Patent Application
20230150946
The Signal Transducer and Activator of Transcription (“STAT”) proteins constitute a family of cytoplasmic transcription factors that play a fundamental role in cell signaling. The STAT protein family consists of 7 members, STAT1 to STAT6, including STAT5 and STAT3. STAT5 can transduce intracellular and extracellular signals to the nucleus and control the expression of genes responsible for multiple physiological processes. STAT proteins are ideal targets for anti-cancer therapy because cancer cells are more dependent on STAT activity than their normal counterparts. Therefore, a need exists in the medicinal arts for compounds, formulation, and methods of STAT modulation.
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for the inhibition of Signal Transducer and Activators of Transcription, for example STAT 5a and 5b (STAT5). Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as, for example, breast cancer and pancreatic cancer.
One aspect of the disclosure provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein,
One aspect of the disclosure provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein
In some embodiments, the disclosure provides a compound having the structure of Formula (IIa), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein
In some embodiments, the disclosure provides a compound having the structure of Formula (IIb), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein
In some embodiments, the disclosure provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein,
In one aspect, described herein is a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof. Also described herein is a pharmaceutical composition comprising a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.
Another aspect of the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), (IIa), (IIb), and (III) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.
Another aspect of the disclosure provides a method of making the compounds and compositions described herein.
Another aspect of the disclosure provides a method of modulating signal transducer and activator of transcription 5a and 5b (STAT5) proteins in a subject in need thereof, comprising administering to a subject a therapeutically effective amount a compound of Formula (I), (II), (IIa), (IIb), and (III), or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of the disclosure provides a method of modulating signal transducer and activator of transcription 3 (STAT3) proteins in a subject in need thereof, comprising administering to a subject a therapeutically effective amount a compound of Formula (I), (II), (IIa), (IIb), and (III), or a pharmaceutically acceptable salt or solvate thereof.
In yet another aspect of the disclosure, the disclosure provides a method comprising administering to a subject with cancer a therapeutically effective amount of a compound of Formula (I), (II), (IIa), (IIb), and (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor or hematologic cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, hepatocellular cancer, colorectal cancer, gastric adenocarcinoma, melanoma, or advanced cancer.
In an aspect of the disclosure, the disclosure provides a composition comprising Compound (1018).
In an aspect of the disclosure, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to a subject with cancer a therapeutically effective amount of Compound (1018).
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
The present disclosure relates to STAT inhibitory compounds, pharmaceutical compositions comprising said compounds, and methods of making and/or using the compounds.
The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.
Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.
The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
“Amino” refers to the —NH2 radical.
“Cyano” refers to the —CN radical.
“Nitro” refers to the —NO2 radical.
“Methoxyl” refers to the —O-Me radical.
“Oxa” refers to the —O— radical.
“Oxo” refers to the ═O radical.
“Thioxo” refers to the ═S radical.
“Imino” refers to the ═N—H radical.
“Oximo” refers to the ═N—OH radical.
“Hydrazino” refers to the ═N—NH2 radical.
“Hydroxy” or “hydroxyl” refers to the —OH radical.
“Hydroxyamino” refers to the —NH—OH radical.
“Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
“Acyl-sulfonamide” refers to a monovalent radical where the carbon atom of a carbonyl is bound to a sulfonamide group. Exemplary acyl-sulfonamides include —C(O)NRaS(O)2Ra, —C(O)NRaS(O)2N(Ra)2, —NRaS(O)2C(O)Ra, —NRaS(O)2C(O)N(Ra)2, —C(O)NRaS(O)2C(O)N(Ra)2, —NRaS(O)2NRaC(O)N(Ra)2, —C(O)NRaS(O)2NRaC(O)N(Ra)2, and —C(O)S(O)2N(Ra)2, where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
“Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a C1-C5 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, —NO2, or —C≡CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (—CH═CH2), 1-propenyl (—CH2CH═CH2), isopropenyl [—C(CH3)═CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C5 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is —CH2—, —CH2CH2—, or —CH2CH2CH2—. In some embodiments, the alkylene is —CH2—. In some embodiments, the alkylene is —CH2CH2—. In some embodiments, the alkylene is —CH2CH2CH2—.
“Alkylamino” refers to a radical of the formula —N(Ra)2 where Ra is an alkyl radical as defined, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7 heterocyloalkyl ring such as:
Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkylamino is optionally substituted with halogen.
“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising at least one aromatic ring. In some embodiments, an aryl comprises hydrogens and 6 to 30 carbon atoms. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —S(O)2NH—C1-C6alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, —NO2, —S(O)2NH2, —S(O)2NHCH3, —S(O)2NHCH2CH3, —S(O)2NHCH(CH3)2, —S(O)2N(CH3)2, or —S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2.
“Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
“Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, “fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, —CH2OCH3, —CH2CH2OCH3, —CH2CH2OCH2CH2OCH3, or —CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
“Heterocyclyl,” “heterocycle,” or “heterocyclic” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused, bridged, or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—CN, —Rb—O—Re—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Re is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
“Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
“Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms that are selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl is a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
The term “spiro” or “spirocyclic” refers to a compound or moiety having one atom as the only common member of two rings.
“Squaryl” refers to a radical comprising a 1,2-dione cyclobutene ring with substituents at the 3- and/or 4-positions. Exemplary substituents on a squaryl include, but are not limited to, amino, hydroxyamino, hydroxyl, substituted or unsubstituted alkylamino, and substituted or unsubstituted alkoxy. In some embodiments, a squaryl is a squaramide, a squarate, or a squaric acid monoamide monoester. “Squaramide” refers to a radical comprising a 1,2-dione cyclobutene ring with substituents at the 3- and 4-positions that are each independently amino, hydroxyamino, or substituted or unsubstituted alkylamino. “Squarate” refers to a radical comprising a 1,2-dione cyclobutene ring with substituents at the 3- and 4-positions that are each independently hydroxyl, or substituted or unsubstituted alkoxy. “Squaric acid monoamide monoester” refers to a radical comprising a 1,2-dione cyclobutene ring wherein one substituent at the 3 or 4 position is hydroxyl, or substituted or unsubstituted alkoxy, and one substituent at the 3 or 4 position is amino, hydroxyamino, or substituted or unsubstituted alkylamino.
The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof. As used herein, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and/or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease. The term “treating” further encompasses the concept of “prevent,” “preventing,” and “prevention,” that is, reducing the probability of developing a disease or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease or condition.
The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
The term “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. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3), mono-substituted (e.g., —CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., —CH2CHF2, —CH2CF3, —CF2CH3, —CFHCHF2, etc.).
The present disclosure also provides compounds that bear a sulfonyl moiety, a suloximinyl moiety, a sulfinyl moiety, or a combination thereof. For example, a compound of the disclosure can bear the divalent radical
where X is O, NRZ, or absent, and RZ is alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl, any of which is substituted or unsubstituted, or hydrogen. In some embodiments, a compound of the disclosure can bear the monovalent radical
where Y is a substituted or unsubstituted 5-membered or 6-membered ring optionally comprising 1-3 hetero ring atoms selected from O, N, and S; and X is O, NRZ, or absent, where RZ is H, alkyl, cycloalkyl, heteroalkyl, or cycloheteroalkyl, any of which is substituted or unsubstituted, or hydrogen. It shall be understood that when X is “absent,” the monovalent radical
shall be equivalent to
As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more oncological disorders or cancers prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for inhibition or negative modulation of STAT proteins (such as STX T5 and STAT3) prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for treatment of one or more oncological disorders or cancers associated with STAT proteins (such as STAT5 and STAT3) dysfunction prior to the administering step. In some embodiments, the subject is suspected of having a condition or disease.
Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., “oxo” or “═O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
The term “substituted,” “substituent” or the like, unless otherwise indicated, can refer to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, oxo, thioxy, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and an aliphatic group. It is understood that the substituent may be further substituted.
The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.
As used herein, C1-Cx (or C1-x) includes C1-C2, C1-C3 . . . C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
Provided herein are STAT5 inhibitory compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting signal transducer and activator of transcription 5a and 5b (STAT5) proteins and for the treatment of a cell proliferative disease such as cancer. In one aspect, herein disclosed compounds are STAT protein inhibitors, such as STAT5 and STAT3 inhibitors.
In one aspect, the instant disclosure provides a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein,
In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R3 is pentafluorophenyl.
In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R12 is substituted or unsubstituted 5-membered or 6-membered heterocycloalkyl. In some embodiments, R12 is
One aspect of the disclosure provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof:
wherein,
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, each R6 is independently selected from H, F, —CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, and substituted or unsubstituted C1-C6 alkoxy. In some embodiments, each R6 is independently selected from H, F, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF3, —CH2CF3, —CH2CH2F, —OCF3, —OH, —OCH3. In some embodiments, each R6 is H. In some embodiments, R6 is D.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, R5 and R6 taken together form an oxo.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, R5 and R6 taken together with the carbon to which they are attached form a substituted or unsubstituted 4, 5, or 6 membered heterocyclic ring. In some embodiments, R5 and R6 taken together with the carbon to which they are attached form an oxetane, azetidine, tetrahydrofuran, or morpholine ring.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, R5 and R6 taken together with the carbon to which they are attached form a substituted or unsubstituted 3, 4, 5, or 6 membered cycloalkyl ring. In some embodiments, R5 and R6 taken together with the carbon to which they are attached form a substituted or unsubstituted cyclobutane, cyclopentane, or cyclohexane.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, X is O.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, X is NR11.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, X is absent.
In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof, the compound has the structure of Formula (II):
wherein
In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof, the compound has the structure of Formula (IIa):
wherein
In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof, the compound has the structure of Formula (IIb):
wherein
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, each of R5 is independently selected from the group consisting of H, F, —OR11, —SR11, —N(R11)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each of R5 is independently selected from the group consisting of H, F, —CN, —NH(CH3), —NH2, —N(CH3)2, —NHR11, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, linear or branched pentyl, linear or branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, —CF3, —CH2CF3, —CH2CH2F, —OCF3, —OH, —SH, —OCH3, —OCH2CH3, —OCH2OMe, and —OCH2CH2OH.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, each of R5 is independently H, methyl, ethyl, propyl, butyl, pentyl, or hexyl, wherein the methyl, ethyl, propyl, butyl, pentyl, or hexyl is linear or branched, substituted or unsubstituted. In some embodiments, each of R5 is independently H, methyl, ethyl, propyl, butyl, pentyl, or hexyl, wherein the methyl, ethyl, propyl, butyl, pentyl, or hexyl is linear or branched, and optionally substituted with 1 to 3 F, methoxy, hydroxy, or amino. In some embodiments, each of R5 is independently H, CH3, CF3, or CH2F. In some embodiments, R5 is D.
In some embodiments of a compound of Formula (IV) or (I), or a pharmaceutically acceptable salt or solvate thereof, each of R7, R8, R9, and R10 is independently selected from the group consisting of H, amino, F, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted mono-C1-C6 alkylamino, substituted or unsubstituted di-C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C1-C6 heteroalkyl, wherein the alkyl is optionally substituted with hydroxy, amino, or methoxy. In some embodiments, each of R7, R1, R9, and R10 is independently selected from the group consisting of H, amino, F, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C1-C6heteroalkyl, wherein the alkyl is optionally substituted with hydroxy, amino, or methoxy. In some embodiments, wherein each of R7, R1, R9, and R10 is independently selected from the group consisting of H, F, —NH(CH3), —NH2, —N(CH3)2, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF3, —CH2CF3, —CH2CH2F, —OCF3, —OH, —OCH3, —OCH2CH3, —OCH2OMe, and —OCH2CH2OH. In some embodiments, R7 is D. In some embodiments, R8 is D. In some embodiments, R9 is D. In some embodiments, R10 is D.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, each of R7, R1, R9, and R10 is independently selected from the group consisting of H, F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, and substituted or unsubstituted C1-C6 heteroalkyl, wherein the alkyl, fluoroalkyl or heteroalkyl is optionally substituted with hydroxy, amino, or methoxy. In some embodiments, each of R7, R8, R9, and R10 is independently H, F, methyl, ethyl, propyl, —CF3, or —CH2CF3. In some embodiments, each of R7, R8, R9, and R10 is H. In some embodiments, R7 is D. In some embodiments, R8 is D. In some embodiments, R9 is D. In some embodiments, R10 is D.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R7 and R, taken together form a substituted or unsubstituted 3, 4, 5, or 6-membered cycloalkyl or heterocycloalkyl ring.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt or solvate thereof, R9 and R10, taken together form a substituted or unsubstituted 3, 4, 5, or 6-membered cycloalkyl or heterocycloalkyl ring.
In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or polymorph thereof, the compound has the structure of Formula (III):
wherein,
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is substituted or unsubstituted phenyl. In some embodiments, R1 is substituted phenyl, and wherein the phenyl is substituted with 1 to 5 substituents independently selected from halogen, D, —CN, —NO2, —OR11, —N(R11)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, and substituted or unsubstituted —C0-6 alkylene-C3-7 heterocycloalkyl. In some embodiments, wherein R1 is substituted phenyl, and wherein the phenyl is substituted with F or Cl. In some embodiments, R1 is substituted phenyl, wherein the phenyl is substituted with —O—C1-C6 alkyl, and wherein the alkyl is substituted or unsubstituted. In some embodiments, R1 is substituted phenyl, and wherein the phenyl is substituted with one or two C1-C6 alkyl, and wherein the alkyl is linear or branched, substituted or unsubstituted. In some embodiments, R1 is substituted phenyl, and wherein the phenyl is substituted with one or two C3-8 cycloalkyl, and wherein the cycloalkyl is substituted or unsubstituted. In some embodiments, R1 is substituted phenyl, wherein the phenyl is substituted with one C3-8 cycloalkyl and one C1-C6 alkyl, and wherein the cycloalkyl and alkyl is substituted or unsubstituted. In some embodiments, R1 is substituted phenyl, wherein the phenyl is substituted with 1, 2, or 3 RA, and wherein each RA is independently halogen, D, —CN, —NO2, —OR11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, or substituted or unsubstituted —C0-6 alkylene-C3-7 heterocycloalkyl.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is substituted phenyl, wherein the phenyl is substituted with 1, 2, or 3 RA, and wherein two RA, taken together with the intervening atoms to which they are attached form a 4, 5, or 6 membered ring. In some embodiments, the 4, 5, or 6 membered ring comprises 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is
In some embodiments, R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is naphthyl.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is substituted or unsubstituted monocyclic heteroaryl containing 1, 2, or 3 nitrogens. In some embodiments, R1 is substituted or unsubstituted pyridinyl, pyridazinyl, or pyrimidinyl. In some embodiments, R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is substituted or unsubstituted bicyclic heteroaryl comprising 1 to 2 N. In some embodiments, R1 is substituted or unsubstituted 5-6, 6-6, or 6-5 fused bicyclic heteroaryl containing 1-3 hetero ring atoms selected from O, N and S. In some embodiments, R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R1 is substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, wherein R1 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R12 is substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, R12 is substituted or unsubstituted 5-membered heteroaryl with 1 to 2 nitrogen atoms. In some embodiments, R12 is 5- or 6-membered heteroaryl substituted with OR11, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, sulfonic acid, sulfinic acid, tetrazole, acyl-sulfonamide, or carboxylic acid or an isostere thereof.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R12 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted triazinyl. In some embodiments, is
wherein RQ is independently —OR11, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, sulfonic acid, sulfinic acid, tetrazole, acyl-sulfonamide, or carboxylic acid or an isostere thereof, and Z is 0, 1, or 2. In some embodiments, R12 is
In some embodiments, R12 is 5 or 6-membered heteroaryl substituted with amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R12 is a substituted or unsubstituted —C0-6 alkylene-squaryl group. In some embodiments, the squaryl group is a squaramide, a squarate, or a squaric acid monoamide monoester. In some embodiments, R12 is substituted or unsubstituted —C1-3 alkylene-squaramide. In some embodiments, R12 is
wherein each RB is independently C1-C3 alkyl, hydroxyl, or hydrogen, and each RB2 is independently C1-C3 alkyl or hydrogen. In some embodiments, R12 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R2 is phenyl or substituted phenyl. In some embodiments, R2 is phenyl substituted with 1 to 5 Rc, and wherein each Rc is independently D, halogen, —OR11, —SR11, —N(R11)2, —CN, —NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, or substituted or unsubstituted —C0-6 alkylene-C3-7 heterocycloalkyl. In some embodiments, R2 is phenyl substituted with 1 to 5 Rc, and wherein each Rc is independently D, F, Cl, Br, —CN, OH, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF3, —CH2CF3, —CH2CH2F, —OCF3, —OH, —OCH3, —OCH2CH3, —OCH2OMe, —OCH2CH2OH, —OC(CH3)3, —OCH2CH2OCH3,
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R2 is
In some embodiments, R2 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R2 is substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl. In some embodiments, R2 is pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, wherein the pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl is substituted with 1 to 4 Rc, and wherein each Rc is independently D, halogen, —OR11, —SR11, —N(R11)2, —CN, —NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, or substituted or unsubstituted —C0-6 alkylene-C3-7heterocycloalkyl. In some embodiments, each Rc is independently D, F, Cl, Br, —CN, OH, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF3, —CH2CF3, —CH2CH2F, —OCF3, —OH, —OCH3, —OCH2CH3, —OCH2OMe, —OCH2CH2OH, —OC(CH3)3, —OCH2CH2OCH3,
In some embodiments, R2 is
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or pharmaceutically acceptable salt or solvate thereof, R2 is substituted or unsubstituted 5-6, 6-6, or 6-5 fused bicyclic heteroaryl containing 1-3 hetero ring atoms selected from O, N and S.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R2 is substituted or unsubstituted bicyclic C5-C8 cycloalkyl. In some embodiments, R2 is bicyclo(1.1.1)pentane.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is substituted heteroaryl. In some embodiments, R3 is 5 or 6-membered substituted heteroaryl. In some embodiments, R3 is pyridinyl. In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, R3 is pentafluorophenyl.
In some embodiments of a compound of Formula (IV), (I), (II), (IIa), (IIb), or (III), or a pharmaceutically acceptable salt or solvate thereof, each R11 is independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, or substituted or unsubstituted —C0-6 alkylene-C3-7 heterocycloalkyl. In some embodiments, each R11 is independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted —C0-6 alkylene-C3-8 cycloalkyl, or substituted or unsubstituted —C0-6 alkylene-C3-7 heterocycloalkyl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with hydroxy, amino, or methoxy. In some embodiments, each R11 is independently H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 heteroalkyl, substituted or unsubstituted —C0-3 alkylene-C3-6 cycloalkyl, or substituted or unsubstituted —C0-3 alkylene-C3-6 heterocycloalkyl. In some embodiments, each R11 is independently H, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, linear or branched pentyl, linear or branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CF3, —CH2OCH3, —CH2NHCH3, or —CH2CH2F.
In one aspect, provided herein is an ester of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the ester is a reaction product of an acid group of the described compound with an alcohol. In some embodiments, the ester is a C1-C6 alkyl ester, C1-C6 heteroalkyl ester or C2-C6 alkenyl ester, and wherein the alkyl, heteroalkyl, and alkenyl is substituted or unsubstituted. In some embodiments, the alcohol that forms an ester with a described compound has a structure of R20OH, wherein R20 is substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, the alcohol that forms ester with a described compound has a structure of R20OH, wherein R20 is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 haloalkyl, or substituted or unsubstituted C1-C12 heteroalkyl.
In one aspect, provided herein is an amide of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the amide is a reaction product of an acid group of the described compound with an amine. In some embodiments, the amide results from reacting the compound with a sulfonamide, NH3, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino. In some embodiments, the amide is a sulfonamide or a phosphoramide. In some embodiments, the amide comprises a —NC(═O)— moiety. In some embodiments, the amine that forms an amide with a described compound has a structure of NH(R21)2, wherein each R21 is independently H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 haloalkyl, or substituted or unsubstituted C1-C12 heteroalkyl.
In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, the abundance of deuterium in each of R5, R6, R7, R, R9, and/or R10 is independently at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, one or more of R1, R2, R3, R5, R6, R7, R8, R9, R10, R11 and/or R12 groups comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R1 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R2 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R3 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R5 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R6 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R7 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R8 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R9 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R10 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R11 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, R12 comprises deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, the percentage of deuterium is at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99%, or 100%.
In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or (V), or a pharmaceutically acceptable salt or solvate thereof, the abundance of deuterium in the compound is higher than the natural abundance of deuterium. In some embodiments, the percentage of deuterium is at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99%, or 100%.
In some embodiments, described herein is a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, described herein is a compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof.
Described herein are compounds, or pharmaceutically acceptable salts or solvates thereof, that are active STAT5 inhibitors. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has an IC50 value that is below 50 μM, below 25 μM, below 20 μM, below 15 μM, below 10 μM, below 5 μM, below 4 μM, below 3 μM, below 2.5 μM, below 2 μM, below 1.9 μM, below 1.8 μM, below 1.7 μM, below 1.6 μM, below 1.5 μM, below 1.4 μM, below 1.3 μM, below 1.2 μM, below 1.1 μM, below 1.0 μM, below 0.9 μM, below 0.8 μM, below 0.7 μM, below 0.6 μM, below 0.5 μM, below 0.4 μM, below 0.3 μM, below 0.2 μM, below 0.1 μM, or below 0.01 μM as determined in a cell cytotoxicity assay. In some embodiments, the IC50 value is determined accordingly to EXAMPLE 1B or EXAMPLE 2B. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has an IC50 value from about 0.001 μM to about 0.5 μM. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has an IC50 value within a range of from about 0.001 μM, 0.01 μM, 0.05 μM, or 0.1 μM to about 0.15 μM, 0.2 μM, 0.25 μM, 0.30 μM, or 0.50 μM. In some embodiments, the IC50 value is determined using MV4-11 cells, wherein the compound and a vehicle control (0.5% DMSO) are added to the cell solution and incubated for 72 h at 37° C. in 5% CO2. In some embodiments, the IC50 value is determined using normal human fibroblast (NHF) cells, wherein the compound and a vehicle control (0.5% DMSO) are added to the cell solution and incubated for 72 h at 37° C. in 5% CO2.
In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a stability such as an in vivo or ex vivo stability as measured by its reactivity profiling with glutathione. In some embodiments, the reactivity profiling is determined according to EXAMPLE B3. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a T1/2 that is that is higher than 5 minutes, higher than 10 minutes, higher than 30 minutes, higher than 60 minutes, higher than 90 minutes, higher than 120 minutes, higher than 180 minutes, higher than 240 minutes, higher than 300 minutes, higher than 360 minutes, higher than 420 minutes, higher than 480 minutes, higher than 540 minutes, higher than 600 minutes, higher than 700 minutes, higher than 800 minutes, higher than 900 minutes, higher than 1000 minutes, higher than 1100 minutes, higher than 1200 minutes, higher than 1300 minutes, higher than 1400 minutes, or higher than 1500 minutes. In some embodiments, the T1/2 is determined in a glutathione (GSH) environment. In some embodiments, the T1/2 is determined according to EXAMPLE B3. In some embodiments, the T1/2 is determined using a solution containing 25 μM of the compound with 0.5% DMSO in the presence of 5 mM GSH at 25° C. In some embodiments, the T1/2 is calculated according to a first order reaction kinetic. In some embodiments, the T1/2 is determined using a solution containing 5 μM of the compound with 0.5% DMSO in the presence of GSH (5 mM) and PBS buffer (pH 7.4) after incubation at 25° C. at 600 rpm, and quenched with 600 μL solution of acetonitrile at 0, 30, 60 and 120 minutes.
In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a cell permeability. In some embodiments, the cell permeability is measured in a parallel artificial membrane permeability assay (PAMPA). In some embodiments, the cell permeability is measured in a PAMPA assay according to EXAMPLE B4. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a permeability of at least 1, at least 2, at least 3, at least 4, at least 5, at least 5.5, at least 6, at least 6.5, or at least 7 as expressed in Log Pe and determined in PAMPA. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a permeability of at most 20, at most 10, at most 8, at most 7, at most 6.5, at most 5.5, at most 5.5, at most 5, or at most 4 as expressed in Log Pe and determined in PAMPA. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, has a permeability within a range of from about 4 or 5 to about 6 or 7 as expressed in Log Pe and determined in PAMPA. In some embodiments, the PAMPA assay is performed using a PVDF (Polyvinylidene fluoride) artificial membrane between a donor compartment and an acceptor compartment with an incubation condition of about 25° C. and 60 rpm for 16 hours. In some embodiments, a starting concentration of the described compound in the donor compartment is 10 μM. In some embodiments, the acceptor compartment comprises 5 μL lecithin in dodecane solution (1.8% solution w/v) and 300 μL PBS buffer at pH 7.4. In some embodiments, the PAMPA assay is performed using a PVDF artificial membrane between a donor compartment and an acceptor compartment with an incubation condition of about 25° C. and 60 rpm for 16 hours, wherein the donor compartment comprises about 300 μL solution comprising the compound at a starting concentration of 10 μM and wherein the acceptor compartment comprises about 5 μL lecithin in dodecane solution (1.8% solution w/v) and 300 μL PBS buffer at pH 7.4. In some embodiments, the concentrations of the compound are determined by LC/MS/MS.
As used herein, “carboxylic acid or an isostere thereof” refers to a carboxylic acid moiety, or a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, hydroxamic acids, hydroxamic esters, sulfinic acids, sulfonic acids, sulfonamides, acyl-sulfonamides, sulfonylureas, acylureas, tetrazole, thiazolidine diones, oxozolidine diones, oxadiazol-5(4H)-one, oxothiadiazole-2-oxide, oxadiazol-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-diones, cyclopentane 1,2-diones, squaryl groups, phosphoric acids, phosphinic acids, and halogenated phenols. For example, a carboxylic acid isostere can be:
—B(OH)2, —S(O)2NH2,
wherein each hydrogen bound to a carbon atom is optionally replaced with methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2, or a different halogen.
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include.
In some instances, the STAT5 inhibitory compounds disclosed herein exist in tautomeric forms. The structures of said compounds are illustrated in the one tautomeric form for clarity. The alternative tautomeric forms are expressly included in this disclosure.
In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
In certain embodiments, the abundance of 2H atoms in the compounds disclosed herein is enriched for some or all of the 1H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.
Deuterium gas and palladium catalysts are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
In some embodiments, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1H hydrogen atoms. In some embodiments, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
In some embodiments, the compounds described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of compounds of the present disclosure and/or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
The compounds described herein can exist in amorphous and/or crystalline forms, all of which are encompassed by the instant disclosure. In some embodiments, a herein described compound exists in an amorphous form. In some embodiments, a herein described compound exists in a crystalline form. One aspect of the present disclosure pertains to a crystalline polymorph of a compound described herein. In some embodiments, the crystalline polymorph is a stable polymorph of a described compound or a salt thereof.
The crystalline form of the described compounds can be identified by its unique solid state signature with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline form can be gauged by any of the following methods for example, thermogravimetric analysis (TGA), DSC and the like. The crystalline polymorph can be prepared by any suitable method known in the art, for example, those described in K. J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc, New York, 1999, incorporated herein by reference in its entirety. In some embodiments, the crystalline polymorph is prepared by recrystallization. In some embodiments, the crystalline polymorph is a stable polymorph of a pharmaceutically acceptable salt of a compound described herein.
The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).
Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.
Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.
In certain embodiments, the STAT5 inhibitory compound as described herein is administered as a pure chemical. In other embodiments, the STAT5 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)).
Provided herein is a pharmaceutical composition comprising at least one STAT5 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, amide, ester, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
In one aspect, the disclosure provides a pharmaceutical composition comprising a herein described compound, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.
In certain embodiments, the STAT5 inhibitory compound as described, such as a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
The compounds and pharmaceutical compositions of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, intraperitoneal, and infusion techniques. The term parenteral also includes injections, into the eye or ocular, intravitreal, intrabuccal, transdermal, intranasal, into the brain, including intracranial and intradural, into the joints, including ankles, knees, hips, shoulders, elbows, wrists, and the like, and in suppository form. In certain embodiments, the compounds and formulations are administered orally. In certain embodiments, the compounds and formulations are administered topically.
In some embodiments, pharmaceutical compositions described herein are administered orally. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)). In some embodiments, for solid dosage forms used in oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents, in the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
Compounds of the disclosure can also be administered via parenteral injection as liquid solution, which can include other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, preservatives, or excipients. Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. For example, compositions described herein can be provided in liquid form, and formulated in saline based aqueous solution of varying pH (5-8), with or without detergents such polysorbate-80 at 0.01-1%, or carbohydrate additives, such mannitol, sorbitol, or trehalose. Commonly used preservatives include chlorobutanol, m-cresol, benzyl alcohol, phenylethyl alcohol, phenol, methylparaben, or propylparaben. Commonly used buffers include histidine, acetate, phosphate, borate, or citrate. Commonly used tonicity adjustors include sodium chloride, mannitol and glycerin. The infusion solution may include 0 to 10% dextrose. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions, for example, a cyclodextrin or organic solvent. Organic solvents can include alcohols, for example, C1-C4 linear alkyl, C3-C4 branched alkyl, ethanol, ethylene glycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol, sorbitol, xylitol; substituted or unsubstituted aryl, and benzyl alcohol. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The dose of the composition comprising at least one STAT5 inhibitory compound as described herein differ, depending upon the subject's condition, that is, stage of the disease, general health status, age, and other factors.
Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the subject, the type and severity of the subject's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject.
By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 mg/kg to about 1 mg/kg body weight of the subject per day. In some embodiments, the dose of compound described herein for the described methods is about 0.001 mg to about 1000 mg per day for the subject being treated. In some embodiments, a compound described herein is administered to a subject at a daily dosage of from about 0.01 mg to about 500 mg, from about 0.01 mg to about 100 mg, or from about 0.01 mg to about 50 mg.
In one aspect, the disclosure provides a method of modulating signal transducer and activator of transcription proteins such as STAT5 and STAT3 in a subject in need thereof. In some embodiments, the methods comprise inhibiting STAT5 and/or STAT3 activities. In some embodiments, the method comprises administering to a subject a therapeutically effective amount a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor or hematologic cancer.
Aberrant activation of STAT5 has been shown to contribute to malignant transformation and tumorigenesis. In particular, oncogenesis mediated by the aberrant activation of STAT5 is characterized in part by the transcriptional upregulation of genes that promote angiogenesis and tumor immune-tolerance. Therefore, modulating STAT5 signaling through the use of small-molecule inhibitors of STAT5 provides an effective and novel strategy for treating a wide variety of human tumors. STAT5-regulated genes include, but are not limited to, VEGF, Bcl.xL, matrix metalloproteinase 9, and c-Myc. In some embodiments, the present disclosure provides a method of decreasing the expression of VEGF, Bcl.xL, matrix metalloproteinase 9, or c-Myc in a cell, comprising contacting a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof with a cell.
In one aspect, the disclosure provides a method of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering to a subject with cancer a therapeutically effective amount of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor or hematologic cancer.
Non-limiting examples of cancers to be treated by the methods of the present disclosure can include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies.
In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a hematological cancer. In some embodiments, the subject has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin's lymphoma (“HL”), Non-Hodgkin's lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some embodiments, a subject or population of subjects to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma.
In some embodiments, provided herein are methods and compositions for treating a disease or condition. Exemplary disease or condition includes refractory or recurrent malignancies whose growth may be inhibited using the methods of treatment of the present disclosure. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, hepatocellular cancer, colorectal cancer, gastric adenocarcinoma, melanoma, or advanced cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary). In some embodiments, a cancer to be treated by the methods of the present disclosure further include sarcomata (for example, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is pancreatic cancer.
In some embodiments, the subject is 5 to 75 years old. In some embodiments, the subject is 5 to 10, 5 to 15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to 15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to 75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 to 65, 15 to 75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years old. In some embodiments, the subject is at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. In some embodiments, the subject is at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old.
Formation of transcriptionally active STAT5 can proceed through a phosphorylation-dimerization pathway, whereby STAT5 is first phosphorylated on a key tyrosine residue to provide phosphorylated STAT5 (pSTAT5), and the resulting phosphotyrosine residue binds to a Src-homology 2 (SH2) domain of another STAT5 or pSTAT5 protein. A pSTAT5 homodimer can then undergo nuclear transport and participate in direct DNA binding. In some embodiments, the present disclosure provides a method of inhibiting the formation of STAT5:pSTAT5 or pSTAT5:pSTAT5 hetero- or homodimers by contacting a cell with a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV). In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) binds to the SH2 domain of STAT5 or pSTAT5. In some embodiments, a compound described herein is an inhibitor of STAT dimerization, an inhibitor of a tyrosine kinase capable of phosphorylating STAT, an antagonist of SH2-pY interactions, an antagonist of STAT DNA binding, a tyrphostin inhibitor, an antagonist of STAT-dependent gene transactivation, an antagonist of IL-6 receptor activation, an antagonist of a cytokine that constitutively activates STAT, or an antagonist of a growth factor that constitutively activates STAT.
As used herein, the term “STAT5” can refer to a transcription factor encoded by the human STAT5a or STAT5b genes. The term is inclusive of splice isoforms or variants, as well as any non-human orthologs or homologs thereof.
Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims.
The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way.
The compounds of TABLE 1 and TABLE 2 have been synthesized according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. The compounds of the disclosure and their syntheses are further illustrated by the following examples. A skilled person in the art would appreciate that other compounds of the disclosure can be synthesized by similar approaches.
An oven-dried reaction vessel is charged with a stir bar, functionalized benzaldehyde (1 eq), tert-butyl 2-(chloroamino)acetate (1-3 eq.) and 1,2-dichloroethane (DCE). After stirring at room temperature for 5 min, acetic acid (2-6 eq) is added in one portion, and the resulting solution is allowed to stir at room temperature for 30 min., then sodium triacetoxyborohydride (2-3 eq.) is added in one portion. The progress of the reaction is monitored by thin-layer chromatography (TLC), and upon completion, the reaction is quenched with a saturated aqueous solution of sodium bicarbonate and extracted (2×) with DCM. The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, and finally adsorbed onto silica. The product (I1) is isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate.
An oven-dried reaction vessel is charged with a stir bar, pentafluorobenzenesulfonyl chloride (1.2 eq.), triethylamine (3 eq.), and dichloromethane (DCM). The reaction vessel is flushed with nitrogen, and then cooled to 0° C. using an ice/water bath. Once cooled, a solution of I1 in DCM is added slowly over a period of 2 min. The progress of the reaction is monitored by TLC and upon completion, the reaction is quenched with a saturated aqueous solution of ammonium chloride and extracted (2×) with DCM. The combined organic phases are washed with brine, dried over anhydrous sodium sulfate and finally adsorbed onto silica. The product is then isolated using an automated flash chromatography system.
The isolated sulfonamide then is dissolved in a minimum volume of DCM and added to a stirring mixture of DCM and trifluoroacetic acid (TFA) (1:1 v/v). The progress of the reaction is monitored by TLC and upon completion, the reaction is concentrated down and residual TFA is removed by azeotropic distillation with chloroform. The crude product 12 shall be sufficiently pure to be used in the subsequent step.
To a solution of pentafluorobenzenesulfonyl chloride (1.1 eq) and sodium bicarbonate (3 eq) in acetone and water (8:2 v/v) is added functionalized benzyl amine (1 eq.) at 0° C., and the mixture is stirred for 1 h and allowed to warm to room temperature (RT). The progress of the reaction is monitored by TLC. Once complete, the reaction is quenched with a saturated aqueous solution of ammonium chloride and extracted (2×) with DCM. The combined organic phases are washed with brine, dried with anhydrous sodium sulfate, and finally adsorbed onto silica. The product (I3) is isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate.
An oven-dried reaction vessel is charged with I3 (1 eq), potassium carbonate (3 eq.), and dimethylformamide (DMF). The resulting mixture is stirred at room temperature for 5 minutes, and then tert-butyl 2-bromoacetate (1.2 eq) is added in one portion. Reaction progress is monitored by TLC. Once complete, the reaction is quenched with a saturated aqueous solution of ammonium chloride and extracted (2×) with ethyl acetate (EtOAc). The combined organic phases are washed with brine (3×), dried over anhydrous sodium sulfate, and adsorbed onto silica. The product is isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate.
The isolated sulfonamide is dissolved in a minimum volume of DCM and added to a stirring mixture of DCM and trifluoroacetic acid (1:1 v/v). The progress of the deprotection is monitored by TLC, and upon completion, the reaction is concentrated in vacuo and residual TFA is removed by azeotropic distillation with chloroform. The crude product 12 shall be sufficiently pure to be used in any subsequent step.
A solution of 1,3-dibromo-5-(tert-butyl)benzene (2.57 mmol) in anhydrous tetrahydrofuran (THF) (0.3M) was cooled to −78° C., followed by the dropwise addition of n-BuLi (2.5 M in hexane, 2.83 mmol), and stirred for 0.5 h at −78° C. under N2. DMF (3.85 mmol) was then slowly added, and the reaction mixture was allowed to gradually warm from −78° C. to RT over 3 hours. The reaction was quenched by the addition of a saturated solution of NH4Cl (20 mL). The two layers were partitioned and the aqueous layer was extracted with Et2O (3×). The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Crude 3-bromo-5-(tert-butyl)benzaldehyde was isolated as a yellow oil (88%) and used directly in the following step. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H) 7.77 (t, J=1.8 Hz, 1H), 1.36 (s, 9H).
An oven dried round bottom flask equipped with a stir bar was charged with 3-bromo-5-(tert-butyl)benzaldehyde (3.11 mmol), cyclopropylboronic acid (4.35 mmol), tricyclohexylphosphine (0.311 mmol) and K3PO4 (12.4 mmol). The flask was then was purged with N2. Toluene (0.2M) and H2O (4M) were then added, followed by Pd(OAc)2 (0.156 mmol) and the reaction mixture was placed in an oil bath at 110° C. and allowed to stir for 10 h. The reaction was then cooled back down to room temperature, filtered through celite, and washed with EtOAc. The filtrate was diluted with EtOAc and H2O, and then transferred to a separatory funnel. The two layers were partitioned, and the aqueous layer was extracted with EtOAc (3×). Combined organic fractions were washed with brine and dried over MgSO4. Crude material was directly adsorbed onto silica and purified using the via flash column chromatography, eluting with a hexanes/EtOAc gradient. 3-(tert-butyl)-5-cyclopropylbenzaldehyde (I4) was obtained as clear oil (452 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.69 (t, J=1.7 Hz, 1H), 7.44 (t, J=1.9 Hz, 1H), 7.34 (t, J=1.5 Hz, 1H), 2.00-1.93 (m, 1H), 1.35 (s, 7H), 1.06-0.96 (m, 2H), 0.79-0.70 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 192.96, 152.07, 144.85, 136.49, 129.91, 124.20, 123.50, 34.78, 31.25, 15.44, 9.49.
To a solution of pyridin-3-amine (1.06 mmol) and acetic acid (1.1 eq) in anhydrous DCE (0.1 M) was added I4 (1.06 mmol). The solution was then stirred at RT for 10 mins, after which Na(OAc)3BH (1.5 eq) was added and the reaction allowed to stir at room temperature. Upon complete consumption of the primary aniline as indicated by TLC, the reaction was diluted with DCM and poured over a saturated solution of NaHCO3. The layers were partitioned and aqueous layer was extracted with DCM (3×). The combined organic fractions were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude sample was adsorbed directly onto silica and purified using an automated flash chromatography system, affording N-(3-(tert-butyl)-5-cyclopropylbenzyl)pyridin-3-amine (I5) as an amorphous beige solid (217 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.13-8.09 (m, 1H), 8.00 (dd, J=4.7, 1.4 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.14-7.07 (m, 2H), 6.93 (ddd, J=8.3, 2.9, 1.4 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 4.29 (s, 2H), 1.92 (tt, J=8.4, 5.1 Hz, 1H), 1.33 (s, 8H), 1.04-0.92 (m, 2H), 0.75-0.61 (m, 2H).
To a stirred solution of I6 (ACS Med. Chem. Lett. 2014, 5, 11, 1202) (1.2 equiv) in CHCl3 (0.08 M) was added Ph3PCl2 (2.5 equiv). The reaction mixture was stirred for 15 min at room temperature, followed by the dropwise addition of I5 (1.0 equiv). The reaction mixture was then irradiated in a microwave at 100° C. for 45 min. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated NaHCO3. The two layers were partitioned and the aqueous layer was extracted with DCM (3×). The combined organic fractions were washed with brine and dried over MgSO4. The crude sample was purified by preparative HPLC, eluting with a gradient of H2O, MeCN and 0.1% formic acid. Compound 1001 was isolated as an amorphous white solid (48%). 1H NMR (400 MHz, Acetonitrile-d3) δ 8.47 (t, J=3.2 Hz, 1H), 8.07 (s, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.28 (t, J=2.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.06 (t, J=1.8 Hz, 1H), 6.88 (s, 1H), 6.61 (t, J=1.7 Hz, 1H), 4.76 (s, 2H), 4.62 (s, 3H), 3.81 (s, 2H), 1.87 (tt, J=8.4, 5.1 Hz, 1H), 1.23 (s, 11H), 0.99-0.88 (m, 2H), 0.64-0.53 (m, 2H).
N-(3-(tert-butyl)-5-cyclopropylbenzyl)-6-methoxypyridin-3-amine (I7) was prepared in an analogous manner as 15 of EXAMPLE A2 using 6-methoxypryidin-3-amine, and was isolated as beige solid (42%).
Compound 1005 was prepared in an analogous manner to Compound 1001, and was isolated as white solid (3%).
Compound 1005 (30 mg, 41.54 μmol) was dissolved in a 4 M solution of hydrochloric acid in 1,2-1,4-dioxane (1 mL) at room temperature. The progress of the reaction was monitored by TLC and upon completion, the reaction mixture was concentrated and purified by preparative HPLC, eluting with a gradient of H2O, MeCN, and 0.1% formic acid. Compound 1002 was lyophilized and isolated as white solid (23%)
N-(3-(tert-butyl)-5-cyclopropylbenzyl)-2-methoxypyrimidin-5-amine (I8) was prepared in an analogous manner as 15 of EXAMPLE A2 using 2-methoxypyrimidin-5-amine, and was isolated as beige solid (70%)
Compound 1003 was prepared in an analogous manner to Compound 1001 using 18, and was isolated as white solid (17%).
To a solution of 5-nitropyridine-2-carboxylic acid (454.08 mg, 2.70 mmol) in CHCl3 (0.5M), pyridine (1.07 g, 13.51 mmol, 1.09 mL) and tBuOH (2.00 g, 27.01 mmol, 2.58 mL) were added followed by the dropwise addition of POCl3 (662.67 mg, 4.32 mmol, 1.46 mL) over 2 mins. After 5 h, the reaction mixture was transferred to a separatory funnel containing ice, DCM and 0.1 M HCl. The two layers were partitioned, and the organic layer was washed with brine and dried over anhydrous MgSO4. The resulting crude sample of tert-butyl 5-nitropicolinate (84% crude yield) was used directly in the next step without further purification.
To a scintillation vial was added tert-butyl 5-nitropyridine-2-carboxylate (37 mg, 165.02 μmol) in acetone (2.69 mL) and water (518.99 μL), followed by the addition of zinc powder (215.82 mg, 3.30 mmol) and ammonium chloride (353.09 mg, 6.60 mmol). The reaction mixture was stirred for 1 h at room temperature. The acetone was then evaporated, and the residue was partitioned between ethyl acetate and a concentrated ammonia solution. The mixture was filtered through celite, and the organic phase was dried over sodium sulfate and concentrated. The product was isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate to afford tert-butyl 5-aminopicolinate (80% yield) as a waxy solid.
To a scintillation vial charged with tert-butyl 5-aminopyridine-2-carboxylate (100 mg, 514.85 μmol), 14 (107.28 mg, 530.30 μmol) dissolved in DCE was added acetic acid (546.94 mg, 9.11 mmol, 520.89 μL) at room temperature, and resulting mixture was allowed to stir for 30 min. Then sodium triacetoxyborohydride (327.35 mg, 1.54 mmol) was added portion-wise. The progress of the reaction was monitored by TLC, and upon completion the reaction was diluted with DCM, filtered, and concentrated onto a small amount of silica. tert-Butyl 5-((3-(tert-butyl)-5-cyclopropylbenzyl)amino)picolinate (I9) was isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate affording a waxy solid (67%).
To a flame-dried microwave vial equipped with a stir bar was added 2-[(4-chlorophenyl)methyl-(2,3,4,5,6-pentafluorophenyl)sulfonyl-amino]acetic acid (I6) (41 mg, 95.41 μmol) and chloroform (954.05 μL), immediately followed by the addition of dichlorotriphenylphosphorane (84.14 mg, 252.54 μmol) at room temperature. The heterogeneous solution was allowed to stir until the solution became homogeneous. Then a solution of I9 (35.59 mg, 93.53 μmol) in chloroform was added dropwise. The vial was sealed and stirred in an oil bath for 1 hour at 110° C. Upon completion, the crude tert-butyl 5-(N-(3-(tert-butyl)-5-cyclopropylbenzyl)-2-(N-(4-chlorobenzyl)-(2,3,4,5,6-pentafluorophenyl)sulfonamido)acetamido)picolinate (I10) was concentrated and used directly in the next step.
To a scintillation vial containing I10 (42 mg, 53.01 μmol) was added DCM (1 mL) and TFA (1 mL) at room temperature. The resulting solution was allowed to stir for 60 mins, and then concentrated under vacuum. The residual TFA was removed by azeotropic distillation with 10 mL chloroform. The crude sample was purified by preparative HPLC eluting with a gradient of water, MeCN and 0.1% formic acid, and then lyophilized to afford Compound 1004 as white solid (32%).
To a round bottom flask containing THE (28.55 mL) was added 5-nitropyrimidin-2-amine (400 mg, 2.86 mmol) at room temperature, followed by addition of tert-butoxycarbonyl tert-butyl carbonate (747.74 mg, 3.43 mmol) and DMAP (34.88 mg, 285.51 μmol). The reaction mixture was allowed to stir at room temperature and the progress was monitored by TLC. Upon completion, the reaction was concentrated, and the product was isolated using an automated flash chromatography system eluting with a gradient of hexanes and ethyl acetate to afford tert-butyl (tert-butoxycarbonyl)(5-nitropyrimidin-2-yl)carbamate (I11) (32%).
To a round bottom flask was added I11 (313 mg, 919.69 μmol) in Acetone (14.83 mL) and water (2.86 mL), followed by the addition of zinc powder (1.20 g, 18.39 mmol) and NH4Cl (1.97 g, 36.79 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. The mixture was filtered through celite, and the organic phase was dried and concentrated. The crude sample of tert-butyl (5-aminopyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (I12) was sufficiently pure to proceed to the next step.
tert-butyl (tert-butoxycarbonyl)(5-((3-(tert-butyl)-5-cyclopropylbenzyl)amino)pyrimidin-2-yl)carbamate (I13) was prepared in an analogous manner to I5 of EXAMPLE A2 using 112, and was isolated as beige solid (21%).
tert-butyl (tert-butoxycarbonyl)(5-(N-(3-(tert-butyl)-5-cyclopropylbenzyl)-2-(N-(4-chlorobenzyl)-(2,3,4,5,6-pentafluorophenyl)sulfonamido)acetamido)pyrimidin-2-yl)carbamate (I14) was prepared in an analogous manner to I10 of EXAMPLE A6, and was isolated as a white solid (63%).
Compound 1006 was prepared in analogous manner to Compound 1004, and was isolated as a white solid (30%).
Compound 1009 was prepared in an analogous manner to Compound 1006, using N-(2-fluorobenzyl)-N-((perfluorophenyl)sulfonyl)glycine in place of I6.
Compound 1017 was prepared in an analogous manner to Compound 1006, using N-((perfluorophenyl)sulfonyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)glycine in place of I6.
In a 50 ml round bottom flask, 3,4-diethoxycyclobut-3-ene-1,2-dione (0.5 g, 2.94 mmol, 420.17 μL) was diluted with Et2O (28.96 mL). Another suspension containing Me2NH2Cl (263.57 mg, 3.23 mmol) and DIPEA (949.40 mg, 7.35 mmol, 1.28 mL) in Et2O (28.96 mL) (5 ml) and MeCN (1 mL) was slowly added and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was then filtrated, washed with Et2O, and concentrated to dryness. The product was isolated using an automated flash chromatography system eluting with a gradient of DCM and MeOH, affording 3-(dimethylamino)-4-ethoxycyclobut-3-ene-1,2-dione as a white solid (98%). 1H NMR (400 MHz, CDCl3) δ 4.74 (q, J=7.1 Hz, 2H), 3.32 (s, 3H), 3.14 (s, 3H), 1.44 (t, J=7.1 Hz, 3H).
In a 25 mL round bottom flask, 3-(dimethylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione (254 mg, 1.50 mmol) was dissolved in EtOH (9.85 mL). Then, tert-butyl N-(2-aminoethyl)carbamate (360.81 mg, 2.25 mmol, 356.53 μL) was added dropwise and the clear solution was stirred for 3 hours at 25° C. The reaction mixture was then concentrated and purified via an automated flash chromatography system using a gradient of DCM and MeOH, affording tert-butyl (2-((2-(dimethylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)carbamate (I15) as a white solid (95%). 1H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J=6.0 Hz, 1H), 6.87 (t, J=5.9 Hz, 1H), 3.54 (q, J=6.0 Hz, 2H), 3.12-3.09 (br, 6+2H), 1.36 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 182.6, 181.7, 167.8, 167.5, 155.7, 77.7, 43.7, 41.0, 38.7, 28.2.
In a 25 ml round bottom flask, 115 (200 mg, 705.91 μmol) was diluted with H2O (6.83 mL). Then, conc. HCl (2.82 mmol, 233.82 μL, 37% purity) was added dropwise, and the resulting suspension was stirred for 16 h at 55° C. After 16 h, the reaction was evaporated to dryness, affording a light yellow oily residue that was recrystallized from MeOH to provide 3-((2-aminoethyl)amino)-4-(dimethylamino)cyclobut-3-ene-1,2-dione (I16) as a white crystalline solid (98%). 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.08 (br, 1H), 3.76 (t, J=6.0 Hz, 2H), 3.18 (s, 6H), 3.00 (br, 2H).
In a 10 ml round bottom flask, 116 (47.10 mg, 177.96 μmol) was dissolved in MeOH (1.41 mL), DIPEA (51.94 mg, 401.88 μmol, 70 μL) and 150 μl of DMF, to obtain a clear solution. 3-tert-butyl-5-cyclopropyl-benzaldehyde (30 mg, 148.30 μmol) and trimethyl orthoformate (311.43 μmol, 34.07 μL) were then added, and the reaction was stirred at room temperature for four hours. NaBH4 (8.42 mg, 222.45 μmol) was added to the reaction vessel in one portion. The progress of the reaction was monitored by TLC and upon completion, was concentrated to dryness and isolated using an automated flash chromatography system eluting with a gradient of DCM and MeOH. 3-((2-((3-(tert-butyl)-5-cyclopropylbenzyl)amino)ethyl)amino)-4-(dimethylamino)cyclobut-3-ene-1,2-dione (I17) was isolated as a white solid (82%). 1H NMR (400 MHz, CDCl3) δ 7.84 (br, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.14 (s, 2H), 3.95 (s, 2H), 3.35 (s, 6+2H), 1.86 (m, 1H), 1.28 (s, 9H), 0.94 (m, 2H), 0.71 (m, 2H).
In a flame dried microwave vial, 2-[(2-fluorophenyl)methyl-(2,3,4,5,6-pentafluorophenyl)sulfonyl-amino]acetic acid (24.5 mg, 59.28 μmol) was dissolved in CHCl3 (1.02 mL), followed by the addition of triphenylphosphine dichloride (51.75 mg, 155.32 μmol). After stirring for 10 minutes, 117 (20.5 mg, 55.48 μmol) was added, and the vial was sealed and refluxed at 110° C. for 1 hr. The reaction was then concentrated and purified by preparative HPLC, eluting with a gradient of H2O, MeCN and 0.1% formic acid, and then lyophilized to afford Compound 1010 as white solid (26%).
Suitable assays can be used to evaluate the efficacy and safety of the described novel STAT inhibitors. For example, considerations such as the potency, selectivity, stability, water-solubility, and bioavailability can be assessed by suitable in vitro and in vivo assays. Suitable assays include, but are not limited to, fluorescence polarization assay (for STAT inhibition), electrophoretic mobility shift assay (EMSA) (for STAT inhibition), western blot analysis (for STAT inhibition), surface plasmon resonance (SPR) studies (for binding affinity), mouse model-based blood brain barrier permeability, and Caco-2 cells permeability. Cell cultures can be used to evaluate the potency and selectivity of the compounds. For example, the potency of the compounds can be assessed using cell lines that harbor aberrant STAT proteins, such as human erythroleukemia K562 and MV-4-11 cells, breast carcinoma lines MDA-MB-231 and MDA-MB-468, androgen-insensitive human PC cell lines DU-145 and PC-3, and human lung cancer cells A549. The selectivity of the compounds can be assessed by cell culture cytotoxicity assays of non-target cells such as normal NIH 3T3 (3T3) cells, mouse thymus stromal epithelial cells, TE-71, Stat3-null mouse embryonic fibroblasts (−/−MEFs), NIH 3T3/v-Ras (v-Ras), normal human fibroblast (NHF) cells, and A2780S cells that do not harbor aberrantly active STAT3.
Several assay protocols and results are provided below for illustration purposes, and alternative assays can be used to evaluate the compounds. A skilled person in the art would appreciate that the disclosed compounds are potent STAT5 inhibitors with minimum off-target effects and superior stability and permeability.
In some embodiments, the potency of the STAT5 inhibitors are evaluated by an in vitro assay such as MV4-11 Cell Cytotoxicity Assay. MV4-11 cells were grown in Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% fetal bovine serum (FBS). 10,000 cells were plated per well in 96-well flat-bottom sterile culture plates with low-evaporation lids. After 24 h, inhibitors and a vehicle control (0.5% DMSO) were added and the cells were incubated for 72 h at 37° C. in 5% CO2. Inhibitors were examined in triplicate at a maximal concentration of 50 μM, followed by 1:2 dilutions in subsequent wells (25, 12.5, 6.25, 3.125, 1.5625, 0.78125, 0.390625, 0.195313 and 0.097656 μM). After 72 h, the wells were treated with CellTiter-Blue® (20 μL/well), and the plates were incubated using standard cell culture conditions for 1 hour. Fluorescence was measured at 560/590 nm. IC50 values were determined using non-linear regression analysis, and are provided in TABLE 3 and TABLE 4 below.
In some embodiments, the off-target effects of the compounds are evaluated in healthy human cells, such as in a normal human fibroblast (NHF) cell cytotoxicity assay.
Cell viability was examined following treatment at various concentrations of inhibitor (0.097656-50 μM) using a cell Titer-Blue cell viability assay. 1×104 normal human fibroblast cells per well were plated in 96-well assay plates in culture medium. All cells are grown in DMEM, IMDM and RPMI-1640 were supplemented with 10% FBS. After 24 hours, test compounds and vehicle controls are added to appropriate wells so the final volume is 100 μl in each well. The cells are cultured for the desired test exposure period (72 hours) at 37° C. and 5% CO2. The assay plates are removed from 37° C. incubator and 20 μL/well of CellTiter-Blue® Reagent is added. The plates are incubated using standard cell culture conditions for 1-4 hours and the plates are shaken for 10 seconds and record fluorescence at 560/590 nm. IC50 values were determined using non-linear regression analysis, and are provided in TABLE 3 and TABLE 4 below. For each sample well, value is normalized between the DMSO control and the highest concentration in case of plateau, and converted into a percentage. In the absence of plateau, minimum lecture is obtained from a different sample within the same experiment. For each concentration, the four replicates are averaged and standard deviation calculated. Data is fitted to a log(inhibitor) vs response curve with variable slope model using Microsoft Excel, obtaining IC50 and Hill slope variables.
In some embodiments, metabolic stability of the compounds are evaluated according to their reactivity profiles with GSH.
3.5 μL of 5 mM stocking solution of the inhibitors in DMSO was added to 697.5 μL of Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% FBS and antibiotic antimycotic solution, with 5 mM glutathione to afford a final concentration of 25 μM inhibitor with 0.5% DMSO. The solution was then immediately placed in the sample tray at 25° C. Sample was analyzed at pre-defined intervals, typically every 1.5 hours, for up to four injections, by HPLC, included at time zero, without further pre-treatment. For each inhibitor, its peak is integrated at different time points and compared to the time zero injection in order to obtain a percentage remaining. Half-life is calculated according to a first order reaction kinetic taking into account those time points for which remaining percentage of inhibitor is above 40%, using the formula: t½=Ln(2)/k, where k is the slope of the linear plot of Ln[Inhibitor] vs time, according to the formula: Ln[A]=Ln[A]0−kt, where [A] is the value resulting from the integration at each time point, [A]0 the value at time zero, and t the time. For each inhibitor, both replicates are averaged and the resulting t½ reported. Selective reactivity against GSH in particular is confirmed by incubation of the inhibitor in the same solution without the presence of GSH, and single analysis after a time longer than the latest time point analyzed for the samples with GSH.
In some embodiments, a PAMPA assay is used to determine the permeability of compounds of the present disclosure. The results of a PAMPA assay can correlate to a compound's permeability across a variety of barriers such as Caco-2 cells. The PAMPA assay can also be used to correlate the bioavailability of the compounds.
Stock solutions of positive controls (testosterone and methotrexate) were prepared in DMSO at the concentration of 10 mM, and further diluted with PBS (pH 7.4) to afford 10 μM solutions of the test compounds.
A 1.8% solution (w/v) of lecithin in dodecane was prepared and sonicated until complete dissolution was observed. 5 μL of the lecithin/dodecane mixture was then pipetted into each acceptor plate well (top compartment) of a 96-well filter plate with 0.45 μm pore size hydrophobic PDVF membrane, avoiding pipette tip contact with the membrane. Immediately after the application of the artificial membrane (within 10 minutes), 300 μL of PBS (pH 7.4) solution was added to each well of the acceptor plate. 300 μL of drug-containing solutions was then added to each well of the donor plate (bottom compartment) in triplicate. The acceptor plate was slowly placed into the donor plate, ensuring that the underside of the membrane maintained contact with the drug-containing solutions in all wells. The plate lid was replaced, and the solutions were incubated and rocked at 25° C., 60 rpm for 16 hours. After incubation, aliquots of 50 μL from each well of acceptor and donor plate were transferred into a 96-well plate. 200 μL of methanol containing 100 nM alprazolam, 200 nM labetalol and 2 μM ketoprofen was placed in each well. The plate lid was then replaced, and the plates were shaken at 750 rpm for 100 seconds. The samples were then centrifuged at 3,220 g for 20 minutes. The concentrations of the compound were determined by LC/MS/MS.
In some embodiments, the activities and other properties of the disclosed exemplary compounds as determined by the above assays are shown in Table 3.
Data are designated within the following ranges:
IC50MV-4-11: 0.00001≤A<1≤B<3.16≤C<100 (μM)
−Log Pe−PAMPA (4% BSA): 5.5≤A<6≤B<6.5<100
t½ GSH HPLC: 247≤B<554≤A<100,000 (minutes)
In some embodiments, the activities and other properties of the disclosed exemplary compounds as determined by the above assays are shown in Table 4.
Data are designated within the following ranges:
IC50 MV-4-11: 0.00001≤A<1≤B<3.16≤C<100 (μM)
This application claims the benefit of U.S. Provisional Application No. 62/985,679, filed Mar. 5, 2020, which is incorporated by reference herein in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/021146 | 3/5/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62985679 | Mar 2020 | US |
