Patent Application
20250066328
Adenosine diphosphate (ADP)-ribosylation is a well conserved post-translational modification found in viruses, bacteria, and eukaryotes. It is catalyzed by members of the ART superfamily of proteins, which transfer ADPr from nicotinamide adenine dinucleotide (NAD+) onto substrates via N—, O—, or S— glycosidic linkages on target molecules. One subset of ART's is the poly(adenosine diphosphate-ribose) polymerases (PARPs), that are members of a family of seventeen known enzymes that regulate fundamental cellular processes including gene expression, protein degradation, and multiple cellular stress responses (M. S. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. (Nat. Chem Biol 14, 236-243 (2018)). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and an emerging approach for novel therapeutics.
Of particular interest is 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a CCCH-type zinc finger domain-containing protein. (Proc. Nat. Acad. Sci. 114 (10) 2681-2686 (2017)). TIPARP is also called PARP7 and ARTD14. PARP7 acts as negative regulator of certain aryl hydrocarbon receptor (AHR) transcriptional targets. AHR, in turn, is activated by many substrates, including cigarette smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and causes tumor regression in a CT26 tumor-bearing, immunocompetent BALB/c mouse model. (Gozgit, et al., Cancer Cell 39, 1214-1226 (2021)).
There are currently no approved PARP7 inhibiting pharmaceuticals. Therefore, it would be useful to provide a PARP7 inhibiting compound with properties suitable for administration as a pharmaceutical agent to a mammal, particularly a human.
Thus, there is a need for improved PARP7 inhibitors for the treatment of cancer.
Provided herein are compounds and pharmaceutical compositions useful as inhibitors of PARP7. Some compounds of the disclosure may find use in pharmaceutical compositions, together with at least one pharmaceutically acceptable excipient, for treating a subject in need thereof.
Provided herein is a compound of Formula (I):
Provided herein is a compound of Formula (I′):
There is also provided a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, of the present disclosure, together with a pharmaceutically acceptable excipient.
Further, there is provided a method of treating cancer, in a subject in need thereof, comprising administering to said patient a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure.
The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
A dash (“—”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
A wavy line
indicates a point of attachment.
The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ±10%. In other embodiments, the term “about” includes the indicated amount ±5%. In certain other embodiments, the term “about” includes the indicated amount 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 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 chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; 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).
“Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
“Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 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 one triple bond and one double bond.
“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
“Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
“Alkylthio” refers to the group “alkyl-S—”.
“Acyl” refers to a group —C(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
“Amido” refers to both a “C-amido” group which refers to the group —C(O)NRyRz and an “N-amido” group which refers to the group —NRyC(O)Rz, wherein Ry and RZ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ry and Rz are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
“Amino” refers to the group —NRyRy wherein each Ry is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl or heteroaryl, each of which is optionally substituted, as defined herein.
“Amidino” refers to —C(NRy)(NRz2), wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-10 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
“Cyano” refers to the group —CN.
“Keto” refers to a group C═O.
“Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group —O—C(O)NRyRz and an “N-carbamoyl” group which refers to the group —NRyC(O)ORz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
“Carboxyl” refers to —C(O)OH.
“Ester” (i.e. carboxyl ester) refers to both —OC(O)R and —C(O)OR, wherein R is a substituent; each of which may be optionally substituted, as defined herein.
“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., 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.
“Guanidino” refers to —NRyC(═NRz)(NRyRz), wherein each Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (—CHF2) and trifluoromethyl (—CF3).
“Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic 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 heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include —OCH3, —CH2OCH3, —SCH3, —CH2SCH3, —NRCH3, and —CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
“Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
“Heterocyclyl” or “heterocycle” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bicyclic heterocyclyl groups, bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring atoms (i.e., 4-20 membered heterocyclyl), 2 to ring atoms (i.e., 4-12 membered heterocyclyl), 4 to 10 ring atoms (i.e., 4-10 membered heterocyclyl), 4 to 8 ring atoms (i.e., 4-8 membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., 4-6 membered heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. A heterocyclyl may contain one or more C═O and/or thiC═O groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, diC═Olanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4-7 membered sultam, 4-7 membered cyclic carbamate, 4-7 membered cyclic carbonate, 4-7 membered cyclic sulfide and morpholinyl. As used herein, the term “bridged-heterocyclyl” refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g. 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged-heterocyclyl includes bicyclic and tricyclic ring systems. Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-C═O-1,2,3,4-tetrahydroisoquinolinyl, 1-C═O-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group attached at two points to another cyclic group, wherein the other cyclic group may itself be a heterocyclic group, or a carbocyclic group.
As used herein, the term “nitrogen or sulfur containing heterocyclyl” means a heterocyclyl moiety that contains at least one nitrogen atom or at least one sulfur atom, or both a nitrogen atom and a sulfur atom within the ring structure. It is to be understood that other heteroatoms, including oxygen, may be present in addition to the nitrogen, sulfur, or combinations thereof. Examples of nitrogen or sulfur containing heterocyclyls include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone 1,2 dithiolyl, piperidinyl, piperazinyl, and the like.
“Hydroxy” or “hydroxyl” refers to the group —OH. “Hydroxyalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl.
“Imino” refers to a group —C(NRy)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;
“Nitro” refers to the group —NO2.
“Sulfonyl” refers to the group —S(O)2R, where R is a substituent, or a defined group.
“Alkylsulfonyl” refers to the group —S(O)2R, where R is a substituent, or a defined group.
“Alkylsulfinyl” refers to the group —S(O)R, where R is a substituent, or a defined group.
“Thiocyanate” refers to the group —SCN.
“Thiol” refers to the group —SR, where R is a substituent, or a defined group.
“ThiC=O” or “thione” refer to the group C(═S) or C(S).
Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. “Optionally substituted” may be zero to the maximum number of possible substitutions, and each occurrence is independent. When the term “substituted” is used, then that substitution is required to be made at a substitutable hydrogen atom of the indicated substituent. An optional substitution may be the same or different from a (required) substitution.
When a moiety is “optionally substituted,” and reference is made to a general term, such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,” “cycloalkyl,” “aryl,” or “heteroaryl,” then the general term can refer to any antecedent specifically recited term, such as (C1-3 alkyl), (C4-6 alkyl), —O(C1-4 alkyl), (C3-10 cycloalkyl), O—(C3-10 cycloalkyl) and the like. For example, “any aryl” includes both “aryl” and “—O(aryl) as well as examples of aryl, such as phenyl or naphthyl and the like. Also, the term “any heterocyclyl” includes both the terms “heterocyclyl” and O-(heterocyclyl),” as well as examples of heterocyclyls, such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl and the like. In the same manner, the term “any heteroaryl” includes the terms “heteroaryl” and “O-(heteroaryl),” as well as specific heteroaryls, such as pyridine and the like.
Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H and 14C, are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
The disclosure also includes “deuterated analogues” or “deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula (I).
The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may 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, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri-cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
The term “substituted” means that any one or more (e.g, 1 to 5, 1 to 4, 1 to 3, and the like) hydrogen atoms on the designated atom or group is replaced with one or more (e.g, 1 to 5, 1 to 3, and the like) substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C═O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. One skilled in the art will recognize that substituents and other moieties of the compounds of the generic formula herein should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds which have such stability are contemplated as falling within the scope of the present disclosure. It should be understood by one skilled in the art that any combination of the definitions and substituents described above should not result in an inoperable species or compound.
As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
In the present context, the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. For example, an effective amount is an amount sufficient to effectuate a beneficial or desired clinical result. The effective amounts can be provided all at once in a single administration or in fractional amounts that provide the effective amount in several administrations. The precise determination of what would be considered an effective amount may be based on factors individual to each subject, including their size, age, injury, and/or disease or injury being treated, and amount of time since the injury occurred or the disease began. One skilled in the art will be able to determine the effective amount for a given subject based on these considerations which are routine in the art.
Provided herein is a compound of Formula (I):
Provided herein is a compound of Formula (I′):
In some embodiments, R3a and R3b are each independently H, F, —OH, or —OCH3, or methyl.
In some embodiments, R3a and R3b are each independently H, F, —OH, or —OCH3.
In some embodiments, R3a and R3b are H.
In some embodiments, R3a is H and R3b is selected from halo, —OH, C1-6 alkyl, and —O(C1-6 alkyl), wherein each C1-6 alkyl is independently optionally substituted with one or more R6. In some embodiments, R3a is H and R3b is selected from halo, —OH, C1-6 alkyl, and —O(C1-6 alkyl), wherein each C1-6 alkyl is independently optionally substituted with one to five R6. In some embodiments, R3a is H and R3b is selected from halo, —OH, and —OMe. In some embodiments, R3a is H and R3b is F. In some embodiments, R3a is H and R3b is —OH or methyl. In some embodiments, R3a is H and R3b is —OH.
In some embodiments, provided is a compound of Formula (I-A):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A, J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (I-B):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A, J, R1, and R2 are as described herein.
In some embodiments, the compound is not 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one, 7-fluoro-2-[(2S,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one, or 7-fluoro-2-[(2R, 4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one.
In some embodiments, provided is a compound of Formula (I-C):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A, J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (I-D):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A, J, R1, and R2 are as described herein.
In some embodiments, A is NH. In some embodiments, A is O.
In some embodiments, provided is a compound of Formula (II-A):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (II-B):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, the compound is not 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one, 7-fluoro-2-[(2S,4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one, or 7-fluoro-2-[(2R, 4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one.
In some embodiments, provided is a compound of Formula (II-C):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (II-D):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (III-A):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (III-B):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (III-C):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (III-D):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J, R1, and R2 are as described herein.
In some embodiments, provided is a compound of Formula (IV-A):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein J is as described herein.
In some embodiments, R1 is methyl, ethyl, —CH2OCF2H, —CH2OCH3, —CF3, or —CH2OH. In some embodiments, R1 is methyl, ethyl, —CH2OCF2H, —CH2OCH3, or —CF3. In some embodiments, R1 is methyl, ethyl or —CH2(OCHF2).
In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl or —CH2(OCHF2). In some embodiments, R1 is ethyl. In some embodiments, R1 is —CH2(OCHF2).
In some embodiments, R2 is H, halo, C1-6 alkyl, —OH, or —O(C1-6 alkyl).
In some embodiments, R2 is H. In some embodiments, R2 is —OH.
In some embodiments, R1 is methyl, ethyl, —CH2OCF2H, —CH2OCH3, —CF3, or —CH2OH, and R2 is H.
In some embodiments, R1 is methyl, ethyl, —CH2OCF2H, —CH2OCH3, —CF3, or —CH2OH; R2 is H; and R3a and R3b are each independently H, F, —OH, —OCH3, or methyl.
The dashed line of Ring J indicates a single or double bond (i.e. X1 is ═N—, ═C(R4)—, or —C(R4)2—).
In some embodiments, J is
In some embodiments, J is
In some embodiments, J is
In some embodiments, J is:
In some embodiments, R4 is F. In some embodiments, R4 is H.
In some embodiments, each R5 is independently selected from H and halo. In some embodiments, each R5 is F. In some embodiments, each R5 is H. In some embodiments, R5 is either F or H.
In some embodiments, R4 is F and each R5 is H. In some embodiments, R4 is F and each R5 is F. In some embodiments, R4 is H, and one or two of R is F, and the remaining R5 is H. In some embodiments, R4 is H and R is either F or H.
In some embodiments, J is selected from the group consisting of:
In some embodiments, J is selected from the group consisting of:
In some embodiments, J is:
In some embodiments, J is:
In some embodiments, J is:
In some embodiments, J is:
In some embodiments, J is:
In some embodiments, J is:
In some embodiments, Z is 4-12 membered heterocyclyl optionally substituted with one to three R7 or 5-12 membered heteroaryl optionally substituted with one to three R7, and each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-3 alkyl), —O(C1-3 alkyl), and C3-6 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to four halo or —OH or CN.
In some embodiments, Z is 4-12 membered heterocyclyl optionally substituted with one or more R7. In some embodiments, Z is 4-12 membered heterocyclyl optionally substituted with one to five R7. In some embodiments, Z is 4-12 membered heterocyclyl optionally substituted with one to three R7. In some embodiments, Z is 4-12 membered heterocyclyl optionally substituted with one to two R7.
In some embodiments, Z is 5-12 membered heteroaryl optionally substituted with one or more R7. In some embodiments, Z is 5-12 membered heteroaryl optionally substituted with one to five R7. In some embodiments, Z is 5-12 membered heteroaryl optionally substituted with one to three R7. In some embodiments, Z is 5-12 membered heteroaryl optionally substituted with one to two R7.
In some embodiments, Z is a 6-membered heteroaryl optionally substituted with one or more R7. In some embodiments, Z is a 6-membered heteroaryl optionally substituted with one to three R7. In some embodiments, Z is an unsubstituted 6-membered heteroaryl. In some embodiments, Z is a 6-membered heteroaryl substituted with one R7. In some embodiments, Z is a 6-membered heteroaryl substituted with two R7. In some embodiments, Z is a 9-membered heteroaryl optionally substituted with one or more R7. In some embodiments, Z is an unsubstituted 9-membered heteroaryl.
In some embodiments, Z is:
In some embodiments, w is zero. In some embodiments, w is one. In some embodiments, w is three.
In some embodiments, t is zero. In some embodiments, t is one. In some embodiments, t is two. In some embodiments, t is three. In some embodiments, t is four.
In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one or more halo or —OH or CN. In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to five halo or —OH or CN. In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to four halo or —OH or CN. In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-3 alkyl), —O(C1-3 alkyl), and C30.6 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to four halo or —OH or CN.
In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one or more halo or —OH. In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to five halo or —OH. In some embodiments, each R7 is independently selected from halo, C1-6 alkyl, —NH2, —SO2(C1-6 alkyl), —O(C1-6 alkyl), and C3-12 cycloalkyl, wherein each C1-6 alkyl optionally substituted with one to four halo or —OH.
In some embodiments, an C1-6 alkyl of R7 is deuterated.
In some embodiments, R7 is halo. In some embodiments, R7 is F. In some embodiments, R7 is Cl.
In some embodiments, R7 is unsubstituted C1-6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl.
In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, or three halo. In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, or three F. In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, or three —OH. In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, three, or four halo or —OH. In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, or three halo or —OH. In some embodiments, R7 is C1-6 alkyl optionally substituted with one, two, or three F or —OH.
In some embodiments, R7 is trifluoromethyl. In some embodiments, R7 is difluoromethyl. In some embodiments, R7 is 1,1-difluoroethyl. In some embodiments, R7 is 2-hydroxypropan-2-yl. In some embodiments, R7 is 1-hydroxyethyl. In some embodiments, R7 is 1,1-difluoro-2-hydroxylethyl. In some embodiments, R7 is 1-hydroxy-2,2,2-trifluoroethyl. In some embodiments, R7 is 1-hydroxy-2,2-difluoroethyl. In some embodiments, R7 is —CH2C(H)(OH)—CF3. In some embodiments, R7 is —C(CH3)(OH)(CF3). In some embodiments, R7 is —C(CH3)(OH)(CHF2). In some embodiments, R7 is tert-butyl. In some embodiments, R7 is 1,2-difluoroethyl. In some embodiments, R7 is —C(CH3)2F.
In some embodiments, R7 is —O(C1-6 alkyl), wherein the C1-6 alkyl is unsubstituted. In some embodiments, R7 is —O(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with one, two, or three halo. In some embodiments, R7 is —O(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with one, two, or three —OH. In some embodiments, R7 is —O(C1-6 alkyl), wherein the C1-6 alkyl is optionally substituted with one, two, or three CN.
In some embodiments, R7 is methoxy. In some embodiments, R7 is trideuteromethoxy. In some embodiments, R7 is difluoromethoxy. In some embodiments, R7 is trifluoromethoxy. In some embodiments, R7 is 2-hydroxyethoxy. In some embodiments, R7 is —OCH2CN. In some embodiments, R7 is —OCF2CH2OH.
In some embodiments, R7 is —NH2.
In some embodiments, R7 is —SO2(C1-6 alkyl). In some embodiments, R7 is —SO2CH3.
In some embodiments, R7 is C3-12 cycloalkyl. In some embodiments, R7 is cyclopropyl.
In some embodiments, Z is
In some embodiments, Z is:
In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, selected from:
Some embodiments provide for a compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, selected from Table 1 or Table 2.
In some embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof:
In some embodiments, provided is a compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof:
Disclosed herein are methods of treatment of a disease in which inhibition of PARP is beneficial, the method comprising administering a compound disclosed herein. Also disclosed herein are methods of treatment of a disease in which inhibition of PARP7 is beneficial, the method comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiment, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, triple-negative breast cancer, urothelial cancer, or cervical cancer.
In some embodiments, the cancer comprises a BRCA1 and/or a BRCA2 mutation.
In some embodiments, the cancer comprising a BRCA1 and/or a BRCA2 mutation is bladder cancer, brain and CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, triple-negative breast cancer, urothelial cancer, or uterus cancer.
Provided herein is a method of treating cancer, comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, or a pharmaceutical composition comprising a compound disclosed herein.
Some embodiments provide for a method of treating cancer, comprising administering to a patient in need thereof an effective amount of compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, or a pharmaceutical composition comprising a compound disclosed herein.
Patients being treated by administration of the PARP7 inhibitors of the disclosure often exhibit diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions can be of an oncology nature or can be related to inflammation, metabolic disorders, gastrointestinal disorders and the like. Thus, one aspect of the disclosure is a method of treating cancer, comprising administering a compound of the disclosure in combination with one or more compounds useful for the treatment of such diseases to a subject, particularly a human subject, in need thereof.
In some embodiments, a compound of the present disclosure is co-formulated with the additional one or more active ingredients. In some embodiments, the other active ingredient is administered at approximately the same time, in a separate dosage form. In some embodiments, the other active ingredient is administered sequentially, and may be administered at different times in relation to a compound of the present disclosure.
In some embodiments, a compound provided herein, or pharmaceutical composition provided herein, is administered with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, the additional therapeutic agent includes, e.g., an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferation agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (e.g., a mono- and multi-specific antibody, or fragment thereof, in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivative), a bi-specific antibody, a non-immunoglobulin antibody mimetic (e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin®), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMPs), an antibody-drug conjugate (ADC), antibody-peptide conjugate), an oncolytic virus, a gene modifier or editor, a cell comprising a chimeric antigen receptor (CAR), e.g., including a T-cell immunotherapeutic agent, an NK-cell immunotherapeutic agent, or a macrophage immunotherapeutic agent, a cell comprising an engineered T-cell receptor (TCR-T), or any combination thereof.
In some embodiments, the one or more additional therapeutic agents include, e.g., an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a target (e.g., polypeptide or polynucleotide), such as: 2-5′-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5′-3′ exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5′-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); absent in melanoma 2 (AIM2; NCBI Gene ID: 9447); acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (ACP3; NCBI Gene ID: 55); adenosine deaminase (ADA, ADAl; NCBI Gene ID: 100); adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI Gene IDs: 134, 135, 136, 137); AKT serine/threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper containing (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietins (ANGPT1, ANGPT2; NCBI Gene IDs: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis inducing factor mitochondria associated 1 (AIFM1, AIF; NCBI Gene ID: 9131); arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asteroid homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine/threonine kinase (ATM; NCBI Gene ID: 472); ATP binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine/threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 558); B and T lymphocyte associated (BTLA, CD272; NCBI Gene ID: 151888); baculoviral IAP repeat containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 682); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2 binding component 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2 like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene IDs: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamate protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain and external domain (BET) bromodomain containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer/testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrases (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 864); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); C—C motif chemokine ligand 21 (CCL21; NCBI Gene ID: 6366); C—C motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); C—C motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDwl98); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cellular communication network factor 2 (CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropin hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208); cluster of differentiation markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD beta (TRB), CD gamma (TRG), CD delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLASTI), CD52, CD55 (DAF), CD58 (LFA3), CD74, CD79a, CD79b, CD80 (B7-1), CD84, CD86 (B7-2), CD96 (TACTILE), CD99 (MIC2), CD115 (CSF1R), CD116 (GMCSFR, CSF2RA), CD122 (IL2RB), CD123 (IL3RA), CD128 (IL8R1), CD132 (IL2RG), CD135 (FLT3), CD137 (TNFRSF9, 4-1BB), CD142 (TF, TFA), CD152 (CTLA4), CD160, CD182 (IL8R2), CD193 (CCR3), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2R), CD223 (LAG3), CD226 (DNAM1), CD244, CD247, CD248, CD276 (B7-H3), CD331 (FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4); NCBI Gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958,960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA, NCBI Gene IDs: 2155, 2159); collagen type IV alpha chains (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily member 10 (COLEC10; NCBI Gene ID: 10584); colony stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene IDs: 718, 727); COP9 signalosome subunit 5 (COPSS; NCBI Gene ID: 10987); C-type lectin domain family member (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI Gene ID: 160364, 170482, 283420); C—X—C motif chemokine ligand 12 (CXCL12; NCBI Gene ID: 6387); C—X—C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595); cyclin dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene ID: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900); cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductase (POR; NCBI Gene ID: 5447); cytokine inducible SH2 containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicases (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta like canonical Notch ligands (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); diablo IAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525); dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI Gene ID: 780, 4921); DNA dependent protein kinase (PRKDC; NCBI Gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene ID: 7150, 7153, 7155, 7156, 8940); dopachrome tautomerase (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1 like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 5169); EMAP like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene ID: 51752, 64167); enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBIGene ID: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene ID: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene ID: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epithelial mitogen (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIFSA; NCBI Gene ID: 1973, 1984); exportin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fas ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptors (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene IDs: 2205, 2214, 2217); Fc receptor like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191); fibroblast growth factor receptors (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI Gene ID: 2335); fins related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene IDs: 2321, 2322, 2324); fins related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); FURIN (FURIN, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534); galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene ID: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate metabotropic receptor 1 (GRM1; NCBI Gene ID: 2911); glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 2950); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 2658); growth factor receptor-bound protein 2 (GRB2, ASH; NCBI Gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI Gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID: 283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID: 3055); heat shock proteins (e.g., HSPAS (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene ID: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatocyte growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associating 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene ID: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc fingers (IKZF1 (LYF1), IKZF3; NCBI Gene ID: 10320, 22806); immunoglobulin superfamily member 11 (IGSF11; NCBI Gene ID: 152404); indoleamine 2,3-dioxygenases (e.g., IDO1, IDO2; NCBI Gene IDs: 3620, 169355); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin like growth factor receptors (e.g., IGF1R, IGF2R; NCBI Gene ID: 3480, 3482); insulin like growth factors (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGAS (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene IDs: 3678, 3685, 3688, 3695, 3698); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin 1 receptor associated kinase 4 (IRAK4; NCBI Gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI Gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., ILlA, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 (CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI Gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); isocitrate dehydrogenases (NADP(+)1) (e.g., IDH1, IDH2; NCBI Gene IDs: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3; NCBI Gene IDs: 3716, 3717, 3718); kallikrein related peptidase 3 (KLK3; NCBI Gene ID: 354); killer cell immunoglobulin like receptor, Ig domains and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285); killer cell lectin like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT proto-oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene, GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4035); leucine rich repeat containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T-cells (LAT; NCBI Gene ID: 27040); luteinizing hormone/choriogonadotropin receptor (LHCGR; NCBI Gene ID: 3973); LY6/PLAUR domain containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activating 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene IDs: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysine demethylase 1A (KDM1A; NCBI Gene ID: 23028); lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 1902); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI Gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA 11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complexes (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULTI; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK interacting serine/threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene IDs: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI Gene ID: 4170); MDM2 proto-oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene IDs: 4157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequences (e.g., MICA, MICB; NCBI Gene IDs: 4277, 100507436); mitogen activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI Gene IDs: 4217, 1326); mitogen-activated protein kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene IDs: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including splice variants thereof (e.g., including MUC1/A, C, D, X, Y, Z and REP)), MUC5AC, MUC16 (CA125); NCBI Gene IDs: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, MAGE family member (NDN; NCBI Gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene IDs: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene IDs: 8828, 8829); neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene IDs: 4914, 4915, 4916); NFKB activating protein (NKAP; NCBI Gene ID: 79576); NIMA related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene IDs: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); nuclear factor kappa B (NFKB1, NFKB2; NCBI Gene IDs: 4790, 4791); nuclear factor, erythroid 2 like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide binding oligomerization domain containing 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI Gene ID: 4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); C=Oglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631); peroxisome proliferator activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinases (PIK3CA (PI3K alpha), PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogene, serine/threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placenta growth factor (PGF; NCBI Gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene IDs: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); polo like kinase 1 (PLK1; NCBI Gene ID: 5347); poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcriptional regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL; NCBI Gene ID: 6490); progesterone receptor (PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); prominin 1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); prosaposin (PSAP; NCBI Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin-endoperoxide synthases (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene ID: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI Gene ID: 5698); protein arginine methyltransferases (e.g., PRMT1, PRMTS; NCBI Gene ID: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptors (PTPRB), PTPRC (CD45R); NCBI Gene ID: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X 7 (P2RX7; NCBI Gene ID: 5027); PVR related immunoglobulin domain containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine/threonine kinase (RAF1, c-Raf; NCBI Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); ras homolog family member C (RHOC); NCBI Gene ID: 389); Ras homolog, mTORCl binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine/threonine protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091); retinoic acid receptors alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916); retinoid X receptors (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho associated coiled-coil containing protein kinases (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta 1; NCBI Gene ID: 6198); ring finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted frizzled related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); secretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene IDs: 6401, 6402, 6403); semaphorin 4D (SEMA4D; CD100; NCBI Gene ID: 10507); sialic acid binding Ig like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene ID: 27036, 27180, 89790); signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); signal transducer and activator of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene IDs: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410); signaling lymphocytic activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK like family member 6 (SLITRK6; NCBI Gene ID: 84189); smoothened, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Spl transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI Gene IDs: 8877, 56848); sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI Gene ID: 1901); spleen associated tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressors of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene ID: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224); syndecan 1 (SDC1, CD138, syndecan; NCBI Gene ID: 6382); synuclein alpha (SNCA, PARKI; NCBI Gene ID: 6622); T cell immunoglobulin and mucin domain containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene ID: 6869, 6870); TANK binding kinase 1 (TBK1; NCBI Gene ID: 29110); tankyrase (TNKS; NCBI Gene ID: 8658); TATA-box binding protein associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); tec protein tyrosine kinase (TEC; NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); three prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene ID: 11277, 11219); thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinases (e.g., TK1, TK2; NCBI Gene IDs: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene IDs: 7606, 7608); thyroid stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI Gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); toll like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); transferrin (TF; NCBI Gene ID: 7018); transferrin receptor (TFRC, CD71; NCBI Gene ID: 7037); transforming growth factors (e.g., TGFA, TGFB1; NCBI Gene ID: 7039, 7040); transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); transforming protein E7 (E7; NCBI Gene ID: 1489079); transglutaminase 5 (TGM5; NCBI Gene ID: 9333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed on myeloid cells (e.g., TREM1 (CD354), TREM2; NCBI Gene ID: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylases (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor associated calcium signal transducer 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB), TNFRSF10A (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TNFR13C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25, NCBI Gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); tyrosine kinase with immunoglobulin like and EGF like domains 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin conjugating enzyme E2 I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHLS; NCBI Gene ID: 51377); ubiquitin specific peptidase 7 (USP7; NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene ID: 79465, 80328, 80328); valosin-containing protein (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene ID: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRN RecQ like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain containing transcription regulator 1 (WWTRI; TAZ; NCBI Gene ID: 25937); X—C motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375); X—C motif chemokine receptor 1 (XCRI, GPRS, CCXCRI; NCBI Gene ID: 2829); YesI associated transcriptional regulator (YAP1; NCBI Gene ID: 10413); zeta chain associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535).
In some embodiments, the one or more additional therapeutic agents include, e.g., an agent targeting 5′-nucleotidase ecto (NTSE or CD73; NCBI Gene ID: 4907); adenosine A2A receptor (ADORA2A; NCBI Gene ID: 135); adenosine A2B receptor (ADORA2B; NCBI Gene ID: 136); C—C motif chemokine receptor 8 (CCR8, CDwl98; NCBI Gene ID: 1237); cytokine inducible SH2 containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha; NCBI Gene ID: 1606); fins like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin associated protein (IAP, CD47; NCBI Gene ID: 961); interleukine-2 (IL2; NCBI Gene ID: 3558); interleukin 2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI Gene ID: 3845; including mutations, such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133); proto-oncogen c-KIT (KIT, CD 117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209); tumor-associated calcium signal transducer 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784); WRN RecQ like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807).
In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of cancer cells within the tumor microenvironment. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in cancer therapeutics. In some embodiments, the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T-cells (Treg) or Treg depletion can alleviate their suppression of antitumor immune responses and have anticancer effects (e.g., reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).
Examples of immune checkpoint proteins or receptors include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID: 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associating 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell co-stimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell co-stimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte associated (BTLA); NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD 112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR related immunoglobulin domain containing (PVRIG, CD 112R; NCBI Gene ID: 79037); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); galectin 9 (LGALS9; NCBI Gene ID: 3965); lymphocyte activating 3 (LAG3, CD223; NCBI Gene ID: 3902); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI Gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI Gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI Gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI Gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI Gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (IPH-2102, IPH-4102)); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A; NCBI Gene ID: 3821); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314; NCBI Gene ID: 22914); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C; NCBI Gene ID: 3822); killer cell lectin like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); killer cell lectin like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3; NCBI Gene ID: 3804); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1; NCBI Gene ID: 3824); killer cell lectin like receptor G1 (KLRG1; CLECI5A, MAFA, 2F1; NCBI Gene ID: 10219); sialic acid binding Ig like lectin 7 (SIGLEC7; NCBI Gene ID: 27036); and sialic acid binding Ig like lectin 9 (SIGLEC9; NCBI Gene ID: 27180).
In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSFI4 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD 112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., JExp Clin Cancer Res. (2018) 37:110.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin like receptor D1 (KLRD1, CD94), killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.
In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of LAG3.
Examples of inhibitors of CTLA4 that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).
Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimzumab (CBT-501), LZM-009, prolgolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dostarlimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, envafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimberelimab (AB122), spartalizumab (PDR-001), and compounds disclosed in WO2018195321, WO2020014643, WO2019160882, or WO2018195321, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1), RO-7247669 (PD-1/LAG-3), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), RG7769 (PD-1/TIM-3), TAK-252 (PD-1/OX40L), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), FS-118 (LAG-3/PD-L1), FPT-155 (CTLA4/PD-L1/CD28), GEN-1046 (PD-L1/4-1BB), bintrafusp alpha (M7824; PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), and INBRX-105 (4-1BB/PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor, such as CA-170, GS-4224, GS-4416 and lazertinib (GNS-1480; PD-L1/EGFR).
Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vibostolimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.
Examples of inhibitors of LAG3 that can be co-administered include leramilimab (LAG525).
Inhibition of regulatory T-cell (Treg) activity or Treg depletion can alleviate their suppression of antitumor immune responses and have anticancer effects. See, e.g., Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J Immunol. (2019) 49:1140-1146. In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more inhibitors of Treg activity or a Treg depleting agent. Treg inhibition or depletion can augment the effect of immune checkpoint inhibitors in cancer therapeutics.
In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate the cellular phenotype and induce production of proinflammatory cytokines. Exemplary Treg inhibitors include without limitation, CCR4 (NCBI Gene ID: 1233) antagonists and degraders of Ikaros zinc-finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF2; NCBI Gene ID: 22807), Aiolos (IKZF3; NCBI Gene ID: 22806), and Eos (IKZF4; NCBI Gene ID: 64375).
Examples of Helios degraders that can be co-administered include without limitation I-57 (Novartis) and compounds disclosed in WO2019038717, WO2020012334, WO20200117759, and WO2021101919.
In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more Treg depleting agents. In some embodiments, the Treg depleting agent is an antibody. In some embodiments, the Treg depleting antibody has antibody-dependent cytotoxic (ADCC) activity. In some embodiments, the Treg depleting antibody is Fc-engineered to possess an enhanced ADCC activity. In some embodiments, the Treg depleting antibody is an antibody-drug conjugate (ADC). Illustrative targets for Treg depleting agents include without limitation CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).
In some embodiments, the Treg inhibitor or Treg depleting agent that can be co-administered comprises an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of C—C motif chemokine receptor 4 (CCR4), C—C motif chemokine receptor 7 (CCR7), C—C motif chemokine receptor 8 (CCR8), C—X—C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), Sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD103), interleukin 7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor alpha (FOLR1), folate receptor beta (FOLR2), leucine rich repeat containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulatory (ICOS; CD278), lymphocyte activating 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25) or a combination thereof.
Examples of Treg depleting anti-CCR8 antibodies that can be administered include without limitation JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in WO2021163064, WO2020138489, and WO2021152186.
Examples of Treg depleting anti-CCR4 antibodies that can be administered include mogamulizumab.
Inhibiting, depleting, or reprogramming of non-stimulatory myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5): 541-550; WO2016049641). Illustrative targets for depleting or reprogramming non-stimulatory myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209). In some embodiments, a compound disclosed herein or an antibody and/or fusion protein provided herein is administered with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g. PY159; antibodies disclosed in WO2019032624) or an anti-TREM-2 antibody (e.g., PY314; antibodies disclosed in WO2019118513).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with agents targeting a cluster of differentiation (CD) marker. Exemplary CD marker targeting agents that can be co-administered include without limitation A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimimar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402/HLA-A0201 restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, rebastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverembatinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept (APG-101), APO-010, and compounds disclosed in WO2016196388, WO2016033570, WO2015157386, WO199203459, WO199221766, WO2004080462, WO2005020921, WO2006009755, WO2007078034, WO2007092403, WO2007127317, WO2008005877, WO2012154480, WO2014100620, WO2014039714, WO2015134536, WO2017167182, WO2018112136, WO2018112140, WO2019155067, WO2020076105, PCT/US2019/063091, WO19173692, WO2016179517, WO2017096179, WO2017096182, WO2017096281, WO2018089628, WO2017096179, WO2018089628, WO2018195321, WO2020014643, WO2019160882, WO2018195321, WO200140307, WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, WO2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170, WO2020068752, Cancer Discov. 2019 Jan. 9(1):8; and Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).
In some embodiments, the CD marker targeting agent that can be co-administered include small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, roblitinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229, telatinib, vorolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, burixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), plerixafor, CTX-5861, or REGN-5678 (PSMA/CD28).
In some embodiments, the CD marker targeting agent that can be co-administered include small molecule agonists, such as interleukin 2 receptor subunit gamma, eltrombopag, rintatolimod, poly-ICLC (NSC-301463), Riboxxon, Apoxxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, resiquimod, selgantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.
In some embodiments, the CD marker targeting agent that can be co-administered include antibodies, such as tafasitamab (MOR208; MorphoSys AG), Inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16/CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenziluma, alemtuzuma, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137/Her2), AFM-13 (CD16/CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA/CD16A), simlukafusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137/HER2), FAP-4-IBBL (4-1BB/FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatlimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, encelimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20.5), MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirilumab (IPH-2102), lacutamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5/6), Iodine (131I) apamistamab (131I-BC8 (lomab-B)), MED10562 (tavolixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in WO 2017096179, WO2017096276, WO2017096189, and WO2018089628.
In some embodiments, the CD marker targeting agent that can be co-administered include cell therapies, such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, 1 iso-cel, lisocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), U.S. Pat. Nos. 7,741,465, 6,319,494, UCART-19, tabelecleucel (EBV-CTL), T tisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19/4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia/Non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silenced IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19/CD20), GC-197 (CD19/CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19/APRIL), ICG-134, ICG-132 (CD19/CD20), CTA-101, WZTL-002, dual anti-CD19/anti-CD20 CAR T-cells (chronic lymphocytic leukemia/B-cell lymphomas), HY-001, ET-019002, YTB-323, GC-012 (CD19/APRIL), GC-022 (CD19/CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (CTL-019)), anti-CD20 CAR T-cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1 (CD19/CD20), WZTL-002 dual anti-CD19/anti-CD20 CAR-T cells, ICG-132 (CD19/CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA/anti-CD38 CAR T-cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer/NSCLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer/NSCLC), AUTO-2, anti-BCMA CAR T-cell therapy, Descartes-011, anti-BCMA/anti-CD38 CAR T-cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D LIGAND MODULATOR), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in WO2012079000 or WO2017049166.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody or a CD47-blocking agent, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), letaplimab (IBI-188) (letaplimab), lemzoparlimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or compounds disclosed in WO199727873, WO199940940, WO2002092784, WO2005044857, WO2009046541, WO2010070047, WO2011143624, WO2012170250, WO2013109752, WO2013119714, WO2014087248, WO2015191861, WO2016022971, WO2016023040, WO2016024021, WO2016081423, WO2016109415, WO2016141328, WO2016188449, WO2017027422, WO2017049251, WO2017053423, WO2017121771, WO2017194634, WO2017196793, WO2017215585, WO2018075857, WO2018075960, WO2018089508, WO2018095428, WO2018137705, WO2018233575, WO2019027903, WO2019034895, WO2019042119, WO2019042285, WO2019042470, WO2019086573, WO2019108733, WO2019138367, WO2019144895, WO2019157843, WO2019179366, WO2019184912, WO2019185717, WO2019201236, WO2019238012, WO2019241732, WO2020019135, WO2020036977, WO2020043188, and WO2020009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments the CD47 inhibitor is magrolimab.
In some embodiments, the CD47 inhibitor is a bispecific antibodies targeting CD47, such as IBI-322 (CD47/PD-L1), IMM-0306 (CD47/CD20), TJ-L1C4 (CD47/PD-L1), HX-009 (CD47/PD-1), PMC-122 (CD47/PD-L1), PT-217, (CD47/DLL3), IMM-26011 (CD47/FLT3), IMM-0207 (CD47/VEGF), IMM-2902 (CD47/HER2), BH29xx (CD47/PD-L1), IMM-03 (CD47/CD20), IMM-2502 (CD47/PD-L1), HMBD-004B (CD47/BCMA), HMBD-004A (CD47/CD33), TG-1801 (NI-1701), or NI-1801.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a SIRPa targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPa targeting agents include SIRPa inhibitors, such as AL-008, RRx-001, and CTX-5861, and anti-SIRPa antibodies, such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPa/PD-L1). Additional SIRPa-targeting agents of use are described, for example, in WO200140307, WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, WO2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170 and WO2020068752.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a FLT3R agonist. In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a FLT3 ligand. In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a FLT3L-Fc fusion protein, e.g., as described in WO2020263830. In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with GS-3583 or CDX-301. In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with GS-3583.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSFlA (NCBI Gene ID: 7132), TNFRSFlB (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11 A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).
Example anti-TNFRSF4 (OX40) antibodies that can be co-administered include MED16469, MEDI6383, tavolixizumab (MED10562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.
Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.
In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.
Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.
In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.
Example anti-TNFRSF18 (GITR) antibodies that can be co-administered include MED11873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, e.g., in WO2017096179 and WO2018089628.
Bi-specific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), AFM-13 (CD16/CD30), odronextamab (REGN-1979; CD20/CD3), AMG-420 (BCMA/CD3), INHIBRX-105 (4-1BB/PDL1), FAP-4-IBBL (4-1BB/FAP), plamotamab (XmAb-13676; CD3/CD20), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), and IMM-0306 (CD47/CD20).
In some embodiments, a compound disclosed herein or antibody and/or fusion protein provided herein is administered with a bi-specific T-cell engager (e.g., not having an Fc) or an anti-CD3 bi-specific antibody (e.g., having an Fc). Illustrative anti-CD3 bi-specific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19/CD3), AMG-211 (CEA/CD3), AMG-160 (PSMA/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3), PF-06671008 (Cadherins/CD3), APV0436 (CD123/CD3), flotetuzumab (CD123/CD3), odronextamab (REGN-1979; CD20/CD3), MCLA-117 (CD3/CLEC12A), JNJ-0819 (heme/CD3), JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), AMG-427 (FLT3/CD3), AMG-562 (CD19/CD3), AMG-596 (EGFRvIII/CD3), AMG-673 (CD33/CD3), AMG-701 (BCMA/CD3), AMG-757 (DLL3/CD3), AMG-211 (CEA/CD3), blinatumomab (CD19/CD3), huGD2-BsAb (CD3/GD2), ERY974 (GPC3/CD3), GEMoab (CD3/PSCA), RG6026 (CD20/CD3), RG6194 (HER2/CD3), PF-06863135 (BCMA/CD3), SAR440234 (CD3/CDw123), JNJ-9383 (MGD-015), AMG-424 (CD38/CD3), tidutamab (XmAb-18087 (SSTR2/CD3)), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), IMCgp100 (CD3/gp100), XmAb-14045 (CD123/CD3), XmAb-13676 (CD3/CD20), tidutamab (XmAb-18087; SSTR2/CD3), catumaxomab (CD3/EpCAM), REGN-4018 (MUC16/CD3), mosunetuzumab (RG-7828; CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), GRB-1302 (CD3/Erbb2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33). As appropriate, the anti-CD3 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific T-cell engagers that can be co-administered target CD3 and a tumor-associated antigen as described herein, including, e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7):e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug. 3; 8(35):57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep. 10; 403:224-230).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Illustrative anti-CD16 bi-specific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens as described herein, including, e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2/neu, HLA Class II and FOLR1. BiKEs and TriKEs are described, e.g., in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.
MCL1 apoptosis regulator, BCL2family member (MCL1) Inhibitors
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcll/EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO2018183418, WO2016033486, and WO2017147410.
In some embodiments, a compound disclosed herein or antibody and/or fusion protein provided herein is administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO2018172984 and WO2017211303.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors include without limitation, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an ASK inhibitor, e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of cyclin dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin dependent kinase 3 (CDK3, NCBI Gene ID: 1018); cyclin dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022), or cyclin dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK 1, 2, 3, 4, 6, 7 and/or 9, include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, samuraciclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, simurosertib hydrate (TAK931), and TG-02.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and/or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO2013/034933 (Imperial Innovations).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a targeted E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and surviving) E3 ubiquitin ligase binding moiety, Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety), and can be used to promote or increase the degradation of targeted proteins, e.g., via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugates comprise a targeting or binding moiety that targets or binds a protein described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugates comprise a targeting or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugates comprise a kinase inhibitor (e.g., a small molecule kinase inhibitor, e.g., of BTK and an E3 ligase ligand or binding moiety. See, e.g., WO2018098280. In some embodiments, the targeted E3 ligase ligand conjugates comprise a binding moiety targeting or binding to Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4); Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF), c-Met/p38, or a BRD protein; and an E3 ligase ligand or binding moiety. See, e.g., WO2019099926, WO2018226542, WO2018119448, WO2018223909, WO2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, e.g., in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.
Indoleamine-pyrrole-2, 3-dioxygenase (IDO1) Inhibitors
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and/or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), ilginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of a LOXL protein, e.g., LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and/or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include the antibodies described in WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of a matrix metallopeptidase (MMP), e.g., an inhibitor of MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP19 (NCBI Gene ID: 4327), MMP20 (NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID: 10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27 (NCBI Gene ID: 64066) and/or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), cipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of KRAS proto-oncogene, GTPase (KRAS; a.k.a., NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C—K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; a.k.a., NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene, GTPase (HRAS; a.k.a., CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; C—H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS/HAS; C-HA-RAS1; NCBI Gene ID: 3265). The Ras inhibitors can inhibit Ras at either the polynucleotide (e.g., transcriptional inhibitor) or polypeptide (e.g., GTPase enzyme inhibitor) level. In some embodiments, the inhibitors target one or more proteins in the Ras pathway, e.g., inhibit one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT and mTOR. Illustrative K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitory peptides, including KRpep-2 and KRpep-2d. Illustrative KRAS mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER™, and siG12D exosomes. Illustrative MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Illustrative Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304 and TAK-580. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib and ulixertinib. Illustrative Ras GTPase inhibitors that can be co-administered include rigosertib. Illustrative PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib, inavolisib (RG6114), ASN-003. Illustrative AKT inhibitors that can be co-administered include capivasertib and GSK2141795. Illustrative PI3K/mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib. gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR/cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) having CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov. 1; 408:130-137. Also, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1/2/4 inhibitor neratinib. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb. 1; 19(2):132-137.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib+trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.
Phosphatidylinositol 3-kinase (PI3K) Inhibitors
In some embodiments, a compound disclosed herein or antibody and/or fusion protein provided herein is administered with an inhibitor of a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P1 OBETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma, p120-PI3K; Gene ID: 5494); and/or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P1 ODELTA, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds described in WO2005113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO2013116562 (Gilead Calistoga), WO2014100765 (Gilead Calistoga), WO2014100767 (Gilead Calistoga), and WO2014201409 (Gilead Sciences).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an inhibitor of spleen associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) and US20150175616.
In some embodiments, a compound disclosed herein or antibody and/or fusion protein provided herein is administered with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, 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, BDB-001, DSP-0509, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014056953 (Janssen), WO2014076221 (Janssen), WO2014128189 (Janssen), US20140350031 (Janssen), WO2014023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). An TLR7/TLR8 agonist that can be co-administered is NKTR-262. Example TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10 and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a tyrosine kinase inhibitor (TKI). TKIs may target epidermal growth factor receptors (EGFRs) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include without limitation afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR targeting agents include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, varlitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII/CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®), and compounds disclosed in Booth, et al., Cancer Biol Ther. 2018 Feb. 1; 19(2):132-137. Antibodies targeting EGFR include without limitation modotuximab, cetuximab sarotalocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomuzotuximab, depatuxizumab (ABT-806), and cetuximab.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a chemotherapeutic agent or anti-neoplastic agent.
As used herein, the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy” in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (e.g., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include but not limited to: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; acetogenins, e.g., bullatacin and bullatacinone; a camptothecin, including synthetic analog topotecan; bryostatin, callystatin; CC-1065, including its adozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including the synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1), dynemicin including dynemicin A, bisphosphonates such as clodronate, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-C═O-L-norleucine, dC=Orubicin (including morpholino-dC=Orubicin, cyanomorpholino-dC=Orubicin, 2-pyrrolino-dC=Orubicin, and deoxydC=Orubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acid replinishers such as frolinic acid; radiotherapeutic agents such as Radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; sabizabulin (Veru-111); platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2′,2″-trichlorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated onto an antibody or any targeting agent described herein to create an antibody-drug conjugate (ADC) or targeted drug conjugate.
Also included in the definition of “chemotherapeutic agent” are anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.
Examples of anti-estrogens and SERMs include tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®).
Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).
Examples of anti-androgens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).
An example progesterone receptor antagonist includes onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone+ethinyl estradiol), norgestimate+ethinylestradiol (Tri-Cyclen) and levonorgestrel.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuparanib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as 1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, α,α′-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3 h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide, angiostatic steroid, carboxy aminoimidazole, metalloproteinase inhibitors such as BB-94, inhibitors of S100A9 such as tasquinimod. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF, and Ang-1/Ang-2. Examples for anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, dilpacimab (ABT-165; DLL4/VEGF), or navicixizumab (OMP-305B83; DLL4/VEGF).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608 relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and US 20040248871, which are herein incorporated by reference.
Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; 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 selenohomocysteine lactone.
Other anti-fibrotic agents are copper chelating agents penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors which block the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases. Examples include the thiolamines, particularly D-penicillamine, and its analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, and sodium-4-mercaptobutanesulphinate trihydrate.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an anti-inflammatory agent. Example anti-inflammatory agents include without limitation inhibitors of one or more of arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) and/or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, e.g., a dual inhibitor of COX-2/COX-1, COX-2/SEH, COX-2/CA, COX-2/5-LOX.
Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742) that can be co-administered include mofezolac, GLY-230, and TRK-700.
Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that can be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, meisuoshuli, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumizole, firocoxib, mavacoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1/COX2 inhibitors that can be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2/carbonic anhydrase (CA) inhibitors that can be co-administered include polmacoxib and imrecoxib.
Examples of inhibitors of secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC 27864, and compounds described in WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, WO2011048004, WO2012087771, WO2012161965, WO2013118071, WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987, and WO2008071173. Metformin has further been found to repress the COX2/PGE2/STAT3 axis, and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.
Examples of inhibitors of carbonic anhydrase (e.g., one or more of CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)) that can be co-administered include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide and dichlorphenamide. A dual COX-2/CA1/CA2 inhibitor that can be co-administered includes CG100649.
Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that can be co-administered include meclofenamate sodium, zileuton.
Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that can be co-administered include compounds described in WO2015148954. Dual inhibitors of COX-2/SEH that can be co-administered include compounds described in WO2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that can be co-administered include compounds described in WO2017160861.
Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression loci-2, TPL2; NCBI Gene ID: 1326) that can be co-administered include GS-4875, GS-5290, BHM-078 and those described in WO2006124944, WO2006124692, WO2014064215, WO2018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an agent that promotes or increases tumor oxygenation or reoxygenation, or prevents or reduces tumor hypoxia. Illustrative agents that can be co-administered include, e.g., Hypoxia inducible factor-1 alpha (HIF-1α) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such as bevasizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and/or an oxygen carrier protein (e.g., a heme nitric oxide and/or oxygen binding protein (HNOX)), such as OMX-302 and HNOX proteins described in WO2007137767, WO2007139791, WO2014107171, and WO2016149562.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody. Example immunotherapeutic agents that can be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, domvanalimab, drozitumab, duligotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, zimberelimab, and 3F8. Rituximab can be used for treating indolent B-cell cancers, including marginal-zone lymphoma, WM, CLL, and small lymphocytic lymphoma. A combination of rituximab and chemotherapy agents is especially effective.
The exemplified therapeutic antibodies can be further labeled or combined with a radioisotope particle such as indium-111, yttrium-90 (90Y-clivatuzumab), or iodine-131.
In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Illustrative ADCs that can be co-administered include without limitation drug-conjugated antibodies, fragments thereof, or antibody mimetics targeting the proteins or antigens listed above and herein. Example ADCs that can be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirine), trastuzumab (e.g., trastuzumab deruxtecan; trastuzamab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab soravtansine), depatuxizumab, vadastuximab, labetuzumab, ladiratuzumab (e.g., ladiratuzumab vedotin), loncastuximab (e.g., loncastuximab tesirine), sacituzumab (e.g., sacituzumab govitecan), datopotamab (e.g., datopotamab deruxtecan; DS-1062; Dato-DXd), patritumab (e.g., patritumab deruxtecan), lifastuzumab, indusatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab rilsodotin), indatuximab, milatuzumab, rovalpituzumab (e.g., rovalpituzumab tesirine), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamab ravtansine), disitamab (e.g., disitamab vedotin), telisotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMGN529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140. ADCs that can be co-administered are described, e.g., in Lambert, et al., Adv Ther (2017) 34:1015-1035 and in de Goeij, Current Opinion in Immunology (2016) 40:14-23.
Illustrative therapeutic agents (e.g., anticancer or antineoplastic agents) that can be conjugated to the drug-conjugated antibodies, fragments thereof, or antibody mimetics include without limitation monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), a calicheamicin, ansamitocin, maytansine or an analog thereof (e.g., mertansine/emtansine (DM1), ravtansine/soravtansine (DM4)), an anthracyline (e.g., dC=Orubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, a microtubule inhibitors (MTI) (e.g., a taxane, a vinca alkaloid, an epothilone), a pyrrolobenzodiazepine (PBD) or dimer thereof, a duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or anti-neoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog, such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agents (e.g., anticancer or antineoplastic agents) that can be conjugated to the drug-conjugated antibodies, fragments thereof, or antibody mimetics include an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.
In some embodiments, the ADCs that can be co-administered include an antibody targeting tumor-associated calcium signal transducer 2 (TROP-2; TACSTD2; EGP-1; NCBI Gene ID: 4070). Illustrative anti-TROP-2 antibodies include without limitation TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics/Gilead, IBC Pharmaceuticals), TROP2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech/Chiome, Yakult Honsha, Shanghai Henlius BioTech), LIV-2008b (LivTech/Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2—SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical/Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), and those described in WO2020016662 (Abmart), WO2020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech/Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), U.S. Pat. No. 9,850,312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead), WO2011068845 (Immunomedics/Gilead), US2016296633 (Immunomedics/Gilead), US2017021017 (Immunomedics/Gilead), US2017209594 (Immunomedics/Gilead), US2017274093 (Immunomedics/Gilead), US2018110772 (Immunomedics/Gilead), US2018185351 (Immunomedics/Gilead), US2018271992 (Immunomedics/Gilead), WO2018217227 (Immunomedics/Gilead), US2019248917 (Immunomedics/Gilead), CN111534585 (Immunomedics/Gilead), US2021093730 (Immunomedics/Gilead), US2021069343 (Immunomedics/Gilead), U.S. Pat. No. 8,435,539 (Immunomedics/Gilead), U.S. Pat. No. 8,435,529 (Immunomedics/Gilead), U.S. Pat. No. 9,492,566 (Immunomedics/Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), U.S. Pat. No. 9,427,464 (LivTech/Chiome), U.S. Ser. No. 10/501,555 (Abruzzo Theranostic/Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Pat. Nos. 7,238,785; 7,517,964 and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer agent linked by a linker. In some embodiments, the linker includes the linkers disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from dC=Orubcin (DOX), epirubicin, morpholinodC=Orubicin (morpholino-DOX), cyanomorpholino-dC=Orubicin (cyanomorpholinoDOX), 2-pyrrolino-dC=Orubicin (2-PDOX), CPT, 10-hydroxy camptothecin, SN-38, topotecan, lurtotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxanes, geldanamycin, ansamycins, and epothilones. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with sacituzumab govitecan.
In some embodiments, the ADCs that can be co-administered include an antibody targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI Gene ID: 634). In some embodiments, the CEACAM1 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the CEACAM1-ADC is as described in WO2010093395 (anti-CEACAM-1-CL2A-SN38). In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with the CEACAM1-ADC IMMU-130.
In some embodiments, the ADCs that can be co-administered include an antibody targeting MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with the HLA-DR-ADC IMMU-140.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with a cancer gene therapy and cell therapy. Cancer gene therapies and cell therapies include the insertion of 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 the 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 activate the patient's own immune system (T cells or Natural Killer cells) to kill cancer cells, or find and kill the cancer cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against cancer.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more cellular therapies. Illustrative cellular therapies include without limitation co-administration of one or more of a population of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) and/or dendritic cells (DCs). In some embodiments, the cellular therapy entails a T cell therapy, e.g., co-administering a population of alpha/beta TCR T cells, gamma/delta TCR T cells, regulatory T (Treg) cells and/or TRuC™ T cells. In some embodiments, the cellular therapy entails a NK cell therapy, e.g., co-administering NK-92 cells. As appropriate, a cellular therapy can entail the co-administration of cells that are autologous, syngeneic or allogeneic to the subject.
In some embodiments, the cellular therapy entails co-administering cells comprising chimeric antigen receptors (CARs). In such therapies, a population of immune effector cells engineered to express a CAR, wherein the CAR comprises a tumor antigen-binding domain. In T cell therapies, the T cell receptors (TCRs) are engineered to target tumor derived peptides presented on the surface of tumor cells.
With respect to the structure of a CAR, 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 costimulatory domain, or both of a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc Epsilon Rlb), CD79a, CD79b, Fcgamma RIIa, DAP10, and DAP12.
In some embodiments, the costimulatory 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, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with 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, ITGAE, CD103, ITGAL, CD1A (NCBI Gene ID: 909), CD1B (NCBI Gene ID: 910), CD1C (NCBI Gene ID: 911), CD1D (NCBI Gene ID: 912), CD1E (NCBI Gene ID: 913), ITGAM, ITGAX, 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.
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, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rbeta, IL2Rgamma, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.
In some embodiments, the TCR or CAR antigen binding domain or the immunotherapeutic agent described herein (e.g., monospecific or multi-specific antibody or antigen-binding fragment thereof or antibody mimetic) binds a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD 117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin 11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y)antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specificembryonic antigen-4 (SSEA-4); CD20; delta like 3 (DLL3); folate receptor alpha; receptor tyrosine-protein kinase, ERBB2 (Her2/neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (Prosome, Macropain) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY—BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); cancer/testis antigen 1 (NY-ESO-1); cancer/testis antigen 2 (LAGE-1α); melanoma associated antigen 1 (MAGE-A1); ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53, (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1(CYP IBI); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen recognized by T-cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation endproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of the tumor associated antigen presented in an MHC.
In some embodiments, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), 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, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 in combination, HER2-HER3 in combination, HERV—K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2/neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, L1-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-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor, alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognate binding molecule (ExoCBM), oncogene product, anti-folate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens, oncofetal antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2-Microgiobuiin, Fc Receptor-like 5 (FcRL5).
In some embodiments, the antigen binding domain binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174); A-kinase anchoring protein 4 (AKAP4; AKAP 82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PR02000; NCBI Gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 57082), centrosomal protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 55165), cancer/testis antigen 1A (CTAGIA; ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1; NCBI Gene ID: 246100), cancer/testis antigen 1B (CTAGIB; CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1; NCBI Gene ID: 1485), cancer/testis antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI Gene ID: 30848), CCCTC-binding factor like (CTCFL; BORIS, CT27, CTCF-T, HMGBIL1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer/testis antigen 83 (CT83; CXorf61, KK-LC-1, KKLC1; NCBI Gene ID: 203413), cyclin A1 (CCNA1; CT146; NCBI Gene ID: 8900), DEAD-box helicase 43 (DDX43; CT13, HAGE; NCBI Gene ID: 55510), developmental pluripotency associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testis expressed 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 neighbor (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain containing 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3; NCBI Gene ID: 10643), leucine zipper protein 4 (LUZP4; CT-28, CT-8, CT28, HOM-TES-85; NCBI Gene ID: 51213), lymphocyte antigen 6 family member K (LY6K; CT97, HSJ001348, URLC10, ly-6K; NCBI Gene ID: 54742), maelstrom spermatogenic transposon silencer (MAEL; CT128, SPATA35; NCBI Gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A1 (MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI Gene ID: 10916), kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI Gene ID: 9585), NUF2 component of NDC80 kinetochore complex (NUF2; CDCA1, CT106, NUF2R; NCBI Gene ID: 83540), nuclear RNA export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 56001), PAS domain containing repressor 1 (PASD1; CT63, CT64, OXTES1; NCBI Gene ID: 139135), PDZ binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI Gene ID: 55872), piwi like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI Gene ID: 55124), preferentially expressed antigen in melanoma (PRAME; CT130, MAPE, OIP-4, OIP4; NCBI Gene ID: 23532), sperm associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI Gene ID: 9043), sperm protein associated with the nucleus, X-linked, family member A1 (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPANX, SPANX-A; NCBI Gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT 11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI Gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTpl1, SPANX-C, SPANX-E, SPANXE; NCBI Gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI Gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI Gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI Gene ID: 6757), synaptonemal complex protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI Gene ID: 50511), testis expressed 14, intercellular bridge forming factor (TEX14; CT113, SPGF23; NCBI Gene ID: 56155), transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI Gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272) and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to an epitope of a cancer testis antigen presented in a major histocompatibility complex (MHC) molecule are known in the art and can be used in the herein described heterodimers. Cancer testis antigens associated with neoplasia are summarized, e.g., in Gibbs, et al., Trends Cancer 2018 October; 4(10):701-712 and the CT database website at cta.lncc.br/index.php. Illustrative TCRs and TCR-like antibodies that bind to an epitope of NY-ESO-1 presented in an MHC are described, e.g., in Stewart-Jones, et al., Proc Natl Acad Sci USA. 2009 Apr. 7; 106(14):5784-8; WO2005113595, WO2006031221, WO2010106431, WO2016177339, WO2016210365, WO2017044661, WO2017076308, WO2017109496, WO2018132739, WO2019084538, WO2019162043, WO2020086158 and WO2020086647. Illustrative TCRs and TCR-like antibodies that bind to an epitope of PRAME presented in an MHC are described, e.g., in WO2011062634, WO2016142783, WO2016191246, WO2018172533, WO2018234319 and WO2019109821. Illustrative TCRs and TCR-like antibodies that bind to an epitope of a MAGE variant presented in an MHC are described, e.g., in WO2007032255, WO2012054825, WO2013039889, WO2013041865, WO2014118236, WO2016055785, WO2017174822, WO2017174823, WO2017174824, WO2017175006, WO2018097951, WO2018170338, WO2018225732 and WO2019204683. Illustrative TCRs and TCR-like antibodies that bind to an epitope of alpha fetoprotein (AFP) presented in an MHC are described, e.g., in WO2015011450. Illustrative TCRs and TCR-like antibodies that bind to an epitope of SSX2 presented in an MHC are described, e.g., in WO2020063488. Illustrative TCRs and TCR-like antibodies that bind to an epitope of KK-LC-1 (CT83) presented in an MHC are described, e.g., in WO2017189254.
Examples of cell therapies include: Algenpantucel-L, Sipuleucel-T, (BPX-501) rivogenlecleucel U.S. Pat. No. 9,089,520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells 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/4-1BBL CAR T cells, autologous 4H11-28z/fIL-12/EFGRt T cell, 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.
In some embodiments, the one or more additional co-administered therapeutic agents can be categorized by their mechanism of action, e.g., into the following groups:
Some chemotherapy agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, dC=Orubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, dC=Orubicin, dC=Orubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, dC=Orubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17 AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, dC=Orubicin, dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, PEGylated liposomal dC=Orubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, R—CHOP (rituximab and CHOP), R—CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).
One modified approach is radioimmunotherapy, wherein 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 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.
The abovementioned therapies can be supplemented or combined with stem cell transplantation or treatment. 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, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Treatment of non-Hodgkin's lymphomas (NHL), especially those of B cell origin, includes using monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, dC=Orubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (Mitoxantrone, Chlorambucil, Prednisolone), all optionally including rituximab (R) and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy.
Examples of unconjugated monoclonal antibodies for the treatment of NHL/B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.
Examples of experimental antibody agents used in treatment of NHL/B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.
Examples of standard regimens of chemotherapy for NHL/B-cell cancers include CHOP, FCM, CVP, MCP, R—CHOP (rituximab, cyclophosphamide, dC=Orubicin, vincristine, and prednisone), R-FCM, R—CVP, and R MCP.
Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).
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 abovementioned therapies may be combined with stem cell transplantation or ICE in order to treat MCL.
An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies like rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.
A modified approach to treat MCL is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.
Other approaches to treating MCL include autologous stem cell transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administering antiangiogenesis agents such as thalidomide, especially in combination with rituximab.
Another treatment approach is administering drugs that lead to the degradation of Bcl-2 protein and increase cancer cell sensitivity to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents.
A further treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN@, VELCADE®, or other chemotherapeutic agents.
Other recent therapies for MCL have been disclosed. Such examples include flavopiridol, palbociclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).
Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM) include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta alethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, dC=Orubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposomal dC=Orubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, ulocuplumab, veltuzumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.
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 body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, dC=Orubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include rituximab (Rituxan®), cyclophosphamide, dC=Orubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy®(polatuzumab vedotin), BR (bendamustine (Treanda®), gemcitabine, oxiplatin, oxaliplatin, tafasitamab, polatuzumab, cyclophosphamide, or combinations thereof. In some embodiments, therapeutic agents used to treat DLBCL include R—CHOP (rituximab+cyclophosphamide+dC=Orubicin hydrochloride (hydroxydaunorubicin)+vincristine sulfate (Oncovin®), +prednisone), rituximab+bendamustine, R-ICE (Rituximab+Ifosfamide+Carboplatin+Etoposide), rituximab+lenalomide, R-DHAP (rituximab+dexamethasone+high-dose cytarabine (Ara C)+cisplatin), Polivy®(polatuzumab vedotin)+BR (bendamustine (Treanda®) and rituximab (Rituxan®), R-GemOx (Gemcitabine+oxaliplatin+rituximab), Tafa-Len (tafasitamab+lenalidomide), Tafasitamab+Revlimid®, polatuzumab+bendamustine, Gemcitabine+oxaliplatin, R-EPOCH (rituximab+etoposide phosphate+prednisone+vincristine sulfate (Oncovin®)+cyclophosphamide+dC=Orubicin hydrochloride (hydroxydaunorubicin)), or CHOP (cyclophosphamide+dC=Orubicin hydrochloride (hydroxydaunorubicin)+vincristine sulfate (Oncovin®)+prednisone). In some embodiments, therapeutic agents used to treat DLBCL include tafasitamab, glofitamab, epcoritamab, Lonca-T (loncastuximab tesirine), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, odronextamab, Auto-03, Allo-501A, or TAK-007.
Therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, dC=Orubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R—CVP, ICE, R-ICE, FCR, and FR.
Therapeutic agents used to treat HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine+daunorubicin and cytarabine+idarubicin. In some embodiments, therapeutic agents used to treat HR MDS include pevonedistat, venetoclax, sabatolimab, guadecitabine, rigosertib, ivosidenib, enasidenib, selinexor, BGB324, DSP-7888, or SNS-301.
Therapeutic agents used to treat LR MDS include lenalidomide, azacytidine, and combinations thereof. In some embodiments, therapeutic agents used to treat LR MDS include roxadustat, luspatercept, imetelstat, LB-100, or rigosertib.
Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, midostaurin (Rydapt®), venetoclax, azacitidine, ivasidenib, gilteritinib, enasidenib, low-dose cytarabine (LoDAC), mitoxantrone, fludarabine, granulocyte-colony stimulating factor, idarubicin, gilteritinib (Xospata®), enasidenib (Idhifa®), ivosidenib (Tibsovo®), decitabine (Dacogen®), mitoxantrone, etoposide, Gemtuzumab ozogamicin (Mylotarg®), glasdegib (Daurismo®), and combinations thereof. In some embodiments, therapeutic agents used to treat AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony stimulating factor (G-CSF) and idarubicin), cytarabine+idarubicin, cytarabine+daunorubicin+midostaurin, venetoclax+azacitidine, cytarabine+daunorubicin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used to treat AML include pevonedistat, venetoclax, sabatolimab, eprenetapopt, or lemzoparlimab.
Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex®), pomalidomide, Cyclophosphamide, Carfilzomib (Kyprolis®), Elotuzumab (Empliciti), and combinations thereof. In some embodiments therapeutic agents used to treat MM include RVS (lenalidomide+bortezomib+dexamethasone), RevDex (lenalidomide plus dexamethasone), CYBORD (Cyclophosphamide+Bortezomib+Dexamethasone), Vel/Dex (bortezomib plus dexamethasone), or PomDex (Pomalidomide+low-dose dexamethasone). In some embodiments, therapeutic agents used to treat MM include JCARH125, TAK-573, belantamab-m, ide-cel (CAR-T).
Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, atezolizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, dC=Orubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, Ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal dC=Orubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer (e.g., HR+/−/HER2+/−) include trastuzumab (Herceptin®), pertuzumab (Perjeta®), docetaxel, carboplatin, palbociclib (Ibrance®), letrozole, trastuzumab emtansine (Kadcyla®), fulvestrant (Faslodex®), olaparib (Lynparza®), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor®), exemestane, eribulin mesylate (Halaven®), and combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab+pertuzumab+docetaxel, trastuzumab+pertuzumab+docetaxel+carboplatin, palbociclib+letrozole, tucatinib+capecitabine, lapatinib+capecitabine, palbociclib+fulvestrant, or everolimus+exemestane. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), balixafortide, elacestrant, or a combination thereof. In some embodiments therapeutic agents used to treat breast cancer include balixafortide+eribulin.
Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, dC=Orubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sacituzumab govitecan (Trodelvy®), pembrolizumab (Keytruda®), cisplatin, dC=Orubicin, epirubicin, or a combination thereof. In some embodiments, therapeutic agents to treat TNBC include atezolizumab+paclitaxel, bevacizumab+paclitaxel, carboplatin+paclitaxel, carboplatin+gemcitabine, or paclitaxel+gemcitabine. In some embodiments, therapeutic agents used to treat TNBC include eryaspase, capivasertib, alpelisib, rucaparib+nivolumab, atezolumab+paclitaxel+gemcitabine+capecitabine+carboplatin, ipatasertib+paclitaxel, ladiratuzumab vedotin+pembrolimab, durvalumab+DS-8201a, trilaciclib+gemcitabine+carboplatin. In some embodiments, therapeutic agents used to treat TNBC include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), balixafortide, adagloxad simolenin, nelipepimut-s (NeuVax®), nivolumab (Opdivo®), rucaparib, toripalimab (Tuoyi®), camrelizumab, capivasertib, durvalumab (Imfinzi®), and combinations thereof. In some embodiments, therapeutic agents use to treat TNBC include nivolumab+rucaparib, bevacizumab (Avastin®)+chemotherapy, toripalimab+paclitaxel, toripalimab+albumin-bound paclitaxel, camrelizumab+chemotherapy, pembrolizumab+chemotherapy, balixafortide+eribulin, durvalumab+trastuzumab deruxtecan, durvalumab+paclitaxel, or capivasertib+paclitaxel.
Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), erdafitinib, eganelisib, lenvatinib, bempegaldesleukin (NKTR-214), or a combination thereof. In some embodiments, therapeutic agents used to treat bladder cancer include eganelisib+nivolumab, pembrolizumab (Keytruda®)+enfortumab vedotin (Padcev®), nivolumab+ipilimumab, duravalumab+tremelimumab, lenvatinib+pembrolizumab, enfortumab vedotin (Padcev®)+pembrolizumab, and bempegaldesleukin+nivolumab.
Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combinations thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or a combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab+leucovorin+5-FU+oxaliplatin (FOLFOX), bevacizumab+FOLFIRI, bevacizumab+FOLFOX, aflibercept+FOLFIRI, cetuximab+FOLFIRI, bevacizumab+XELOX, and bevacizumab+FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib+encorafenib+cetuximab, trametinib+dabrafenib+panitumumab, trastuzumab+pertuzumab, napabucasin+FOLFIRI+bevacizumab, nivolumab+ipilimumab.
Therapeutic agents used to treat esophageal and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof. In some embodiments, therapeutic agents used to treat gastroesophageal junction cancer (GEJ) include herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, therapeutic agents used to treat GEJ cancer include ALX-148, AO-176, or IBI-188.
Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, Irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.
Therapeutic agents used to treat head & neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.
Therapeutic agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivolumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents used to treat HNSCC include pembrolizumab+carboplatin+5-FU, cetuximab+cisplatin+5-FU, cetuximab+carboplatin+5-FU, cisplatin+5-FU, and carboplatin+5-FU. In some embodiments, therapeutic agents used to treat HNSCC include durvalumab, durvalumab+tremelimumab, nivolumab+ipilimumab, rovaluecel, pembrolizumab, pembrolizumab+epacadostat, GSK3359609+pembrolizumab, lenvatinib+pembrolizumab, retifanlimab, retifanlimab+enobituzumab, ADU-S100+pembrolizumab, epacadostat+nivolumab+ipilimumab/lirilumab.
Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combinations thereof. In some embodiments, therapeutic agents used to treat NSCLC include alectinib (Alecensa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif*), nivolumab (Opdivo®), gefitinib (Iressa®), and combinations thereof. In some embodiments, therapeutic agents used to treat NSCLC include dabrafenib+trametinib, pembrolizumab+carboplatin+pemetrexed, pembrolizumab+carboplatin+nab-paclitaxel, ramucirumab+docetaxel, bevacizumab+carboplatin+pemetrexed, pembrolizumab+pemetrexed+carboplatin, cisplatin+pemetrexed, bevacizumab+carboplatin+nab-paclitaxel, cisplatin+gemcitabine, nivolumab+docetaxel, carboplatin+pemetrexed, carboplatin+nab-paclitaxel, or pemetrexed+cisplatin+carboplatin. In some embodiments, therapeutic agents used to NSCLC include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumab vedotin (Padcev®), durvalumab, canakinumab, cemiplimab, nogapendekin alfa, avelumab, tiragolumab, domvanalimab, vibostolimab, ociperlimab, or a combination thereof. In some embodiments, therapeutic agents used to treat NSCLC include datopotamab deruxtecan+pembrolizumab, datopotamab deruxtecan+durvalumab, durvalumab+tremelimumab, pembrolizumab+lenvatinib+pemetrexed, pembrolizumab +olaparib, nogapendekin alfa (N-803)+pembrolizumab, tiragolumab+atezolizumab, vibostolimab+pembrolizumab, or ociperlimab+tislelizumab.
Therapeutic agents used to treat small cell lung cancer (SCLC) include atezolizumab, bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, dC=Orubicin, etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combinations thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, trilaciclib, or combinations thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab+carboplatin+etoposide, atezolizumab+carboplatin, atezolizumab+etoposide, or carboplatin+paclitaxel.
Therapeutic agents used to treat ovarian cancer include 5-flourouracil, albumin bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, dC=Orubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal dC=Orubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combinations thereof.
Therapeutic agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane®), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents used to treat pancreatic cancer include 5-FU+leucovorin+oxaliplatin+irinotecan, 5-FU+nanoliposomal irinotecan, leucovorin+nanoliposomal irinotecan, and gemcitabine+nab-paclitaxel.
Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi®), leuprolide, trifluridine, tipiracil (Lonsurf), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitoxantrone, bicalutamide, LHRH, flutamide, ADT, sabizabulin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide+leuprolide, trifluridine+tipiracil (Lonsurf), cabazitaxel+prednisone, abiraterone+prednisone, docetaxel+prednisone, mitoxantrone+prednisone, bicalutamide+LHRH, flutamide+LHRH, leuprolide+flutamide, and abiraterone+prednisone+ADT.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more therapeutic agents selected from a PI3K inhibitor, a Trop-2 binding agent, CD47 antagonist, a SIRPa antagonist, a FLT3R agonist, a PD-1 antagonist, a PD-L1 antagonist, an MCL1 inhibitor, a CCR8 binding agent, an HPK1 antagonist, a DGKa inhibitor, a CISH inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a beta-catenin degrader, a helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGIT antagonist, a TREM1 binding agent, a TREM2 binding agent, a CD137 agonist, a GITR binding agent, an OX40 binding agent, and a CAR-T cell therapy.
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more therapeutic agents selected from a PI3Kd inhibitor (e.g., idealisib), an anti-Trop-2 antibody drug conjugate (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), an anti-CD47 antibody or a CD47-blocking agent (e.g., magrolimab, DSP-107, AO-176, ALX-148, letaplimab (IBI-188), lemzoparlimab, TTI-621, TTI-622), an anti-SIRPa antibody (e.g., GS-0189), a FLT3L-Fc fusion protein (e.g., GS-3583), an anti-PD-1 antibody (pembrolizumab, nivolumab, zimberelimab), a small molecule PD-L1 inhibitor (e.g., GS-4224), an anti-PD-L1 antibody (e.g., atezolizumab, avelumab), a small molecule MCL1 inhibitor (e.g., GS-9716), a small molecule HPK1 inhibitor (e.g., GS-6451), a HPK1 degrader (PROTAC; e.g., ARV-766), a small molecule DGKa inhibitor, a small molecule CD73 inhibitor (e.g., quemliclustat (AB680)), an anti-CD73 antibody (e.g., oleclumab), a dual A2a/A2b adenosine receptor antagonist (e.g., etrumadenant (AB928)), an anti-TIGIT antibody (e.g., tiragolumab, vibostolimab, domvanalimab, AB308), an anti-TREM1 antibody (e.g., PY159), an anti-TREM2 antibody (e.g., PY314), a CD137 agonist (e.g., AGEN-2373), a GITR/OX40 binding agent (e.g., AGEN-1223) and a CAR-T cell therapy (e.g., axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel).
In some embodiments, a compound disclosed herein or the antibody and/or fusion protein provided herein is administered with one or more therapeutic agents selected from idealisib, sacituzumab govitecan, magrolimab, GS-0189, GS-3583, zimberelimab, GS-4224, GS-9716, GS-6451, quemliclustat (AB680), etrumadenant (AB928), domvanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtagene ciloleucel and brexucabtagene autoleucel.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations (compositions). The formulations, both for veterinary and for human use, of the disclosure comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The camer(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.) which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
In certain embodiments, formulations suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
In certain embodiments, the pharmaceutical formulations include one or more compounds of the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
The amount of active ingredient that is combined with the inactive ingredients to produce a dosage form will vary depending upon the host treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weight: weight). In some embodiments, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg or 1 to 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain no more than about 400 mg of the compound of Formula (I). In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
It should be understood that in addition to the ingredients particularly mentioned above the formulations disclosed herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier are further provided.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
One or more compounds of Formula (I) (herein referred to as the active ingredients), or a pharmaceutically acceptable salt thereof, are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this disclosure is that they are orally bioavailable and can be dosed orally. Accordingly, in one embodiment, the pharmaceutical compositions described herein are oral dosage forms. In certain embodiments, the pharmaceutical compositions described herein are oral solid dosage forms.
Hard gelatin capsules containing the following ingredients are prepared:
The above ingredients are mixed and filled into hard gelatin capsules.
A tablet Formula is prepared using the ingredients below:
The components are blended and compressed to form tablets.
A dry powder inhaler formulation is prepared containing the following components:
The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Tablets, each containing 30 mg of active ingredient, are prepared as follows:
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
Suppositories, each containing 25 mg of active ingredient are made as follows:
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Suspensions, each containing 50 mg of active ingredient per 5.0 mL dose are made as follows:
The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
A subcutaneous formulation may be prepared as follows:
Formulation Example 8
An injectable preparation is prepared having the following composition:
Formulation Example 9
A topical preparation is prepared having the following composition:
All of the above ingredients, except water, are combined and heated to 60° C. with stirring. A sufficient quantity of water at 60° C. is then added with vigorous stirring to emulsify the ingredients and water then added q.s. 100 g.
Sustained release formulations of this disclosure may be prepared as follows: compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnesium stearate) and compressed into tablets. Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols). The resulting tablets may be coated with an optional film-forming agent, for identification, taste-masking purposes and to improve ease of swallowing. The film forming agent will typically be present in an amount ranging from between 2% and 4% of the tablet weight. Suitable film-forming agents are well known to the art and include hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm. Pharma) and the like. These film-forming agents may optionally contain colorants, plasticizers and other supplemental ingredients.
The compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression. The tablet size will depend primarily upon the amount of compound in the tablet. The tablets will include from 300 to 1100 mg of compound free base. Preferably, the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg and 900-1100 mg.
In order to influence the dissolution rate, the time during which the compound containing powder is wet mixed is controlled. Preferably the total powder mix time, i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following granulation, the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60° C.
A tablet Formula is prepared using the ingredients below:
The components are blended and compressed to form tablets.
The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
In the general schemes shown below, compounds of the present disclosure may be prepared by the synthetic route shown, wherein R3b′ is selected from H, F, optionally protected OH, or OMe, PG is a suitable protecting group, and the remaining variables are as defined herein.
Stereoisomers described herein were prepared via an asymmetric synthesis as described herein or separated as described herein. For compounds separated via chiral separation, stereocenters were arbitrarily assigned.
Step 1. In a flask were placed 6-bromo-7-fluoro-2H-isoquinolin-1-one (5.0 g, 20.7 mmol), tert-butyl N-[(1S)-4-bromo-1-methyl-3-oxo-butyl]carbamate (6.08 g, 21.7 mmol), cesium carbonate (16.8 g, 51.6 mmol) in DMF (103 mL). The solution was stirred at room temperature overnight, filtered through a pad of Celite® and concentrated. The crude residue was purified by flash chromatography (Hexanes/EtOAc) to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-1-methyl-3-oxo-butyl]carbamate. ES/MS m/z: 442.9 [M+H]+.
Step 2. In a flask were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-1-methyl-3-oxo-butyl]carbamate (9.12 g, 20.7 mmol) and THF (200 mL) and NaBH4 (1.17 g, 31.0 mmol) was added. After stirring overnight, the solution is carefully quenched with water (20 mL) and the pH is adjusted to ˜4 with 1N HCl. The mixture was diluted with water, extracted with EtOAc, and concentrated in vacuo to give tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-hydroxy-1-methyl-butyl]carbamate (Intermediate 1). ES/MS m/z: 444.9 [M+H]+.
Step 3. In a flask were placed tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-hydroxy-1-methyl-butyl]carbamate (9.16 g, 20.7 mmol) and TFA (10 mL) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours and concentrated to give 2-[(4S)-4-amino-2-hydroxy-pentyl]-6-bromo-7-fluoro-isoquinolin-1-one. ES/MS m/z: 345.4 [M+2H]++.
Step 4. In a flask were placed 2-[(4S)-4-amino-2-hydroxy-pentyl]-6-bromo-7-fluoro-isoquinolin-1-one (7.09 g, 20.7 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (8.15 g, 24.8 mmol), triethylamine (14.4 mL, 103 mmol), and DMF (40 mL). The mixture was heated to 85° C. for 3 hours, concentrated, and purified by flash chromatography (Hexanes/EtOAc) to give 6-bromo-7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. ES/MS m/z: 636.9 [M+H]+.
Step 5. In a flask were placed 6-bromo-7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one (4.96 g, 7.80 mmol), (diethylamino)difluorosulfonium tetrafluoroborate (2.68 g, 11.7 mmol), triethylamine trihydrofluoride (3.8 mL, 23.4 mmol), and DCE (78 mL). The mixture was heated to 75° C. and stirred overnight. The solution was cooled to room temperature and quenched with saturated aq. NaHCO3 and diluted with DCM and water. Brine was added to the organic layer to break down the emulsion. The layers were separated and filtered over a pad of Celite®. The remaining organic and aqueous layers were separated again, concentrated in vacuo, and purified by flash chromatography eluting with EtOAc in hexanes 0-100% to afford 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. ES/MS m/z: 638.9 [M+H]+.
Step 6. A flask was charged with 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one (2.26 g, 3.55 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (579 mg, 0.71 mmol), potassium acetate (1.39 g, 14.2 mmol), and bis(pinacolato)diboron (2.70 g, 10.6 mmol) and flushed with nitrogen gas. Dioxane (35 mL) was added and the solution was heated to 100° C. for 4 h. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (1.46 g, 5.32 mmol), CataCXium Pd G4 (132 mg, 0.18 mmol), cesium carbonate (3.47 g, 10.6 mmol), and water (8.75 mL) were added. The solution was then stirred at 80° C. overnight. The solution is cooled and filtered through a pad of Celite® with EtOAc. The filtrate is diluted with EtOAc and water and the layers are stirred vigorously stirred for 10 minutes. The organic layer is concentrated in vacuo and purified by column chromatography eluting with EtOAc in hexanes 0-100% to afford 7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 705.3 [M+H]+.
Step 7. A vial was charged with 7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (2.50 g, 3.54 mmol), TFA (7 mL), and DCM (7 mL). The solution was stirred for 1 h and concentrated in vacuo. MeOH (7 mL) and ethylenediamine (0.7 mL) were added and the solution was stirred for 15 minutes before being purified by column chromatography eluting with EtOAc in hexanes 0-100% and then MeOH in DCM 0-20% to afford Example 1, 7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.49 (d, J=0.9 Hz, 2H), 8.45 (d, J=7.1 Hz, 1H), 8.05 (dd, J=11.3, 4.9 Hz, 1H), 7.91 (d, J=13.7 Hz, 1H), 7.48 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 6.52 (ddd, J=19.7, 9.0, 3.7 Hz, 1H), 5.25-4.76 (m, 1H), 4.46-4.00 (m, 3H), 2.27-1.75 (m, 2H), 1.24 (dd, J=10.2, 6.3 Hz, 3H). ES/MS: m/z 575.1 [M+H]+.
Step 1. Examples 2 and Example 3 were separated via chiral SFC (AD-H, 5 μm, 21×250 mm column; 35% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (R)-configuration (Example 2), and the second eluting peak was arbitrarily assigned as the (S)-configuration (Example 3).
Example 2: 1H NMR (400 MHz, Methanol-d4) δ 9.34 (d, J=0.9 Hz, 2H), 8.49 (d, J=7.0 Hz, 1H), 8.16 (d, J=11.3 Hz, 1H), 7.99 (s, 1H), 7.48-7.25 (m, 1H), 6.84 (d, J=7.4 Hz, 1H), 5.20-4.96 (m, 1H), 4.48 (ddd, J=28.6, 14.4, 2.8 Hz, 1H), 4.26 (ddd, J=18.8, 14.4, 7.5 Hz, 2H), 2.31-1.95 (m, 2H), 1.39 (d, J=6.5 Hz, 4H). ES/MS: m/z 574.9 [M+H]+.
Example 3: 1H NMR (400 MHz, Methanol-d4) δ 9.32 (d, J=0.9 Hz, 2H), 8.47 (d, J=7.0 Hz, 1H), 8.13 (d, J=11.3 Hz, 1H), 7.95 (s, 1H), 7.41 (d, J=7.5 Hz, 1H), 6.82 (d, J=7.4 Hz, 1H), 5.06 (dt, J=50.5, 8.6 Hz, 1H), 4.48 (ddd, J=29.3, 14.4, 2.8 Hz, 1H), 4.21 (ddt, J=18.1, 14.4, 6.6 Hz, 2H), 2.25-1.88 (m, 2H), 1.46-1.17 (m, 4H). ES/MS m/z: 574.9 [M+H].
The title compound was synthesized as described in Example 1, using 2-chloro-5-(difluoromethyl)pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 2 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.25 (d, J=1.2 Hz, 2H), 8.42 (d, J=7.2 Hz, 1H), 8.04 (d, J=11.2 Hz, 1H), 7.93 (s, 1H), 7.53-7.06 (m, 2H), 6.84 (d, J=7.4 Hz, 1H), 6.55 (dd, J=9.0, 3.6 Hz, 1H), 4.92 (dd, J=50.7, 9.7 Hz, 1H), 4.44-4.09 (m, 3H), 2.12 (ddd, J=39.4, 13.1, 9.6 Hz, 1H), 1.97-1.79 (m, 1H), 1.23 (d, J=6.4 Hz, 3H). ES/MS m/z: 557.1 [M+H]+.
The title compound was synthesized as described in Example 1, using 2-chloro-5-(difluoromethyl)pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 3 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.25 (d, J=1.2 Hz, 2H), 8.42 (d, J=7.2 Hz, 1H), 8.03 (d, J=11.3 Hz, 1H), 7.90 (s, 1H), 7.57-6.95 (m, 2H), 6.84 (d, J=7.4 Hz, 1H), 6.50 (dd, J=8.5, 3.9 Hz, 1H), 5.00 (d, J=52.0 Hz, 1H), 4.50-3.99 (m, 4H), 2.19-1.84 (m, 2H), 1.40-1.11 (m, 4H). ES/MS m/z: 557.1 [M+H]+.
The title compound was synthesized as described in Example 1, using 2-bromo-5-methoxy pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 2 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.75 (s, 2H), 8.29 (d, J=7.3 Hz, 1H), 8.07-7.88 (m, 2H), 7.43 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.55 (dd, J=9.1, 3.6 Hz, 1H), 5.06-4.77 (m, 1H), 4.43-4.10 (m, 3H), 4.00 (s, 3H), 2.25-1.97 (m, 1H), 1.96-1.75 (m, 1H), 1.23 (d, J=6.3 Hz, 3H). ES/MS m/z: 537.1 [M+H]+.
The title compound was synthesized as described in Example 1, using 2-bromo-5-methoxy pyrimidine in place of 2-iodo-5-(trifluoromethyl)pyrimidine chiral separation was performed as described in Example 3 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.75 (s, 2H), 8.29 (d, J=7.3 Hz, 1H), 8.07-7.82 (m, 2H), 7.44 (d, J=7.4 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.64-6.39 (m, 1H), 5.16-4.80 (m, 1H), 4.45-4.06 (m, 3H), 4.00 (s, 3H), 2.22-1.81 (m, 2H), 1.25 (d, J=6.3 Hz, 3H). ES/MS m/z: 537.1 [M+H]+.
The title compound was synthesized as described in Example 1, using 2-(2-chloropyrimidin-5-yl)propan-2-ol in place of 2-iodo-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 2 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.07 (s, 2H), 8.34 (d, J=7.2 Hz, 1H), 8.07-7.88 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 6.82 (d, J=7.4 Hz, 1H), 6.56 (dd, J=9.0, 3.7 Hz, 1H), 4.93 (d, J=50.3 Hz, 1H), 4.44-4.12 (m, 3H), 2.24-2.00 (m, 1H), 1.88 (d, J=13.1 Hz, 1H), 1.55 (s, 6H), 1.24 (d, J=6.4 Hz, 3H). ES/MS m/z: 565.1 [M+H].
The title compound was synthesized as described in Example 1, using 2-(2-chloropyrimidin-5-yl)propan-2-ol in place of 2-iodo-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 3 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.07 (s, 2H), 8.34 (d, J=7.2 Hz, 1H), 8.07-7.88 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 6.82 (d, J=7.4 Hz, 1H), 6.56 (dd, J=9.0, 3.7 Hz, 1H), 4.93 (d, J=50.3 Hz, 1H), 4.44-4.12 (m, 3H), 2.24-2.00 (m, 1H), 1.88 (d, J=13.1 Hz, 1H), 1.55 (s, 6H), 1.24 (d, J=6.4 Hz, 3H). ES/MS m/z: 565.1 [M+H]+.
The title compound was synthesized as described in Example 1, starting with Intermediate 1 and with the following modification in step 1.
Step 1. tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-hydroxy-1-methyl-butyl]carbamate (intermediate 1, 400 mg, 0.902 mmol) was dissolved in DMF (9.4 mL) and iodomethane was added followed by silver(I) oxide (460 mg, 1.99 mmol). Solution was then heated to 50° C. and stirred overnight. Solution mixture was filtered through Celite®, concentrated in vacuo, and purified via column chromatography (0-100% EtOAc-Hexane) to afford Example 10, tert-butyl N-[(1S)-4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-methoxy-1-methyl-butyl]carbamate. 1H NMR (400 MHz, DMSO-d6) δ 12.59-12.35 (m, 1H), 9.49 (d, J=1.0 Hz, 2H), 8.44 (d, J=7.2 Hz, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.87 (s, 1H), 7.46 (dd, J=7.4, 4.8 Hz, 1H), 6.84 (dd, J=8.3, 4.7 Hz, 1H), 6.50 (dd, J=8.3, 4.0 Hz, 1H), 4.10 (dh, J=26.7, 7.1, 6.4 Hz, 2H), 3.64 (s, 1H), 3.23 (d, J=7.0 Hz, 3H), 1.90-1.59 (m, 2H), 1.27-1.13 (m, 3H). ES/MS: m z 587.1 [M+H]+.
Step 1. In a round-bottomed flask 1-methoxy-4-[[(1S)-1-methylbut-3-enoxy]methyl]benzene (4.00 g, 19.4 mmol) was dissolved in DCM (20 mL, 1M) and cooled to 0° C. Triethylamine trihydrofluoride (7.89 mL, 48.5 mmol) was added, followed by N-iodosuccinimide (4.8 g, 21.3 mmol) and the solution was warmed room temperature and stirred for 8 h. The solution is quenched by addition of saturated aq. NaHCO3 (50 ml), and the aqueous layer was extracted with DCM (3×75 mL). The combined organic layers were washed with saturated aq. Na2S2O3 (100 mL), and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-20% EtOAc in Hexane) to give 1-[[(1S)-3-fluoro-4-iodo-1-methyl-butoxy]methyl]-4-methoxy-benzene. ES/MS: m z 353.1 [M+H]+.
Step 2. In a round-bottomed flask was added −[[(1S)-3-fluoro-4-iodo-1-methyl-butoxy]methyl]-4-methoxy-benzene (0.695 g, 1.97 mmol), 6-bromo-7-fluoro-2H-isoquinolin-1-one (0.525 g, 2.17 mmol), and cesium carbonate (1.29 g, 3.95 mmol) in DMF (10 mL). The solution was stirred for 48 h at room temperature, and then quenched with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were then washed with 10% LiCl(aq) solution (100 mL) and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one. ES/MS: m z 467.1 [M+H]+.
Step 3. In a round-bottomed flask, 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one (0.624 g, 1.34 mmol) was dissolved in DCM/Water (27 mL, 19:1 DCM/water) and cooled to 0° C. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.22 g, 5.35 mmol) was added in one portion, and the solution was allowed to warm to room temperature and stirred for 2 h at room temperature. The solution was filtered over Celite©, diluted with DCM (50 mL), and washed with sat. aq. NaHCO3 (3×25 mL). The combined organic layer were dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-hydroxy-pentyl]isoquinolin-1-one. ES/MS: m z 347.1 [M+H]+.
Step 4. In a flask were placed 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-hydroxy-pentyl]isoquinolin-1-one (0.435 g, 1.26 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (0.689 g, 1.88 mmol), DIPEA (0.66 mL, 3.77 mmol), and DMF (7 mL). The mixture was heated to 85° C. for 48 h, then quenched with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 10% LiCI solution(aq) (100 mL) and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]isoquinolin-1-one. ES/MS: m z 638.1 [M+H]+.
Step 5. A round-bottomed flask was charged with 6-bromo-7-fluoro-2-[(4S)-2-fluoro-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]isoquinolin-1-one (0.225 g, 0.352 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (29 mg, 0.35 mmol), potassium acetate (104 mg, 1.06 mmol), and bis(pinacolato)diboron (134 mg, 0.53 mmol) and 1,4-dioxane (5 mL). The solution was purged with nitrogen gas for 15 minutes, and the solution was heated to 80° C. for 4 h. After cooling, 2-chloro-5-(trifluoromethyl)pyrimidine (97 mg, 0.529 mmol), CataCXium Pd G4 (26 mg, 0.035 mmol), and 2 N sodium carbonate solution (0.39 mL, 0.77 mmol) were added. The solution was then stirred at 80° C. for 15 minutes, cooled and filtered through a pad of Celite® with EtOAc. The organic layer is concentrated and purified by flash chromatography (0-100% EtOAc in hexane) to give 7-fluoro-2-((4S)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one.
Step 6. A vial was charged with 7-fluoro-2-((4S)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one (136 mg, 0.194 mmol), TFA (5 mL), and DCM (15 mL). The solution was stirred for 1 h and concentrated in vacuo. The residue is then treated with 2 N ammonia in methanol (3 ml), stirred for 15 minutes, concentrated in vacuo and directly purified by reverse phase prep-HPLC (5-100% MeCN in water, 0.1% TFA) to afford Example 11, 7-fluoro-2-((4S)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. ES/MS: m z 576.1 [M+H]+.
Step 1. Example 12 and Example 13 were separated via chiral SFC (AD-H, 5 μm, 4.6×100 mm column; 30% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (R)-configuration (Example 12), and the second eluting peak was arbitrarily assigned as the (S)-configuration (Example 13).
Example 12: 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.49 (d, J=0.9 Hz, 2H), 8.45 (d, J=7.1 Hz, 1H), 8.29 (s, 1H), 8.03 (d, J=11.3 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 5.21 (m, 1H), 5.12 (d, J=5.1 Hz, 1H), 5.03-4.96 (m, 1H), 4.42 (dd, J=14.3, 2.8 Hz, 1H), 4.35 (dd, J=14.4, 2.8 Hz, 1H), 4.20 (m, 2H), 2.23-2.01 (m, 2H), 1.39 (d, J=6.1 Hz, 3H). ES/MS: 576.1 m/z [M+H]+.
Example 13: 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.49 (d, J=0.9 Hz, 2H), 8.45 (d, J=7.2 Hz, 1H), 8.32 (s, 1H), 8.05 (d, J=11.3 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 5.21-5.12 (m, 1H), 5.12-5.02 (m, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 2.22-2.01 (m, 2H), 1.36 (d, J=6.0 Hz, 3H). ES/MS m/z: 576.1 [M+H]+.
Example 14: 6-(4-amino-5-(difluoromethyl)pyrimidin-2-yl)-7-fluoro-2-((2R,4S)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)isoquinolin-1(2H)-one
The title compound was synthesized as described in Example 1, using 2-chloro-5-(difluoromethyl)pyrimidin-4-amine in place of 2-chloro-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 2 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.18 (d, J=7.1 Hz, 1H), 7.95 (d, J=11.0 Hz, 1H), 7.56 (s, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.10 (t, J=54.2 Hz, 1H), 6.77 (d, J=7.4 Hz, 1H), 5.26-5.15 (m, 1H), 5.15-4.93 (m, 1H), 4.46-4.27 (m, 1H), 4.24-4.10 (m, 1H), 2.25-1.99 (m, 2H), 1.39 (d, J=6.1 Hz, 3H). ES/MS m/z: 537.1 [M+H]+.
The title compound was synthesized as described in Example 1, using 2-chloro-5-(difluoromethyl)pyrimidin-4-amine in place of 2-chloro-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 3 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 8.18 (d, J=7.1 Hz, 1H), 7.97 (d, J=11.1 Hz, 1H), 7.58 (s, 2H), 7.44 (d, J=7.4 Hz, 1H), 7.10 (t, J=54.1 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 5.22-5.11 (m, 1H), 5.11-4.87 (m, 1H), 4.45-4.28 (m, 1H), 4.26-4.11 (m, 1H), 2.22-1.96 (m, 2H), 1.36 (d, J=6.0 Hz, 3H). ES/MS m/z: 573.1 [M+H]+.
Step 1. In a round-bottomed flask, 1-methoxy-4-[[(1S)-1-methylbut-3-enoxy]methyl]benzene (4.70 g, 22.8 mmol) was dissolved in DCM (100 mL). mCPBA (8.43 g, 34.2 mmol) was added in one portion and stirred for 8 h. The gel-like suspension was filtered to remove excess benzoic acid, and washed with 50 mL of 2 N Na2CO3(aq) solution. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-30% EtOAc in hexane) to give 2-[(2S)-2-[(4-methoxyphenyl)methoxy]propyl]oxirane.
Step 2. In a round-bottomed flask was added 2-[(2S)-2-[(4-methoxyphenyl)methoxy]-propyl]oxirane (1.38 g, 6.23 mmol), 6-bromo-7-fluoro-2H-isoquinolin-1-one (1.66 g, 6.85 mmol), and cesium carbonate (4.06 g, 12.5 mmol) in DMF (31 mL). The solution was stirred for 48 h at room temperature, and then quenched with water (100 mL) and extracted with EtOAc (3×75 mL). The organic extracts were then washed with 10% LiCl solution (100 mL) and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-hydroxy-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one.
Step 3. In a round bottomed flask, 6-bromo-7-fluoro-2-[(4S)-2-hydroxy-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one (1.07 g, 2.30 mmol) was dissolved in THF (15 mL, 0.15 M) followed by DIPEA (2.01 mL, 11.5 mmol), and bromomethyl methyl ether (0.564 mL, 6.91 mmol) was added at room temperature. The solution is monitored by LCMS, and when the reaction no longer proceeds, the suspension is filtered over Celite®, concentrated, and resubjected to the reaction conditions. A total of five cycles was required for reaction completion. Upon completion, the solution is filtered over Celite®, concentrated by rotary evaporation, and directly purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one.
Step 4. In a round-bottomed flask, 6-bromo-7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[(4-methoxyphenyl)methoxy]pentyl]isoquinolin-1-one (0.950 g, 1.87 mmol) was dissolved in DCM/Water (40 mL, 19:1 DCM/water) and cooled to 0° C. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.70 g, 7.47 mmol) was added in one portion, and the solution was allowed to warm to room temperature and stirred for 2 h at room temperature. The solution was filtered over Celite®, diluted with DCM (100 mL), and washed with saturated aq. NaHCO3 (3×50 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-4-hydroxy-2-(methoxymethoxy)pentyl]isoquinolin-1-one.
Step 5. In a flask were placed 6-bromo-7-fluoro-2-[(4S)-4-hydroxy-2-(methoxymethoxy)pentyl]isoquinolin-1-one (0.624 g, 1.61 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (0.881 g, 2.41 mmol), DIPEA (0.84 mL, 4.82 mmol), and DMF (8 mL). The mixture was heated to 85° C. for 48 h and then quenched with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were then washed with 10% LiCI solution (100 mL) and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]isoquinolin-1-one.
Step 6. A round-bottomed flask was charged with 6-bromo-7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]isoquinolin-1-one (0.500 g, 0.735 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (120 mg, 0.147 mmol), potassium acetate (216 mg, 2.20 mmol), and bis(pinacolato)diboron (280 mg, 1.10 mmol) and 1,4-dioxane (16 mL). The solution was purged with nitrogen gas for 15 minutes, and the solution was heated to 80° C. for 4 hours. After cooling, 2-chloro-5-(trifluoromethyl)pyrimidine (201 mg, 1.10 mmol), CataCXium Pd G4 (109 mg, 0.147 mmol), and 2 N sodium carbonate solution (1.10 mL, 2.20 mmol) were added. The solution was then stirred at 80° C. for 15 minutes, cooled and filtered through a pad of Celite® with EtOAc. The organic layer is concentrated and purified by flash chromatography (0-100% EtOAc in hexane) to give 7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one.
Step 7. In a vial 7-fluoro-2-[(4S)-2-(methoxymethoxy)-4-[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]oxy-pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one (152 mg, 0.203 mmol) was dissolved in 4 N HCl in dioxane (15.00 mL). The solution was heated at 40° C. for 8 h, concentrated by rotary evaporation, and directly purified by reverse phase prep-HPLC (5-100% MeCN in water, 0.1% TFA) to afford 7-fluoro-2-[(4S)-2-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]oxy]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 13.32-13.19 (m, 1H), 9.60-9.39 (m, 3H), 8.47-8.40 (m, 2H), 8.33-8.22 (m, 1H), 8.10-7.96 (m, 1H), 7.55-7.37 (m, 1H), 6.91-6.71 (m, 1H), 5.36-5.03 (m, 2H), 4.25-4.10 (m, 1H), 4.06-3.90 (m, 1H), 3.84-3.71 (m, 1H), 2.00-1.72 (m, 1H), 1.72-1.57 (m, 1H), 1.40-1.30 (m, 4H). ES/MS: m/z 574.00 [M+H]+.
Step 1. Examples 17 and Example 18 were separated via chiral SFC (AD-H, 5 mm, 4.6×100 mm column; 30% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (R)-configuration (Example 17), and the second eluting peak was arbitrarily assigned as the (S)-configuration (Example 18).
Example 17: 1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 9.49 (s, 2H), 8.44 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 5.17-5.07 (m, 1H), 4.24-4.16 (m, 1H), 4.04-3.95 (m, 1H), 3.81-3.73 (m, 1H), 1.97-1.87 (m, 1H), 1.80-1.72 (m, 1H), 1.37 (d, J=6.0 Hz, 3H). ES/MS: m/z 574.0 [M+H]+.
Example 18: 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.49 (s, 2H), 8.44 (d, J=7.1 Hz, 1H), 8.30 (s, 1H), 8.05 (d, J=11.4 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 5.22-5.02 (m, 1H), 4.26-4.07 (m, 1H), 4.03-3.91 (m, 1H), 1.91-1.76 (m, 1H), 1.73-1.56 (m, 1H), 1.34 (d, J=6.1 Hz, 3H). ES/MS m/z: 574.0 [M+H]+.
The title compound was synthesized as described in Example 16, using 2-chloro-5-(difluoromethyl)pyrimidine in place of 2-chloro-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 17 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.24 (s, 2H), 8.39 (d, J=7.2 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J=11.4 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.31 (t, J=54.8 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 5.18-5.06 (m, 1H), 4.20-4.10 (m, 1H), 4.02-3.91 (m, 1H), 3.82-3.73 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.59 (m, 1H), 1.33 (d, J=6.1 Hz, 3H). ES/MS m/z: 556.1 [M+H]+.
The title compound was synthesized as described in Example 16, using 2-chloro-5-(difluoromethyl)pyrimidine in place of 2-chloro-5-(trifluoromethyl)pyrimidine and chiral separation was performed as described in Example 18 (stereochemistry was arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.24 (s, 2H), 8.39 (d, J=7.2 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J=11.4 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.31 (t, J=54.8 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 5.18-5.06 (m, 1H), 4.20-4.10 (m, 1H), 4.02-3.91 (m, 1H), 3.82-3.73 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.59 (m, 1H), 1.33 (d, J=6.1 Hz, 3H). ES/MS m/z: 556.1 [M+H]+.
Step 1. A flask was charged with 6-bromo-7-fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one (330 mg, 0.493 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (376 mg, 1.5 mmol), potassium acetate (194 mg, 1.97 mmol), and bis(pinacolato)diboron (376 mg, 1.48 mmol) and flushed with nitrogen gas. Dioxane (10.0 mL) was added and the solution was heated to 100° C. for 4 h. After cooling, 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (371 mg, 1.88 mmol), CataCXium Pd G4 (17.4 mg, 0.024 mmol), 2 M Na2CO3(aq) (0.70 mL, 1.4 mmol) was added. The solution was then stirred at 80° C. overnight. The solution is cooled and filtered through a pad of Celite® and washed with EtOAc. The filtrate is diluted with EtOAc and water and the layers are stirred vigorously for 10 minutes. The organic layer is concentrated in vacuo and purified by column chromatography (hexanes/EtOAc) to give 7-fluoro-2-[(4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]isoquinolin-1-one. ES/MS: m/z 573.5 [M+H]+.
Step 2. A vial was charged with 6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one (110 mg, 0.16 mmol), TFA (0.25, 3.3 mmol), and DCM (2.0 mL). The solution was stirred for 1 h and concentrated. MeOH (2.0 mL) and ethylenediamine (0.22 mL, 3.3 mmol) were added and the solution was stirred for 15 minutes before being purified by column chromatography with EtOAc in hexanes 0-100%, followed by MeOH in DCM 0-20% to give Example 21, 7,6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-7-fluoro-2-((4S)-2-hydroxy-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.44 (m, 1H), 9.08 (m, 1H), 8.57 (m, 1H), 8.17-8.02 (m, 1H), 7.99-7.84 (m, 2H), 7.76 (m, 1H), 7.44 (m, 1H), 7.29 (m, 1H), 7.05-6.49 (m, 2H), 4.30-3.40 (m, 5H), 1.69 (m, 2H), 1.21 (m, 3H). ES/MS: m/z 543.9 [M+H]+.
Step 1. Examples 22 and Example 23 were separated via chiral SFC (AD-H, 5 μm, 4.6×100 mm column; 30% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (R)-configuration (Example 22), and the second eluting peak was arbitrarily assigned as the (S)-configuration (Example 23).
Example 22: 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.08 (d, J=6.8 Hz, 1H), 8.57 (d, J=6.9 Hz, 1H), 8.04 (d, J=11.2 Hz, 1H), 7.99-7.93 (m, 1H), 7.89 (s, 1H), 7.76 (m, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.29 (m, 1H), 7.02-6.93 (m, 1H), 6.82 (d, J=7.4 Hz, 1H), 4.28-4.00 (m, 4H), 3.79 (m, 1H), 1.83 (m, 1H), 1.60 (m, 1H), 1.21 (m, 3H). ES/MS: m/z 544.1 [M+H]+.
Example 23: 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.08 (d, J=6.8 Hz, 1H), 8.57 (d, J=6.9 Hz, 1H), 8.04 (d, J=11.2 Hz, 1H), 7.99-7.93 (m, 1H), 7.89 (s, 1H), 7.76 (m, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.29 (m, 1H), 7.02-6.93 (m, 1H), 6.82 (d, J=7.4 Hz, 1H), 4.28-4.00 (m, 4H), 3.79 (m, 1H), 1.83 (m, 1H), 1.60 (m, 1H), 1.21 (m, 3H). ES/MS m/z: 544.1 [M+H]+.
Step 1. Methyl (4S)-4-(tert-butoxycarbonylamino)pentanoate (5200 mg, 22.5 mmol) in THF (100 mL) was added to a solution of LDA (45 ml, 2 M in THF, 89.9 mmol) in THF (100 mL) at −78° C. After 45 minutes, the solution was transferred via cannula to a solution of NFSI (19.7 g, 112 mmol) in THF (100 mL) at −78° C. After 30 minutes, the solution mixture was quenched with saturated aq. NH4Cl (25 mL), followed by the addition of dimethyl sulfide (9.0 mL, 135 mmol). The mixture was diluted with EtOAc, washed with saturated aq. NH4Cl, saturated aq. NaHCO3 (2×), water, and brine. The combined organic layers were dried over MgSO4, concentrated, and the resulting residue was purified via column chromatography (0-100% EtOAc in hexanes) to afford methyl (2R,4S)-4-(tert-butoxycarbonylamino)-2-fluoro-pentanoate. ES/MS: m/z 250.0 [M+H]+.
Step 2. NaBH4 (3375 mg, 89.2 mmol) was added to methyl (2R,4S-4-(tert-butoxycarbonylamino)-2-fluoro-pentanoate in THE (100 ml) at 0° C. The solution was allowed to warm to room temperature and stirred at this temperature for 16 h. Upon completion, the solution was cooled to 0° C., and slowly quenched with saturated aq. NH4Cl and extracted with EtOAc. Organic layer was dried over MgSO4, concentrated, and the resulting residue was purified via column chromatography (0-100% EtOAc in hexanes) to afford tert-butyl N-[(1S,3R)-3-fluoro-4-hydroxy-1-methyl-butyl]carbamate. ES/MS: m/z 222.0 [M+H]+.
Step 3. Iodine (1.74 g, 6.87 mmol) was added to a solution of triphenylphosphine (1.80 g, 6.87 mmol) and imidazole (0.468 g, 6.87 mmol) in DCM (50 ml). The mixture was stirred at room temperature for 30 minutes and then tert-butyl N-[(1S,3R)-3-fluoro-4-hydroxy-1-methyl-butyl]carbamate (1.22 g, 5.50 mmol) was added. The solution was then heated at 40° C. for 18 h. Upon completion, the mixture was cooled to room temperature and the mixture was filtered and then concentrated. The residue is dissolved in EtOAc and washed with saturated aq. sodium bisulfite and then brine. The organic phase is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using a gradient of EtOAc/hexane (0 to 100%) as eluent to give tert-butyl N-[(1S,3R)-3-fluoro-4-iodo-1-methyl-butyl]carbamate. ES/MS: m/z 331.9 [M+H]+.
Step 4. To a mixture of 6-bromo-4,7-difluoro-2H-isoquinolin-1-one (1572 mg, 6.05 mmol) and tert-butyl N-[(1S,3R)-3-fluoro-4-iodo-1-methyl-butyl]carbamate (1820 mg, 5.50 mmol) in DMF (25.0 mL) was added Cs2CO3 (5372 mg, 16.5 mmol) and the solution was stirred at room temperature for 18 h. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl N-[(1S,3R)-4-(6-bromo-4,7-difluoro-1-oxo-2-isoquinolyl)-3-fluoro-1-methyl-butyl]carbamate. ES/MS: m/z 464.9 [M+H]+.
Step 5. To a solution of tert-butyl N-[(1S,3R)-4-(6-bromo-4,7-difluoro-1-oxo-2-isoquinolyl)-3-fluoro-1-methyl-butyl]carbamate (503 mg, 1.09 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (2.0 mL) at room temperature and the mixture was stirred for 1 h. Upon completion, the solvent was removed under reduced pressure to afford 2-[(2R,4S)-4-amino-2-fluoro-pentyl]-6-bromo-4,7-difluoro-isoquinolin-1-one which was used without further purification. ES/MS: m/z 364.218 [M+H]+.
Step 6. A mixture of 2-[(2R,4S)-4-amino-2-fluoro-pentyl]-6-bromo-4,7-difluoro-isoquinolin-1-one (394 mg, 1.08 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (764 mg, 1.63 mmol), and N,N-diisopropylethylamine (1.89 mL, 10.8 mmol) in DMF (20 mL) was stirred at room temperature for 2 h. Upon completion, the solution was diluted with EtOAc, washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to provide 6-bromo-4,7-difluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. ES/MS: m/z 657.0 [M+H]+.
Step 7. In a flask was placed 6-bromo-4,7-difluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one (100 mg, 0.153 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.5 mg, 0.015 mmol), potassium acetate (44.9 mg, 0.334 mmol), and bis(pinacolato)diboron (58.1 mg, 0.229 mmol) in dioxane (3 mL). The mixture was purged with nitrogen gas for 5 minutes and then stirred at 80° C. for 18 h. The solution was cooled to room temperature and cataCXium Pd G4 (11.3 mg, 0.015 mmol), 2 M aqueous sodium carbonate (0.16 mL, 0.334 mmol), and 2-chloro-5-(difluoromethyl)pyrimidin-4-amine (41.1 mg, 0.229 mmol) were added. The mixture was then stirred at 90° C. for 3 h. Upon completion, the mixture was cooled to room temperature, diluted with EtOAc and filtered through a plug of Celite®. The volatiles were evaporated in vacuo and the residue was purified via flash chromatography using MeOH in DCM 0-20% to give 6-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-4,7-difluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. ES/MS m/z: 720.1 [M+H].
Step 8. In a vial was placed 6-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-4,7-difluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one (110 mg, 0.153 mmol), and trifluoroacetic acid (1 ml) in DCM (5.0 mL). The mixture was stirred for 1 h, and was concentrated under vacuum. The resulting crude product was dissolved in methanol (4 mL) and 2.0 M ammonia in methanol (1.0 mL, 2.29 mmol) was added and the mixture was stirred for 30 minutes and then concentrated under vacuum. The resulting crude product was purified by reverse phase prep-HPLC (5-100% MeCN in water, 0.1% TFA) to afford Example 24, 6-[4-amino-5-(difluoromethyl)pyrimidin-2-yl]-4,7-difluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 8.06-7.92 (m, 1H), 7.86 (s, 1H), 7.69 (d, J=6.7 Hz, 1H), 7.58 (s, 2H), 7.03 (t, J=54.1 Hz, 1H), 6.53-6.40 (m, 1H), 4.27-4.06 (m, 3H), 2.19-1.88 (m, 1H), 1.86-1.70 (m, 1H), 1.16 (d, J=6.4 Hz, 3H). ES/MS m/z: 590.0 [M+H]*.
The following Examples were synthesized as described in Example 24 or a modification of the procedure above from the corresponding intermediates.
1H NMR/MS [M + H]+
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.77 (s, 2H), 8.35 (d, J = 7.0 Hz, 1H), 8.12-8.00 (m, 1H), 7.94 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 6.60-6.40 (m, 1H), 4.94 (d, J = 47.3 Hz, 1H), 4.38-4.09 (m, 3H), 4.01 (s, 3H), 2.22-2.01 (m, 1H), 1.97-1.78 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: m/z 555.0 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.10 (s, 2H), 8.39 (d, J = 7.0 Hz, 1H), 8.16-8.02 (m, 1H), 7.94 (s, 1H), 7.77 (d, J = 6.7 Hz, 1H), 6.60-6.42 (m, 1H), 4.94 (d, J = 50.3 Hz, 1H), 4.38-4.19 (m, 4H), 2.23-2.01 (m, 1H), 1.96-1.77 (m, 1H), 1.55 (s, 6H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: m/z 582.1 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.75 (s, 2H), 8.29 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.58-6.51 (m, 1H), 5.03-4.79 (m, 1H), 4.37- 4.12 (m, 3H), 2.22-2.02 (m, 1H), 1.93- 1.81 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: m/z 540.0 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.09 (s, 2H), 8.14 (m, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.79 (m, 1H), 6.63- 6.39 (m, 1H), 5.09-4.69 (m, 1H), 4.40-3.96 (m, 3H), 3.55 (m, 1H), 2.28-1.75 (m, 2H), 1.55 (s, 6H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: m/z 583.1 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.27 (d, J = 1.2 Hz, 2H), 8.44 (d, J = 6.8 Hz, 1H), 8.11 (dd, J = 11.1, 1.9 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.32 (t, J = 54.7 Hz, 1H), 6.58-6.46 (m, 1H), 5.04-4.84 (m, 1H), 4.34-4.12 (m, 3H), 2.22-2.01 (m, 1H), 1.96-1.81 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: m/z 575.1 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.50 (s, 2H), 8.47 (d, J = 6.8 Hz, 1H), 8.13 (dd, J = 11.1, 1.9 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J = 6.7 Hz, 1H), 6.59-6.46 (m, 1H), 5.06-4.82 (m, 1H), 4.36-4.12 (m, 3H), 2.25- 1.99 (m, 1H), 1.96-1.80 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: m/z 593.0 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 7.1 Hz, 1H), 7.97 (d, J = 11.0 Hz, 1H), 7.93 (s, 1H), 7.57 (br s, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 54.2 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.60-6.49 (m, 1H), 5.05-4.80 (m, 1H), 4.39-4.28 (m, 1H), 4.24-4.14 (m, 2H), 2.22- 2.00 (m, 1H), 1.94-1.79 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: m/z 589.0 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.51 (d, J = 0.9 Hz, 2H), 8.33-8.19 (m, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 7.6, 1.8 Hz, 1H), 6.54 (dd, J = 8.8, 4.1 Hz, 1H), 5.13-4.74 (m, 1H), 4.44- 4.02 (m, 3H), 2.12 (ddd, J = 39.7, 14.0, 9.4 Hz, 1H), 1.97-1.80 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: 593.1 m/z [M + H]+.
Step 1. To a stirred solution of 3-(2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)propan-1-ol (2.93 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (3.51 g, 18.4 mmol) followed by DMAP (75 mg, 0.62 mmol). The mixture was stirred at room temperature for 16 h. Upon completion, the mixture was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 5-100% to afford 3-(2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)propyl 4-methylbenzenesulfonate. ES/MS: m/z 393.0 [M+H]+.
Step 2. To a mixture of 6-bromo-7-fluoroisoquinolin-1(2H)-one (3.4 g, 14.0 mmol) and 3-(2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)propyl 4-methylbenzenesulfonate (5.51 g mg, 14.0 mmol) in DMF (50 mL) was added Cs2CO3 (5.49 g, 16.9 mmol) and the solution was stirred at room temperature for 2 h. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 5-100% to afford 6-bromo-7-fluoro-2-(3-(2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)propyl)isoquinolin-1(2H)-one. ES/MS: m/z 344.0 [M-C8H6O+H]+.
Step 3. To a solution of 6-bromo-7-fluoro-2-(3-(2-(4-methoxyphenyl)-1,3-dioxolan-4-yl)propyl)isoquinolin-1(2H)-one (3.5 g, 7.57 mmol) in DCM (80 mL) at −78° C. was added diisobutylaluminum hydride (1.0 M in DCM, 23 mL, 22.7 mmol). The solution was stirred at −78° C. for 2 h and then quenched slowly with MeOH (40 mL). The mixture was allowed to warm up to room temperature and 100 mL of saturated aqueous Rochelle salt was added. The mixture was vigorously stirred until two clear phases were obtained. After separation, the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 5-100% to afford 6-bromo-7-fluoro-2-(5-hydroxy-4-((4-methoxybenzyl)oxy)pentyl)isoquinolin-1(2H)-one. ES/MS: m/z 486.1 [M+Na]+.
Step 4. To a mixture of 6-bromo-7-fluoro-2-(5-hydroxy-4-((4-methoxybenzyl)oxy)pentyl)isoquinolin-1(2H)-one (1.8 g, 3.9 mmol) and KHF2 (908 mg, 11.6 mmol) in DCM (7 mL) and water (7 mL) was added [bromo(difluoro)methyl]-trimethyl-silane (1.2 g, 5.8 mmol) dropwise. The solution was stirred at room temperature for 2 h. Additional equivalence of [bromo(difluoro)methyl]-trimethyl-silane (1.2 g, 5.8 mmol) was added and the solution was stirred at room temperature for 2 h. Upon completion, the mixture was diluted with DCM, washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 5-100% to afford 6-bromo-2-(5-(difluoromethoxy)-4-((4-methoxybenzyl)oxy)pentyl)-7-fluoroisoquinolin-1(2H)-one. ES/MS: m/z 536.1 [M+Na]+.
Step 5. To a solution of 6-bromo-2-(5-(difluoromethoxy)-4-((4-methoxybenzyl)oxy)pentyl)-7-fluoroisoquinolin-1(2H)-one (1.48 g, 2.9 mmol) in DCM (40 mL) and water (2 mL) at 0° C. was added DDQ (2.6 g, 11.5 mmol). The solution was stirred at room temperature for 2 h. The mixture was filtered, and the mother liquor was washed with saturated aqueous NaHCO3. After separation, the aqueous phase was extracted with DCM. The combined organic layers were washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 5-100% to afford 6-bromo-2-(5-(difluoromethoxy)-4-hydroxypentyl)-7-fluoroisoquinolin-1(2H)-one. ES/MS m/z: 394.1 [M+H]+.
Step 6. A solution of 6-bromo-2-(5-(difluoromethoxy)-4-hydroxypentyl)-7-fluoroisoquinolin-1(2H)-one (1.02 g, 2.59 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (1.7 g, 5.18 mmol), and N,N-diisopropylethylamine (1.35 mL, 7.76 mmol) in DMF (10 mL) was stirred at 85° C. for 24 h. Upon cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EA in hexanes 0-100% to afford 6-bromo-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoroisoquinolin-1(2H)-one. ES/MS: m/z 686.1 [M+H]+.
Step 7. Using 6-bromo-2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoroisoquinolin-1(2H)-one and 2-(2-chloropyrimidin-5-yl)propan-2-ol, 2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized following the procedure described in the step 6 of Example 1. ES/MS: m/z 744.3 [M+H]+.
Step 8. Using 2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one, 2-(5-(difluoromethoxy)-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized following the procedure described in the step 7 of Example 1.
1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 9.06 (s, 2H), 8.32 (t, J=3.6 Hz, 2H), 7.97 (d, J=11.2 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 6.87-6.77 (m, 1H), 5.21 (d, J=6.4 Hz, 1H), 4.12 (dd, J=11.5, 2.5 Hz, 1H), 4.00 (m, 3H), 2.56-2.51 (m, 7H), 1.85-1.70 (m, 4H), 1.55 (s, 6H). ES/MS: m/z 614.2 [M+H]+.
Examples 34 and Example 35 were separated via chiral SFC (AD-H, 5 μm, 21×250 mm column; 45% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (S)-configuration (Example 34), and the second eluting peak was arbitrarily assigned as the (R)-configuration (Example 35).
Example 34: 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 9.06 (s, 2H), 8.35-8.28 (m, 2H), 7.97 (d, J=11.3 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.66 (t, J=75.2 Hz, 1H), 5.25-5.15 (m, 1H), 4.12 (dd, J=11.6, 2.6 Hz, 1H), 4.00 (tt, J=11.6, 6.3 Hz, 3H), 1.79 (m, 5H), 1.55 (s, 6H). ES/MS: m/z 614.1 [M+H]+.
Example 35: 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 9.06 (s, 2H), 8.35-8.28 (m, 2H), 7.97 (d, J=11.3 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.66 (t, J=75.2 Hz, 1H), 5.25-5.15 (m, 1H), 4.12 (dd, J=11.6, 2.6 Hz, 1H), 4.00 (m, 3H), 1.79 (m, 5H), 1.55 (s, 6H). ES/MS m/z: 614.1 [M+H]+.
The following Examples were synthesized as described in the reference examples noted in the table or a modification of the procedure from the corresponding intermediates (stereochemistry was arbitrarily assigned).
1H NMR/MS [M + H]+
1H NMR (400 MHz, DMSO-d6) δ 13.34-13.09 (m, 1H), 9.55-9.27 (m, 2H), 8.36-8.20 (m, 3H), 7.99-7.91 (m, 1H), 5.19-4.84 (m, 2H), 4.41-4.33 (m, 2H), 2.17-1.97 (m, 2H), 1.37- 1.26 (m, 3H). ES/MS: 577.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.34-13.28 (m, 1H), 9.07 (s, 1H), 8.36-8.27 (m, 2H), 8.04- 7.94 (m, 1H), 7.49-7.41 (m, 1H), 6.81 (d, J = 7.3 Hz, 1H), 5.51 (s, 1H), 5.27-4.90 (m, 2H), 4.46-4.11 (m, 2H), 2.21-2.00 (m, 2H), 1.55 (s, 6H), 1.42-1.34 (m, 3H). ES/MS: 566.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (d, J = 3.9 Hz, 1H), 9.08 (s, 2H), 8.49-8.14 (m, 3H), 7.97 (m, 1H), 5.37-4.79 (m, 2H), 4.57-3.99 (m, 2H), 4.06-2.98 (m, 1H), 2.31-1.91 (m, 2H), 1.55 (s, 6H), 1.38 (m, 3H). ES/MS: 567.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.51 (s, 2H), 8.49-8.22 (m, 3H), 8.04 (d, J = 10.5 Hz, 1H), 5.27-4.83 (m, 2H), 4.53-4.09 (m, 2H), 2.25-2.03 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 577.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.29 (s, 1H), 8.12 (d, J = 7.1 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 10.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.28-5.16 (m, 1H), 5.15-4.92 (m, 1H), 4.47-4.28 (m, 1H), 4.28-4.07 (m, 1H), 3.94 (s, 3H), 2.22-1.99 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 553.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.46 (s, 1H), 8.47 (d, J = 7.1 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J = 11.3 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 5.26-5.17 (m, 1H), 5.16-4.94 (m, 1H), 4.49-4.29 (m, 1H), 4.29-4.11 (m, 1H), 3.49 (s, 3H), 2.24-2.00 (m, 2H), 1.39 (d, J = 6.0 Hz, 3H). ES/MS: 586.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 8.53-8.49 (m, 1H), 8.32 (s, 1H), 7.99 (dd, J = 6.5, 1.6 Hz, 1H), 7.58 (br. s, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 54.1 Hz, 1H), 6.74 (dd, J = 7.5, 1.8 Hz, 1H), 5.16 (q, J = 6.2 Hz, 1H), 5.10- 4.87 (m, 1H), 4.33 (ddd, J = 29.9, 14.3, 3.0 Hz, 1H), 4.14 (ddd, J = 17.1, 14.3, 8.0 Hz, 1H), 2.21- 2.01 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 591.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.17 (s, 2H), 8.32 (s, 1H), 8.18 (dd, J = 6.7, 1.7 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.80 (dd, J = 7.5, 1.9 Hz, 1H), 5.16 (h, J = 6.1 Hz, 1H), 5.09- 4.90 (m, 1H), 4.34 (ddd, J = 29.7, 14.3, 3.0 Hz, 1H), 4.15 (ddd, J = 17.2, 14.3, 7.9 Hz, 1H), 2.22- 2.01 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 560.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.77 (s, 2H), 8.32 (s, 1H), 8.10 (dd, J = 6.8, 1.7 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 7.5, 1.9 Hz, 1H), 5.24-5.12 (m, 1H), 5.11- 4.87 (m, 1H), 4.33 (ddd, J = 29.7, 14.2, 3.0 Hz, 1H), 4.14 (ddd, J = 17.2, 14.2, 7.9 Hz, 1H), 4.01 (s, 3H), 2.21-1.98 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 556.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.75 (s, 2H), 8.35-8.26 (m, 2H), 7.98 (d, J = 11.3 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 5.24-5.11 (m, 1H), 5.11-4.89 (m, 1H), 4.36 (ddd, J = 29.7, 14.3, 3.0 Hz, 1H), 4.19 (ddd, J = 17.4, 14.4, 7.9 Hz, 1H), 4.00 (s, 3H), 2.19-2.00 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 538.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.28 (s, 2H), 8.33 (s, 1H), 8.21 (dd, J = 6.7, 1.7 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.9 Hz, 1H), 5.25-5.12 (m, 1H), 5.11- 4.89 (m, 1H), 4.35 (ddd, J = 29.7, 14.3, 3.0 Hz, 1H), 4.16 (ddd, J = 17.2, 14.3, 7.9 Hz, 1H), 2.15 (t, J = 19.4 Hz, 3H), 2.18-2.02 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H). ES/MS: 590.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.53-9.48 (m, 2H), 8.33 (s, 1H), 8.25 (dd, J = 6.6, 1.7 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 7.5, 1.8 Hz, 1H), 5.25-5.12 (m, 1H), 5.12-4.88 (m, 1H), 4.35 (ddd, J = 29.7, 14.3, 3.0 Hz, 1H), 4.16 (ddd, J = 17.2, 14.3, 7.9 Hz, 1H), 2.22-2.02 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 594.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.28-9.23 (m, 2H), 8.42 (d, J = 7.2 Hz, 1H), 8.33 (s, 1H), 8.04 (d, J = 11.3 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.31 (t, J = 54.8 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 5.26-5.12 (m, 1H), 5.11-4.90 (m, 1H), 4.38 (ddd, J = 29.8, 14.2, 3.0 Hz, 1H), 4.21 (ddd, J = 17.3, 14.3, 7.9 Hz, 1H), 2.23- 2.02 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 558.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.07 (s, 2H), 8.38-8.27 (m, 2H), 8.00 (d, J = 11.2 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 5.52 (s, 1H), 5.71 (q, J = 6.2 Hz, 1H), 5.11-4.89 (m, 1H), 4.37 (ddd, J = 29.7, 14.2, 3.0 Hz, 1H), 4.20 (ddd, J = 17.3, 14.3, 7.9 Hz, 1H), 2.22-2.01 (m, 2H), 1.55 (s, 6H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 566.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.27 (d, J = 1.3 Hz, 2H), 8.45 (d, J = 6.9 Hz, 1H), 8.29 (s, 1H), 8.10 (dd, J = 11.1, 2.0 Hz, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.32 (t, J = 54.7 Hz, 1H), 5.25-5.16 (m, 1H), 5.16-4.96 (m, 1H), 4.40- 4.10 (m, 2H), 2.23-2.01 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 576.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.78 (s, 2H), 8.35 (d, J = 7.0 Hz, 1H), 8.29 (s, 1H), 8.04 (dd, J = 11.2, 2.0 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 5.20 (q, J = 6.0 Hz, 1H), 5.16-4.95 (m, 1H), 4.38-4.13 (m, 2H), 4.01 (s, 3H), 2.19- 2.03 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 556.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.56-8.49 (m, 1H), 8.31-8.24 (m, 2H), 8.03 (dd, J = 10.9, 2.0 Hz, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.62 (br s, 2H), 7.10 (t, J = 54.1 Hz, 1H), 5.24-5.16 (m, 1H), 5.16-4.95 (m, 1H), 4.38- 4.18 (m, 2H), 2.20-2.01 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 591.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.51 (d, J = 0.9 Hz, 2H), 8.48 (d, J = 6.8 Hz, 1H), 8.29 (s, 1H), 8.12 (dd, J = 11.1, 1.9 Hz, 1H), 7.82 (d, J = 6.7 Hz, 1H), 5.19 (p, J = 6.3 Hz, 1H), 5.07 (dt, J = 50.0, 3.9 Hz, 1H), 4.42-4.13 (m, 2H), 2.20-2.02 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 594.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.09 (s, 2H), 8.38 (d, J = 6.9 Hz, 1H), 8.32 (s, 1H), 8.08 (dd, J = 11.0, 2.0 Hz, 1H), 7.77 (d, J = 6.7 Hz, 1H), 5.16 (q, J = 6.1 Hz, 1H), 5.01 (dd, J = 48.2, 6.6 Hz, 1H), 4.42-4.12 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 584.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.77 (s, 2H), 8.33 (m, 2H), 8.24 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 10.5 Hz, 1H), 5.30-4.89 (m, 2H), 4.49-4.16 (m, 2H), 4.01 (s, 3H), 2.28- 1.97 (m, 2H), 1.40 (d, J = 6.1 Hz, 3H). ES/MS: 538.6 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.51 (d, J = 1.0 Hz, 2H), 8.43-8.28 (m, 3H), 8.02 (d, J = 10.5 Hz, 1H), 5.28-5.17 (m, 1H), 5.16-4.97 (m, 1H), 4.47-4.33 (m, 1H), 4.32- 4.19 (m, 1H), 2.23-2.08 (m, 2H), 1.40 (d, J = 6.1 Hz, 3H). ES/MS: 577.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 10.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.28-4.86 (m, 2H), 4.46-4.29 (m, 1H), 4.29-4.10 (m, 1H), 3.94 (s, 3H), 2.22-1.98 (m, 0H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 553.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.46 (s, 2H), 8.47 (d, J = 7.1 Hz, 1H), 8.32 (s, 1H), 8.06 (d, J = 11.3 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 5.27-4.87 (m, 2H), 4.49-4.29 (m, 1H), 4.29-4.11 (m, 1H), 3.49 (s, 3H), 2.23-2.00 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H). ES/MS: 586.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 9.07 (s, 2H), 8.33 (d, J = 7.2 Hz, 1H), 8.30 (d, J = 1.0 Hz, 1H), 7.99 (d, J = 11.2 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 5.52 (s, 1H), 5.22 (p, J = 6.0 Hz, 1H), 5.16-4.94 (m, 1H), 4.38 (ddd, J = 30.9, 14.3, 2.7 Hz, 1H), 4.20 (ddd, J = 17.0, 14.3, 8.1 Hz, 1H), 2.25-2.01 (m, 2H), 1.55 (s, 6H), 1.40 (d, J = 6.0 Hz, 3H). ES/MS: 566.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.30-9.23 (m, 2H), 8.45 (d, J = 6.9 Hz, 1H), 8.32 (s, 1H), 8.12 (dd, J = 11.1, 2.0 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.32 (t, J = 54.7 Hz, 1H), 5.24-5.11 (m, 1H), 5.11-4.89 (m, 1H), 4.40- 4.12 (m, 2H), 2.21-2.01 (m, 2H), 1.36 (d, J = 6.0 Hz, 2H). ES/MS: 576.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.77 (s, 2H), 8.35 (d, J = 7.0 Hz, 1H), 8.32 (s, 1H), 8.06 (dd, J = 11.1, 2.0 Hz, 1H), 7.76 (d, J = 6.8 Hz, 1H), 5.22-5.11 (m, 1H), 5.11-4.90 (m, 1H), 4.40-4.11 (m, 2H), 4.01 (s, 3H), 2.20- 2.01 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 556.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 8.52 (d, J = 1.4 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J = 6.8 Hz, 1H), 8.05 (dd, J = 10.9, 2.0 Hz, 1H), 7.76 (d, J = 6.7 Hz, 1H), 7.57 (br s, 2H), 7.10 (t, J = 54.1 Hz, 1H), 5.20-5.11 (m, 1H), 5.10-4.90 (m, 1H), 4.38-4.22 (m, 2H), 2.20-1.99 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 591.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.51 (d, J = 0.9 Hz, 2H), 8.48 (d, J = 6.8 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J = 11.1, 1.9 Hz, 1H), 7.80 (d, J = 6.7 Hz, 1H), 5.16 (q, J = 6.1 Hz, 1H), 5.11- 4.90 (m, 1H), 4.40-4.12 (m, 2H), 2.23-2.02 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H). ES/MS: 594.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.09 (s, 2H), 8.38 (d, J = 6.9 Hz, 1H), 8.29 (s, 1H), 8.06 (dd, J = 11.0, 2.0 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 5.20 (q, J = 6.0 Hz, 1H), 5.07 (dd, J = 49.5, 4.6 Hz, 1H), 4.43-4.09 (m, 2H), 2.23- 2.02 (m, 2H), 1.39 (d, J = 6.1 Hz, 3H). ES/MS: 584.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.70 (s, 2H), 8.34-8.21 (m, 2H), 8.16 (d, J = 6.9 Hz, 1H), 7.89 (d, J = 10.5 Hz, 1H), 5.22-4.79 (m, 2H), 4.48-4.03 (m, 2H), 3.94 (s, 3H), 2.21- 1.94 (m, 2H), 1.30 (d, J = 6.0 Hz, 3H). ES/MS: 538.7 m/z [M + H]+.
To a solution of Example 51 (136.0 mg, 0.241 mmol) in acetonitrile (2.50 mL) was added NBS (47.2 mg, 0.265 mmol). The reaction mixture was stirred at room temperature for 60 minutes and then purified by reverse phase prep-HPLC (5-100% MeCN in water, 0.1% TFA) to afford 4-bromo-7-fluoro-2-((2R,4S)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.10 (s, 2H), 8.45 (d, J=7.0 Hz, 1H), 8.32 (s, 1H), 8.10 (d, J=10.9 Hz, 1H), 7.93 (s, 1H), 5.52 (s, 1H), 5.21-5.11 (m, 1H), 5.09-4.91 (m, 1H), 4.38 (td, J=15.1, 14.7, 3.0 Hz, 1H), 4.29-4.19 (m, 1H), 2.19-2.02 (m, 2H), 1.55 (s, 6H), 1.36 (d, J=6.0 Hz, 3H). ES/MS m/z: 644.10 [M+H].
Step 1. NaI (3.8 g, 25 mmol) and LiBr (610 mg, 7.0 mmol) were heated with a heat gun under vacuum and then cooled under a stream of dry N2. 2-chloropyrimidine-5-carbaldehyde (1.0 g, 7.0 mmol), [bromo(difluoro)methyl]-trimethyl-silane (2.9 mL, 18 mmol), and DME (10 mL) were added to the dried inorganics. The reaction was heated at 80° C. for 4 hours before additional [bromo(difluoro)methyl]-trimethyl-silane (2.9 mL, 18 mmol) was charged. After an additional 16 hours at 80° C., the reaction was cooled to ambient temperature. TFA (1.0 mL, 14 mmol) and EtOH (5 mL) were added and the reaction was stirred an additional 90 minutes before the reaction was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was evaporated, and the crude residue was purified via flash chromatography (100% hex→70% EtOAc/Hex) to afford a mixture of 1-(2-chloropyrimidin-5-yl)-2,2-difluoro-2-iodo-ethanol and 1-(2-iodopyrimidin-5-yl)-2,2-difluoro-2-iodo-ethanol, which was carried forward without further purification.
Step 2. The mixture 1-(2-chloropyrimidin-5-yl)-2,2-difluoro-2-iodo-ethanol and 1-(2-iodopyrimidin-5-yl)-2,2-difluoro-2-iodo-ethanol (˜0.75 mmol) was taken up in toluene (4.7 mL) and tri-n-butyltin hydride (0.40 mL, 1.5 mmol) was added. The reaction was heated to 80° C. before the addition of 2,2′-azobis(isobutyronitrile) (12 mg, 0.07 mmol). After 30 minutes, the reaction was cooled, diluted with EtOAc, and filtered through a pad of Celite®. The filtrate was evaporated, and the crude residue was purified via flash chromatography (100% hex→100% EtOAc) to afford 1-(2-chloropyrimidin-5-yl)-2,2-difluoro-ethanol. ES/MS m/z: 194.8 [M]+.
2-chloro-5-iodo-pyrimidine (1.0 g, 4.2 mmol) was dissolved in THF and cooled to −78° C. in a dry ice/acetone bath. A solution of n-butyllithium (2.5 M, 5.2 mmol) was added slowly and the reaction was maintained in the cooling bath. After 40 minutes, 1,1-difluoroacetone (0.51 mL, 6.2 mmol) was then added dropwise. The reaction was stirred for an additional 2 hours in the cooling bath at which, a solution of 10% aq. KHSO4 was added, and the mixture was allowed to warm to room temperature. The mixture was extracted (3x) with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hex→70% EtOAc/Hex) to afford 2-(2-chloropyrimidin-5-yl)-1,1-difluoro-propan-2-ol. ES/MS m/z: 209.4 [M+H]+.
Step 1. 2-bromopyrimidin-5-ol (200 mg, 1.1 mmol) was dissolved in THF (7.2 mL) and stirred at ambient temperature. Sodium hydride (60% in oil, 48 mg, 1.3 mmol) was then added followed by Pd(OAc)2 (2.6 mg, 0.01 mmol) and triphenylphosphine (12 mg, 0.04 mmol). The reaction was then cooled in an ice/water bath. 3-bromo-3,3-difluoro-prop-1-ene (0.17 mL, 1.7 mmol) was added as a solution in THF (1.2 mL). The reaction was then warmed to 40° C. for 1.5 hours before being cooled and quenched with addition of saturated bicarbonate and extracted (3x) with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hex→60% EtOAc/Hex) to afford 2-bromo-5-(1,1-difluoroallyloxy)pyrimidine. ES/MS m/z: 250.9/252.8 [M]+.
Step 2. 2-bromo-5-(1,1-difluoroallyloxy)pyrimidine (250 mg, 0.96 mmol) was dissolved in dioxane (8.8 mL) and water (8.8 mL) and stirred at ambient temperature. Potassium osmate dihydrate (18 mg, 0.05 mmol) and NaIO4 (620 mg, 2.9 mmol) were then added. After 4 hours, LC/MS indicated incomplete conversion and 2,6-lutidine (0.22 mL, 1.9 mmol) was added. After stirring for 84 hours, the reaction was quenched via addition of saturated sodium thiosulfate and extracted (3x) with EtOAc. The combined organic layers were washed with saturated sodium thiosulfate and brine before being dried over Na2SO4, filtered, and evaporated. The crude residue was then dissolved in MeOH (8.0 mL) and stirred at ambient temperature. NaBH4 (180 mg, 4.8 mmol) was added, and the reaction stirred for 2.5 hours at which point it was quenched with 10% KHSO4. The mixture was extracted (3x) with EtOAc and the combined organics dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hex→100% EtOAc) to afford 2-(2-bromopyrimidin-5-yl)oxy-2,2-difluoro-ethanol. ES/MS m/z: 254.9/256.8 [M]+.
2-bromopyrimidin-5-ol (250 mg, 1.4 mmol) and K2CO3 (490 mg, 3.6 mmol) were taken up in DMF (3.0 mL) and stirred at ambient temperature. 2-(trifluoromethyl)oxirane (0.12 mL, 1.4 mmol) was then added. After 2.5 hours, additional 2-(trifluoromethyl)oxirane (24 μL, 0.28 mmol) was added and the reaction was stirred for an additional 96 hours at which point it was diluted with water and extracted (3x) with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hex→100% EtOAc) to afford 3-(2-bromopyrimidin-5-yl)oxy-1,1,1-trifluoro-propan-2-ol. ES/MS m/z: 286.9/288.8 [M]+.
Step 1. Ethyl 2-(2-chloropyrimidin-5-yl)acetate (500 mg, 2.5 mmol) and NFSI (2.4 g, 7.5 mmol) were dissolved in THF (12.5 mL) and cooled to −78° C. LHMDS (1.0 M, 9.4 mmol) was then added slowly. After 2 hours, the cooling bath was removed, and the reaction was quenched with 10% KHSO4 and extracted (3x) with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude was then purified via flash chromatography (100% hex→40% EtOAc/hex) to afford ethyl 2-(2-chloropyrimidin-5-yl)-2,2-difluoro-acetate. ES/MS: m/z 236.9 [M+H]+.
Step 2. A vial was charged with 6-bromo-7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one (370 mg, 0.56 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (20 mg, 0.03 mmol), potassium acetate (160 mg, 1.7 mmol), and bis(pinacolato)diboron (190 mg, 0.72 mmol) and flushed with nitrogen gas. Dioxane (4.5 mL) was added, and the reaction was heated to 100° C. for 80 minutes. After cooling, 2-iodo-5-(trifluoromethyl)pyrimidine (0.56 mmol) was charged as a solution in dioxane (2.0 mL) followed by [di(adamantan-1-yl)(butyl)phosphine](methanesulfonato-κO)[2′-(methylamino)-2-biphenylyl]palladium (CataCXium Pd G4, 20 mg, 0.03 mmol), and aqueous sodium carbonate (2.0 M, 0.83 mL). The mixture was bubbled with nitrogen gas briefly. The reaction was then stirred at 80° C. for 90 minutes before being diluted with EtOAc and filtered through a plug of Celite®. The filtrate was evaporated and the crude purified via flash chromatography (100% heptanes→100% [3:1 EtOAc:EtOH]) to afford 2,2-difluoro-2-[2-[7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-1-oxo-6-isoquinolyl]pyrimidin-5-yl]acetic acid. ES/MS: m/z 731.2 [M+H]+.
Step 3. 2,2-difluoro-2-[2-[7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-1-oxo-6-isoquinolyl]pyrimidin-5-yl]acetic acid (190 mg, 0.25 mmol) was taken up in THF (4.0 mL) and treated with TEA (53 μL, 0.38 mmol) before being cooled to 0° C. Ethyl chloroformate (36 μL, 0.38 mmol) was added and the reaction stirred for 30 minutes. The mixture was then filtered through a frit directly into a stirred solution of NaBH4 (38 mg, 1.0 mmol) in THF (3.5 mL) and water (1.0 mL) at 0° C. The frit was rinsed with a small amount of additional THF. After 50 minutes, additional NaBH4b (150 mg, 4 mmol) was added before allowing to stir an additional 2 hours at which point the reaction was quenched by addition of 1000 KHSO4. The mixture was extracted 2x with EtOAc and the combined organic layers were dried over MgSO4, filtered, and evaporated. The crude purified via flash chromatography (100% heptanes→80% [3:1 EtOAc:EtOH]/heptanes) to afford 6-[5-(1,1-difluoro-2-hydroxy-ethyl)pyrimidin-2-yl]-7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one. ES/MS: m/z 717.3 [M+H]+.
The following Examples were synthesized as described in Example 24 or a modification of the procedure from the corresponding intermediates.
1H NMR/MS [M + H]+
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.56-8.47 (m, 1H), 8.34 (s, 1H), 8.20- 8.10 (m, 1H), 7.98-7.88 (m, 2H), 7.59 (s, 2H), 7.10 (t, J = 54.1 Hz, 1H), 6.58-6.43 (m, 1H), 5.05-4.79 (m, 1H), 4.40-4.25 (m, 3H), 2.26-2.04 (m, 1H), 1.98-1.81 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 573.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.35-9.18 (m, 2H), 8.47-8.25 (m, 2H), 8.10-7.87 (m, 2H), 7.31 (t, J = 54.8 Hz, 1H), 6.64-6.44 (m, 1H), 5.01-4.86 (m, 1H), 4.41- 4.17 (m, 3H), 2.27-2.06 (m, 1H), 2.00- 1.81 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: 558.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.61-9.41 (m, 2H), 8.42-8.33 (m, 2H), 8.04 (d, J = 10.5 Hz, 1H), 7.94 (s, 1H), 6.62- 6.41 (m, 1H), 5.07-4.80 (m, 1H), 4.43-4.20 (m, 3H), 2.28-2.04 (m, 1H), 2.00-1.80 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: 576 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.44 (d, J = 0.9 Hz, 2H), 8.77 (d, J = 1.7 Hz, 1H), 8.56-8.50 (m, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.61-6.49 (m, 1H), 5.07-4.79 (m, 1H), 4.43-4.12 (m, 3H), 2.23- 2.00 (m, 1H), 1.97-1.76 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 557.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 11.7 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 6.80-6.76 (m, 1H), 6.74 (d, J = 7.4 Hz, 1H), 6.60-6.51 (m, 1H), 5.05-4.77 (m, 1H), 4.38-4.10 (m, 2H), 2.22- 1.97 (m, 1H), 1.97-1.72 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 495.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.84-8.73 (m, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.05-7.87 (m, 4H), 7.54-7.48 (m, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.59-6.50 (m, 1H), 5.06-4.80 (m, 1H), 2.23-2.01 (m, 1H), 1.96-1.79 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 506.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.07 (s, 0H), 8.58 (dd, J = 9.7, 1.8 Hz, 1H), 8.13-7.99 (m, 2H), 7.93 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.61- 6.45 (m, 1H), 5.13-4.74 (m, 1H), 4.42- 4.13 (m, 2H), 2.25-1.98 (m, 1H), 1.98-1.78 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 592.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.21-9.11 (m, 1H), 8.41 (dd, J = 8.5, 2.4 Hz, 1H), 8.32 (d, J = 7.3 Hz, 1H), 8.17-8.10 (m, 1H), 8.05 (d, J = 11.6 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.61-6.51 (m, 1H), 5.05-4.83 (m, 1H), 4.40-4.12 (m, 2H), 2.22-2.02 (m, 1H), 1.94-1.79 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 574.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.29-9.15 (m, 2H), 8.38 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 6.60-6.49 (m, 1H), 5.05-4.80 (m, 1H), 4.41-4.12 (m, 3H), 2.22-2.01 (m, 1H), 1.95- 1.80 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 591.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.89 (s, 2H), 8.32 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.60- 6.49 (m, 1H), 5.46 (s, 2H), 5.03-4.81 (m, 1H), 4.40-4.12 (m, 3H), 2.22-2.01 (m, 1H), 1.93-1.81 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 562.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.11 (s, 2H), 8.39 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.94 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.38 (br s, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.61-6.49 (m, 1H), 5.54 (q, J = 7.2 Hz, 1H), 5.04-4.82 (m, 1H), 4.40-4.13 (m, 3H), 2.22-2.02 (m, 1H), 1.95-1.80 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 605.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.03 (s, 2H), 8.37 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.59-6.51 (m, 1H), 6.26 (td, J = 55.2, 3.6 Hz, 1H), 5.08 (td, J = 12.2, 3.6 Hz, 1H), 5.03-4.81 (m, 1H), 4.41-4.12 (m, 3H), 2.23- 2.00 (m, 1H), 1.97-1.80 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 587.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.03 (s, 2H), 8.37 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.59-6.51 (m, 1H), 6.26 (td, J = 55.3, 3.6 Hz, 1H), 5.08 (td, J = 12.5, 12.0, 3.7 Hz, 1H), 5.03-4.82 (m, 1H), 4.40-4.13 (m, 3H), 2.22-2.02 (m, 1H), 1.94-1.80 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 587.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.99 (d, J = 1.0 Hz, 2H), 8.37 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.64-6.46 (m, 1H), 5.04-4.81 (m, 1H), 4.40-4.12 (m, 3H), 3.98 (t, J = 10.3 Hz, 2H), 2.22-2.00 (m, 1H), 1.94-1.81 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 603.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.80 (s, 2H), 8.30 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.59- 6.50 (m, 1H), 5.03-4.82 (m, 1H), 4.57- 4.45 (m, 2H), 4.42-4.12 (m, 4H), 2.21-2.01 (m, 1H), 1.95-1.80 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 635.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.19 (s, 2H), 8.39 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.20 (br s, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.60-6.50 (m, 1H), 5.04-4.82 (m, 1H), 4.40-4.13 (m, 3H), 2.22-2.02 (m, 1H), 1.94-1.80 (m, 4H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 619.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.18 (d, J = 0.9 Hz, 2H), 8.41 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.60-6.51 (m, 1H), 5.04-4.83 (m, 1H), 4.40-4.14 (m, 3H), 4.03 (t, J = 13.6 Hz, 2H), 2.22-2.02 (m, 1H), 1.96-1.80 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 587.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.09 (s, 2H), 8.36 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.59- 6.50 (m, 1H), 6.47 (s, 1H), 6.14 (t, J = 55.7 Hz, 1H), 5.03-4.82 (m, 1H), 4.39-4.13 (m, 3H), 2.24-2.00 (m, 1H), 1.95-1.80 (m, 1H), 1.66 (d, J = 1.8 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 601.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.09 (s, 2H), 8.36 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.64- 6.51 (m, 1H), 6.47 (s, 1H), 6.14 (t, J = 55.6 Hz, 1H), 5.03-4.82 (m, 1H), 4.39-4.14 (m, 3H), 2.22-2.01 (m, 1H), 1.94-1.80 (m, 1H), 1.66 (d, J = 1.7 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 601.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.06 (s, 2H), 8.32 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.59- 6.51 (m, 1H), 5.09-4.79 (m, 1H), 4.42- 4.13 (m, 3H), 2.22-2.02 (m, 1H), 1.95-1.80 (m, 1H), 1.41 (s, 9H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 563.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 11.66 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.60-6.51 (m, 1H), 5.04-4.81 (m, 1H), 4.32 (ddd, J = 28.2, 14.2, 3.2 Hz, 1H), 4.20 (ddd, J = 17.7, 14.2, 7.7 Hz, 2H), 2.23- 2.01 (m, 1H), 1.95-1.80 (m, 1H), 1.40 (s, 6H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 590.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.99 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.59- 6.51 (m, 1H), 5.05 (s, 2H), 5.04-4.81 (m, 1H), 4.41-4.12 (m, 2H), 2.23-2.01 (m, 2H), 1.96-1.80 (m, 1H), 1.57 (s, 6H), 1.23 (d, J = 6.3 Hz, 3H) ES/MS: 577.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.03-8.97 (m, 1H), 8.26 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 11.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.44 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.60-6.51 (m, 1H), 5.03-4.81 (m, 1H), 4.32 (ddd, J = 28.0, 14.2, 3.2 Hz, 1H), 4.20 (ddd, J = 18.3, 14.2, 7.5 Hz, 2H), 3.20 (tt, J = 6.4, 2.9 Hz, 2H), 2.70 (tt, J = 14.4, 7.1 Hz, 2H), 2.12 (dddd, J = 39.5, 14.7, 9.0, 2.5 Hz, 1H), 1.95-1.79 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 582.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.96 (s, 2H), 8.35 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 11.3 Hz, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.91-7.59 (m, 1H), 7.42 (dd, J = 21.3, 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.74- 6.24 (m, 2H), 5.06-4.74 (m, 1H), 4.44-4.05 (m, 4H), 3.48-3.19 (m, 1H), 2.25-1.97 (m, 1H), 1.98-1.78 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 570.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.96 (s, 2H), 8.35 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 11.3 Hz, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.91-7.59 (m, 1H), 7.42 (dd, J = 21.3, 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.74- 6.24 (m, 2H), 5.06-4.74 (m, 1H), 4.44-4.05 (m, 4H), 3.48-3.19 (m, 1H), 2.25-1.97 (m, 1H), 1.98-1.78 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 570.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.96 (s, 2H), 8.35 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 11.3 Hz, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.91-7.59 (m, 1H), 7.42 (dd, J = 21.3, 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.74- 6.24 (m, 2H), 5.06-4.74 (m, 1H), 4.44-4.05 (m, 4H), 3.48-3.19 (m, 1H), 2.25-1.97 (m, 1H), 1.98-1.78 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 570.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.77 (s, 2H), 8.32 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 11.4 Hz, 1H), 7.94 (s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.55 (dq, J = 7.0, 3.7 Hz, 1H), 5.04-4.81 (m, 1H), 4.40-4.12 (m, 3H), 2.10-2.03 (m, 1H), 1.96- 1.80 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H), 1.15- 1.09 (m, 2H), 0.98-0.94 (m, 2H). ES/MS: 547.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.09 (d, J = 0.7 Hz, 2H), 8.36 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.55 (dd, J = 9.0, 3.6 Hz, 1H), 5.11- 4.79 (m, 1H), 4.44-4.08 (m, 3H), 2.12 (ddd, J = 39.6, 14.1, 9.5 Hz, 1H), 1.79 (d, J = 22.5 Hz, 7H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 567.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.99 (s, 2H), 8.35 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.78- 7.19 (m, 2H), 6.83 (d, J = 7.3 Hz, 1H), 6.55 (dd, J = 9.0, 3.6 Hz, 1H), 5.15-4.72 (m, 1H), 4.51-4.09 (m, 2H), 2.12 (ddd, J = 39.5, 14.1, 8.9 Hz, 1H), 1.97-1.76 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 572.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.28 (d, J = 1.0 Hz, 2H), 8.21 (dd, J = 6.6, 1.7 Hz, 1H), 7.93 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.8 Hz, 1H), 6.54 (dd, J = 9.1, 3.5 Hz, 1H), 5.04-4.81 (m, 1H), 4.40- 4.07 (m, 2H), 2.14 (t, J = 19.4 Hz, 3H), 1.99- 1.80 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). ES/MS: 588.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.77 (s, 2H), 8.10 (dd, J = 6.8, 1.7 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 7.5, 1.8 Hz, 1H), 6.63-6.44 (m, 1H), 5.05-4.75 (m, 1H), 4.42-4.05 (m, 3H), 2.25-1.96 (m, 1H), 1.96-1.75 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 554.9 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.38-9.23 (m, 2H), 8.31-8.17 (m, 1H), 7.93 (s, 1H), 7.52-7.15 (m, 2H), 6.82 (dd, J = 7.5, 1.8 Hz, 1H), 6.54 (dd, J = 9.1, 3.7 Hz, 1H), 5.09-4.76 (m, 1H), 4.45-3.98 (m, 2H), 2.25-1.97 (m, 1H), 1.97-1.80 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H). ES/MS: 575.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.51 (d, J = 1.4 Hz, 1H), 7.99 (dd, J = 6.5, 1.7 Hz, 1H), 7.93 (s, 1H), 7.59 (s, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 54.1 Hz, 1H), 6.74 (dd, J = 7.5, 1.8 Hz, 1H), 6.54 (dd, J = 8.8, 3.7 Hz, 1H), 2.21-2.02 (m, 1H), 1.94-1.81 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H). broad water signal obstructing peaks from 4-5 ppm. ES/MS: 590.0 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.42 (m, 2H), 8.05 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.66-6.44 (m, 1H), 5.07-4.64 (m, 1H), 4.42-3.99 (m, 3H), 2.22-1.98 (m, 1H), 1.94-1.72 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 496.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.19-8.05 (m, 3H), 7.93 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.55 (m, 1H), 4.92 (m, 1H), 4.51-4.04 (m, 3H), 2.37-1.67 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 511.7 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.14 (m, 1H), 8.87 (m, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 11.5 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.55 (m, 1H), 4.93 (m, 1H), 4.20 (m, 1H), 3.46 (m, 2H), 2.11 (m, 1H), 1.88 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 507.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.76 (s, 2H), 8.30 (d, J = 7.3 Hz, 1H), 8.05-7.81 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.63-6.33 (m, 1H), 5.14-4.79 (m, 1H), 4.43-4.11 (m, 5H), 3.78 (m, 2H), 2.24-1.69 (m, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 567.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.36 (d, J = 3.7 Hz, 1H), 8.13 (d, J = 7.1 Hz, 1H), 7.95 (m, 2H), 7.61 (s, 2H), 7.42 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.55 (m, 1H), 4.92 (m, 1H), 4.63-3.74 (m, 3H), 2.22-1.65 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 539.4 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.21 (s, 2H), 8.30 (s, 1H), 8.25 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 10.4 Hz, 1H), 7.87 (s, 1H), 6.47 (m, 1H), 5.02-4.64 (m, 1H), 4.46- 4.06 (m, 4H), 2.07 (m, 3H), 1.90-1.70 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H). ES/MS: 572.6 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.05 (s, 2H), 8.27 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H) 7.86 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.53- 6.43 (m, 1H), 5.05-4.71 (m, 1H), 4.43- 4.03 (m, 3H), 2.19-1.90 (m, 1H), 1.81 (m, 1H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS: 525.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.95 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.86 (s, 1H), 7.53 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.48 (m, 1H), 4.86 (m, 1H), 4.37-3.92 (m, 3H), 2.18-1.56 (m, 2H), 1.16 (d, J = 6.3 Hz, 3H). ES/MS: 507.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.86 (s, 2H), 8.32 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.63- 6.37 (m, 1H), 5.09-4.81 (m, 1H), 4.51- 4.10 (m, 3H), 2.37 (s, 3H), 2.23-2.01 (m, 1H), 1.89 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 521.3 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.97 (s, 2H), 8.34 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.47- 7.40 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.55 (dd, J = 8.8, 3.2 Hz, 1H), 5.59 (s, 1H), 5.02- 4.81 (m, 2H), 4.40-4.13 (m, 3H), 2.21-2.02 (m, 1H), 1.95-1.80 (m, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 551.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.97 (s, 2H), 8.34 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.47- 7.40 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.55 (dd, J = 8.8, 3.2 Hz, 1H), 5.59 (s, 1H), 5.02- 4.81 (m, 2H), 4.40-4.13 (m, 3H), 2.21-2.02 (m, 1H), 1.95-1.80 (m, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 551.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.61 (s, 1H), 8.12 (d, J = 7.1 Hz, 1H), 8.04 (s, 1H), 7.97 (d, J = 11.1 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.55 (dd, J = 9.0, 3.3 Hz, 1H), 5.01- 4.80 (m, 1H), 4.37-4.29 (m, 1H), 4.28-4.11 (m, 5H), 2.21-2.01 (m, 1H), 1.94-1.79 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). ES/MS: 564.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.97 (s, 2H), 8.34 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 7.47- 7.40 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.55 (dd, J = 8.8, 3.2 Hz, 1H), 5.59 (s, 1H), 5.02- 4.81 (m, 2H), 4.40-4.13 (m, 3H), 2.21-2.02 (m, 1H), 1.95-1.80 (m, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 551.2 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.76 (s, 2H), 8.33 (s, 1H), 8.23 (d, J = 6.9 Hz, 1H), 7.98-7.91 (m, 2H), 6.58-6.47 (m, 1H), 5.02-4.81 (m, 1H), 4.41-4.31 (m, 1H), 4.30-4.15 (m, 2H), 2.23-2.05 (m, 1H), 1.96- 1.81 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H). ES/MS: 541.2 m/z [M + H]+.
The title compound was synthesized as described in Example 1, using tert-butyl N-[(1S)-4-iodo-1,3-dimethyl-butyl]carbamate in place of 6-bromo-7-fluoro-2H-isoquinolin-1-one in step 1 of the synthesis. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (d, J=3.7 Hz, 1H), 9.49 (d, J=1.0 Hz, 2H), 8.44 (d, J=7.2 Hz, 1H), 8.04 (d, J=11.4 Hz, 1H), 7.97 (s, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.31-6.22 (m, 1H), 4.18-3.65 (m, 3H), 2.16-1.91 (m, 1H), 1.75 (m, 1H), 1.34 (m, 1H), 1.18 (d, J=6.2 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H). ES/MS m/z: 571.1 [M+H]+.
The title compound was synthesized as described in Example 24, with the following modification in step 4.
Step 4. To a mixture of 5-bromo-6-fluoro-isoindolin-1-one (150 mg, 0.652 mmol) and tert-butyl N-[(1S,3R)-3-fluoro-4-iodo-1-methyl-butyl]carbamate (864 mg, 2.61 mmol) in DMF (6.5 mL) was added Cs2CO3 (1416 mg, 2.61 mmol) and the solution was stirred at 60° C. for 18 h. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO4, and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl N-[(1S,3R)-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-3-fluoro-1-methyl-butyl]carbamate. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.47 (s, 2H), 8.32 (d, J=6.5 Hz, 1H), 7.94 (s, 1H), 7.70 (d, J=9.7 Hz, 1H), 7.67-7.50 (m, 1H), 6.63-6.47 (m, 1H), 4.88 (d, J=50.2 Hz, 1H), 4.73-4.54 (m, 2H), 4.19 (s, 2H), 2.23-1.77 (m, 2H), 1.22 (d, J=6.3 Hz, 3H). ES/MS m/z: 563.0 [M+H]+.
The title compound was synthesized as described in Example 24, using methyl (4S)-4-(tert-butoxycarbonylamino)hexanoate in place of methyl (4S)-4-(tert-butoxycarbonylamino)pentanoate. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.48 (d, J=1.0 Hz, 2H), 8.45 (d, J=7.1 Hz, 1H), 8.05 (d, J=11.3 Hz, 1H), 7.93 (s, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 6.48 (dd, J=8.3, 4.1 Hz, 1H), 5.02-4.78 (m, 1H), 4.40-4.13 (m, 2H), 4.04 (s, 2H), 2.19-1.81 (m, 2H), 1.66-1.53 (m, 2H), 0.85 (t, J=7.3 Hz, 3H). ES/MS m/z: 589.1 [M+H]+.
The title compounds were synthesized as described in Examples 33-35, using 2-chloro-5-(trifluoromethyl)pyrimidine in place of 2-(2-chloropyrimidin-5-yl)propan-2-ol. Examples 119 and Example 120 were separated via chiral SFC (AD-H, 5 μm, 21×250 mm column; 45% EtOH as co-solvent; 100 bar; 40° C.). The first eluting peak was arbitrarily assigned as the (R)-configuration (Example 119), and the second eluting peak was arbitrarily assigned as the (S)-configuration (Example 120).
Example 119: 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.48 (d, J=0.9 Hz, 2H), 8.44 (d, J=7.2 Hz, 1H), 8.32 (s, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 6.66 (t, J=75.1 Hz, 1H), 5.21 (d, J=6.6 Hz, 1H), 4.12 (dd, J=11.6, 2.6 Hz, 1H), 4.06-3.95 (m, 3H), 1.88-1.70 (m, 4H). ES/MS m/z: 624.0 [M+H]+.
Example 120: 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.48 (d, J=0.9 Hz, 2H), 8.44 (d, J=7.2 Hz, 1H), 8.32 (s, 1H), 8.03 (d, J=11.4 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 6.66 (t, J=75.1 Hz, 1H), 5.21 (d, J=6.6 Hz, 1H), 4.12 (dd, J=11.6, 2.6 Hz, 1H), 4.06-3.95 (m, 3H), 1.88-1.70 (m, 4H). ES/MS: m/z 624.0 [M+H]+.
Step 1. (4R)-4-(2-fluoro-3-iodopropyl)-2-(4-methoxyphenyl)-1,3-dioxolane was synthesized as described in Step 1 of Example 11, using (4R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxolane. ES/MS: m/z 366.5 [M+H]+.
Steps 2-8. 2-((4R)-5-(difluoromethoxy)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one was synthesized as described in Steps 2-8 of Example 33, using (4R)-4-(2-fluoro-3-iodopropyl)-2-(4-methoxyphenyl)-1,3-dioxolane. ES/MS: m/z 632.1 [M+H]+.
Step 9. Examples 121 and Example 122 were separated via chiral SFC (AD-H, 5 μm, 21×250 mm column; 45% EtOH as co-solvent; 100 bar; 40° C.) of 2-((4R)-5-(difluoromethoxy)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)pentyl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)isoquinolin-1(2H)-one. The first eluting peak was arbitrarily assigned as the (2R,4R)-configuration (Example 121), and the second eluting peak was arbitrarily assigned as the (2S,4R)-configuration (Example 122).
Example 121: 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.07 (s, 2H), 8.33 (d, J=7.4 Hz, 2H), 7.99 (d, J=11.2 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.69 (t, J=75.1 Hz, 1H), 5.35 (d, J=6.6 Hz, 1H), 5.15-4.93 (m, 1H), 4.46-4.15 (m, 3H), 4.02 (dd, J=11.7, 6.1 Hz, 1H), 2.29-2.07 (m, 2H). ES/MS: m/z 632.1 [M+H]+.
Example 122: 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.33 (d, J=7.4 Hz, 2H), 7.98 (d, J=11.2 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.69 (t, J=75.0 Hz, 1H), 5.42 (d, J=6.3 Hz, 1H), 5.23-5.01 (m, 1H), 4.38 (ddd, J=30.1, 14.3, 2.8 Hz, 1H), 4.29-4.13 (m, 2H), 4.08 (dd, J=11.6, 6.8 Hz, 1H), 2.35-2.05 (m, 2H). ES/MS m/z: 632.1 [M+H]+.
Step 1. To a solution of triethyl 2-fluoro-2-phosphonoacetate (1.0 g, 4.36 mmol) in THF (20.0 mL) at −78° C. was added a solution of n-butyllithium (4.8 mmol, 1.9 mL) and the mixture was stirred for 10 minutes. The cooling bath was then removed, and the mixture was stirred for 20 minutes, and then cooled back down to −78° C. A solution of tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (1.00 g, 4.36 mmol) in THF (20 mL) was then added slowly and the mixture was stirred for 1 h at 78° C. and quenched with a solution of saturated NH4Cl(aq) and allowed to warm to room temperature. The mixture was extracted 3× with EtOAc, dried over MgSO4, and evaporated. The crude residue was purified via flash chromatography (100% hexanes→35% EtOAc) to afford tert-butyl (4R)-4-[€-3-ethoxy-2-fluoro-3-oxo-prop-1-enyl]-2,2-dimethyl-oxazolidine-3-carboxylate. ES/MS: m/z 339.6 [M+Na]+.
Step 2. Tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-prop-1-enyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.2 g, 3.47 mmol) and 10% Pd/C (185 mg, 0.17 mmol) were taken up in EtOH (29.0 mL) and stirred at ambient temperature. The reaction headspace was evacuated/backfilled with nitrogen gas four times then with hydrogen gas four times. The reaction was then stirred under a balloon of hydrogen gas for 1 hour before the catalyst was filtered off through a plug of Celite® and washed with additional EtOH. The filtrate was evaporated to provide tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 342.0 [M+H+Na]+.
Step 3. tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.1 g, 3.47 mmol) was dissolved in THF (14.5 mL) and cooled to 0° C. LiBH4 (2.0 M, 6.94 mmol) was added slowly. Thirty minutes after complete addition, the cooling bath was removed, and the reaction was stirred a further 16 hours at ambient temperature. The reaction was then cooled again to 0° C. and quenched with 10% KHSO4. The mixture was extracted 3× with EtOAc. The combined organics were dried over MgSO4, filtered, and evaporated to afford tert-butyl 4-(2-fluoro-3-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 300.0 [M+H+Na]+.
Step 4. Tert-butyl 4-(2-fluoro-3-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate (941 mg, 3.22 mmol) was dissolved in DCM (24 mL) and TEA (1.1 mL, 8.1 mmol). The mixture was then cooled to 0° C. before the addition of toluene-4-sulfonyl chloride (799 mg, 4.19 mmol) and DMAP (33 mg, 0.27 mmol). The cooling bath was then removed, and the mixture was stirred for 18 h. The reaction was quenched with 10% KHSO4 and extracted 3× with EtOAc. The combined organics were dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hexanes+35% EtOAc) to afford tert-butyl 4-[2-fluoro-3-(p-tolylsulfonyloxy)propyl]-2,2-dimethyl-oxazolidine-3-carboxylate. ES/MS: m/z 433.2 [M+H]+.
Step 5. Tert-butyl 4-[2-fluoro-3-(p-tolylsulfonyloxy)propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (1.4 g, 3.1 mmol), 6-bromo-7-fluoro-2H-isoquinolin-1-one (972 mg, 4.02 mmol), and Cs2CO3 (2.5 g, 7.72 mmol) were suspended in DMF (14 mL) and stirred at 45° C. for 18 hours. The reaction was then diluted with water and 10% KHSO4 and extracted 3× with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hexanes+80% EtOAc) to afford tert-butyl 4-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-fluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylate. ES/MS: m/z 501.0/502.9 [M]+.
Step 6. To a solution of tert-butyl (4R)-4-[(2R)-3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-fluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (1.2 g mg, 2.31 mmol) in dichloromethane (16.5 mL) was added trifluoroacetic acid (3.5 mL) at room temperature and the mixture was stirred for 1 h. The reaction was then diluted with water and trifluoroacetic acid (3.5 mL) and stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the excess solvent was removed by forming an azeotrope with toluene to afford 2-[(2R,4S)-4-amino-2-fluoro-pentyl]-6-bromo-4,7-difluoro-isoquinolin-1-one, which was used without further purification. ES/MS: m/z 361.218 [M+H]+.
Step 7. In a flask were placed 2-[(2R,4R)-4-amino-2-fluoro-5-hydroxy-pentyl]-6-bromo-7-fluoro-isoquinolin-1-one (835 mg, 2.31 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (1.41 g, 3.01 mmol), DIPEA (4.0 mL, 2.31 mmol), and DMF (16.4 mL). The mixture was heated to 60° C. for 3 h, then quenched with water and extracted with EtOAc (3X). The combined organic layers were washed with brine and dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a crude oil which was purified by flash chromatography (0-100% EtOAc in hexane) to give 6-bromo-7-fluoro-2-[(2R,4R)-2-fluoro-5-hydroxy-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]isoquinolin-1-one, Intermediate 8. ES/MS: m z 655.1 [M+H]+.
The title compound was synthesized as described in Steps 7-8 of Example 24, using Intermediate 8. 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.49 (d, J=1.0 Hz, 2H), 8.45 (d, J=7.1 Hz, 1H), 8.05 (d, J=11.3 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 6.51-6.39 (m, 1H), 5.08-4.83 (m, 1H), 4.41-4.16 (m, 2H), 4.16-4.04 (m, 1H), 3.57-3.43 (m, 2H), 2.15-1.85 (m, 2H). ES/MS m/z: 591.2 [M+H]+.
The following Examples were synthesized as described in Example 123 or a modification of the procedure above from the corresponding reagents and Intermediate 8.
1H NMR/MS [M + H]+
1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.15 (s, 2H), 8.37 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 11.3 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.50- 6.40 (m, 1H), 5.06-4.82 (m, 1H), 4.40- 4.15 (m, 2H), 4.15-4.04 (m, 1H), 3.56-3.44 (m, 2H), 2.15-1.85 (m, 2H). ES/MS: 557.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.25 (d, J = 1.2 Hz, 2H), 8.42 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 11.3 Hz, 1H), 7.90 (s, 1H), 7.50-7.15 (m, 2H), 6.84 (d, J = 7.4 Hz, 1H), 6.51-6.40 (m, 1H), 5.07-4.84 (m, 1H), 4.41-4.16 (m, 2H), 4.16-4.04 (m, 1H), 3.56- 3.44 (m, 2H), 2.14-1.86 (m, 2H). ES/MS: 573.1 m/z [M + H]+.
Step 1. Triethyl 2-fluoro-2-phosphonoacetate (8.7 g, 36 mmol) was dissolved in DCM (150 mL) and stirred at room temperature, followed by the addition of DBU (5.7 ml, 38.0 mL). After 50 minutes, tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (5.0 g, 22 mmol) was added via an addition funnel as a solution in DCM (100 mL) over the course of 60 minutes. The reaction was stirred for an additional 3 hours, at which point it was quenched by the slow addition of pre-chilled 10% KHSO4(aq). The mixture was then extracted 3× with DCM, dried over MgSO4, and evaporated. The crude residue was purified via flash chromatography (100% hexanes→35% EtOAc) to afford tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-prop-1-enyl)-2,2-dimethyl-oxazolidine-3-carboxylate as a mixture of isomers. Note that the C—N stereocenter was racemized in this reaction. ES/MS: m/z 339.6 [M+Na]+.
Step 2. tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-prop-1-enyl)-2,2-dimethyl-oxazolidine-3-carboxylate (950 mg, 2.8 mmol) and 10% Pd/C (160 mg, 0.15 mmol) were taken up in EtOH (25.0 mL) and stirred at room temperature. The reaction headspace was evacuated/backfilled with nitrogen gas four times and then filled with hydrogen gas four times. The reaction was then stirred under a balloon of hydrogen gas for 1 hour before the catalyst was filtered off through a plug of Celite® and washed with additional EtOH. The filtrate was evaporated to provide tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 342.0 [M+H+Na]+.
Step 3. Tert-butyl 4-(3-ethoxy-2-fluoro-3-oxo-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.8 mmol) was dissolved in THF (20.0 mL) and cooled to 0° C. LiBH4 (2.0 M, 5.7 mmol) was added slowly. 30 minutes after complete addition, the cooling bath was removed, and the reaction was stirred for 16 hours at room temperature. The reaction was then cooled to 0° C. and quenched with 10% KHSO4(aq). The mixture was extracted 3× with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford tert-butyl 4-(2-fluoro-3-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 300.0 [M+H+Na]+.
Step 4. tert-butyl 4-(2-fluoro-3-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.8 mmol) was dissolved in DCM (20.0 mL) and TEA (0.94 mL, 6.8 mmol). The reaction was then cooled to 0° C. before the addition of toluene-4-sulfonyl chloride (670 mg, 3.5 mmol) and DMAP (33.0 mg, 0.27 mmol). The cooling bath was removed, and the reaction was stirred for 2 hours before an additional portion of TEA (0.94 mL, 6.8 mmol) was added. The reaction was stirred for 18 hours, and then was quenched with 10% KHSO4(aq) and extracted 3× with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford tert-butyl 4-[2-fluoro-3-(p-tolylsulfonyloxy)propyl]-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 432.0 [M+H]+.
Step 5. Tert-butyl 4-[2-fluoro-3-(p-tolylsulfonyloxy)propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (2.7 mmol), 6-bromo-7-fluoro-2H-isoquinolin-1-one (850 mg, 3.5 mmol), and Cs2CO3 (2.2 g, 6.8 mmol) were suspended in DMF (7.0 mL) and stirred at 45° C. for 12 hours. The reaction was then diluted with water and 10% KHSO4 and extracted 3× with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hexanes>80% EtOAc) to afford tert-butyl 4-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-fluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylate. ES/MS: m/z 501.0/502.9 [M]+.
Step 6. Tert-butyl 4-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-fluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylate (810 mg, 1.5 mmol) was taken up in CAN (15 mL) and stirred at room temperature, followed by the addition of BiBr3 (69 mg, 0.15 mmol). The reaction was stirred for 18 hours, followed by the addition of another portion of BiBr3 (69 mg, 0.15 mmol). After 24 hours, the reaction was quenched with sat. NaHCO3(aq) and extracted 3× w/EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to afford tert-butyl 4-[3-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-2-fluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylate, which was carried forward without purification. ES/MS: m/z 501.0/502.9 [M]+.
Step 7. tert-butyl N-[4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-3-fluoro-1-(hydroxymethyl)butyl]carbamate (1.5 mmol) was taken up in DCM (4.0 mL) and water (3.5 mL) and stirred at room temperature. Potassium acetate (1.2 g, 12 mmol) was charged followed by [bromo(difluoro)methyl]-trimethyl-silane (0.96 mL, 6.1 mmol). After stirring for 3 hours, an additional portion of [bromo(difluoro)methyl]-trimethyl-silane (0.96 mL, 6.1 mmol) was added. After an additional 1 hour, the reaction was cooled to 0° C. and quenched by slow addition of sat. NaHCO3(aq). The mixture was extracted 3× w/DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude residue was purified via flash chromatography (100% hexanes→80% EtOAc) to afford tert-butyl N-[4-(6-bromo-7-fluoro-1-oxo-2-isoquinolyl)-1-(difluoromethoxymethyl)-3-fluoro-butyl]carbamate. ES/MS: m/z 511.0/512.9 [M]+.
Steps 8-11. The title compound was synthesized as described in steps 7-8 of Example 24, using Intermediate 9 to provide 2-((2R)-5-(difluoromethoxy)-2-fluoro-4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-7-fluoro-6-(5-(trifluoromethyl)pyrimidin-2-yl)isoquinolin-1(2H)-one. 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.49 (d, J=0.9 Hz, 2H), 8.45 (d, J=7.2 Hz, 1H), 8.05 (d, J=11.3 Hz, 1H), 7.93 (s, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.90-6.54 (m, 2H), 6.63-6.42 (m, 1H), 5.08-4.84 (m, 1H), 4.49-4.16 (m, 3H), 4.02-3.90 (m, 2H), 2.22-1.85 (m, 2H). ES/MS m/z: 641.1 [M+H]+.
The following Examples were synthesized as described in Example 126 or a modification of the procedure above from the corresponding reagents and Intermediate 9.
1H NMR/MS [M + H]+
1H NMR (400 MHz, DMSO-d6) δ 12.63-12.34 (m, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.19 (d, J = 7.0 Hz, 1H), 8.00-7.94 (m, 1H), 7.93 (s, 1H), 7.62 (br s, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 54.1 Hz, 1H), 6.90- 6.48 (m, 3H), 5.19-4.82 (m, 1H), 4.53-4.11 (m, 3H), 4.04-3.91 (m, 2H), 2.20-1.87 (m, 2H). ES/MS: 638.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.52 (d, J = 9.5 Hz, 1H), 8.75 (s, 2H), 8.29 (d, J = 7.3 Hz, 1H), 7.97 (dd, J = 11.3, 4.1 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 6.90-6.46 (m, 3H), 5.20-4.80 (m, 1H), 4.53-4.11 (m, 3H), 4.00 (s, 3H), 3.99-3.92 (m, 2H), 2.20- 1.86 (m, 2H). ES/MS: 603.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.64-12.36 (m, 1H), 9.07 (s, 2H), 8.33 (d, J = 7.2 Hz, 1H), 8.04-7.96 (m, 1H), 7.93 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.91-6.45 (m, 3H), 5.19-4.82 (m, 1H), 4.53-4.11 (m, 3H), 4.06-3.89 (m, 2H), 2.21-1.86 (m, 2H), 1.55 (s, 6H). ES/MS: 631.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.25 (t, J = 1.3 Hz, 2H), 8.42 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 11.3 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 54.8 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.68 (t, J = 75.4 Hz, 1H), 6.63-6.55 (m, 1H), 5.09-4.83 (m, 1H), 4.48-4.16 (m, 3H), 4.03-3.89 (m, 2H), 2.21-1.87 (m, 2H). ES/MS: 623.1 m/z [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ 12.71-12.35 (m, 1H), 9.26 (d, J = 0.9 Hz, 2H), 8.40 (d, J = 7.1 Hz, 1H), 8.05-7.97 (m, 1H), 7.93 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.91-6.48 (m, 3H), 5.18-4.85 (m, 1H), 4.56- 4.10 (m, 3H), 4.04-3.90 (m, 2H), 2.23- 1.86 (m, 5H). ES/MS: 637.1 m/z [M + H]+.
Step 1. tert-butyl N-[(1S,3R)-3-(iodomethyl)cyclohexyl]carbamate (544.0 mg, 1.56 mmol), 6-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (499.0 mg, 1.87 mmol), and Cs2CO3 (2.03 g, 6.24 mmol) were taken up in DMF (1.4 mL) and stirred at ambient temperature for 16 hours at which point the reaction was heated to 60° C. After an additional 5 hr, the reaction was deemed complete by LC/MS analysis and was cooled to ambient temperature. The mixture was then diluted with water and extracted 3× with EtOAc The combined organics were washed with brine, dried over Na2SO4, filtered, and evaporated to afford tert-butyl N-[(1S,3R)-3-[(6-bromo-7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)methyl]cyclohexyl]carbamate. ES/MS m/z: 434.3/436.4 [M]+.
Step 2. tert-butyl N-[(1S,3R)-3-[(6-bromo-7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)methyl]cyclohexyl]carbamate (676 mg, 1.48 mmol) was dissolved in THF (41.8 mL) and water (17.3 mL) and stirred at ambient temperature. NaHCO3 (904 mg, 1.48 mmol) and iodine (2.82 g, 11.1 mmol) were then added sequentially. After 90 minutes, the reaction was quenched with saturated Na2S2O3 and extracted 3× with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude material was purified via flash chromatography (100% hex→100% EtOAc) to afford tert-butyl N-[(1S,3R)-4-(6-bromo-7-fluoro-1-oxo-3,4-dihydroisoquinolin-2-yl)-3-fluoro-1-methyl-butyl]carbamate. ES/MS m/z: 447.0/449.0 [M]+.
Step 3. tert-butyl N-[(1S,3R)-3-[(6-bromo-7-fluoro-1-oxo-3,4-dihydroisoquinolin-2-yl)methyl]cyclohexyl]carbamate (91.0 mg, 0.193 mmol) was dissolved in DCM (2.0 mL) and the solution was stirred at room temperature, followed by the addition of TFA (0.15 mL, 1.93 mmol). After 1 hour, the mixture was evaporated to dryness in vacuo and the crude 2-[(2R,4S)-4-amino-2-fluoro-pentyl]-6-bromo-7-fluoro-3,4-dihydroisoquinolin-1-one was carried forward without purification. ES/MS m/z: 347.0/349.0 [M]+.
Step 4. 2-[(2R,4S)-4-amino-2-fluoro-pentyl]-6-bromo-7-fluoro-3,4-dihydroisoquinolin-1-one (67.0 mg, 0.193 mmol) and 5-chloro-4-(trifluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (118 mg, 0.251 mmol) were dissolved in DMF (2.50 mL). DIPEA (0.34 mL, 1.93 mmol) was then added and the reaction was stirred at 60° C. for 3 hours, at which point it was cooled to room temperature, diluted w/10% aq. KHSO4, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude material was purified via flash chromatography (100% hex→100% EtOAc) to afford 6-bromo-7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyridazin-4-yl]amino]pentyl]-3,4-dihydroisoquinolin-1-one, Intermediate 9. ES/MS m/z: 639.1/641.1 [M]+.
Steps 5-6. The title compound was synthesized as described in steps 7-8 of Example 24, using Intermediate 9 to provide 7-fluoro-2-[(2R,4S)-2-fluoro-4-[[6-oxo-5-(trifluoromethyl)-1H-pyridazin-4-yl]amino]pentyl]-6-[5-(trifluoromethyl)pyrimidin-2-yl]-3,4-dihydroisoquinolin-1-one. H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.44 (d, J=0.9 Hz, 2H), 8.05 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.74 (d, J=11.2 Hz, 1H), 6.61-6.47 (m, 1H), 4.97-4.71 (m, 1H), 4.27-4.10 (m, 1H), 3.88-3.68 (m, 2H), 3.68 (t, J=6.5 Hz, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.20-1.95 (m, 1H), 1.95-1.78 (m, 1H), 1.23 (d, J=6.3 Hz, 3H). ES/MS m/z: 577.1 [M+H]+.
v. Biological Data
LANCE Ultra phospho-STAT1 (Tyr701) kits are designed for the detection of phosphorylated STAT1 in cell lysates using a simple, homogeneous LANCE Ultra sandwich assay (Cat. #TRF4028M). This assay is intended for assessing compound induction of endogenous levels of cellular STAT1 (phosphorylated at Tyr701) in NCI-H1373 cells. The NCI-H1373 cells are cultured in RPMI 1640 media containing 10% heat inactivated FBS, GlutaMAX, 1% Penicillin-Streptomycin. An Echo acoustic liquid handler is used to transfer 60 nanoliters of compound dilutions using the Echo Qualified, 384-well polypropylene microplate clear flat bottom source plates into a Greiner (#781080) cell culture microplate. NCI-H1373 cells are seeded into these compound-spotted culture plates at 30,000 cells/well in a 60 uL volume in growth media. The plates are incubated in a 5% CO2 humidified incubator at 37° C. for 48 hours. The media is removed and the cells are processed according to the manufacturer's suggested protocol. Briefly, 20 mL of supplemented lysis buffer is added to each well and allowed to shake for 1 hour at 400 rpm. Next, 5 ul of remixed antibody solutions (vol/vol) prepared in detection buffer are added to each well and allowed to incubate at room temperature overnight. After spinning the plate down at 300 rpm for 1 min, the plate is read on an EnVision plate reader set up for Eu3+ Cryptate and fluorescence emission is measured at two different wavelengths (665 nm and 620 nm). The HTRF ratio is then calculated (665 nM/620 nM) for each well to determine the amount of pSTAT1 in the cell lysate, and the data is then normalized to 10 uM (S)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one positive and DMSO negative controls. The values were then plotted as a function of compound concentration and a 4-parameter fit was applied to derive the EC50 values.
This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Ser. No. 63/515,755, filed Jul. 26, 2023, the contents of which are hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63515755 | Jul 2023 | US |
