is a member of the CD28 family of T-cell co-stimulatory receptors that includes the CD28 member of the superfamily of immunoglobulins, CTLA-4, inducible co-stimulator (ICOS), and BTLA. PD-1 is highly expressed on activated T-cells and activated B-cells. PD-1 expression can also be detected on subsets of memory T-cells with varying levels of expression. Two specific ligands for PD-1 have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). PD-L1 and PD-L2 have been shown to downregulate T-cell activation under binding to PD-1 in both the murine (mouse) and human systems (Okazaki et al., Int. Immunol., 2007; 19: 813 -824). The interaction of PD-1 with its ligands, PD-L1 and PD-L2, which are expressed on antigen presenting cells (APCs) and dendritic cells (DCs), transmits negative regulatory stimuli to inframodulate the activated T-cell immune response. . Blocking PD-1 suppresses this negative signal and amplifies T-cell responses. Numerous studies indicate that the cancerous microenvironment manipulates the PD-L1 / PD-1 signaling pathway and that the induction of PD-L1 expression is associated with the inhibition of immune responses against cancer, thus allowing the progression and metastasis of cancer. The PD-L1 / PD-1 signaling pathway is a primary mechanism for immune evasion from cancer due to several reasons. This pathway is involved in the negative regulation of immune responses of activated effector T cells found in the periphery. PD-L1 is overloaded in cancerous microenvironments, while PD-1 is also overloaded in cancerous
[00318] [00318] The first immune checkpoint inhibitor to be tested in a clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 mAb. CTLA-4 belongs to the immunoglobulin receptor superfamily, which also includes PD-1, BTLA, TIM-3, and suppressor of immunoglobulin V-domain T-cell activation (VISTA). anti-CTLA-4 mAb is a potent immune checkpoint inhibitor that removes the "break" of both naïve cells and antigen-experienced cells.
[00319] [00319] The therapy intensifies the antitumor function of CD8 + T-cells, increases the ratio between CD8 + T-cells and Foxp3 + regulatory T-cells, and inhibits the suppressive function of regulatory T-cells. TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8 + T-cells. In mouse cancer models, most dysfunctional tumor infiltrating CD8 + T-cells have actually been shown to coexpress PD-1 and LAG-3. LAG-3 is another recently identified inhibitory receptor that acts to limit the function of effector T cells and to increase the suppressive activity of regulatory T cells. It has recently been reported that PD-1 and LAG-3 are extensively coexpressed by tumor-infiltrating T-cells in mice, and that combined blocking of PD-1 and LAG-3 elicits potent synergistic antitumor immune responses in cancer models in mouse.
[00320] [00320] Thus, in one embodiment, the present description provides for the use of immune checkpoint inhibitors of formula (I) described herein in combination with one or more immune checkpoint inhibitors
[00321] [00321] In addition, PD-1 can also be labeled with AMP-224, which is a recombinant PD-L2-IgG fusion protein. Additional antagonists of inhibitory pathways in the immune response include IMP321, a soluble LAG-3 Ig fusion protein and MHC class II agonist, which is used to enhance an immune response to tumors. Lirilumab is an antagonist for the KIR receptor and BMS 986016 is an LAG3 antagonist. The TIM-3-Galectin-9 pathway is another checkpoint inhibitory pathway that is a promising target for checkpoint inhibition. RX518 recognizes and activates the glucocorticoid-induced tumor necrosis factor receptor (GITR), a member of the TNF receptor superfamily that is expressed on the surface of multiple types of immune cells, including regulatory T cells, effector T cells, B-cells, natural killer cells (NK), and activated dendritic cells. Thus, in one embodiment, the compound (s) of formula (I) can be used in combination with IMP321, Lirilumab and / or BMS 986016.
[00322] [00322] Anti-PD-1 antibodies that can be used in compositions and
[00323] [00323] In one embodiment, the compound of formula (I) is administered in combination with the anti-PD-1 antibody nivolumab, pembrolizumab, and / or pidilizumab to a patient who needs it. In one embodiment, the anti-PD-L1 antibody useful for combination treatment with a compound of formula (I) is BMS-936559, atezolizumab, or avelumab. In one embodiment, the immunomodulatory agent inhibits an immune checkpoint pathway. In another modality, the immune checkpoint pathway is selected from CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200 and PD-1. Additional antibodies that can be used in combination with a compound of formula (I) in compositions and methods described herein include the anti-PD-1 and anti-PD-L1 antibodies described in US Patent Nos. 8,008,449 and 7,943,743, respectively .
[00324] [00324] In one embodiment, the one or more additional therapeutic agent (s) is (are) an anti-inflammatory agent. In certain other modalities, the anti-inflammatory agent is an inhibitor of tumor necrosis factor alpha (TNF-α). As used herein, the terms "TNF-alpha", "TNF-α", and "TNFα", are interchangeable. TNF-α is a proinflammatory cytokine secreted predominantly by macrophages but also by a
[00325] [00325] The above therapeutic agents in combination with a compound (s) described herein, can be used, for example, in those quantities indicated in the reference manuals for example, “Physicians Desk Reference” or in quantities generally known by a qualified health professional, that is, a person commonly versed in the technique. In the methods of the present description, such other therapeutic agent (s) can be administered prior to, simultaneously with, or after administration of the compound (s) of formula (I). Certain other therapeutic agents can be combined into a single formulation or a kit when treatable. For example, tablet, capsule or liquid formulations can be combined with another tablet, capsule or liquid formulations in a fixed or combined dose formulation or a fixed or combined dose regimen. Other combinations can be given separately, simultaneously or otherwise. Combination Therapy for HBV
[00326] [00326] In certain embodiments, a method is provided to treat or prevent an HBV infection in a human having or at risk of having the infection, comprising administering to the human a quantity
[00327] [00327] In certain embodiments, the present description provides a method for treating an HBV infection, comprising administering to a patient, who needs it, a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one to two, one to three, or one to four) additional therapeutic agents that are suitable for treating an HBV infection.
[00328] [00328] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In additional embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. One, two, three, four or more
[00329] [00329] In certain embodiments, when a compound described herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.
[00330] [00330] Co-administration of a compound described herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound described herein and one or more additional therapeutic agents, so that therapeutically effective amounts of each agent are present in the patient's body.
[00331] [00331] Co-administration includes administration of unit dosages of the compounds described herein before or after administration of unit dosages of one or more additional therapeutic agents. The compound described herein can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound described herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound described herein within seconds or minutes. In some embodiments, a unit dose of a compound described herein is administered first, followed, after a period of hours (for example, 1-12 hours), by administration of a unit dose of
[00332] [00332] In certain embodiments, a compound described herein is combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
[00333] [00333] In certain embodiments a compound of formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating hepatitis B virus (HBV). In certain embodiments, the tablet may contain another active ingredient to treat hepatitis B virus (HBV).
[00334] [00334] In certain embodiments, such tablets are suitable for dosing once a day.
[00335] [00335] The compounds described herein can be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and an "antibody-like" therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drug conjugate (CAF), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, endonucleases guided, synthetic nucleases, TALENs), cell therapies such as CAR-T agent (T-cell with chimeric antigen receptor), and TCR-T agent (a modified T-cell receptor) or any combination thereof.
[00336] [00336] In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, the additional therapeutic agent can be selected from the group consisting of combination drugs against
[00337] [00337] In some embodiments, a method is provided here for treating hepatitis B virus (HBV) in a patient who needs it, comprising administering an effective amount of a compound described herein in combination with an effective amount of one or more agents anti-HCV, such as an NS5A inhibitor, an NS5B inhibitor, an NS3 inhibitor, or a combination thereof. In some embodiments, a method of treating hepatitis B virus (HBV) infection in a human in need is provided, comprising administering to the patient an effective amount of a compound described herein in combination with an effective amount of an NS5A inhibitor . In some embodiments, the NS5A inhibitor is ledipasvir or velpatasvir. In some embodiments, a method of treating hepatitis B virus (HBV) infection in a human in need is provided, comprising administering to the patient an effective amount of a compound described herein in combination with an effective amount of an NS5B inhibitor . In some embodiments, the NS5B inhibitor is sofosbuvir or mericitabine. In some embodiments, a method of treating hepatitis B virus (HBV) infection in a human in need is provided, comprising administering to the patient an effective amount of a compound described herein in combination with an effective amount of an NS3 inhibitor. . In some embodiments, the NS3 inhibitor is voxilaprevir.
[00338] [00338] In some embodiments, the patient is administered with an effective amount of a compound described herein in combination with an effective amount of both an effective amount of an NS5A inhibitor and an effective amount of an NS5B inhibitor. In some embodiments, the NS5A inhibitor is ledipasvir and the NS5B inhibitor is sofosbuvir. In some modalities, the patient is administered with an effective amount
[00339] [00339] In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of both an effective amount of an NS5A inhibitor and an effective amount of an NS5B inhibitor. In some embodiments, the NS5A inhibitor is ledipasvir and the NS5B inhibitor is sofosbuvir. In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of a fixed dose combination of an NS5A inhibitor and an NS5B inhibitor. In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of a fixed dose combination of ledipasvir and sofosbuvir (for example, ledipasvir 90 mg / sofosbuvir 400 mg). In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of Harvoni®. In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of a fixed dose combination of velpatasvir and sofosbuvir (for example, velpatasvir 100 mg / sofosbuvir 400 mg). In some embodiments, the patient is administered an effective amount of a compound from Table 1 in combination with an effective amount of Epclusa®.
[00340] [00340] In some embodiments, the patient is administered an effective amount of compound 139 in combination with an effective amount of both an effective amount of an NS5A inhibitor and an
[00341] [00341] In some embodiments, the patient is administered with an effective amount of a compound described herein in combination with an effective amount of both an effective amount of an NS5A inhibitor and an effective amount of an NS5B inhibitor, and optionally an NS3 inhibitor. In some embodiments, the patient is administered an effective amount of a compound described herein in combination with an effective amount of sofosbuvir, velpatasvir, and voxilaprevir (for example, sofosbuvir 400 mg / velpatasvir 100 mg / voxilaprevir 100 mg). In some embodiments, the patient is administered an effective amount of a compound described herein (e.g., compound 139) in combination with an effective amount of Vosevi ™.
[00342] [00342] In certain embodiments, a compound of formula (I) is
[00343] [00343] In certain embodiments, a compound of the present description, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from combination drugs against HBV, vaccines against HBV, inhibitors of HBV DNA polymerase, Toll-type receptor modulating (TLR) immunomodulators,
[00344] [00344] Examples of combination drugs for the treatment of HBV include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800 (INO-9112 and RG7944). Other HBV Drugs
[00345] [00345] Examples of other drugs for the treatment of HBV include alpha-hydroxytropolones, andoxovir, beta-hydroxycytosine nucleosides, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), JNJ-5613637ida, nitaz , birinapanto, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotylate, feron, GST-HG-131, levamisole, Ka Shu Ning, aloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN -co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB- nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna ,
[00346] [00346] HBV vaccines include both prophylactic and therapeutic vaccines. Examples of prophylactic HBV vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb- vaccine Hib-IPV, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, prophylactic vaccine against hepatitis B (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant vaccine against hepatitis B (intramuscular, Kangtai Biological Products), recombinant vaccine against hepatitis B (yeast Hansenula polymorpha, intramuscular, Hualan Biological Engineering), recombinant vaccine against hepatitis B surface antigen, Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV -Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib- vaccine HBV, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B +, Fendrix, DT wP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, pentavalent vaccine against HBI (Infantile Hepatitis B), LBVD, Infanrix HeXa, and
[00347] [00347] Examples of therapeutic vaccines against HBV include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsílonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B +, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP- 02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant therapeutic vaccine based on VLP (infection by HBV, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, TG-1050, and Lm HBV. HBV DNA Polymerase Inhibitors
[00348] [00348] Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), entricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir hemofenamide fumarate alafenamide, tenofovir dipivoxil, tenofovir disoproxil fumarate, tenovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), pradefovir, ribavine, clevudine, clevudine, , phosphazide, fanciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, disoproxil tenovir aspartate, disoproxil tenofovir orotate, and HS-
[00349] [00349] Examples of immunomodulators include rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleucine, hydroxyurea, mycophenolate mofetil (MPA) and its mycophenolate ester derivative of mofetil (MMF, WF, RAP, IL-12, INO-9112, polyethyleneimine polymer (PEI), Gepon, VGV-1, MOR-22, BMS-936559,
[00350] [00350] TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, GS-9688 and ND-1.1.
[00351] [00351] Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M- 052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, RG-7854, and the compounds described in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).
[00352] [00352] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compounds described in US20140045849 (Janssen), US20140073642 (Janssen ), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (US Array Biopharma), US20080306029, (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US25220, 2011, 2015, US252752 (2016) Novira Therapeutics).
[00353] [00353] Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054 , DV-1079, DV-1179, AZD-1419, leftolimode (MGN-1703), litenimode, and CYT-003-QbG10. Interferon-Alpha Receptor Binders
[00354] [00354] Examples of alpha-interferon receptor ligands include interferon-alpha-2b (INTRON A®), pegylated interferon-alpha-2a (PEGASYS®), PEGylated interferon-alpha-1b, interferon-alpha-1b (HAPGEN® ), Veldona, Infradure, Roferon-A, YPEG-interferon-alfa-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon-gamma), rSIFN-co (recombinant supercompound interferon), Ypeginterferon -alpha-2b (YPEG-rhIFNalpha-2b), MOR-22, peginterferon-alpha-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon-alpha-n1 (HUMOFERON®), interferon-beta-1a (AVONEX®), Shaferon, interferon-alpha-2b (Axxo), Alpha-interferon, interferon-alpha-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON -B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, interferon-alpha-2b (IFN, Laboratorios Bioprofarma), alpha interferon 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon-alpha-2b (Zydus- Cadilla), interferon-alpha-2a, Optipeg A, Real fa 2B, Reliferon, interferon-alfa-2b (Amega), interferon-alfa-2b (Virchow), ropeginterferon-alfa-2b, rHSA-IFN-alfa-2a (recombinant human serum albumin fusion protein - inferferon-alpha- 2a), rHSA-IFN-alpha-2b, human recombinant interferon-alpha- (1b, 2a, 2b), peginterferon-alfa-2b (Amega), peginterferon-alfa-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon-alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstate, rHSA-IFN alfa-2b, SFR-9216, and Interapo (Interapa). Hyaluronidase inhibitors
[00355] [00355] Examples of hyaluronidase inhibitors include astodrimer. Hepatitis B Virus Surface Antigen Inhibitors (HBsAg)
[00356] [00356] Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139-Ca , REP-2165, REP-2055, REP-2163, REP-2165, REP-
[00357] [00357] Examples of inhibitors of HBsAg secretion include BM601. Cytotoxic T-Lymphocyte-Associated Protein-4 Inhibitors (ipi4)
[00358] [00358] Examples of protein-4 inhibitors associated with cytotoxic T-lymphocyte include AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, mAbs Probody, tremelimumab, and JHL-1155. Cyclophylline Inhibitors
[00359] [00359] Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds described in US8513184 ( Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences). HBV Viral Entry Inhibitors
[00360] [00360] Examples of HBV viral entry inhibitors include Myrcludex B. Antisense Oligonucleotide Targeted by Viral mRNA
[00361] [00361] Examples of antisense oligonucleotide targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004. Short Interfering RNAs (siRNA) and ddRNAi.
[00362] [00362] Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.
[00363] [00363] Examples of directed RNA interference with DNA construct introduction (ddRNAi) (DNA-directed RNA interference, ddRNAi) include BB-HB-331. Endonuclease Modulators
[00364] [00364] Examples of endonuclease modulators include PGN-514. Ribonucleotide Reductase Inhibitors
[00365] [00365] Examples of ribonucleotide reductase inhibitors include Trimidox. HBV Antigen E Inhibitors
[00366] [00366] Examples of HBV E antigen inhibitors include wogonin. Covalently Closed Circular DNA Inhibitors (cccDNA)
[00367] [00367] Examples of cccDNA inhibitors include BSBI-25, and CHR-
[00368] [00368] Example of farnesoid X receptor agonist such as EYP-001. Anti-HBV antibodies
[00369] [00369] Examples of anti-HBV antibodies that target hepatitis B virus surface antigens include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and therapy with fully human monoclonal antibodies (hepatitis B virus infection, Humabs BioMed). Examples of anti-HBV antibodies, including monoclonal antibodies and polyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088). Fully human monoclonal antibodies such as HBC-34. CCR2 Chemokine Antagonists
[00370] [00370] Examples of CCR2 chemokine antagonists include propaganium. Thymosin agonists
[00371] [00371] Examples of thymosin agonists include Timalfasin, recombinant thymosin-alpha-1 (GeneScience). Cytokines
[00372] [00372] Examples of cytokines include recombinant IL-7, CYT-107,
[00373] [00373] Nucleoprotein modulators can be either HBV core protein inhibitors or HBV capsid protein inhibitors. Examples of nucleoprotein modulators include AB-423, AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, morphotiadin mesylate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158 and DVR -23.
[00374] [00374] Examples of capsid protein inhibitors include the compounds described in US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO20140 ), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2014161888 (Janssen), WO2014161888 (Janssen) (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Jsen). Retinoic Acid-Inducible Gene-1 Stimulators
[00375] [00375] Examples of retinoic acid-inducible gene-1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, and ORI- 7170, RGT-100. NOD2 stimulators
[00376] [00376] Examples of NOD2 stimulators include SB-9200. Phosphatidylinositol-3-Kinase (PI3K) inhibitors
[00377] [00377] Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib,
[00378] [00378] Examples of IDO inhibitors include epacadostate (INCB24360), resminostat (4SC-201), indoximode, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218 , and the compounds described in US201.00015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.). PD-1 inhibitors
[00379] [00379] Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400. PD-L1 inhibitors
[00380] [00380] Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN -PDL, STI-A1014, CX-072, and BMS-936559.
[00381] [00381] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with compounds such as those described in WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057456, US20180045446, US20180045446,
[00382] [00382] Examples of recombinant thymosin-alpha-1 include NL-004 and PEGylated thymosin-alpha-1. Bruton Tyrosine Kinase Inhibitors (BTK)
[00383] [00383] Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB- 3111, ML-319, MSC- 2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP- 0158, TP-4207, HM-71224, KBP-7536, M- 2951, TAK-020, AC-0025, and the compounds described in US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical). KDM inhibitors
[00384] [00384] Examples of KDM5 inhibitors include the compounds described in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epither17), US401932, (2014) , US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).
[00385] [00385] Examples of KDM1 inhibitors include compounds
[00386] [00386] Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038, and Xingantie. Arginase Inhibitors
[00387] [00387] Examples of arginase inhibitors include CB-1158, C-201, and resminostat. Gene Therapy and Cell Therapy
[00388] [00388] Gene Therapy and Cell Therapy including genetic modification to silence gene; genetic approaches to directly kill infected cells; the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; genetic approaches to modify cell activity to additionally alter endogenous immune responsiveness to infection. Gene editors
[00389] [00389] The genome editing system is selected from the group consisting of: a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a guided endonuclease system, and a meganuclease system; for example, elimination of cccDNA via targeted cleavage, and alteration of one or more of the hepatitis B virus (HBV) viral genes. Alteration (for example, knocking out) and / or attenuation (knocking down) of the PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reduction or elimination of gene expression PreC, C, X, PreSI, PreS2, S, P or SP, (2) interference with Precore, Core, protein X, Long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), protein polymerase, and / or
[00390] [00390] A population of immune effector cells modified to express a chimeric antigen receptor (CAR), in which the CAR comprises an HBV antigen binding domain. The immune effector cell is a T-cell or an NK cell. In some embodiments, the T-cell is a CD4 + T-cell, a CD8 + T-cell, or a combination thereof. The cells can be autologous or allogeneic. T-Cell-TCR Therapy
[00391] [00391] T-cells expressing HBV-specific T-cell receptors. T-T-TCR cells are modified to target HBV-derived peptides presented on the surface of cells infected by the virus.
[00392] [00392] T-cells expressing TCR specific for HBV surface antigen (HBsAg).
[00393] [00393] T-cell-TCR therapy directed to HBV treatment, such as LTCR-H2-1. Combination Therapy for HBV
[00394] [00394] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agent (s) selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir alafenamide fumarate, tenofovir hemifumarate
[00395] [00395] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor. In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, ligands of alpha-interferon receptors, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg assembly or secretion inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral entry inhibitors, modulators NTCP, antisense oligonucleotide targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus E antigen inhibitors, SARS proteins
[00396] [00396] In another specific modality, a compound described here,
[00397] [00397] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one additional additional therapeutic agent selected from the group consisting of: immunomodulators, modulators of TLR, HBsAg inhibitors, therapeutic vaccines against HBV, anti-HBV antibodies including anti-HBV antibodies that target hepatitis B virus antigens and bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, gene-1 stimulators
[00398] [00398] In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one additional additional therapeutic agent selected from the group consisting of: inhibitors of viral entry HBV inhibitors, NTCP modulators, HBx inhibitors, cccDNA inhibitors, anti-HBV antibodies that target hepatitis B virus antigens, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (core protein inhibitors or HBV capsid protein). HBV Drug Combination Therapy
[00399] [00399] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least one additional therapeutic agent group selected in immunomodulators, TLR modulators, alpha-interferon receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg assembly or secretion inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines , HBV viral entry inhibitors, NTCP modulators, antisense oligonucleotide that targets viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus E antigen inhibitors,
[00400] [00400] In a specific embodiment, a compound described here,
[00401] [00401] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir fumarate
[00402] [00402] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least one additional agent group. consisting of HBV viral entry inhibitors, NTCP modulators, HBx inhibitors, cccDNA inhibitors, anti-HBV antibodies that target hepatitis B virus antigens, siRNA, miRNA gene therapy agents, sshRNAs, inhibitors of KDM5, and nucleoprotein modulators (modulators of the core protein or HBV capsid protein).
[00403] [00403] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a
[00404] [00404] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®);
[00405] [00405] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and one, two, three, or four additional therapeutic agents selected from the group consisting of immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors, inhibitors of HBsAg assembly or secretion, therapeutic vaccines against HBV, anti-HBV antibodies including antibodies anti-HBV that target the antigens of the HIV virus
[00406] [00406] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with compounds such as those described in US Publication No. 2010/0143301 (Gilead Sciences), US Publication No. 2011/0098248 (Gilead Sciences) , US Publication No. 2009/0047249 (Gilead Sciences), US Patent No. 8722054 (Gilead Sciences), US Publication No. 2014/0045849 (Janssen), US Publication No. 2014/0073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US Publication No. 2014/0350031 (Janssen), WO2014 / 023813 (Janssen), US Publication No. 2008/0234251 (Array Biopharma), US Publication No. 2008/0306050 (Array Biopharma) , US Publication No. 2010/0029585 (Ventirx Pharma), US Publication No. 2011/0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), US Publication No. 2012/0082658 (Ventirx Pharma), US Publication No. 2012/0219615 (Ventirx Pharma), US Publication No. 2014/0066432 (Ventirx Pharma), US Publication No. 2014/0 088085 (Ventirx Pharma), U.S. Publication No. 2014/0275167 (Novira Therapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2014/0030221 (Gilead Sciences), Publication
[00407] [00407] In certain embodiments, a compound as described herein (for example, any compound of formula I) can be combined with one or more (for example, one, two, three, four, one to two, one to three, or one to four) additional therapeutic agents in any amount of
[00408] [00408] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. a compound as described herein (for example, a compound of formula I) can be combined with the agents provided herein in any dosage amount of the compound (for example, from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
[00409] [00409] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 250 mg; 100 mg to 300 mg; 100 mg to 350 mg; 150 mg to 200 mg; 150 mg to 250 mg; 150 mg to 300 mg; 150 mg to 350 mg; 150 mg to 400 mg; 200 mg to 250 mg; 200 mg to 300 mg; 200 mg to 350 mg; 200 mg to 400 mg; 250 mg to 350 mg; 250
[00410] [00410] In one embodiment, kits are provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (for example, one, two, three, four, one to two, or one to three , or one to four) additional therapeutic agents.
[00411] [00411] Any pharmaceutical composition provided in the present description can be used in the kits, the same as if each and every composition were specifically and individually listed for use in a kit. Synthesis
[00412] [00412] The compounds of the description can be prepared using methods described herein and routine modifications thereof which will be apparent from the description of the present invention and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings of the present invention. THE
[00413] [00413] Typical embodiments of compounds according to the present invention can be synthesized using the general reaction schemes and / or the examples described below. It will be evident from the description here that the general schemes can be changed by replacing the starting materials with other materials having similar structures to result in products that are correspondingly different. The following summary descriptions provide numerous examples of how starting materials can vary to produce corresponding products. The starting materials are typically obtained from commercial suppliers or are synthesized using published methods to synthesize the compounds that are embodiments of the present description, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product in general will make it clear the identity of the starting materials required by a simple inspection process, given the examples here. The symbols of substituting groups (for example, R1, Ra, Rb) used in the reaction schemes of the present invention are for illustrative purposes only and, unless otherwise specified, do not necessarily coincide in name or function with the symbols of substituent groups used elsewhere to describe the compounds of formula (I) or aspects or fragments thereof. Synthesis Reaction Parameters
[00414] [00414] The compounds of this description can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be recognized that where they are presented
[00415] [00415] Additionally, as will be evident to those skilled in the art, conventional protective groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Protective groups suitable for various functional groups, and also conditions suitable for protecting and unprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
[00416] [00416] In addition, the compounds of this description may contain one or more chiral centers. Consequently, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers or as mixtures enriched in stereoisomers. All such stereoisomers (and enriched mixtures) are included within the scope of this description, unless otherwise stated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be prepared using, for example, chiral column chromatography, chiral resolving agents, and the like.
[00417] [00417] The starting materials for the following reactions are generally known compounds or can be prepared by
[00418] [00418] The terms "solvent", "inert organic solvent" or "inert solvent" refer to an inert solvent under the conditions of the reaction being described together with it (including, for example, benzene, toluene, acetonitrile, tetra -hydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless otherwise specified, the solvents used in the reactions of the present description are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
[00419] [00419] The term “q.s.” means adding an amount sufficient to achieve a specified function, for example, to bring a solution to the desired volume (ie, 100%).
[00420] [00420] Compounds as provided herein can be synthesized according to the general schemes provided below. In the Schemes below, it must be recognized that each of the compounds shown therein may have protecting groups, as required, present on any stage. Standard protecting groups are well within the knowledge of a person skilled in the art.
[00421] [00421] Scheme 1 shows exemplary synthetic routes for the synthesis of compounds of formula (I). In Scheme 1, Q, RE, RW, Z1, Z3, n, m, are as defined herein, each R50 is independently C1-6 alkyl or two R50 together with the atom to which they are attached form a ring, X is halo , and each FG is independently a functional group capable of forming a covalent bond with compound 105. Scheme 1
[00422] [00422] In Scheme 1, compound 100 is coupled with compound 101 under standard metal catalyzed coupling conditions (for example, using a palladium (0) catalyst) in a suitable solvent (for example, DMF) under an atmosphere inert to provide compound 102. Compounds of formula (I) are then provided by converting compound 102 with appropriately substituted compound 106 under standard metal catalyzed coupling conditions. Alternatively, compound 102 is contacted with compound 103 under standard metal catalyzed coupling conditions to provide compound 104. Compound 104 is then reacted with compound 105 under suitable conditions to provide compounds of formula (I). Exemplary conditions include, but are not
[00423] [00423] Symmetric compounds, as provided herein, such as those of formula (Id), can be synthesized according to Scheme 2 below. In Scheme 2, Q, RE, RW, Z1, Z2, n, m, are as defined herein, each R50 is independently C1-6 alkyl or two R50 together with the atom to which they are attached form a ring, X is halo , and FG is a functional group capable of forming a covalent bond with compound 105. Scheme 2
[00424] [00424] In Scheme 2, synthetic compounds of formula (Id) can be provided by coupling compound 100 with at least a two-fold excess of compound 101 appropriately substituted under standard metal catalyzed coupling conditions (for example, using a catalyst palladium (0)) in a suitable solvent (eg DMF) under an inert atmosphere. Alternatively, compound 100 is contacted with compound 200 under standard metal-catalyzed coupling conditions to provide compound 201. Compound 201 is then reacted with compound 105 under conditions suitable to provide compounds of formula (Id). Conditions
[00425] [00425] Compounds 100, 101, 103, 106 and 105 suitably substituted for use in the methods provided herein can be purchased from commercial suppliers or can be synthesized by known methods. The resolution of the isomers of formula (I) can be carried out, as needed, using standard chiral resolution / separation conditions (for example, chromatography, crystallization, etc.). EXAMPLES
[00426] [00426] The compounds were named using the IUPAC naming convention or using ChemBioDraw Ultra Version 14.0. The structures are designed by ChemBioDraw.
[00427] [00427] When the production of starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as described in the Examples. A person skilled in the art will recognize that the synthetic methodologies described herein are only representative of the methods for preparing the compounds described herein, and that other known methods and variants of the methods described herein can be used. The methods or attributes described in the various Examples can be combined or adapted in several ways to provide additional ways to prepare the compounds described herein. Exemplifying procedures for selected intermediaries: lactam intermediaries:
[00428] [00428] To the appropriate alcohol (above), as can be obtained according to PCT International Order No. WO 2015/150995, triethylamine (2.0 equiv.) And dichloromethane (0.1 M) were added at room temperature. The mixture was cooled to 0 ° C, and mesyl chloride (1.1 equiv.) Was added by dropping. The mixture was stirred at 0 ° C for 1 hour before the reaction was quenched with water. The organic layer was separated and taken once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel. The mesylate was dissolved in dimethylformamide (0.5M) at room temperature, and sodium azide (5.0 equiv.) Was added. The mixture was heated to 85 ° C overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The organic layer was then washed once with brine, dried over magnesium sulfate, filtered, and concentrated. the azide was used without further purification. To an oven dried 40 ml flask, azide in ethyl acetate was added at room temperature. the flask was purged with nitrogen, and palladium on carbon was added (10 mol%). The flask was then purged with hydrogen. After stirring for 4 hours, the contents were filtered through Celite and concentrated. The crude amide was dissolved in ether and precipitated by the addition of 1.0 equiv. of HCl in dioxane. The solid HCl salt was isolated by filtration. Pyrazine Intermediate:
[00429] [00429] A 30 percent w / w solution of NaOMe in MeOH (168 mL, 896 mmol) was added to a stirred suspension of 3,5-dibromopyrazin-2-amine (200 g, 791 mmol) in dry MeOH (900 mL). The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and concentrated to 1/3 of the volume. The resulting mixture was then partitioned between dichloromethane (DCM) and saturated aqueous NaHCO3 solution. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution. The combined aqueous portions were extracted with DCM. The combined organic portions were washed with brine, dried with Na2SO4, filtered and concentrated to produce 5-bromo-3-methoxypyrazin-2-amine. 1H NMR: (400 MHz, CDCl3) δ 7.64 (s, 1H), 4.79 (s, 2H), 4.00 (s, 3H).
[00430] [00430] A mixture of 5-bromo-3-methoxypyrazin-2-amine (20 g, 98 mmol), 55% aqueous HI solution (55%, 200 mL, 1,462 mmol) and acetonitrile (200 mL) in water ( 300 ml) was stirred at 0 ° C for 0.5 h. And a solution of sodium nitrite (120 g, 1740 mmol) in H2O (200 mL) was added by dripping. The reaction mixture was heated to 23 ° C, and then it was stirred for 20 h at 50 ° C. After cooling, the solution was poured into 20% NaOH aqueous solution and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with saturated aqueous sodium metabisulfite solution (200 ml) and brine (200 ml), dried with Na2SO4, filtered and concentrated in vacuo to produce the crude product. The crude product was purified by silica gel column chromatography
[00431] [00431] Isopropylmagnesium chloride - lithium chloride complex solution (1.3 M in tetrahydrofuran, 59.22 mL, 75.6 mmol) was added via syringe over 5 min to a stirred solution of 5-bromo- 2-iodo-3-methoxypyrazine (21 g, 66.69 mmol) in anhydrous tetrahydrofuran (147 mL) under an atmosphere of dry nitrogen at −40 ° C. After 25 min, anhydrous N, N-dimethylformamide (15.54 mL, 200.34 mmol) was added via syringe over 2 min, and the resulting mixture was allowed to warm to −18 ° C for 25 min. Aqueous solution of citric acid (5% w / v, 200 ml) was added slowly, and the resulting heterogeneous mixture was stirred vigorously and warmed to room temperature. After 10 min, ethyl acetate (450 ml) was added. The organic layer was washed with water (2 × 300 ml), dried with anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% ethyl acetate in hexanes) to provide 5-bromo-3-methoxypyrazine-2-carbaldehyde. 1H NMR: (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.43 (s, 1H), 4.14 (s, 3H). 2,2 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (4,4,5,5-tetramethyl-1,3,2-dioxaborolane ):
[00432] [00432] A mixture of 3-bromo-2-chlorophenol (73.5 g, 0.355 mol, 1.0 eq), B2Pin2 (98 g, 0.391 mol, 1.1 eq), KOAc (96.7 g, 0.987 mol, 2.78 eq) and Pd (dppf) Cl2-DCM (25.97 g, 35.5 mmol, 0.1 eq) suspended in dioxane (1.2 L) was stirred at 80 ° C for 15 h under positive nitrogen pressure. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with dioxane (500 ml). The filtrates were combined.
[00433] [00433] 3-Bromo-2-chlorophenol (73.5 g, 0.355 mol, 1.0 eq), K2CO3 (122 g, 0.888 mol, 2.5 eq) and Pd (dppf) Cl2-DCM (8.8 g, 10.65 mmol, 0.03 eq) were added to the filtrate prepared above. The reaction was stirred at 80 ° C for 8 h under positive pressure of nitrogen. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with dioxane (500 ml). The filtrate was combined and concentrated. The residue was dissolved with ethyl acetate (2 L). The solution was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (PE: EA = 5: 1) to produce 2,2'-dichloro [1,1'-biphenyl] -3,3'-diol.
[00434] [00434] To a solution of 2,2'-dichloro- [1,1'-biphenyl] -3,3'-diol (63.8 g, 0.251 mol, 1.0 eq) and DIPEA (121.5 g , 0.944 mol, 3.76 eq) in DCM (2 L) at 0 ° C, Tf2O (166 g, 0.590 mol, 2.35 eq) was added slowly by dropping. then the reaction mixture was warmed to room temperature and stirred for 2 h. The pH of the reaction solution was higher than
[00435] [00435] A mixture of bis (trifluoromethanesulfonate) of 2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl (150 g, 0.289 mol, 1.0 eq), Bin2Pin2 ( 180 g,
[00436] [00436] To a solution of aldehyde (3.5 g, 20.4 mmol) in 60 ml of DCM at 0 ° C was added ethylenediamine (1.50 ml, 22.44 mmol) by dripping. The solution was stirred at 0 ° C for 30 minutes, then N-bromosuccinimide (3.99 g, 22.44 mmol) was added as one portion (at once), and the reaction mixture was stirred for 16 hours with gradual heating to room temperature. The reaction mixture was collected in DCM and stirred vigorously for 15 min with a 1: 1 mixture of saturated sodium thiosulfate solution and saturated sodium carbonate solution. The organic layer was dried with MgSO4, filtered and concentrated to provide 6-chloro-3- (4,5-dihydro-1H-imidazol-2-yl) -2-methoxypyridine. General reductive amination procedures: Procedure A - Reductive amination with DMF / TEA; NaBH (OAc) 3
[00437] [00437] Aldehyde (1 equiv) was suspended in DMF (0.025 M) and to this suspension (3S) -4-amino-3-hydroxybutanoic acid (6 equiv) followed by triethylamine (6 equiv) and the reaction mixture was shaken up
[00438] [00438] A solution of aldehyde (1 equiv) in DMF (0.014 M) was added to a solution of (S) -4-amino-3-hydroxybutanoic acid in 1N NaOH (10 equiv). After 2h sodium triacetoxyborohydride (10 equiv) was added. After 30 min the reaction was complete and TFA was added. Solids were removed by filtration and rinsed with MeOH. The organic phase was removed under reduced pressure, and the crude product was subjected to purification by HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) producing the final compound after lyophilization as the bis-TFA salt. Procedure C - Reductive amination with DMF / AcOH; NaCNBH3 + NaBH (OAc) 3
[00439] [00439] To a stirred mixture of aldehyde (1 equiv) and (S) -3-aminobutanoic acid (15 equiv) in a 6: 1 mixture of DMF / AcOH (0.02 M) at room temperature were added sequentially cyanoboro- sodium hydride (9 equiv) and sodium triacetoxyborohydride (9 equiv). After 15 min, trifluoroacetic acid was added until the solution became clear. The resulting mixture was purified by HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) producing the final compound after lyophilization as the bis-TFA salt.
[00440] [00440] To a stirred mixture of aldehyde (1 equiv) and acid (1R, 2R) -2-aminocyclopentane-1-carboxylic acid (15 equiv) in a 5: 1 mixture of DMSO / AcOH (0.008 M) at room temperature sodium triacetoxyborohydride (9 equiv). After 1 h, TFA was added until the solution became clear. The resulting homogeneous mixture was purified by HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) producing the final compound after lyophilization as the bis-TFA salt. Procedure E - Reductive amination with MeOH / AcOH; 2- methylpyridinaborane
[00441] [00441] Aldehyde A (1 equiv) was suspended in a 10: 1 mixture of MeOH / AcOH (0.01M) and to this mixture (3S) -4-amino-3-hydroxybutyric acid (3 equiv) was added at temperature environment. The mixture was stirred at room temperature under argon for 1 hour. To this solution was added 2-methylpyridinaborane (3 equiv) at room temperature and the reaction was stirred for an additional 2 hours. At this point, TFA was added by dripping to the reaction mixture until the solution became clear. The reaction was filtered and purified by HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) producing the final compound after lyophilization as the bis-TFA salt. Procedure F - Reductive amination with DMF / MeOH / AcOH; 2- methylpyridinaborane
[00442] [00442] Aldehyde (1 equiv) was suspended in a 6: 3: 1 DMF / MeOH / AcOH mixture (0.01 M) and to this mixture (3S) -4-amino-3-hydroxybutyric acid (10 equiv) at room temperature. The mixture was stirred at room temperature under argon for 1 hour. To this solution was added 2-methylpyridinaborane (10 equiv) at room temperature and the reaction was stirred for an additional 2 hours. At this point, TFA was added by dripping to the reaction mixture until the solution became
[00443] [00443] To the aldehyde in DCM (0.05M) was added a solution of pre-sonicated 0.1N KOH (10 equiv) and (3S) -4-amino-3-hydroxybutanoic acid (10 equiv) in EtOH. The reaction was stirred for 1 hour at room temperature before Na (OAc) ₃BH (10 equiv) and AcOH (10 equiv) were added. The cloudy reaction mixture was sonicated for 1 min, and stirred at room temperature for 2 h. The reaction was inactivated with the addition of 1M HCl until the solution became clear. The solution was concentrated in vacuo, diluted with a mixture of MeCN / H2O / DMF (1: 1: 1), and purified by purified by HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) producing the compound after lyophilization as the bis-TFA salt. Procedure H - Reductive amination with DCM / DMF / DIPEA; Na (OAc) 3BH
[00444] [00444] 6,6 '- ((((2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (methylene)) bis (oxy)) bis ( 5-chloro-2-methoxyinicotinaldehyde) (50 mg, 1equiv) was added to a vial and dissolved in DCM (1.5 ml). The (2S, 4R) - 4-hydroxypiperidine-2-carboxylic acid (125 mg, 10equiv) was dissolved in a mixture of DMF (3 ml), and DIPEA (0.15 ml, 10equiv) in another bottle. These two solutions were mixed together and sonicated for 5 min, and allowed to stir for 1 h at room temperature. To the well stirred mixture was added Na (OAc) ₃BH at once and the mixture was sonicated for 5 min to solubilize everything and allowed to stir overnight. The solution was concentrated under reduced pressure. The crude product was diluted with a mixture of MeCN / H2O / (2: 1, with 0.1% TFA), the solids
[00445] [00445] A 40 mL reaction flask, equipped with a stir bar, was loaded with arylboronic acid (16 mmol), aryl bromide (16 mmol), Pd (dppf) (0.8 mmol) and potassium carbonate (32 mmol). DriSolv 1,4-Dioxane (27 ml) and distilled water (3 ml) were then added by syringe, and the mixture was degassed by bubbling argon for 5 min while mixing. The reaction flask was then sealed with a septum cap and the reaction was heated to 85 ° C using a heating block, the reaction was monitored by CL / EM (Liquid Chromatography / Mass Spectrometry). After the complete consumption of the
[00446] [00446] A 100 mL round-bottom flask equipped with a stir bar, was loaded with aryl alcohol (10.37 mmol), N, N-diisopropylethylamine (41 mmol), dichloromethane (100 mL), left under an argon atmosphere and cooled to 0 ° C with an ice water bath. While mixing triflic anhydride (26 mmol) was added by drip syringe and allowed to mix for 1 h. The reaction was then inactivated with a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layers were collected, the volatiles were removed and the crude mixture was purified by silica gel column chromatography. The desired product eluted in ~ 14% EtOAc / Hexanes.
[00447] [00447] A 40 ml flask with screw cap, equipped with a stir bar, was loaded with aryl triflate (6.87 mmol), bis (pinacolato) diboro (17.17 mmol), potassium acetate (27, 46 mmol) and Pd (dppf) (1.03 mmol). DriSolv 1,4-Dioxane (27 mL) was then added by syringe, and the mixture was degassed by bubbling argon through it for 5 min while under mixing. The flask was then sealed and the mixture was heated to 85 ° C for 5 h. The reaction was inactivated with saturated aqueous NaCl solution and extracted three times with ethyl acetate. The organic layers were collected, the volatiles were removed and the crude mixture was purified by silica gel column chromatography.
[00448] [00448] A 40 mL reaction flask, equipped with a stir bar, was loaded with aryl bromide (0.97 mmol), aryl-Bpin (0.46 mmol), Pd (PPh3) 4 (23 µmol) and potassium carbonate (1 mmol). DriSolv 1,4- Dioxane (3.6 mL) and distilled water (0.9 mL) were then added by
[00449] [00449] A 20 mL reaction flask, equipped with a stir bar, was loaded with dialdehyde (0.14 mmol), amine salt (0.5 mmol), trimethylamine (0.57 mmol) and dimethylformamide (1 , 4 mL) and allowed to mix for 0.5 h. Sodium triacetoxyborohydride (0.57 mmol) was then added and the reaction was allowed to mix overnight. The next day the reaction was inactivated with trifluoroacetic acid (0.65 mmol), filtered, diluted with a 1: 4 solution of DMF / water and purified by HPLC. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.74 ( d, J = 7.4 Hz, 1H), 7.68 - 7.44 (m, 4H), 4.82 - 4.03 (m, 16H), 2.58 (d, J = 8.2 Hz , 4H), 2.46 (d, J = 8.0 Hz, 4H). ES / MS m / z: 699,200 M + 1. Procedure 2: (S) -5 - ((((5- (3 '- (5 - ((((1-acetylazetidin-3-yl) amino) methyl) -6-methoxypyrazin-2-yl) -2,2 '-dichloro- [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one
[00450] [00450] A solution of (S) -5- (aminomethyl) pyrrolidin-2-one (3.29 g, 2.8 mmol) and 5-bromo-3-methoxypyrazine-2-carbaldehyde (5.0 g, 2 , 3 mmol) in dimethylformamide (10 mL) was stirred for 90 minutes. Sodium triacetoxyborohydride (5.59 g, 3.1 mmol), acetic acid (1.78 ml, 3.1 mmol) and dimethylformamide (10 ml) were added. After 16 hours di-tert-butyl dicarbonate (7.54 g, 3.5 mmol) and trimethylamine (8.42 ml, 6.0 mmol) were added. After 2 hours the reaction was partitioned with water (100 ml) and ethyl acetate (100 ml). The aqueous phase was extracted with ethyl acetate (2 x 75 ml). The combined organic phases were washed with brine (2 x 25 ml) and dried with sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-20% methanol / dichloromethane). The product-containing fractions were combined and the solvent was removed under reduced pressure providing (S) - ((5-bromo-3-methoxypyrazin-2-yl) methyl) (((5-oxopyrrolidin-2-yl) methyl) carbamate tert-butyl.
[00451] [00451] A mixture of 2,2 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolane) (2.29 g, 4.8 mmol), (S) - ((5-bromo-3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl ) tert-butyl carbamate (2.00 g, 4.8 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (1.05 g, 4.8 mmol), tetrakis (triphenylphosphine) palladium (0) ( 1.1 g, 0.96 mmol), potassium carbonate (2.00 g, 14.4 mmol) in dimethylformamide (40 mL) and water (6 mL) was degassed with argon for 10 minutes. The mixture was heated to 100 ° C for 2h. The mixture was partitioned with water (50 ml) and ethyl acetate (200 ml). The organic phase was washed with 5% lithium chloride solution (2 x 50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-20% methanol / dichloromethane). The product-containing fractions were combined and the solvent was removed under reduced pressure, providing (S) - ((5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyrazin-2-yl) - Tert-butyl [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate.
[00452] [00452] A solution of (S) - ((5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3- yl) -3-methoxypyrazin-2-yl) methyl) (tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (10 mg, 0.014 mmol), 1- (3-aminoazetidin-1-yl hydrochloride ) ethan-1-one (6.6 mg, 0.058 mmol) and N, N-diisopropylethylamine (12.6 µL, 0.072 mmol) in dichloromethane (1 mL) and ethanol (1mL) was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (30.6 mg, 0.144 mmol) and acetic acid (1 drop) were added. After 30 minutes the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was added. After 15 minutes the solvent was removed under reduced pressure. The residue was taken up in methanol (1 ml), water (0.75 ml). The solution was subjected to preparative HPLC (eluent 0.1% trifluoroacetic acid in water / 0.1% trifluoroacetic acid in
[00453] [00453] A vigorously stirred mixture of 2.2 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (4,4,5,5-tetramethyl -1,3,2-dioxaborolane) (3.50 g, 7.37 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (3.52 g, 16.2 mmol), tetrakis (triphenylphosphine) palladium ( 0) (596 mg, 0.516 mmol), potassium carbonate (5.09 g, 36.8 mmol), water (5.0 mL), and 1,4-dioxane (24 mL) was heated to 100 ° C. After 40 min, the resulting mixture was cooled to room temperature. Ethyl acetate (125 ml) was added, and the organic layer was washed with a mixture of water and brine (1: 1 v: v, 100 ml), dried with anhydrous sodium sulfate, filtered through Celite, and was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (0 to 50% ethyl acetate in hexanes) to yield 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3, 3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde) contaminated with pinacol. Dichloromethane (50 mL) was
[00454] [00454] A vigorously stirred mixture of 2.2 '- (2,2'-dichloro [1,1'-biphenyl] -3,3'-diyl) bis (4,4,5,5-tetramethyl -1,3,2-dioxaborolane) (750 mg, 1.58 mmol), 3,5-dichloropyrazine-2-carbaldehyde (3.52 g, 16.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (92 mg, 0.13 mmol), cesium carbonate (3.09 g, 9.47 mmol), water (1.8 mL), and 1,4-dioxane (11 mL) was heated to 100 ° C. After 60 min, the resulting mixture was cooled to room temperature, filtered through Celite, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 70% ethyl acetate in hexanes) to yield 5,5'- (2,2'-dichloro- [1,1'-biphenyl] -3, 3'-di-yl) bis (3-chloropyrazine-2-carbaldehyde).
[00455] [00455] A stirred mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-chloropyrazine-2-carbaldehyde) (55 , 0 mg, 0.019 mmol) and methylamine solution (2.0 M in tetrahydrofuran, 6.0 mL, 12 mmol) was heated to 70 ° C. After 60 min, acetic acid (0.5 ml) and water (2.0 ml) were added sequentially. After 30 min, the resulting mixture was cooled to room temperature. Ethyl acetate (15 ml) was added, and the organic layer was washed with water (2 × 15 ml), dried with anhydrous sodium sulfate, filtered, and was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (1.5 ml) and acetic acid (0.15 ml) and the mixture stirred at room temperature. (1R, 3R) -3- (aminomethyl) cyclobutan-1-ol hydrochloride (41.8 mg, 0.304 mmol), N, N-diisopropylethylamine (79.4 µL, 0.456 mmol), and triacetoxyborohydride sodium (64.4 mg, 0.304 mmol) was added sequentially, and the resulting mixture was heated to 57 ° C. After 60 min, the resulting mixture was cooled to room temperature and purified by preparative HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) to produce (1R, 1'R, 3R, 3'R) -3,3 '- (((((((2,2'-dichloro [1,1'-biphenyl] -3,3'-di-yl) bis (3- (methylamino) pyrazine-5,2-di -yl)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (cyclobutan-1-ol). Procedure 5: 1,1 '- ((((2,2'-dichloro [1,1'-biphenyl] -3,3'-di-yl) bis (pyrazine-5,2-di-yl)) bis (methylene)) bis (azetidin-3-ol)
[00456] [00456] A vigorously stirred mixture of 2.2 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (4,4,5,5-tetramethyl -1,3,2-dioxaborolane) (150 mg,
[00457] [00457] Sodium triacetoxyborohydride (82.8 mg, 0.391 mmol) was added to a stirred mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3.3' -di-) bis (pyrazine-2-carbaldehyde) (17 mg, 0.039 mmol), 3-hydroxyazetidine hydrochloride (42.8 mg, 0.391 mmol), N, N-diisopropylethylamine (102 µL, 0.586 mmol) , acetic acid (0.15 ml), and dimethyl sulfoxide (1.5 ml) at 57 ° C. After 60 min, the resulting mixture was cooled to room temperature and purified by preparative HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) to yield 1.1 '- (((2.2'- dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (pyrazine-5,2-di-yl)) bis (methylene)) bis (azetidin-3-ol). Procedure 6: 1,1 '- ((((2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (3-ethylpyrazine-5,2-di-yl) ) bis (methylene)) bis (azetidin-3-ol)
[00458] [00458] A stirred mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-chloropyrazine-2-carbaldehyde) (84 , 2 mg, 0.167 mmol),
[00459] [00459] A mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-vinylpyrazine-2-carbaldehyde) (53, 8 mg, 0.110 mmol) and palladium on carbon (10% by weight, 23.5 mg, 0.022 mmol) in ethanol (2.0 mL) and tetrahydrofuran (1.0 mL) was stirred under an atmosphere of hydrogen gas at room temperature. After 90 min, the reaction mixture was filtered through Celite and was concentrated under reduced pressure to produce 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di- il) bis (3-ethylpyrazine-2-carbaldehyde).
[00460] [00460] Sodium triacetoxyborohydride (43.1 mg, 0.204 mmol) was added to a stirred mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3.3' -di-) bis (3-ethylpyrazine-2-carbaldehyde) (10 mg, 0.020 mmol), 3-hydroxyazetidine hydrochloride (22.3 mg, 0.204 mmol), N, N-diisopropylethylamine (53.2 µL , 0.305 mmol), acetic acid (0.15 ml), and dimethyl sulfoxide (1.5 ml) at 57 ° C. After 60 min, the resulting mixture was cooled to room temperature and purified by preparative HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) to yield 1.1 '- (((2.2'- dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-ethylpyrazine-5,2-diyl)) bis (methylene)) bis (azetidin-3-ol). Procedure 7: 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (2 - ((3-methoxyazetidin-1-yl) methyl) -3- (methylthio) pyrazine)
[00461] [00461] Sodium methanethiolate (72.3 mg, 1.03 mmol) was added to a stirred mixture of 5.5 '- (2,2'-dichloro [1,1'-biphenyl] -3,3' -di-yl) bis (3-chloropyrazine-2-carbaldehyde) (104 mg, 0.206 mmol), in N, N-dimethylformamide (2.0 ml) at room temperature. After 20 min, diethyl ether (20 ml) and ethyl acetate (20 ml) were added. The organic layer was washed sequentially with aqueous sodium hydroxide solution (0.2 M, 30 ml) and water (30 ml), dried with anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure to produce 5, 5'- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (3- (methylthio) pyrazine-2-carbaldehyde).
[00462] [00462] 5,5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (2 - (((3-methoxyazetidin-1-yl) methyl) -3- (methylthio) pyrazine) was synthesized in a similar manner to Procedure 6 using 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] - 3,3'-di-yl) bis (3- (methylthio) pyrazine-2-carbaldehyde) in place of 5.5 '- (2,2'-dichloro [1,1'-biphenyl] -3,3'-diyl) bis (3- ethylpyrazine-2-carbaldehyde) and using 3-methoxyazetidine hydrochloride in place of 3-hydroxyazetidine hydrochloride. Procedure 8: 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (2 - ((3-methoxyazetidin-1-yl) methyl) -3-methylpyrazine)
[00463] [00463] A vigorously stirred mixture of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-chloropyrazine-2-carbaldehyde) ( 60 mg, 0.12 mmol), tetramethyl tin (165 µL, 1.19 mmol), and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (8.7 mg, 0.012 mmol) in N, N - dimethylformamide (2.0 ml) was heated to 110 ° C. After 60 min, the resulting mixture was cooled to room temperature. An aliquot of the reaction mixture (0.4 mL) was removed via syringe and added to a stirred mixture of 3-methoxyazetidine hydrochloride (26.7 mg, 0.216 mmol) and N, N-diisopropylethylamine (56.4 µL, 0.324 mmol) in N, N-dimethylformamide (1.5 mL)
[00464] [00464] A stirred mixture of 2-chloro-6-methoxypyrazine (2.00 g, 13.8 mmol), hexabutyltin (8.74 mL, 17.3 mmol), and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (304 mg, 0.415 mmol) in toluene (22 mL) was heated to 115 ° C. After 18 h, the resulting mixture was cooled to room temperature, filtered through Celite, and was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (0-10% ethyl acetate in hexanes) to produce 2-methoxy-6- (tributylstannyl) pyrazine.
[00465] [00465] Lithium diisopropylamide solution (2.0 M in tetrahydrofuran / heptane / ethylbenzene, 2.4 mL, 4.8 mmol) was added over 2 min via syringe to a stirred solution of 2-methoxy- 6- (tributyltanil) pyrazine (872 mg, 2.19 mmol) in tetrahydrofuran (18 mL) at −78 ° C. After 100 min, N, N, -dimethylformamide (846 µL, 10.9 mmol) was added via syringe. After 45 min, saturated aqueous ammonium chloride solution (20 mL) and water (20 mL) were added sequentially, and the resulting biphasic mixture was warmed to room temperature with vigorous stirring. Diethyl ether
[00466] [00466] Iodine (79.1 mg, 0.312 mmol) was added to a stirred solution of 3-methoxy-5- (tributyltanil) pyrazine-2-carbaldehyde (133 mg, 0.312 mmol) in tetrahydrofuran (2 mL) at room temperature in the dark. After 15 h, sodium thiosulfate (20 mg) was added, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% methanol in dichloromethane) to produce 5-iodo-3-methoxypyrazine-2-carbaldehyde.
[00467] [00467] N-butyl lithium solution (1.94 M in cyclohexane, 19.8 mL, 38.5 mmol) was added over 2 min via syringe to a stirred solution of 2,2,6,6- tetramethylpiperidine (6.49 ml, 38.5 mmol) in tetrahydrofuran (64 ml) at 0 ° C. After 10 min, the resulting mixture was cooled to −78 ° C for 15 min. Triisopropyl borate (14.8 mL, 64.1 mmol) was added over 2 min via syringe. After 8 min, a solution of 2,2'-dibromo-1,1'-biphenyl (2.00 g, 6.41 mmol) in tetrahydrofuran (15 mL) at −78 ° C was added over 5 min. cannula. After 3.5 h, triisopropyl borate (7.40 mL, 32.1 mmol) was added over 5 min via syringe, and the resulting mixture was allowed to warm to −45 ° C for 15.5 h. Aqueous hydrogen chloride solution (1 M, 100 mL) was added, and the resulting biphasic mixture was
[00468] [00468] A stirred mixture of (2,2'-dibromo- [1,1'-biphenyl] - 3,3'-diyl) diboroic acid (40 mg, 0.100 mmol), 5-iodo-3-methoxypyrazine -2- carbaldehyde (52.9 mg, 0.200 mmol), tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.010 mmol), and saturated aqueous sodium carbonate solution (400 µL) in 1,2-dimethoxyethane (2 , 0 mL) was heated to 100 ° C. After 2 h, the resulting mixture was cooled to room temperature. Ethyl acetate (30 ml) was added. The organic layer was washed with brine (20 ml), dried with anhydrous sodium sulfate, filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 35% ethyl acetate in hexanes) to yield 5.5 '- (2,2'-dibromo- [1,1'-biphenyl] -3, 3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde).
[00469] [00469] 1,1 '- ((((2,2'-dibromo- [1,1'-biphenyl] -3,3'-di-yl) bis (3-methoxypyrazine-5,2-di-yl) ) bis (methylene)) bis (azetidin-3-ol) was synthesized in a similar manner to Procedure 6 using 5.5 '- (2,2'-dibromo- [1,1'- biphenyl] -3,3' -di-yl) bis (3-methoxypyrazine-2-carbaldehyde) in place of 5.5 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (3-ethylpyrazine-2-carbaldehyde).
[00470] [00470] A vigorously stirred mixture of 5- (2,2'-dichloro-3'- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1 ' -biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde (35 mg, 0.072 mmol), 6-chloro-3- (4,5-dihydro-1H-imidazol-2-yl) -2- methoxypyridine (32 mg, 0.15 mmol), chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-isopropyl-1,1′-biphenyl) [2- (2′-amino-1, 1′-biphenyl)] palladium (II) (3 mg, 0.004 mmol), and saturated aqueous sodium carbonate solution (180 µL) in 1,4-dioxane (1.5 mL) was heated to 105 ° C. After 60 min, the resulting mixture was cooled to room temperature. Ethyl acetate (30 ml) was added, and the organic layer was washed with brine (20 ml), dried with anhydrous sodium sulfate, filtered, and was concentrated under reduced pressure to produce 5- (2,2'- dichloro-3 '- (5- (4,5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) - [1,1'-biphenyl] -3-yl) -3 -methoxypyrazine-2-carbaldehyde.
[00471] [00471] 2 - ((5- (2,2'-dichloro-3 '- (5- (4,5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) -2,6-diazaspiro [3.4] octan-7-one was synthesized in a similar manner to Procedure 6 using 5- (2,2'-dichloro-3 '- (5- (4,5-dihydro-1H-imidazol-2-yl) -
[00472] [00472] A stirred mixture of 1,3-dibromo-2-chloro-5-fluorobenzene (1.08 g, 3.75 mmol, boronic acid (3-bromo-2-chlorophenyl) (0.420 g, 1.79 mmol , aqueous sodium carbonate solution (2.0 M, 5.35 mL, 10.71 mmol), and tetrakis (triphenylphosphine) palladium (0) (103.15 mg, 0.089 mmol) in 1,4-dioxane (7 ml) was heated to 105 ° C in a heating block After 60 min, the resulting mixture was allowed to cool to room temperature Ethyl acetate (30 ml) was added, and the organic layer was washed with brine (20 ml ), was dried over anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure.The residue was purified by
[00473] [00473] A stirred mixture of 3,3'-dibromo-2,2'-dichloro-5-fluoro-1,1'-biphenyl (0.443 g, 1.11 mmol), 4.4.4 ', 4' , 5.5,5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (0.705 g, 2.78 mmol), potassium acetate (0.545 g, 5.55 mmol) , [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.041 g, 0.056 mmol) in dioxane (4 mL) was heated to 100 ° C in a heating block. After 90 min, the resulting mixture was allowed to cool to room temperature and filtered through a pad of Celite, was rinsed with EtOAc (10 ml), and was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (0 to 50% ethyl acetate in hexane) to produce 2,2 '- (2,2'-dichloro-5-fluoro- [1,1'-biphenyl ] -3,3'-diyl) bis (4,4,5,5-tetramethyl-1,3,2-dioxaborolane).
[00474] [00474] A stirred mixture of 2.2 '- (2,2'-dichloro-5-fluoro- [1,1'-biphenyl] -3,3'-di-yl) bis (4,4,5, 5-tetramethyl-1,3,2-dioxaborolane) (53 mg, 0.107 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (49 mg, 0.226 mmol), aqueous sodium carbonate solution (2.0 M , 323 µL, 0.645 mmol), and chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-isopropyl-1,1′-biphenyl) [2- (2′-amino- 1,1 ′ -biphenyl)] palladium (II) (4 mg, 0.005 mmol) in 1,4-dioxane (0.5 mL) was heated to 105 ° C in a heating block. After 60 min, the resulting mixture was allowed to cool to room temperature. Ethyl acetate (5 ml) was added, and the organic layer was washed with brine (2 ml), dried with anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure to produce 5.5 '- (2, 2'-dichloro-5-fluoro- [1,1'-biphenyl] -3,3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde).
[00475] [00475] N, N-diisopropylethylamine (76 µL, 0.430 mmol) was added via syringe to a stirred mixture of 5.5 '- (2,2'-dichloro-5-fluoro- [1,1'-biphenyl ] - 3,3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde), (15 mg, 0.029 mmol) and (S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (44 mg, 0.290 mmol) in
[00476] [00476] 2 - ((5- (2,2'-Dichloro-3 '' - methoxy-4 '' - - ((7-oxo-2,6-diazaspiro [3.4] octan-2-yl) methyl) - [1,1 ': 3', 1 '' - terphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) -2,6-diazaspiro [3.4] octan-7-one was synthesized in a way similar to 2 - ((5- (2,2'-dichloro-3 '- (5- (4,5-dihydro-1H-imidazol-2-yl) -6-methoxypyridin-2-yl) - [ 1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) -2,6-diazaspiro [3.4] octan-7-one (Procedure 10) using 4-bromo-2-methoxybenzaldehyde in instead of 6-chloro-3- (4,5-dihydro-1H-imidazol-2-yl) -2-methoxypyridine. Procedure 13: (S) -2 ', 2' '- dichloro-3' '- (6-methoxy-5 - ((((((5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrazin-2-yl ) -4 - (((6-oxo-2,5-diazaspiro [3.4] octan-2-yl) methyl) - [1,1 ': 3', 1 '' - terphenyl] -3-carbonitrile
[00477] [00477] 2,2 '- (2,2'-Dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (4,4,5,5-tetramethyl-1,3, 2-dioxaborolane) (302 mg, 0.64 mmol) and (S) - ((5-bromo-3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) tert-carbamate butyl (220 mg, 0.53 mmol) were suspended in 1,4-dioxane (2 mL) and H2O (0.3 mL), added potassium carbonate (95 mg, 0.69 mmol) and tetrakis (triphenylphosphine) palladium (0) (61 mg, 0.05 mmol). The mixture was heated to 85 ° C. After 90 min, CL-EM showed almost complete conversion. The mixture was filtered through a plug of Celite, washed with EtOAc. The filtrate was partitioned between EtOAc and brine. The organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel using Hexanes / EtOAc as the eluent to produce (S) - ((5- (2,2'-dichloro-3 '- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate tert-butyl.
[00478] [00478] (S) - ((5- (2,2'-dichloro-3 '- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1.1 '-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) (tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate (100 mg, 0.15 mmol) and 5-bromo -2- formylbenzonitrile (53 mg, 0.25 mmol) were suspended in 1,4-dioxane (5 mL) and H2O (0.5 mL), added potassium carbonate (22.3 mg, 0.16 mmol) and tetrakis (triphenylphosphine) palladium (0) (34.3 mg, 0.03 mmol). The mixture
[00479] [00479] The title compound was synthesized according to general reductive amination procedure G. Procedure 14: (S) -5 - ((((5- (2, 2'-dichloro-3 '- (5 - ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) -6- methoxypyridin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one
[00480] [00480] 2,2 '- (2,2'-Dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (4,4,5,5-tetramethyl-1,3, 2-dioxaborolane) (3.32 g, 7.00 mmol) and 6-chloro-2-methoxy-nicotinaldehyde (1 g, 5.83 mmol) were suspended in 1,4-dioxane (18 mL) and H2O (2.4 ml), added potassium carbonate (1.05 g, 7.58 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.67 g, 0.58 mmol). The mixture was
[00481] [00481] 6- (2,2'-Dichloro-3 '- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1'-biphenyl] -3 -yl) -2-methoxyynicotinaldehyde (423 mg, 0.87 mmol) and (S) - ((5-bromo-3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) carbamate of tert-butyl (330 mg, 0.79 mmol) were suspended in 1,4-dioxane (3 mL) and H2O (0.6 mL), potassium carbonate (132 mg, 0.95 mmol) and tetrakis ( triphenylphosphine) palladium (0) (92 mg, 0.08 mmol). The mixture was heated to 84 ° C. After 90 minutes, CL-EM showed almost complete conversion. The mixture was filtered through a plug of Celite, washed with EtOAc. The filtrate was partitioned between EtOAc and brine. The organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel using Hexanes / EtOAc as the eluent to produce (S) - ((5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyridin-2-yl ) Tert-butyl [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) (tert-butyl (5-oxopyrrolidin-2-yl) methyl) carbamate.
[00482] [00482] The title compound was synthesized according to the general procedure G of reductive amination followed by standard deprotection of Boc with TFA. Procedure 15: (S) -5 - ((((5- (3 '- (5 - ((R) -1-aminoethyl) -6-methoxypyrazin-2-yl) -2,2'-dichloro- [1 , 1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one
[00483] [00483] To an oven dried 40 ml flask were added 5-bromo-3-methoxypyrazine-2-carbaldehyde, dichloromethane (0.5M), and (R) -2-methylpropane-2-sulfinamide (1.0 equiv .) at room temperature. The titanium tetroxide (2.0 equiv.) Was then added to the flask. The mixture was stirred overnight before being diluted with sodium bicarbonate solution. The contents of the flask were filtered through Celite, and the filtrate was washed once with water and once with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate gradient to produce (R, E) -N - ((5-bromo-3-methoxypyrazin-2-yl) methylene) -2-methylpropane-2 -sulfinamide.
[00484] [00484] To an oven dried 40 ml flask was added (R, E) - N - (((5-bromo-3-methoxypyrazin-2-yl) methylene) -2-methylpropane-2-sulfinamide and
[00485] [00485] To an oven dried 40 ml flask were added (R) -N - ((R) -1- (5-bromo-3-methoxypyrazin-2-yl) ethyl) -2-methylpropane-2-sulfinamide , 5- (2,2'-dichloro-3 '- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1'-biphenyl] -3-yl ) -3-methoxypyrazine-2-carbaldehyde (1.0 equiv.), Potassium carbonate (2.0 equiv.), Pd (dppf) Cl2 (10 mol%), dimethylformamide (0.2M), and water ( 10% by vol). The contents of the flask were sparged with nitrogen for 30 seconds then heated to 90 ° C for 45 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed once with water and once with brine before being dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with a gradient of methanol / dichloromethane to produce (R) -N - ((R) -1- (5- (2,2'-dichloro-3 '- (5-formyl -6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) ethyl) -2-methylpropane-2-sulfinamide.
[00486] [00486] (S) -5- (Aminomethyl) pyrrolidin-2-one (3 equiv.) Was reacted with (R) -N - ((R) -1- (5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) ethyl) -2-methylpropane-2-sulfinamide following reductive amination procedure C to produce (R) -N - ((R) -1- (5- (2,2'-dichloro-3 '- (6-methoxy-5 - (((((S) -5 -oxopyrrolidin-2-
[00487] [00487] To an oven dried 20 ml flask were added (R) -N - ((R) -1- (5- (2,2'-dichloro-3 '- (6-methoxy-5 - (( ((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) ethyl ) -2-methylpropane-2-sulfinamide, methanol and 4M HCl in dioxane (2.0 equiv.). The mixture was stirred at room temperature for 30 minutes before being concentrated and purified by HPLC to produce (S) -5 - (((((5- (3'- (5 - ((R) -1-aminoethyl) -6 -methoxypyrazin-2-yl) -2,2'-dichloro- [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one. Procedure 16: (S) -5 - ((((5- (2,2'-dichloro-3 '- (5 - ((2,5-dimethyl-1H-pyrrol-1-yl) methyl) -6- methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin-2-one
[00488] [00488] (S) - ((5- (2,2'-Dichloro-3 '- (5-formyl-6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) - 3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-
[00489] [00489] To an oven dried 40 ml flask were added (S) - ((5- (2,2'-dichloro-3 '- (5 - ((2,5-dimethyl-1H-pyrrole-1- il) methyl) -6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) ((5-oxopyrrolidin-2-yl) methyl) tert-butyl carbamate, dichloromethane (0.5M), and trifluoroacetic acid (10 equiv.) at room temperature. The mixture was stirred for 30 minutes before being concentrated and purified by HPLC to yield (S) -5 - ((((5- (2,2'-dichloro-3 '- (5 - ((2,5-dimethyl -1H-pyrrol-1-yl) methyl) -6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) amino) methyl) pyrrolidin -2-one. Procedure 17: 2,2 '- ((((2-bromo-2'-chloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-methoxypyrazine-5,2-di- il)) bis (methylene)) bis (2,6-diazaspiro [3.4] octan-7-one)
[00490] [00490] 2,2 '- ((((2-Bromo-2'-chloro- [1,1'-biphenyl] -3,3'-diyl) bis (3-methoxypyrazine-5,2-di- il)) bis (methylene)) bis (2,6-diazaspiro [3.4] octan-7-one) was synthesized in a similar manner to Procedure 18 using boronic (2-chlorophenyl) acid in place of (2-fluorophenyl) boronic. Procedure 18: 2,2 '- ((((2-bromo-2'-fluoro- [1,1'-biphenyl] -3,3'-diyl) bis (3-methoxypyrazine-5,2-di- il)) bis (methylene)) bis (2,6-diazaspiro [3.4] octan-7-one)
[00491] [00491] A stirred mixture of 1-bromo-2-iodobenzene (0.6 g, 4.29 mmol, boron (2-fluorophenyl) acid (1.213 g, 4.29 mmol, potassium carbonate (1.48 g, 10.72 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.149 g, 0.129 mmol) in dimethoxyethane (12.88 mL) and water (1.72 mL) was heated to 95 ° C in a heating block. After 60 min, the resulting mixture was allowed to cool to room temperature, ethyl acetate (50 ml) was added, and the organic layer was washed with brine (25 ml), dried with anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column (0-10% ethyl acetate in hexane) to produce 2-bromo-2'-fluoro-1,1'-biphenyl.
[00492] [00492] N-butyllithium solution (3.42 mL, 2.5 M in hexane, 8.56 mmol) was added via syringe to a stirred solution of 2,2,6,6-tetramethylpiperidine (1.44 mL, 8.56 mmol) in anhydrous tetrahydrofuran (10.70 mL) at 0 ° C. The resulting mixture was stirred for 10 min and cooled to - 78 ° C. Triisopropyl borate (3.29 mL, 14.27 mmol) was added and stirred for 8 min. 2-Bromo-2'-fluoro-1,1'-biphenyl was added via syringe and the mixture was slowly warmed to room temperature
[00493] [00493] A stirred mixture of diboroic acid (2-bromo-2'-fluoro- [1,1'-biphenyl] -3,3'-diyl) (0.263 g, 0.776 mmol, 5-bromo-3- methoxypyrazine-2-carbaldehyde (0.50 g, 2.33 mmol, potassium carbonate (1.48 g, 10.72 mmol), aqueous sodium carbonate solution (2.0 M, 3.16 mL, 6.21 mmol ) and chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-isopropyl-1,1′-biphenyl) [2- (2′-amino- 1,1′-biphenyl)] palladium (II ) (0.031 g, 0.039 mmol) in dimethoxyethane (4 mL) was heated to 100 ° C in a heating block After 60 min, the resulting mixture was allowed to cool to room temperature. Ethyl acetate (40 mL) was added , and the organic layer was washed with brine (20 ml), dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography on a silica gel column (ethyl acetate 0 50% in hexane) to produce 5.5 '- (2-bromo-2'-fluoro- [1,1'-biphenyl] -3,3'-diyl) bis (3-methoxypyrazine-2-carbaldehyde ).
[00494] [00494] N, N-Di-isopropylethylamine (79 µL, 0.453 mmol) was added via syringe to a stirred mixture of 5.5 '- (2-bromo-2'-fluoro- [1,1'-biphenyl] - 3,3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde), (15.8 mg, 0.030 mmol) and 2,6-diazospiro 4-methylbenzenesulfonate [3.4] octan-7-one (90 mg , 0.302 mmol) in dimethyl sulfoxide (1 mL) at room temperature. After 10 min, sodium triacetoxyborohydride (64 mg, 0.302 mmol) was added as a solid, and the resulting mixture was heated to 60 ° C in a heating block. After 30 min, the resulting mixture was allowed to cool to room temperature. The mixture was filtered and was purified by HPLC
[00495] [00495] (5S, 5'S) -5.5 '- ((((((2,2'-dichloro-5,5'-difluoro- [1,1'-biphenyl] -3,3'- di-il ) bis (3-methoxypyrazine-5,2-di-yl)) bis (methylene)) bis (azanediyl)) bis (methylene)) bis (pyrrolidin-2-one) was synthesized in a manner similar to Procedure 11 using 2- (3-bromo-2-chloro-5-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of (3-bromo-2-chlorophenyl) boronic acid. Procedure 20: (5S, 5'S) -5.5 '- ((((((2,2'-dichloro- [1,1'-biphenyl] -3,3'-diyl) bis (3- (methylamino ) pyrazine-5,2-di-yl)) bis (methylene)) bis (methylazanediyl)) bis (methylene)) bis (pyrrolidin-2-one)
[00496] [00496] To an oven dried 40 ml flask were added
[00497] [00497] Sodium triacetoxyborohydride (122 mg, 0.577 mmol) was
[00498] [00498] Chlorosulfonic acid (9.6 µL, 0.060 mmol) was added via syringe to a stirred mixture of ((5- (2,2'-dichloro-3 '- (6-methoxy-5 - ((((( S) -5- oxopyrrolidin-2-yl) methyl) amino) methyl) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) (( (S) -5-oxopyrrolidin-2-yl) methyl) tert-butyl carbamate (43 mg, 0.055 mmol) and triethylamine (27 µL, 0.19 mmol) in dichloromethane (1.0 mL) at 0 ° C. After 5 min, the resulting mixture was warmed to room temperature. After 40 min, trifluoroacetic acid (1.0 mL) was added. After 30 min, the resulting mixture was concentrated under reduced pressure and was purified by preparative HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) to produce acid ((5- (2,2'-dichloro-3 '- (6-methoxy-5 - (((((((S) -5-oxopyrrolidin-2-yl) methyl) amino) methyl) pyrazin-
[00499] [00499] 2,2-Difluoropropane-1,3-diamine dihydrochloride (22.2 mg, 0.121 mmol) was added to a vigorously stirred mixture of 5.5'- (2.2'-dichloro- [1.1 '-biphenyl] -3,3'-di-yl) bis (3-methoxypyrazine-2-carbaldehyde) (10 mg, 0.020 mmol) and potassium carbonate (33.5 mg, 0.242 mmol) in tetrahydrofuran (0 , 7 ml) and ethanol (1.3 ml) at room temperature, and the resulting mixture was heated to 80 ° C. After 20 min, the resulting mixture was cooled to room temperature over 5 min, and N-bromosuccinimide (28.8 mg, 0.162 mmol) was added. After 45 min, the resulting mixture was filtered and was purified by preparative HPLC in reverse phase (0.1% trifluoroacetic acid in acetonitrile / water) to produce 2.2 '- ((2,2'-dichloro- [1, 1'-biphenyl] -3,3'-di-yl) bis (3-methoxypyrazine-5,2-di-yl)) bis (5,5-difluoro-1,4,5,6-tetrahydropyrimidine) . Procedure 23: (S) -5 - ((((6- (2,2'-dichloro-3 '- (6-methoxy-5 - (((((S) -5-oxopyrrolidin-2-yl) methyl ) amino) methyl) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -2-methoxypyridin-3-yl) methyl) amino) methyl) pyrrolidin-2-one
[00500] [00500] A vigorously stirred mixture of 6- (2,2'-dichloro-3'- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1 ' -biphenyl] -3-yl) -2- methoxyynicotinaldehyde (1.00 g, 2.07 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (672 mg, 3.10 mmol), chlorine (2-dicyclo -hexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (81.3 mg, 0.103 mmol), and saturated aqueous sodium carbonate solution (5.16 mL) in 1,4-dioxane (15 mL) was heated to 85 ° C. After 60 min, the resulting mixture was cooled to room temperature, and ethyl acetate (100 ml) was added. The organic layer was washed with brine (60 ml), dried with anhydrous sodium sulfate, filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 50% ethyl acetate in hexanes) to yield 5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyridin-2- il) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde.
[00501] [00501] Sodium triacetoxyborohydride (1.21 g, 5.71 mmol) was added to a vigorously stirred mixture of 5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyridin-2 -yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde (565 mg, 1.14 mmol), (S) -5- (aminomethyl) pyrrolidin-2-one ( 392 mg, 3.431 mmol), and acetic acid (65 µL, 1.1 mmol) in dichloromethane (25 mL) at room temperature. After 60 min, aqueous sodium hydroxide solution (2 M, 10 mL) was added, and the resulting biphasic mixture was stirred
[00502] [00502] A vigorously stirred mixture of 5- (2,2'-dichloro-3'-
[00503] [00503] A stirred mixture of 3-chloro-5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyrazin-2-yl) - [1,1'-biphenyl] -3-yl ) pyrazine-2-carbaldehyde (81.0 mg, 0.162 mmol) and methylamine solution (2.0 M in tetrahydrofuran, 3.0 mL, 6.0 mmol) was heated to 70 ° C. After 60 min, acetic acid (0.4 ml) and water (1.0 ml) were added sequentially, and the resulting biphasic mixture was stirred vigorously. After 15 min, the biphasic mixture was cooled to room temperature, and ethyl acetate (15 ml) was added. The organic layer was washed sequentially with water (15 ml) and a mixture of saturated aqueous sodium bicarbonate solution and brine (1: 1 v: v, 15 ml), dried with anhydrous sodium sulfate, filtered, and was concentrated under reduced pressure to produce 5- (2,2'-dichloro-3 '- (5-formyl-6- (methylamino) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) - 3-methoxypyrazine-2-carbaldehyde.
[00504] [00504] 2 - ((5- (2,2'-Dichloro-3 '- (6- (methylamino) -5 - ((6-oxo-2,5-diazospiro [3.4] octan-2-yl) methyl ) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazin-2-yl) methyl) -2,5-diazaspiro [3.4] octan-6-one was synthesized in a similar to Procedure 6 using 5- (2,2'-dichloro-3 '- (5-formyl- 6- (methylamino) pyrazin-2-yl) - [1,1'-biphenyl] -3-yl) - 3-methoxypyrazine-2-carbaldehyde instead of 5.5 '- (2,2'-dichloro [1,1'-biphenyl] -3,3'-di-yl) bis (3-
[00505] [00505] A stirred mixture of 2,2 '- (2,2'-dichloro- [1,1'-biphenyl] -3,3'-di-yl) bis (4,4,5,5-tetramethyl- 1,3,2-dioxaborolane) (1.24 g, 2.54 mmol, 5-bromo-3-methoxypyrazine-2-carbaldehyde (0.500 g, 2.30 mmol, aqueous sodium carbonate solution (2.0 M , 4.61 ml, 9.22 mmol), and tetrakis (triphenylphosphine) palladium (0) (133 mg, 0.115 mmol) in 1,4-dioxane (6 ml) was heated to 105 ° C in a heating block. After 60 min, the resulting mixture was allowed to cool to room temperature, ethyl acetate (30 ml) was added, and the organic layer was washed with brine (20 ml), dried with anhydrous magnesium sulfate, filtered, and was concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column (0 to 40% ethyl acetate in hexane) to yield 5- (2,2'-dichloro-3 '- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde.
[00506] [00506] A stirred mixture of 5- (2,2'-dichloro-3 '- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - [1,1'- biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde (50 mg, 0.103 mmol), 5-chloro-3-methoxypyridine-2-carbaldehyde (22.1 mg, 0.129 mmol), aqueous sodium carbonate solution (2.0 M, 206 µL, 0.412
[00507] [00507] N, N-diisopropylethylamine (42 µL, 0.243 mmol) was added via syringe to a stirred mixture of 5- (2,2'-dichloro-3 '- (5-formyl-6-methoxypyridin-2- il) - [1,1'-biphenyl] -3-yl) -3-methoxypyrazine-2-carbaldehyde (8 mg, 0.016 mmol) and 3-methoxyazetidine hydrochloride (20 mg, 0.162 mmol) in dimethyl sulfoxide (1 mL ) at room temperature. After 10 min, sodium triacetoxyborohydride (34.3 mg, 0.162 mmol) was added as a solid, and the resulting mixture was heated to 60 ° C in a heating block. After 30 min, the resulting mixture was allowed to cool to room temperature. The mixture was filtered and was purified by preparative reverse phase HPLC (0.1% trifluoroacetic acid in acetonitrile / water) to yield 5- (2,2'-dichloro-3 '- (6-methoxy-5 - (( 3-methoxyzetidin-1-yl) methyl) pyridin-2-yl) - [1,1'-biphenyl] -3-yl) -3-methoxy-2 - (((3-methoxyzetidin-1-yl) methyl) pyrazine . 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.72 (ddd, J = 12.2, 7 , 7, 1.7 Hz, 2H), 7.60 (q, J = 7.6 Hz, 3H), 7.53 - 7.43 (m, 2H), 7.41 (d, J = 7, 5 Hz, 2H), 4.76 (s, 2H), 4.52 (s, 2H), 4.15 (s, 3H), 4.12 (d, J = 1.4 Hz, 5H), 3 , 41 (s, 3H), 3.40 (s, 4H).
[00508] [00508] The following compounds were prepared according to the procedures described here (and indicated in Table 1 under Procedure) using the appropriate starting material (s) and the appropriate protecting group chemistry as needed. Table 1
[00509] [00509] NMR data for the selected compounds are shown in Table 2. Table 2 NMR No. 1H-NMR (400 MHz, Methanol-d4) δ 8.70 (d, J = 2.1 Hz, 1H), 8, 52 (s, 1H), 8.21 (s, 1H), 7.74 (d, 1 J = 7.4 Hz, 1H), 7.68 - 7.44 (m, 4H), 4.82 - 4.03 (m, 16H), 2.58 (d, J = 8.2 Hz, 4H), 2.46 (d, J = 8.0 Hz, 4H). 1H NMR (400 MHz, Methanol-d4) δ 8.67 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.19 (td, J = 7.2, 2 , 7 2 Hz, 1H), 7.71 (dd, J = 7.3, 2.2 Hz, 1H), 7.65 - 7.42 (m, 4H), 4.72 (s, 9H), 4.34 (d, J = 34.3 Hz, 1H), 4.14 (d, J = 21.4 Hz, 9H). 1H NMR (400 MHz, Methanol-d4) δ 8.67 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.71 (d, J = 7.1 Hz, 3 1H), 7.65 - 7.41 (m, 4H), 4.72 (s, 6H), 4.39 (s, 6H), 4.14 (d, J = 21.3 Hz, 8H), 3.37 (s, 6H). 1H NMR (400 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.49 (s, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.71 ( d, 4 J = 8.0 Hz, 1H), 7.66 - 7.43 (m, 4H), 4.79 - 4.02 (m, 24H), 1.86 (s, 6H). 1H NMR (400 MHz, Methanol-d4) δ 8.77 - 8.66 (m, 1H), 8.53 (s, 1H), 8.26 - 8.14 (m, 1H), 7.80 5 - 7.67 (m, 1H), 7.66 - 7.43 (m, 4H), 4.49 (d, J = 6.5 Hz, 4H), 4.18 (s, 3H), 4 , 13 (s, 3H), 3.95 - 3.83 (m, 4H). 1H NMR (400 MHz, Methanol-d4) δ 8.80 - 8.66 (m, 1H), 8.62 - 8.51 (m, 1H), 8.31 - 8.11 (m, 6 1H ), 7.83 - 7.40 (m, 5H), 4.66 - 4.43 (m, 4H), 4.23 - 4.05 (m, 7H), 3.05 (d, J = 6 , 2 Hz, 2H), 2.52 - 2.32 (m, 5H), 1.97 (d, J = 8.9 Hz, 2H). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.15 (s, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.50 ( s, 1H), 7.75 (dt, J = 7.6, 1.6 Hz, 2H), 7.63 (dq, J = 7.6, 4.0 Hz, 3H), 7.55 (ddd , J = 7.5, 5.7, 1.8 7 Hz, 2H), 4.46 (s, 2H), 4.22 (d, J = 7.0 Hz, 2H), 4.01 (d , J = 7.8 Hz, 6H), 3.93 (m, 1H), 3.20 (s, 2H), 2.48 - 2.42 (m, 5H), 2.25 - 2.09 ( m, 3H), 1.81 (m, 1H), 1.78 (s, 1H). 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.56 (d, J = 7.4 Hz, 2H), 7.76 (dt, J = 7.7, 2 , 0 Hz, 2H), 7.68 - 7.59 (m, 3H), 7.56 (dd, J = 7.9, 1.8 Hz, 2H), 4.46 (s, 2H), 4 , 33 (s, 2H), 4.02 (s, 8 6H), 3.94 (t, J = 6.9 Hz, 1H), 3.22 (s, 3H), 3.17 (s, 1H ), 2.25 - 2.13 (m, 2H), 2.14 (s, 6H), 1.80 (dd, J = 11.9, 6.3 Hz, 1H). 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.14 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7, 74 (ddd, J = 8.6, 7.6, 1.8 Hz, 2H), 7.68 - 7.58 (m, 3H), 7.55 (ddd, J = 7.6, 5.1 , 1.8 Hz, 2H), 4.68 9 (s, 2H), 4.55 (s, 2H), 4.46 (s, 2H), 4.01 (d, J = 9.2 Hz, 6H), 3.94 (s, 1H), 3.19 (s, 2H), 2.24 - 2.09 (m, 3H), 1.85 - 1.74 (m, 1H), 1.69 (s, 3H). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7, 74 10 (ddd, J = 9.2, 7.6, 1.8 Hz, 2H), 7.68 - 7.51 (m, 6H), 4.65 (s, 2H), 4.46 (s , 2H), 4.40 (s, 2H), 4.02 (s, 2H), 3.99 (s, 3H), 3.94 (s, 2H), 3.20 (s, 2H), 2 , 25 - 2.09 (m, 4H), 1.78 (s, 1H). 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 2H), 9.21 (s, 2H), 8.57 (d, J = 2.4 Hz, 2H), 7.75 ( dd, J = 7.7, 1.8 Hz, 2H), 7.68 - 7.59 (m, 3H), 7.56 (dd, J = 7.6, 1.8 Hz, 2H), 5 , 62 (s, 1H), 4.47 11 (s, 5H), 4.09 - 3.95 (m, 6H), 3.96 - 3.83 (m, 2H), 3.70 (s, 1H), 3.50 (dd, J = 9.4, 3.8 Hz, 1H), 3.19 (s, 2H), 2.24 - 2.09 (m, 3H), 1.78 (s , 1H). 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 2H), 9.21 (s, 2H), 8.56 (d, J = 7.1 Hz, 2H), 7.76 ( dt, J = 7.6, 1.9 Hz, 2H), 7.68 - 7.59 (m, 3H), 7.56 (dd, J = 7.6, 1.8 Hz, 2H), 4 , 46 (s, 2H), 4.32 (s, 12 2H), 4.02 (s, 6H), 3.94 (s, 1H), 3.19 (s, 2H), 2.67 (s , 1H), 2.26 - 2.09 (m, 3H), 2.03 (s, 3H), 1.85 - 1.75 (m, 1H). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 2H), 9.14 (s, 1H), 8.55 (d, J = 16.1 Hz, 2H), 7.79 - 13 7.52 (m, 9H), 4.46 (s, 3H), 4.32 (s, 1H), 4.01 (m, 6H), 3.43 (s, 1H), 3.25 ( d, J = 6.7 Hz, 2H), 2.52 (s, 1H), 2.25 - 2.19 (m, 2H), 2.23 - 2.09 (m, 3H), 1.80 (dd, J = 11.8, 6.3 Hz, 1H).
[00510] [00510] The compounds were tested in protein-protein interaction biochemical assays to determine whether they can specifically block the interaction between the extracellular domains of PD-1 / PD-L1 or CTLA / CD80. The binding of protein pairs is measured using a bead based Amplified Luminescent Proximity Homogeneous Assay (ALPHA) platform. The binding of each pair of proteins results in the proximity of the donor and acceptor spheres which results in an increase in ALPHA signal. Interruption of protein-protein interaction with a test compound results in a decrease in ALPHA signal. The assays are performed in 25 mM Hepes (pH 7.4), 150 mM NaCl, 3.4 mM EDTA, 0.005% Tween 20, and 0.01% BSA. Final protein concentrations in the assays were 0.3 nM (His-tagged PD-L1), 2.5 nM (biotinylated Fc-PD-1), 1 nM (His-tagged CTLA4) and 1 nM (biotinylated CD80). After a test reaction time of 60 minutes at 25 ° C, the binding was measured with the addition of 20 µg / ml of ALPHA acceptor test beads (coated with anti-His antibody) and 20 µg / ml of donor beads ALPHA assay (coated with streptavidin). IC50 values were calculated from the adjustment of the dose response curves for an equation of four parameters. Representative data are shown below in Table 3. Table 3 IC50 No. PD-L1-PD1 (nM) 1 0.080 2 0.135 3 0.318 4 0.086 5 0.213 6 0.099 7 0.430 8 0.590 9 0.490 10 0.270 11 0.172 12 1.492 13 0.482
[00511] [00511] The above data shows that the compounds of the present description are generally effective in blocking the interaction of PD-1 / PD-L1. PD-1 / PD-L1 NFAT Reporter Assay:
[00512] [00512] The compounds were tested in a functional coculture reporter assay in which TCR-mediated NFAT activity is inhibited by the interaction of PD-1 with PD-L1. Blocking the PD-1 / PD-L1 interaction prevents PD-1-mediated decrease in TCR signaling and significantly increases NFAT-mediated luciferase transcription. CHO cells that express surface-bound anti-CD3 antibodies and PD-L1 (artificial antigen-presenting cells, aAPC-PD-L1) were first seeded overnight. Jurkat cells that overexpress PD-1 and express a luciferase construct under NFAT control are diluted in RPMI assay medium (RPMI 1640 with 2% FBS), mixed with compounds, and immediately seeded over the aAPC-PD- monolayer L1. The coculture is then incubated for 6 hours at 37 ° C. Luciferase activity is assessed by adding the ONE-Glo reagent and by measuring luminescence with a plate reader. EC50 values are calculated from the adjustment of the dose response curves for a four-parameter equation (Table 4). Biochemical Assay of Protein-Protein Interaction with Dimerization
[00513] [00513] The compounds were tested in protein-protein interaction biochemical assays to determine whether they can specifically dimerize the extracellular domains of PD-L1. Protein dimerization (His-tagged PD-L1 and FLAG-tagged PD-L1) is measured using a bead based Amplified Luminescent Proximity Homogeneous Assay (ALPHA) platform. The dimerization of PD-L1, induced by the compound, results in the proximity of the donor and acceptor spheres which results in an increase in the ALPHA signal. The assays are performed in 25 mM Hepes (pH 7.4), 150 mM NaCl, 3.4 mM EDTA, 0.005% Tween 20, and 0.01% BSA. The final protein concentrations in the assays were 0.5 nM (His-tagged PD-L1) and 0.5 nM (FLAG-tagged PD-L1). After a 2 hour test reaction time at 25 ° C, 20 µg / mL (final test concentration) of ALPHA test acceptor beads (coated with anti-His antibody) were added and incubated for 60 minutes at 25 ° C . Binding was measured after a final 60-minute incubation with 40 µg / ml (final assay concentration) of ALPHA assay donor beads (coated with anti-FLAG antibody). The CA50 values were calculated from the adjustment of the dose response curves for a four-parameter equation (Table 4). Table 4 CA50 PDL1 CE50 NFAT No. Luciferase Dimer 1 240.33 66 2 202.6 90 3 392.74 218 4 335.51 59 5 393.97 274 6 305.57 126 7 583.46 3442 8 644.47 5852 9 607.65 375 10 403.62 142 11 462.83 163 12 757.1 299 13 347.99 403
[00514] [00514] This example shows the effect of compound 139 undergoes the function of HBV-specific T-cells in peripheral blood mononuclear cells obtained from patients with chronic hepatitis B (CHB). It has been reported that inhibition of the interaction between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) with specific monoclonal antibodies enhances the antiviral function of HBV-specific T-cells. This study evaluated the ability of a PD-L1 inhibitor described here (i.e. compound 139) to enhance HBV-specific T-cell functions in peripheral blood mononuclear cells (PBMC) isolated from patients with chronic hepatitis B ( CHB). PBMCs from patients with CHB were treated for 6 days with compound 139 or DMSO in the presence of HBV core peptides, followed by restimulation for 16 hours before CD8 + and CD4 + T-cell analysis by flow cytometry. Compared to controls treated with DMSO, treatment with compound 139 increased the percentage of interferon-γ (IFN-γ) + CD8 + T-cells by 2.5 times (p = 0.01) and IFN- T-cells γ + CD4 + 2.5 times (p = 0.003). Compound 139 also significantly increased granzyme expression
[00515] [00515] Compound 139 was dissolved in 100% DMSO to prepare a 10 mM stock solution and the solution was stored at -20 ° C. Ab (antibody) durvalumab anti-PD-L1 was produced and purified at Gilead Sciences. In all assays, compound 139 was evaluated at a dose of 650 nM, it is 2x concentration above the EC90 value as determined in a polyclonal activation test of human blood. Durvalumab (durva) was used at a concentration of 10 μg / mL as per previously reported studies (Boni et al. J. Virol, 2007; 81 (8); 4215-4225). Donor Whole Blood with CHB
[00516] [00516] Donors with CHB were provided by C&M LabPro, LLC (San Francisco, CA, USA), MT Group, Inc. (Van Nuys, CA, USA), and BioIVT (Westbury, NY, USA). Whole blood from donors with CHB was aspirated into K2 EDTA Tubes (Becton Dickinson, Franklin Lakes, NJ, USA) and sent overnight to Gilead Sciences, Inc. PBMCs from blood samples were isolated at Gilead Sciences using the protocol described below. Table 5 summarizes the reactivity of HBV antigen s (HBsAg) and antigen and HBV antigen (HBeAg) and also the demographic data of patients with CHB in this study. Table 5. Demographic data of patients with CHB.
[00517] [00517] PBMCs were isolated from whole blood using a standard Ficoll® Paque gradient. Briefly, 25-30 mL of blood was gently superimposed on top of a 15 mL Ficoll® Paque Plus solution (GE Healthcare, Chicago, IL, USA) in a 50 mL Falcon tube, and centrifuged in an Allegra X-14R centrifuge ( Beckman Coulter, Indianapolis, IN, USA) at 520g for 20 minutes at 25 ° C. The mononuclear cell layer was washed twice with Wash Buffer (Medium RPMI 1640 - GlutaMAX-I (Life Technologies, Carlsbad, CA, USA)) supplemented with 10% Heat Inactivated Bovine Serum (Fetal Bovine Serum, FBS ; Hyclone, Logan, UT, USA). The cells were then centrifuged at 520g for 5 minutes and red blood cells (RBC, Red Blood Cells) were lysed for 5 minutes at room temperature using RBC Lysis Buffer (eBioscience, San Diego , CA, USA). After a final wash with PBMC wash buffer, cells were resuspended in cell culture medium consisting of RPMI 1640 culture medium supplemented with 25 mM HEPES (Life Technologies), 100 U / mL Penicillin / Streptomycin (Sigma Aldrich , St Louis, MO, USA), 1x non-essential amino acids (Life Technologies, Carlsbad, CA, USA), 10% FBS, and 20 U / mL interleukin-
[00518] [00518] PBMCs were seeded at 2-4 × 105 cells / well in 96-well round bottom plates (Corning, NY, USA). A collection (pool) of 15-mer (15 amino acid) peptides with 11-amino acid (AA) overlap covering the entire HBV core sequence was added at a concentration of 100-300 ng / mL in the presence of 650 nM of compound 139, or 10 µg / ml durvalumab, or the equivalent volume of DMSO (Sigma Aldrich). PBMCs were incubated for 7 days at 37 ° C with 5% CO2 in a humidified incubator. The cell culture medium (as described above) was replaced with fresh medium containing IL-2 (without peptides, compound 139, or durvalumab) after 4 days. On Day 6, PBMCs were restimulated by the addition of 100-300 ng / mL of HBV core peptides, or DMSO. Compound 139 or durvalumab was also added during restimulation. To inhibit protein transport, a 1 μg / mL solution of brefeldin A (Sigma) was added to each well. After overnight incubation, the cells were processed for immunostaining and flow cytometry as described herein. Immunostaining and Flow Cytometry
[00519] [00519] After restimulation overnight with the pool (pool) of peptides and compound 139 or durvalumab, the PBMCs were pelleted by centrifugation on Day 7 and washed twice with PBS. The washed cells were resuspended in “Live / Dead Aquamine Stain” (Invitrogen) according to the manufacturer's instructions to determine the
[00520] [00520] Flow cytometry data was analyzed using “FlowJo Flow Cytometry Analysis Software v10” (TreeStar, Ashland, OR,
[00521] [00521] To assess the effects of compound 139 on the activation of HBV-specific T-cells, PBMCs isolated from 14 CHB donors were stimulated with a 15-mer peptide pool (15 amino acids) spanning the sequence of the HBV core. During stimulation with peptides, PBMCs were treated with compound 139 (650 nM) or control vehicle (DMSO) for 6 days. After 6 days of peptide stimulation and treatment with compound 139, PBMCs were restimulated for 16 hours with fresh peptides and compound 139 or DMSO. As substitutes for effector function, intracellular levels of IFN-γ (antiviral cytokine) and GrB (a marker of cytotoxic function), were measured by flow cytometry in CD3 + CD4 + and CD3 + CD8 + T-cell populations.
[00522] [00522] In PBMCs stimulated by HBV core peptide isolated from 14 CHB donors, compound 139 significantly increased the frequencies of both CD8 + IFN-γ + T cells (2.5 times, p = 0.01 ) and CD8 + GrB + T-cells (1.2 times, p = 0.015), compared to PBMCs treated with DMSO (Figure 1A and Table 7). For control purposes, durvalumab, a monoclonal antibody labeled anti-α-PD-L1, was also tested in PBMCs isolated from 9 of the 14 CHB donors. We found that both compound 139 and durvalumab induced a comparable increase in CD8 + IFN-γ + T-cells (2.5 times versus 2.7 times respectively, p = 0.21) and CD8 + GrB + (1, 2 times versus 1.1- times, respectively, p = 0.53) (Figure 1B and Table 7). These data are in agreement with a previous report in which IFN-γ + cells in CD4 + T-cells
[00523] [00523] Additionally, treatment of CD4 + T-cell with compound 139 significantly increased the frequency of HBV-specific IFN-γ + cells (2.5 times, p = 0.003) and HBV-specific GrB + cells (1.8 times, p = 0.045) compared to PBMCs treated with DMSO (Figure 2A and Table 8). The frequencies of CD4 + IFN-γ + T-cells between PBMCs treated with compound 139 and PBMCs treated with durvalumab were not statistically significant (2.5% versus 3.1% respectively; p = 0.2018). Compound 139 and durvalumab also increased the frequency of CD4 + GrB + T-cells to similar levels (4.7% versus 4.3% respectively, p = 0.07) (Figure 2B), compared to DMSO treatment (3, 5%) (Table 8).
[00524] [00524] Compound 139 significantly increased the frequencies of HBV-specific IFN-γ + cells in both CD4 + T-cells (2.5 times, p = 0.01) and CD8 + T-cells (2.5 times, p = 0.003). Compound 139 also increased the frequency of GrB + cells among HBV-specific CD8 + T-cells (1.2 times, p = 0.015) and HBV-specific CD4 + T-cells (1.8 times, p = 0.045). In addition, the ability of compound 139 to enhance, in vitro, the antiviral functions of HBV-specific CD4 + and CD8 + T-cells was comparable to those of durvalumab, of a commercialized anti-α-PD-L1 antibody. Taken together, these data indicate that compound 139 enhances, in vitro, the antiviral / effector functions of HBV-specific CD4 + and CD8 + T cells of patients with CHB. Biological Example 3: Pharmacological Evaluation in a Mouse Tumor Model
[00525] [00525] The compounds described here are molecular inhibitors
[00526] [00526] Compound 139 does not bind to murine PD-L1, preventing the use of traditional syngeneic murine tumor models to assess compound 139 activity in vivo. However, compound 139 blocks the interaction between mouse PD-1 and human PD-L1 as determined by a biochemical binding assay. Therefore, a mouse colorectal MC38 tumor model, which expresses human PD-L1, was used to evaluate the activity of compound 139 in vivo. An anti-α-PD-L1 antibody that is unable to bind to murine PD-L1 was included as a positive control.
[00527] [00527] At 10, 25, and 50 mg / kg of compound 139 or 10 mg / kg of anti-PD-L1 antibody, PD-L1 Target Occupation (OA)> 90% on tumor cells was observed for at least least 24 hours. This result translated into Tumor Growth Inhibition (ICT) from 32% to 38% for both compound 139 and anti-PD-L1 antibody in the indicated dose groups. In parallel, plasma concentrations of compound 139 were determined at the same time points used to determine intratumoral OA. At 10 mg / kg, plasma concentrations of compound 139 fell below the blood EC90 value for compound 139 but OA> 90% was maintained, indicating that compound 139 OA over the tumor extended beyond plasma exposure . In addition, there was no treatment-related effect on body weight, indicating that compound 139 was well tolerated at all doses throughout the entire study. Materials and Methods Test Articles
[00528] [00528] Compound 139 was synthesized at Gilead Sciences, Inc. (Foster City, CA, USA). Durvalumab: anti-α-PD-L1 antibody, and Isotype control antibody (human IgG1, hIgG1) were produced and purified at Gilead Sciences. In Vivo Formulation of Compound 139
[00529] [00529] The vehicle formulation for compound 139 was 10% ethanol, 40% PEG 300 and 50% DI water and was formulated in a single batch during the entire study. Compound 139 formulations were prepared weekly and stored under refrigerated conditions (4 ° C-8 ° C). Before dosing, the solution was warmed to room temperature while stirring. The solution was constantly stirred during the entire dosing process. Compound 139 was formulated as a 2 mg / ml and 5 mg / ml solution in the vehicle. Compound 139 powder was brought to room temperature before use, weighed and added to a suitable container. Appropriate volume of ethanol was dispensed into the container. Then, an appropriate volume of PEG-300 was added to the vessel while stirring. As soon as the powder was completely dissolved, an appropriate volume of water was added slowly while stirring. The powder was allowed to dissolve completely in the solution and the pH was adjusted to 3 using 1N NaOH. The solution was sterile filtered using a nylon syringe filter prior to administration. In Vivo Formulation of Durvalumab and Control Isotype Antibody
[00530] [00530] The isotype control antibody (hIgG1) contains the same mutation in the Fc domain as the durvalumab anti-α-PD-L1 antibody. Control isotype antibody and durvalumab stock solutions (20 mM Histidine-HCl pH 5.8, 9% Sucrose and 0.05% Tween-80) were diluted in PBS to 2 mg / mL. The dosage volume was 5 ml / kg. Animals
[00531] [00531] Female C57BL / 6 mice were purchased from Shanghai Lingchang Bio-Technology. The animals were between 8 and 10 weeks old when the tumors were inoculated. The mice were acclimated for 1 week before tumor inoculation. MC38 Colorectal Tumor Model Expressing Human PD-L1
[00532] [00532] To create a MC38 tumor cell line that expresses human PD-L1 (Crown Bioscience), inactivated (knockout) cells in murine PD-L1 were generated using the CRISPR-Cas9 system (Figure 3). Stable clones expressing human PD-L1 (expression driven by a cytomegalovirus promoter) were then generated, from the inactivated cells (knockout), by transfection by Lipofectamine ™ (Thermo Fisher Scientific). Cell Culture
[00533] [00533] MC38 tumor cells expressing human PD-L1 were cultured in DMEM medium (GE Healthcare) supplemented with 10% heat-inactivated fetal bovine serum (ExCell Biology) and 50 μg / mL of hygromycin B at 37ºC atmosphere of 5% CO2 in air. Tumor inoculation
[00534] [00534] Prior to inoculation, MC38 tumor cells expressing human PD-L1 were measured by trypan blue staining to assess viability. Cells with viability greater than 90% were used for inoculation. Each mouse was inoculated subcutaneously (SC) in the right rear flank with tumor cells (1 × 106 cells suspended in 100 μL of PBS for each mouse). After inoculation, the remaining cells were measured again for viability by trypan blue staining to confirm that viability did not decrease below 90%. Group Randomization
[00535] [00535] 108 mice were used in the study. All animals were randomly allocated to the study groups. Day 0 was
[00536] [00536] After inoculation of tumor cells, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any tumor growth effects, changes in behavior such as mobility, food and water consumption, body weight gain / loss (body weights were measured twice a week). Mortality and observed clinical signs were recorded for individual animals. Body weight was measured twice a week.
[00537] [00537] Tumor volumes were measured twice a week in two dimensions using a caliper, and the volume was expressed in mm3 using the formula: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L). Termination
[00538] [00538] Any animal with a tumor size exceeding 2,500 mm3 (or a group of mice with an average tumor size exceeding 2,500 mm3)
[00539] [00539] The tumors were collected from the mice, washed in PBS with extra tissues removed (ie, blood vessel, adipose tissue and
[00540] [00540] 1 × 106 Tumor cells were resuspended in 15 ml centrifuge tubes (Corning) with 200 μL of Staining Buffer (BD Biosciences) and 1 μg / mL of Mouse Fc Block ™ (“ Purified Rat α-Mouse CD16 / CD32 ”, BD Biosciences). The tubes were incubated for 15 minutes in the dark at 4 ° C. The antibody cocktail (Table 9) was added to each tube and subsequently incubated for 30 minutes in the dark at 4 ° C. 2 ml of ice-cold PBS was added and the tubes were centrifuged at 300 x g for 5 minutes. The washing step was performed twice. after the
[00541] [00541] In parallel to the evaluation of OA on tumor cells at predetermined time points, 100 μL of WB were collected into “K2EDTA Lavender” tubes (BD Biosciences), mixed by inversion and subjected to centrifugation. Plasma was transferred to tubes labeled microcentrifuge and the tubes were stored at -80ºC until analysis.
[00542] [00542] To an aliquot of 10 μL of each plasma sample with the exception of matrix blanks, 60 μL of 100 ng / mL of Carbutamide in acetonitrile (ACN) was added. The matrix blank samples received only 60 μL of acetonitrile. The precipitated proteins were removed by centrifugation and 50 μL of supernatant was transferred into a clean 96-well deep plate (Thermo Fisher Scientific). An aliquot of 50 μL of water was added to each sample. A 5 μL aliquot was injected into a “Sciex API-5500 LC / MS / MS” system
[00543] [00543] The OA of compound 139 or durvalumab anti-α-PD-L1 antibody, was calibrated using mice having tumors treated with either a control vehicle or isotype control antibody using the following equation: OA = [(Prommed Group IFM Control - Prommed MFI of the Sample) ÷ (Prommed MFI of the Control Group)] × 100 where: OA is the Target Occupation (that is,% of PD-L1 occupied); Sample Mean Promed MFI is the Mean Mean Fluorescence Intensity of tumors treated with either compound 139 or durvalumab anti-α-PD-L1 antibody (n = 3); and Prommed MFI of the Control Group is the Average Mean Fluorescence Intensity of the tumors treated with either the control vehicle or with the isotype control antibody (n = 3). Calculation of ICT by Compound 139 in MC38 Tumor Model Expressing Human PD-L1
[00544] [00544] ICT of groups with compound 139 or with durvalumab anti-α-PD-L1 antibody was calibrated using tumor volumes obtained from the groups either with control vehicle or with isotype control antibody on day 15 after dosing using the following equation: ICT = [(Promised Volume of Tumor in the Control Group - Promised Volume of Tumor in the Sample) ÷ (Promised Volume of Tumor in the Control Group)] × 100 where: ICT is% of Tumor Growth Inhibition; Control Group's Promised Tumor Volume is the
[00545] [00545] This example demonstrated that compound 139 can block the interaction between mouse PD-1 and human PD-L1 in a biochemical functional binding assay with a potency of <0.75 nM (Table 10). Therefore, an MC38 colorectal tumor model that expresses human PD-L1 was used to demonstrate the activity of compound 139 in vivo. Table 10. Activity of Compound 139 and Durvalumab Against Interaction of Mouse PD-1 / Human PD-L1 Linkage Blockage of PD-1 and PD-L1 (CI50) Mouse PD-1 / Human PD (nM) Mouse (μM) Human L1 (nM) Compound 139 <0.15a 61 <0.75a durvalumab <0.15a> 1 <0.75a anti-α-PD-L1 antibody a Values were rounded to the lowest theoretical value of the test.
[00546] [00546] The aim of this study was to evaluate the relationship between HR and OA of compound 139, as well as changes in body weight and tumor volume. MC38 tumor cells expressing human PD-L1 were implanted sSC in the right flank of female C57BL / 6 mice. As soon as the tumors reached an average volume of about 50 mm3, the mice were randomized and administered with treatment as an IP injection.
[00547] [00547] The plasma concentration of compound 139 was determined at 1, 6 and 24 hours after dosing on day 6 when the tumors were ~ 250 mm3 in size (Table 12). In parallel, OA was measured at those same time points and assessed by flow cytometry, measured
[00548] [00548] With OA greater than 90% observed, comparable ICT between 31.8% and 37.9% was obtained at 10, 25, and 50 mg / kg of compound 139 (Tables 13 and 14), which was similar to ICT of 37.3% achieved with the anti-α-PD-L1 antibody dosed at 10 mg / kg twice a week (Figure 5). Compound 139 was well tolerated at all doses throughout the study in effect on body weights. Table 11. HR and OA in Experimental Groups with Compound 139 Instances of Time After Last Dose on Day 6 (Nd) Test Items Schedule 1h 6h 24h Human IgG1 isotype BIWa (days 1, 4, 6) 3 3 3 BIDb vehicle * 6 (days 1 - 6) 3 3 3 50 mg / kg (compound 139) QDc * 6 (days 1 - 6) 3 3 3 25 mg / kg (compound 139) IDB * 6 (days 1 - 6) 3 3 3 10 mg / kg (compound 139) QD * 6 (days 1 - 6) 3 3 3 1 mg / kg (compound 139) QD * 6 (days 1 - 6) 3 3 3 anti-α-PD-L1 antibody ( durvalumab) BIW (days 1, 4, 6) 3 3 3 to BIW, twice a week. b IDB, twice a day. c QD, once a day. d N, Number of animals.
[00549] [00549] The in vivo activity of compound 139 was evaluated in a mouse colorectal model MC38, which expresses human PD-L1. Intraperitoneal administration of 10 (QD), 25 (BID), and 50 mg / kg (QD) of compound 139 showed OA greater than 90% over tumors for at least 24 hours after dosing and resulted in antitumor activity comparable with the antibody anti-PD-L1.

权利要求:
Claims (35)
[1]
1. Compound, characterized by the fact that it is of Formula (I): (I) where: each n is independently 0, 1, 2, 3 or 4; each Z1 is independently halo, -ORa, -NO2, -CN, -NRaRb, -N3, -S (O) 2Ra, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -O2 alkynyl - C1-6 alkyl, -O-C1-6 haloalkyl, -C3-8 cycloalkyl or -C1-6 alkyl- C3-8 cycloalkyl; each alkyl, alkenyl, alkynyl, and cycloalkyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, -N3, - ORa, halo, and cyano; Q is aryl, heteroaryl or heterocyclyl, with each aryl, heteroaryl and heterocyclyl group optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, oxo, - ORa, -SRa, N3, NO2, -CN, -NR1R2 , -S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, - NRaC (O) Ra, -C (O) Ra, -C (O) ORa, -C (O) NRaRb, -NRaC (O) ORa, - NRaC (O) NR1R2, -OC (O) NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, - C1-6alkyl, -AlkenylC2-6, - C2-6 alkynyl, -O-C1-6 alkyl, -C3-8 cycloalkyl, -C1-6 alkyl-C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and RN; the alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyan, -NRaRb , -C (O) Ra, -C (O) ORa, -O-C1-6-alkyl-CN, - C (O) NRaRb, NRaC (O) Ra, -NRaC (O) ORa, -S (O) 2Ra , -NRaS (O) 2Rb, -
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S (O) 2NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb and -C3-8 cycloalkyl; and the heteroaryl or heterocyclyl group may be oxidized to a nitrogen atom to form an N-oxide or oxidized to a sulfur atom to form a sulfoxide or sulfone; m is 0, 1 or 2; each Z3 is independently halo, oxo, -ORa, SRa, N3, NO2, - CN, -NR1R2, -S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, -NRaC (O) Ra , -C (O) Ra, - C (O) ORa, -C (O) NRaRb, -NRaC (O) ORa, -NRaC (O) NR1R2, -OC (O) NRaRb, - NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -O-C1-6 alkyl, -CycloalkylC3-8, -C1-6 alkyl-cycloalkylC3-8, aryl, heteroaryl , heterocyclyl and RN; the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyano, -NRaRb, - C (O) Ra, -C (O) ORa, -O-C1-6-alkyl-CN, - C (O) NRaRb, NRaC (O) Ra, -NRaC (O) ORa, -S (O) 2Ra, - NRaS (O) 2Rb, - S (O) 2NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb and -C3-8 cycloalkyl; each RN is independently -C1-6alkyl-NR1R2, -O-C1-6alkyl-NR1R2, -C1-6alkyl-O-C1-6alkyl, -NRa-C1-6alkyl-NR1R2, -C1-6alkyl (O ) NR1R2, -O-C1-6 alkyl-C (O) NR1R2, -O-C1-6 alkyl-C (O) OR1, -S-C1-6 alkyl-NR1R2, -C1-6 alkyl-ORa, or L1 V L2 A ; where: L1 is independently a bond, O, NRa, S, S (O), or S (O) 2; V is independently selected from the group consisting of a bond, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; the alkyl, alkenyl or alkynyl group being optionally substituted with -ORa, halo, cyano, NRaRb and -C 3-8 cycloalkyl;
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L2 is independently a bond, O, NRa, S, S (O), or S (O) 2; ring A is independently cycloalkyl, aryl, heteroaryl or heterocyclyl; the cycloalkyl, aryl, heteroaryl, or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, - ORa, halo, cyano, -C1-6alkyl, -haloalkylC1-6, -C2-6 alkenyl, -C2-6 alkynyl, -O-haloC1-6 alkyl, NRaRb, -C (O) Ra, -C (O) ORa, -O-C1-6 alkyl-CN, - C (O) NRaRb, - NRaC (O) Ra, -NRaC (O) ORa, -NRaC (O) ORa, -C (O) N (Ra) ORb, - S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Rb, -NRaS (O) 2NRaRb, - C (O) NRaS (O) 2NRaRb, C3-8 cycloalkyl and C1-6 alkyl-C3-8 cycloalkyl; the alkyl, alkenyl or alkynyl group being optionally substituted with -ORa, halo, cyano, NRaRb and -C 3-8 cycloalkyl; RE and RW are each independently -NR1R2, -C1-6alkyl- NR1R2, -O-C1-6alkyl-NR1R2, -C1-6alkyl-O-C1-6alkyl-NR1R2, -NRa-C1-6alkyl-NR1R2, - C1-6alkyl-N + R1R2R3, -S-C1-6alkyl-NR1R2, - C (O) NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - (CH2) uNRaS (O) 2NRaRb , - S (O) 2NRa-C1-6-NR1R2, -NRaS (O) 2-C1-6-NR1R2, - (CH2) uC (O) NRaS (O) 2NRaRb, - (CH2) uN + R1R2O-, - (CH2) uP + RbRcRd, - (CH2) uP + RcRdO-, - (CH2) uP + O [NRaRb] [NRcRd], - (CH2) uNRcP (O) (ORc) 2, - (CH2) uCH2OP ( O) (ORc) (ORd), - (CH2) uOP (O) (ORc) (ORd), - (CH2) uOP (O) NRaRb) (ORa), or
; where: V2 is independently a bond, O, NRa, S, S (O), S (O) 2, C (O) NRa, NRaC (O), S (O) 2NR1, or NRaS (O) 2; L3 is independently a bond, O, NRa, S, S (O), S (O) 2, C (O) NRa, NRaC (O), S (O) 2NR1, or NRaS (O) 2;
4/27 ring B is cycloalkyl, aryl, heteroaryl or heterocyclyl; T is independently H, -ORa, (CH2) qNR1R2, (CH2) qNRaC (O) Re or (CH2) qC (O) Re; p is independently 0, 1, 2, 3, 4, or 5; q is independently 0, 1, 2, 3, 4, or 5; u is 0, 1, 2, 3 or 4; z is 0, 1, 2 or 3; and the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group of RE and RW is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NRaRb, halo, cyano, oxo, -ORa, -C1-6alkyl, -haloalkylC1 -6, -C1-6 cyanoalkyl, -C1-6alkyl-NRaRb, -C1-6alkyl-OH, -C3-8 cycloalkyl and -C1-3alkylC3-8 cycloalkyl; provided that at least one of V2, L3, ring B and T contains a nitrogen atom; each R1 is independently selected from the group consisting of H, -C1-8 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-aryl, -C1-6alkyl-heteroaryl , - C1-6 alkyl-heterocyclyl, -C1-6 alkyl (O) ORa, -C2-6-C alkenyl (O) ORa, - S (O) 2Ra, -S (O) 2ORa, -S (O) 2NRaRb , -C (O) NRaS (O) 2Ra, and C1-6alkylC3-8-cycloalkyl; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, -NO2, halo, C1-6alkyl, -C1-6alkyl-ORa , -C1-6-cyanoalkyl, -C1-6-haloalkyl, C3-8-cycloalkyl, heteroaryl, heterocyclyl, -C1-3-cycloalkylC3-8, - C (O) Ra, -C1-6-alkyl (O) Ra, -C (O ) ORa, -C1-6-C (O) ORa, -NRaRb, - OC (O) NRaRb, -NRaC (O) ORb, -NRaC (O) Rb, -C1-6-NRaRb, -C (O) NRaRb, -C1-6-alkyl (C) NRaRb, -S (O) 2Ra, -S (O) 2ORa, -C1-6-alkyl (S) 2Ra, -
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S (O) 2NRaRb, -C1-6alkyl-S (O) 2NRaRb, -C (O) NRaS (O) 2Rb, -NRaC (O) NRb, --C1-6-alkyl (C) NRaS (O) 2Rb, -NRaC (O) Rb, and -C1-6alkyl-NRaC (O) Rb; each R2 is independently selected from the group consisting of H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-alkyl, -C1-6-heteroaryl , - C1-6-alkyl-heterocyclyl, -C2-6-alkyl-ORa, -C1-6-alkyl-C (O) ORa, and - C2-6-C-alkyl (O) ORa; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl-ORa, -cyanoalkylC1 -6, -C1-6-haloalkyl, -C3-8-cycloalkyl, -C1-3-alkyl-C3-8-cycloalkyl, -C (O) Ra, -C1-6-alkyl-O (O) Ra, - C (O) ORa, -C1- alkyl 6-C (O) ORa, -NRaRb, -C1-6alkyl-NRaRb, -C (O) NRaRb, C1-6-alkyl (O) NRaRb, -S (O) 2Ra, -C1-6alkyl (O ) 2Ra, -S (O) 2NRaRb, - C1-6alkyl-S (O) 2NRaRb, -C (O) NRaS (O) 2Rb and -NRaC (O) Rb; or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, -C1- alkyl 6, -C3-8 cycloalkyl, -C2-6 alkenyl, --C2-6 alkynyl, aryl, heteroaryl, heterocyclyl, -ORa, -CN, halo, -C (O) ORa, --C1-6 cyanoalkyl, -C1-6-alkyl-ORa, -haloC1-6alkyl, -C1-3alkyl-C3-8 cycloalkyl, -C (O) Ra, C1-6alkyl (C) Ra, -C1-6alkyl (O) ORa, -NRaRb, -C1-6alkyl NRaRb, -C (O) NRaRb, -NRaC (O) ORb, -NRaC (O) NRaRb, - NRaS (O) 2NRaRb, -NRaS (O) 2Rb, -C1-6-alkyl (O) NRaRb, -S (O) 2Ra, -C1-6 alkyl to 6-S (O) 2R, -S (O) 2NRaRb, and C1-6-S (O) 2NRaRb alkyl; each R3 is independently H, -C1-6 alkyl, -C2-6 alkenyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6alkyl, -C1-6alkyl, heteroaryl, -C1-6alkyl, -Heterocyclyl, -C2alkyl -6-ORa, -C1-6-alkyl-C (O) ORa,
6/27 or -C2-6-C-alkenyl (O) ORa; each Ra is independently selected from the group consisting of H, -C1-6alkyl, -C1-6haloalkyl, -C3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3alkylC3-8 -C1-6alkyl, -C1-6alkyl -6-heteroaryl, and -C1-6alkyl-heterocyclyl; each Rb is independently selected from the group consisting of H, -C1-6alkyl, -C1-6haloalkyl, -C3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3alkylC3-8, -C1-6alkyl, -C1-6alkyl -6-heteroaryl, and -C1-6alkyl-heterocyclyl; or Ra and Rb can combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S; the ring being optionally substituted with 1 to 4 groups independently selected from the group consisting of –ORf, -CN, halo, -C1-6-alkyl-ORf, - cyanoalkylC1-6, -haloalkylC1-6, -cycloalkylC3-8, -alkylC1 -3- C3-8 cycloalkyl, -C (O) Rf, -C1-6alkyl (O) Rf, -C (O) ORf, -C1-6alkyl- C (O) ORf, -NRfRg, -C1-6alkyl -NRfRg, -C (O) NRfRg, C1-6alkyl (O) NRfRg, - S (O) 2Rf, -C1-6alkyl-S (O) 2Rf, -S (O) 2NRfRg, -C1-6alkyl- S (O) 2NRfRg, - C (O) NRfS (O) 2Rg and –NRfC (O) Rg; each Rc is independently selected from the group consisting of H, OH, -C1-6alkyl, -C3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3alkylC3-8alkyl, -C1-6alkyl, -C1-6alkyl- heteroaryl, and -C1-6alkyl-heterocyclyl; each Rd is independently selected from the group consisting of H, -C1-6 alkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8-cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; each Re is independently selected from the group consisting of H, -C1-6 alkyl, -O-C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -O-cycloalkylC3-8, -O-aryl, -O-heteroaryl , -O-
7/27 heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6 alkyl-aryl, -C1-6 alkyl-heteroaryl, -NRfRg, -C1-6 alkyl-NRfRg, -C (O) NRfRg, -C1-6 alkyl C (O) NRfRg, -NHS (O) 2Rf, -C1-6alkyl (S) 2Rf, and -C1-6-alkyl (S) 2NRfRg; each Rf is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and - C1-6alkyl-heterocyclyl; each Rg is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8-cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[2]
2. Compound, characterized by the fact that it is of Formula (I): (I) where: each n is independently 0, 1, 2, 3 or 4; each Z1 is independently halo, -ORa, -NO2, -CN, -NRaRb, -N3, -S (O) 2Ra, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -O2 alkynyl - C1-6 alkyl, -O-C1-6 haloalkyl, monocyclic-C3-8 cycloalkyl or -C1-6-cycloalkylC3-8 cycloalkyl; each alkyl, alkenyl, alkynyl, and cycloalkyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, -N3, - ORa, halo, and cyano; Q is monocyclic aryl, monocyclic heteroaryl or
8/27 monocyclic heterocyclyl optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, oxo, -ORa, N3, NO2, -CN, -NR1R2, -S (O) 2Ra, -S (O) 2NRaRb, - NRaS (O) 2Ra, -NRaC (O) Ra, - C (O) Ra, -C (O) ORa, -C (O) NRaRb, -NRaC (O) ORa, -NRaC (O) NR1R2, - OC (O) NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -O-monocyclic alkyl -6, -CyloalkylC3-8 monocyclic , - monocyclic C1-6 alkyl-C3-8 cycloalkyl, monocyclic aryl, and RN; the monocyclic alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, or monocyclic aryl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyan, -NRaRb, - C (O) Ra, -C (O) ORa, -O-C1-6-alkyl-CN, - C (O) NRaRb, NRaC (O) Ra, -NRaC (O) ORa, -S (O) 2Ra, - NRaS (O) 2Rb, - S (O) 2NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb and monocyclic -cycloalkylC3-8; and the monocyclic heteroaryl or monocyclic heterocyclyl group may be oxidized to a nitrogen atom to form an N-oxide or oxidized to a sulfur atom to form a sulfoxide or sulfone; m is 0, 1 or 2; each Z3 is independently halo, oxo, -ORa, N3, NO2, -CN, - NR1R2, -S (O) 2Ra, -S (O) 2NRaRb, -NRaS (O) 2Ra, -NRaC (O) Ra, - C (O) Ra, - C (O) ORa, -C (O) NRaRb, -NRaC (O) ORa, -NRaC (O) NR1R2, -OC (O) NRaRb, - NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -O-C1-6 alkyl,-monocyclic-cycloalkylC3-8, monocyclic -C1-6 alkyl-cycloalkyl, monocyclic aryl, and RN; the monocyclic alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, or monocyclic aryl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyan, -NRaRb, - C (O) Ra, -C (O) ORa, -O-C1-6-alkyl-CN, - C (O) NRaRb, NRaC (O) Ra, -NRaC (O) ORa, -S (O) 2Ra, - NRaS (O) 2Rb, -
9/27
S (O) 2NRaRb, -NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb and monocyclic-cycloalkylC3-8; each RN is independently -C1-6alkyl-NR1R2, -O-C1-6alkyl-NR1R2, -C1-6alkyl-O-C1-6alkyl, -NRa-C1-6alkyl-NR1R2, -C1-6alkyl (O ) NR1R2, -O-C1-6 alkyl-C (O) NR1R2, -O-C1-6 alkyl-C (O) OR1, -S-C1-6 alkyl-NR1R2, -C1-6 alkyl-ORa, or L1 V L2 A ; where: L1 is independently a bond, O, NRa, S, S (O), or S (O) 2; V is independently selected from the group consisting of a bond, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; the alkyl, alkenyl or alkynyl group being optionally substituted with monocyclic -ORa, halo, cyano, NRaRb and -C3-8 cycloalkyl; L2 is independently a bond, O, NRa, S, S (O), or S (O) 2; ring A is independently monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl; and the monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, N3, -ORa, halo, cyan, -C1-6alkyl, - haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -O-haloalkylC1-6, NRaRb, -C (O) Ra, - C (O) ORa, -O-alkylC1-6-CN, -C (O ) NRaRb, -NRaC (O) Ra, -NRaC (O) ORa, - NRaC (O) ORa, -C (O) N (Ra) ORb, -S (O) 2Ra, -S (O) 2NRaRb, - NRaS (O) 2Rb, - NRaS (O) 2NRaRb, -C (O) NRaS (O) 2NRaRb, monocyclic C3-8 cycloalkyl and monocyclic C1-6-cycloalkylC3-8 alkyl; the alkyl, alkenyl or alkynyl group being
10/27 optionally substituted with monocyclic -ORa, halo, cyano, NRaRb and -C3-8 cycloalkyl; RE and RW are each independently -NR1R2, -C1-6alkyl- NR1R2, -O-C1-6alkyl-NR1R2, -C1-6alkyl-C1-6-NR1R2alkyl, -NRa-C1-6-NR1R2alkyl, -C1-alkyl 6-N + R1R2R3, -S-C1-6-alkyl1R2, - C (O) NR1R2, -S (O) 2Ra, - (CH2) uS (O) 2NR1R2, - (CH2) uNRaS (O) 2NRaRb, - S (O) 2NRa-C1-6 alkyl-NR1R2, -NRaS (O) 2-C1-6 alkyl-NR1R2, - (CH2) uC (O) NRaS (O) 2NRaRb, - (CH2) uN + R1R2O-, - ( CH2) uP + RbRcRd, - (CH2) uP + RcRdO-, - (CH2) uP + O [NRaRb] [NRcRd], - (CH2) uNRcP (O) (ORc) 2, - (CH2) uCH2OP (O) (ORc) (ORd), - (CH2) uOP (O) (ORc) (ORd), - (CH2) uOP (O) NRaRb) (ORa), or
; where: V2 is independently a bond, O, NRa, S, S (O), S (O) 2, C (O) NRa, NRaC (O), S (O) 2NR1, or NRaS (O) 2; L3 is independently a bond, O, NRa, S, S (O), S (O) 2, C (O) NRa, NRaC (O), S (O) 2NR1, or NRaS (O) 2; ring B is independently monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl or spirocyclic heterocyclyl; T is independently H, -ORa, (CH2) qNR1R2, (CH2) qNRaC (O) Re or (CH2) qC (O) Re; p is independently 0, 1, 2, 3, 4, or 5; q is independently 0, 1, 2, 3, 4, or 5; u is 0, 1, 2, 3 or 4; z is 0, 1, 2 or 3; and the alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl or spirocyclic heterocyclyl is optionally substituted with 1 to 3
11/27 substituents independently selected from the group consisting of NRaRb, halo, cyano, oxo, -ORa, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6-cyanoalkyl, -C1-6-alkyl-NRaRb, -C1-6-OH, monocyclic C3-8 cycloalkyl and monocyclic C1-3 alkyl-C3-8 cycloalkyl; provided that at least one of V2, L3, ring B and T contains a nitrogen atom; each R1 is independently selected from the group consisting of monocyclic H, -C1-8 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, -C1-6-monocyclic aryl, - monocyclic C1-6 alkyl-heteroaryl, monocyclic C1-6 alkyl-heterocyclyl, -C1-6-C alkyl (O) ORa, - C2-6-C alkenyl (O) ORa, -S (O) 2Ra, -S (O) 2NRaRb , -C (O) NRaS (O) 2Ra, and monocyclic C1-6 alkyl-C3-8 cycloalkyl; each alkyl, alkenyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl ORa, -C1-6-cyanoalkyl, -C1-6-haloalkyl, monocyclic-C3-8 cycloalkyl, -C1-3-cycloalkyl-C3-8 monocyclic, - C (O) Ra, -C1-6-C (O) Ra, -C (O) ORa, -C1-6-C (O) ORa, -NRaRb, - OC (O) NRaRb, NRaC (O) ORb, -C1-6 alkyl-NRaRb, -C (O) NRaRb, -C1-6 alkyl- ( O) NRaRb, -S (O) 2Ra, -C1-6alkyl-S (O) 2Ra, -S (O) 2NRaRb, -C1-6alkyl- S (O) 2NRaRb, -C (O) NRaS (O) 2Rb , -C1-6alkyl-C (O) NRaS (O) 2Rb, -NRaC (O) Rb, and -C1-6alkyl-NRaC (O) Rb; each R2 is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, -C1-6-monocyclic aryl, - monocyclic C1-6 alkyl-heteroaryl, -C1-6 monocyclic heterocyclyl, -C2-6 alkyl-ORa, -
12/27 C1-6alkyl-C (O) ORa, and -C2-6alkylene (O) ORa; each alkyl, alkenyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl ORa, -C1-6-cyanoalkyl, -C1-6-haloalkyl, - monocyclic -C3-8 cycloalkyl, monocyclic -C1-3-cycloalkyl, -C (O) Ra, -C1-6-C (O) Ra, -C (O) ) ORa, -C1-6-C (O) alkyl ORa, -NRaRb, -C1-6-NRaRb alkyl, -C (O) NRaRb, C1-6-C alkyl (O) NRaRb, -S (O) 2Ra, --C1 alkyl -6-S (O) 2Ra, -S (O) 2NRaRb, -C1-6alkyl (O) 2NRaRb, - C (O) NRaS (O) 2Rb and -NRaC (O) Rb; or R1 and R2, when attached to the same atom, can combine with the atom to which they are attached to form a monocyclic heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of monocyclic oxo, -C1-6 alkyl, -C3-8 cycloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -ORa, -C (O) ORa, -cyanoalkylC1-6, -C1-6alkyl-ORa, -C1-6haloalkyl, -C1-3alkylC3-8 cycloalkyl monocyclic, -C (O) Ra, C1-6-C (O) alkyl Ra, -C1-6-alkyl (O) ORa, -NRaRb, -C1-6alkyl- NRaRb, -C (O) NRaRb, -C1-6alkyl (O) NRaRb, -S (O) 2Ra, -C1-6alkyl-S (O) 2Ra, -S (O (O) ) 2NRaRb, and C1-6-S-alkyl (O) 2NRaRb; each R3 is independently H, -C1-6 alkyl, -C2-6 alkenyl, - monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, -C1-6-aryl, -C1-6alkyl-monocyclic-alkyl, 1-6 -monocyclic heterocyclyl, -C2-6-alkyl-ORa, -C1-6-alkyl (O) ORa, or -C2-6-C-alkenyl (O) ORa; each Ra is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl
13/27 monocyclic, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic-C1-3 alkyl- C3-8 cycloalkyl, monocyclic-alkyl C1-6-aryl, monocyclic-alkylC1-6-monocyclic heteroaryl, and monocyclic-heteroaryl; each Rb is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, monocyclic -C1-3 alkyl-, monocyclic -C1-6 alkyl, monocyclic-alkyl, monocyclic C 1-6 alkyl-heteroaryl, and monocyclic C 1-6 alkyl-heterocyclyl; or Ra and Rb, when attached to the same atom, can combine together to form a monocyclic ring consisting of 3-8 ring atoms that are C, N, O, or S; the ring being optionally substituted with 1 to 4 groups independently selected from the group consisting of –ORf, -CN, halo, -C1-6-alkyl-ORf, -cyanoalkylC1-6, - haloC1-6 alkyl, -cycloalkylC3-8 monocyclic, - monocyclic C1-3alkyl-C3-8alkyl, -C (O) Rf, -C1-6alkyl (O) Rf, -C (O) ORf, -C1-6alkyl-C (O) ORf, -NRfRg, -C1alkyl -6-NRfRg, -C (O) NRfRg, C1-6-alkyl (O) NRfRg, -S (O) 2Rf, --C1-6-S-alkyl (O) 2Rf, -S (O) 2NRfRg, -C1- alkyl 6-S (O) 2NRfRg, - C (O) NRfS (O) 2Rg and –NRfC (O) Rg; each Rc is independently selected from the group consisting of monocyclic H, OH, -C1-6 alkyl, -C3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, -C1-3alkylcyclic-cycloalkyl -C1-6-monocyclic-alkyl , monocyclic-C 1-6 alkyl-heteroaryl, and monocyclic-C 1-6 alkyl heterocyclyl; and each Rd is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C3-C8-cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, monocyclic -C1-3alkyl -C1-6-cycloalkyl, -C1-6-alkyl, monocyclic-alkyl -C1-6 alkyl-monocyclic heteroaryl, and -C1-6 alkyl-monocyclic heterocyclyl; each Re is independently selected from the group
14/27 consisting of monocyclic H, -C1-6 alkyl, -O-C1-6 alkyl, -C3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, -O- monocyclic C3-8 cycloalkyl, -O-monocyclic aryl, -O -monocyclic heteroaryl,-monocyclic -O-heterocyclyl, -C1-3 alkyl-C3-8 monocyclic, -C1-6 alkyl-monocyclic aryl, -NRfRg, -Cyl6-heteroaryl, -NRfRg, -C6- ) NRfRg, -C1-6- alkyl (C) NRfRg, -NHS (O) 2Rf, -C1-6alkyl-S (O) 2Rf, and -C1-6-alkyl (S) 2NRfRg; each Rf is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, monocyclic -C1-3-cycloalkyl, monocyclic -3-cycloalkyl, -C1-6 alkyl - monocyclic aryl, monocyclic C1-6 alkyl-heteroaryl, and monocyclic C1-6 alkyl-heterocyclyl; each Rg is independently selected from the group consisting of monocyclic H, -C1-6 alkyl, -C3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocycly, monocyclic -C1-3 alkyl-, monocyclic -C1-6 alkyl, monocyclic-alkyl, monocyclic C 1-6 alkyl-heteroaryl, and monocyclic C 1-6 alkyl-heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[3]
3. A compound according to claim 1, characterized by the fact that it is represented by Formula (Ia): (Ia) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: each X is independently CH, CZ3 or N; each m is independently 0, 1 or 2; and
15/27 Z1, Z3, RE, RW and n are as defined in claim 1.
[4]
4. Compound according to claim 1, characterized by the fact that it is represented by Formula (Ib): (Ib) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined in claim 1.
[5]
5. Compound according to claim 1, characterized by the fact that it is represented by Formula (Ic): (Ic) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined in claim 1.
[6]
6. Compound according to claim 1, characterized by the fact that it is represented by Formula (Id): (Id) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, being that:
16/27 each m is independently 0, 1 or 2; and Z1, Z3, RE, RW and n are as defined in claim 1.
[7]
7. Compound according to claim 1, characterized by the fact that it is represented by Formula (II): (II) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: Z1, Z3 , RE and RW are as defined in claim 1.
[8]
8. Compound, characterized by the fact that it is of Formula (III): (III) where: each X is independently CH, CZ3 or N; each Z1 is independently halo or -C1-6alkyl; each n is independently 0, 1, 2, 3 or 4; each Z3 is independently halo or -O-C1-6alkyl; each m is independently 0, 1 or 2; each R1 is independently selected from the group consisting of H, -C1-8 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-aryl, -C1-6alkyl-heteroaryl , - C1-6 alkyl-heterocyclyl, -C1-6 alkyl (O) ORa, -C2-6-C alkenyl (O) ORa, - S (O) 2Ra, -S (O) 2NRaRb, -C (O) NRaS (O) 2Ra, and C1-6alkyl-C3-8-cycloalkyl; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo,
17 / 27C1-6alkyl, -C1-6alkyl-ORa, -C1-6cyanoalkyl, -C1-6haloalkyl, C3-8 cycloalkyl, -C1-3alkylC3-8-cycloalkyl, -C (O) Ra, -C1-6alkyl-C (O) Ra, - C (O) ORa, -C1-6alkyl-O (O) ORa, -NRaRb, -OC (O) NRaRb, NRaC (O) ORb, --C1-6-alkyl-NRaRb, -C (O ) NRaRb, -C1-6-alkyl (C) NRaRb, -S (O) 2Ra, --C1-6-alkyl (O) 2Ra, -S (O) 2NRaRb, -C1-6-alkyl (S) 2NRaRb, - C (O) NRaS (O) 2Rb, -C1-6alkyl (C) NRaS (O) 2Rb, -NRaC (O) Rb, and -C1-6alkyl- NRaC (O) Rb; each R2 is independently selected from the group consisting of H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-alkyl, -C1-6-heteroaryl , - C1-6-alkyl-heterocyclyl, -C2-6-alkyl-ORa, -C1-6-alkyl-C (O) ORa, and - C2-6-C-alkyl (O) ORa; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl-ORa, -cyanoalkylC1 -6, -C1-6-haloalkyl, -C3-8-cycloalkyl, -C1-3-alkyl-C3-8-cycloalkyl, -C (O) Ra, -C1-6-alkyl-O (O) Ra, - C (O) ORa, -C1- alkyl 6-C (O) ORa, -NRaRb, -C1-6alkyl-NRaRb, -C (O) NRaRb, C1-6-alkyl (O) NRaRb, -S (O) 2Ra, -C1-6alkyl (O ) 2Ra, -S (O) 2NRaRb, - C1-6alkyl-S (O) 2NRaRb, -C (O) NRaS (O) 2Rb and -NRaC (O) Rb; or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, -C1- alkyl 6, -C3-8cycloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -ORa, -C (O) ORa, -C1-6 cyanoalkyl, -C1-6alkyl-ORa, --C1-6 haloalkyl, -C1-3alkylalkylC3 -8, -C (O) Ra, C1-6 alkyl-C (O) Ra, - C1-6 alkyl-C (O) ORa, -NRaRb, -C1-6 alkyl-NRaRb, -C (O) NRaRb, -Calkyl -6- C (O) NRaRb, -S (O) 2Ra, -C1-6alkyl-O (2) 2Ra, -S (O) 2NRaRb, and C1-6alkyl-
18/27
S (O) 2NRaRb; R5 is independently selected from the group consisting of NRaRb, halo, cyano, -ORa, -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 cyanoalkyl, -C1-6-NRaRb alkyl, -C1-6-OH, -CyloalkylC3-8 and -C1-3alkyl- C3-8 cycloalkyl; each Ra is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; each Rb is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8-cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; or Ra and Rb can combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S; the ring being optionally substituted with 1 to 4 groups independently selected from the group consisting of –ORf, -CN, halo, -C1-6-alkyl-ORf, - cyanoalkylC1-6, -haloalkylC1-6, -cycloalkylC3-8, -alkylC1 -3- C3-8 cycloalkyl, -C (O) Rf, -C1-6alkyl (O) Rf, -C (O) ORf, -C1-6alkyl- C (O) ORf, -NRfRg, -C1-6alkyl -NRfRg, -C (O) NRfRg, C1-6alkyl (O) NRfRg, - S (O) 2Rf, -C1-6alkyl-S (O) 2Rf, -S (O) 2NRfRg, -C1-6alkyl- S (O) 2NRfRg, - C (O) NRfS (O) 2Rg and –NRfC (O) Rg; each Rf is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and - C1-6alkyl-heterocyclyl; each Rg is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl -C3-8 cycloalkyl, -C1-6 alkyl, -C1-6 alkyl-
19/27 heteroaryl, and -C1-6alkyl-heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[9]
9. Compound, characterized by the fact that it is of Formula (IIIa): (IIIa) where: each X is independently CH, CZ3 or N; each Z1 is independently halo or -C1-6alkyl; each Z3 is independently halo or -O-C1-6alkyl; each R1 is independently selected from the group consisting of H, -C1-8 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-aryl, -C1-6alkyl-heteroaryl , - C1-6 alkyl-heterocyclyl, -C1-6 alkyl (O) ORa, -C2-6-C alkenyl (O) ORa, - S (O) 2Ra, -S (O) 2NRaRb, -C (O) NRaS (O) 2Ra, and C1-6alkyl-C3-8-cycloalkyl; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl-ORa, -cyanoalkylC1 -6, -C1-6-haloalkyl, C3-8-cycloalkyl, -C1-3-alkyl-C3-8-cycloalkyl, -C (O) Ra, -C1-6-alkyl (O) Ra, - C (O) ORa, -C1-6alkyl -C (O) ORa, -NRaRb, -OC (O) NRaRb, NRaC (O) ORb, - C1-6alkyl-NRaRb, -C (O) NRaRb, -C1-6alkyl (O) NRaRb, -S (O) 2Ra, - C1-6alkyl (O) 2Ra, -S (O) 2NRaRb, -C1-6alkyl (S) 2NRaRb, - C (O) NRaS (O) 2Rb, -C1-6alkyl C (O) NRaS (O) 2Rb, -NRaC (O) Rb, and -C1-6alkyl- NRaC (O) Rb; each R2 is independently selected from the group consisting of H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-6-alkyl, -C1-6-heteroaryl , -
20 / 27C1-6alkyl-heterocyclyl, -C2-6alkyl-ORa, -C1-6alkyl-C (O) ORa, and -C2-6-C-O (O) ORaalkenyl; each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group being optionally substituted with 1 to 4 groups independently selected from the group consisting of -ORa, -CN, halo, C1-6alkyl, -C1-6alkyl-ORa, -cyanoalkylC1 -6, -C1-6-haloalkyl, -C3-8-cycloalkyl, -C1-3-alkyl-C3-8-cycloalkyl, -C (O) Ra, -C1-6-alkyl-O (O) Ra, - C (O) ORa, -C1- alkyl 6-C (O) ORa, -NRaRb, -C1-6alkyl-NRaRb, -C (O) NRaRb, C1-6-alkyl (O) NRaRb, -S (O) 2Ra, -C1-6alkyl (O ) 2Ra, -S (O) 2NRaRb, - C1-6alkyl-S (O) 2NRaRb, -C (O) NRaS (O) 2Rb and -NRaC (O) Rb; or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, -C1- alkyl 6, -C3-8cycloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, -ORa, -C (O) ORa, -C1-6 cyanoalkyl, -C1-6alkyl-ORa, --C1-6 haloalkyl, -C1-3alkylalkylC3 -8, -C (O) Ra, C1-6 alkyl-C (O) Ra, - C1-6 alkyl-C (O) ORa, -NRaRb, -C1-6 alkyl-NRaRb, -C (O) NRaRb, -Calkyl -6- C (O) NRaRb, -S (O) 2Ra, -C1-6alkyl (O) 2Ra, -S (O) 2NRaRb, and C1-6- S (O) 2NRaRb alkyl; each Ra is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; each Rb is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8-cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; or Ra and Rb can combine together to form a ring
21/27 consisting of 3-8 ring atoms that are C, N, O, or S; the ring being optionally substituted with 1 to 4 groups independently selected from the group consisting of –ORf, -CN, halo, -C1-6-alkyl-ORf, - cyanoalkylC1-6, -haloalkylC1-6, -cycloalkylC3-8, -alkylC1 -3- C3-8 cycloalkyl, -C (O) Rf, -C1-6alkyl (O) Rf, -C (O) ORf, -C1-6alkyl- C (O) ORf, -NRfRg, -C1-6alkyl -NRfRg, -C (O) NRfRg, C1-6alkyl (O) NRfRg, - S (O) 2Rf, -C1-6alkyl-S (O) 2Rf, -S (O) 2NRfRg, -C1-6alkyl- S (O) 2NRfRg, - C (O) NRfS (O) 2Rg and –NRfC (O) Rg; each Rf is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8 cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and - C1-6alkyl-heterocyclyl; each Rg is independently selected from the group consisting of H, -C1-6 alkyl, -C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, -C1-3 alkyl-C3-8-cycloalkyl, -C1-6-alkyl, -C1-6-heteroaryl, and -C1-6alkyl-heterocyclyl; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[10]
10. Compound according to claim 9, characterized by the fact that it is represented by Formula (IIIb): (IIIb) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: Z1, Z3 , R1 and R2 are as defined in claim 9.
[11]
11. Compound according to claim 9, characterized by the fact that it is represented by Formula (IIIc):
22/27 (IIIc) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein: Z1, Z3, R1 and R2 are as defined in claim 9.
[12]
12. Compound according to claim 9, characterized by the fact that it is represented by Formula (IIId): (IIId) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, where: Z1, Z3 , R1 and R2 are as defined in claim 9.
[13]
13. Compound, characterized by the fact that it is selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[14]
14. Compound, characterized by the fact that it is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[15]
15. Compound, characterized by the fact that it is:
23/27 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[16]
16. Compound, characterized by the fact that it is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[17]
17. Compound, characterized by the fact that it is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[18]
18. Compound, characterized by the fact that it is: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
[19]
19. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, and at least one pharmaceutically acceptable excipient.
[20]
20. Pharmaceutical composition according to claim 19, characterized by the fact that it additionally comprises at least
24/27 an additional anti-cancer agent or an additional anti-cancer therapy selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab, and at least one pharmaceutically acceptable excipient.
[21]
Pharmaceutical composition according to claim 19, characterized in that the additional anticancer agent is nivolumab, pembrolizumab, atezolizumab, or ipilimumab.
[22]
22. Method for inhibiting PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1, characterized in that it comprises administering a compound as defined in any of claims 1 to 18 or a pharmaceutically acceptable salt , stereoisomer, mixture of stereoisomers or tautomer thereof, to a patient who needs it.
[23]
23. Method for treating cancer, characterized in that it comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, to a patient who needs it.
[24]
24. Method according to claim 23, characterized by the fact that the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cancer cervical, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS (Central Nervous System) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, cancer of small cell lung or colon cancer.
[25]
25. Method according to claim 23, characterized by the fact that the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), lymphoma
25/27 small lymphocytic (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL) , follicular lymphoma, Waldenstrom macroglobulinemia (WM), T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL).
[26]
26. Method according to claim 22 or 23, characterized in that it additionally comprises administering at least one additional anti-cancer agent or one additional anti-cancer therapy selected from among nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiotherapy, and resection therapy, to a patient who needs it.
[27]
27. The method of claim 22 or 23, characterized in that the additional anti-cancer agent or additional anti-cancer therapy is nivolumab, pembrolizumab, artezolizumab, and nivolumab, pembrolizumab, atezolizumab, or ipilimumab.
[28]
28. Method for improving T-cell function in patients with chronic hepatitis B (CHB), characterized in that it comprises administering to them an effective amount of a compound as defined in any of claims 1 to 18 or a salt pharmaceutically acceptable, stereoisomer, mixture of stereoisomers or tautomer thereof.
[29]
A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, characterized in that it is for use in therapy.
[30]
A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, characterized in that it is for use in the manufacture of a medicament to treat cancer.
26/27
[31]
31. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and at least one additional anticancer agent selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab, characterized by the fact that it is for use in the manufacture of a medicine to treat cancer.
[32]
32. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, characterized in that it is for use in the manufacture of a medicament to enhance T-cell function. in patients with chronic hepatitis B (CHB).
[33]
33. Kit to treat or prevent cancer or a disease or condition that is responsive to treatment by inhibiting PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1, in a patient who it requires it, characterized in that it comprises: a) a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; b) a checkpoint inhibitory monoclonal antibody or antigen-binding fragment thereof; and optionally c) a label or instructions for use.
[34]
34. Kit to treat or prevent cancer or a disease or condition that is responsive to treatment by inhibiting PD-1, PD-L1 and / or the interaction of PD-1 / PD-L1, in a patient who it requires it, characterized in that it comprises: a) a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; b) a checkpoint inhibitory monoclonal antibody or
27/27 antigen-binding fragment thereof; and optionally c) an additional therapeutic agent; and optionally: d) a label or instructions for use.
[35]
35. Kit to treat or prevent cancer or a disease or condition in a subject who needs it, characterized in that it comprises: a) a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer , mixture of stereoisomers, or tautomer thereof; b) an anti-MMP9 antibody or antigen-binding fragment thereof; and optionally c) an additional therapeutic agent; and optionally; d) a label or instructions for use.

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优先权:

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申请号 | 申请日 | 专利标题

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US201862630187P| true| 2018-02-13|2018-02-13|

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US201862763116P| true| 2018-04-19|2018-04-19|

---

US62/763,116|2018-04-19|

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US201862747029P| true| 2018-10-17|2018-10-17|

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US62/747,029|2018-10-17|

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PCT/US2019/017721|WO2019160882A1|2018-02-13|2019-02-12|Pd-1/pd-l1 inhibitors|

---