Patent Application
20240158383
Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds for inhibiting ribonucleotide reductase (RNR).
Ribonucleotide reductase (RNR), also known as ribonucleotide diphosphate reductase (rNDP), is composed of a hetero-oligomer of a large subunit M1 and a small subunit M2, and expression of both is required for enzyme activity. RNR is a highly regulated enzyme in the deoxyribonucleotide synthesis pathway that is ubiquitously present in human, bacteria, yeast, and other organisms. RNR is responsible for the de novo conversion of ribonucleotide diphosphate to 2′-deoxyribonucleotide diphosphate, a process that is essential for DNA synthesis and repair. RNR is directly involved in DNA synthesis and repair, tumor growth, metastasis, and drug resistance. In various types of solid tumors and blood cancers, numerous correlations have been reported with overexpression of M2 and their prognosis. In addition, cell growth inhibition by inhibiting RNR and anti-tumor effect in vivo have been reported in cell lines derived from several cancer types and in nonclinical models.
The proliferation of cancer cells requires excess deoxyribonucleotide triphosphates (dNTPs) for DNA synthesis. Therefore, an increase in RNR activity is necessary as it helps provide extra dNTPs for DNA replication in primary and metastatic cancer cells. Because of this critical role in DNA synthesis, RNR represents an important target for cancer therapy. However, existing chemotherapies that target RNR are nucleoside-based analogs. Hence, they are promiscuous, leading to nonspecific binding of other nucleoside binding proteins which results in unwanted side effects. Therefore, there is a need for compositions and methods for specifically targeting and inhibiting RNR activity in neoplastic cells in the treatment of cancer.
Described herein are RNR inhibitors that are useful in treating cancer. Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
wherein:
R1 is hydrogen, deuterium, halogen, —CN, —NO2, —OH, —OR, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R4 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring A is a 3- to 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B;
each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa;
or two RA on the same atom are taken together to form an oxo;
each RAa is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or two RAa on the same atom are taken together to form an oxo;
n is 0-5;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each RB is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RBa;
or two RB on the same atom are taken together to form an oxo;
each RBa is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, -ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or two RBa on the same atom are taken together to form an oxo;
m is 0-5;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, -OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, , —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and
each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, -OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
Also disclosed herein is a method of inhibiting ribonucleotide reductase in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the inhibition of ribonucleotide reductase occurs in a tumor cell in the subject in need thereof.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
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.
“Oxo” refers to ═O.
“Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having 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-C8 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, or —NO2. 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. In some embodiments, the alkyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having 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 conformation 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-C8 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. In some embodiments, the alkenyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having 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 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. In some embodiments, the alkynyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“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 optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is 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. In some embodiments, the alkoxy is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“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 aminoalkyl is aminomethyl.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. 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, as-indacene, s-indacene, 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, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. 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 optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Cycloalkyl” refers to a 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) or bridged 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. In some embodiments, the cycloalkyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro. In some embodiments, halogen is bromo. In some embodiments, halogen is iodo.
“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, phosphorus, 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, phosphorus, 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. In some embodiments, the heteroalkyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“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.
“Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated, not fully aromatic 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. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen. 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 quatemized. 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. In some embodiments, the heterocycloalkyl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
“Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring comprising at least one heteroatom. 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 quatemized. 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. In some embodiments, the heteroaryl is optionally substituted with —COOH, —COOMe, —CONH2, —CONHMe, or —CONMe2.
The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.
The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The terms “treat,” “treated,” “treatment,” or “treating” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment 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 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%.
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.
Described herein are RNR inhibitor that are useful for the treatment of cancer.
Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
wherein:
R1 is hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R4 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring A is a 3- to 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B;
each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa;
or two RA on the same atom are taken together to form an oxo;
each RAa is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or two RAa on the same atom are taken together to form an oxo;
n is 0-5;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each RB is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RBa;
or two RB on the same atom are taken together to form an oxo;
each RBa is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or two RBa on the same atom are taken together to form an oxo;
m is 0-5;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and
each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments the compound of Formula (I) exists as its tautomeric equivalent:
In some embodiments of a compound of Formula (I), R1 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), R1 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), R1 is C1-C6alkyl or cycloalkyl. In some embodiments of a compound of Formula (I), R1 is C1-C6alkyl.
In some embodiments of a compound of Formula (I), R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R2 is hydrogen.
In some embodiments of a compound of Formula (I), R3 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R3 is hydrogen. In some embodiments of a compound of Formula (I), R3 is C1-C6alkyl.
In some embodiments of a compound of Formula (I), R4 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R4 is hydrogen. In some embodiments of a compound of Formula (I), R4 is C1-C6alkyl.
In some embodiments of a compound of Formula (I), Ring A is a monocyclic 3- to 6-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), Ring A is a monocyclic 3- to 6-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A is a monocyclic 5- or 6-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A comprises 1-3 heteroatoms. In some embodiments of a compound of Formula (I), Ring A comprises 1 or 2 heteroatoms. In some embodiments of a compound of Formula (I), Ring A comprises 1 heteroatom. In some embodiments of a compound of Formula (I), Ring A comprises 2 heteroatoms. In some embodiments of a compound of Formula (I), Ring A comprises 3 heteroatoms. In some embodiments of a compound of Formula (I), Ring A is phenyl or a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is phenyl. In some embodiments of a compound of Formula (I), Ring A is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is a 6-membered heteroaryl.
In some embodiments of a compound of Formula (I), Ring A is a bicyclic 6- to 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), Ring A is a bicyclic 6- to 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), Ring A is a bicyclic 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), Ring A is a bicyclic 6- to 10-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A is naphthalene. In some embodiments of a compound of Formula (I), Ring A is a chromane. In some embodiments of a compound of Formula (I), Ring A is a cycloalkyl. In some embodiments of a compound of Formula (I), Ring A is a 4- to 6-memebered cycloalkyl. In some embodiments of a compound of Formula (I), Ring A is cyclohexyl. In some embodiments of a compound of Formula (I), Ring A is a heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is a 4- to 6-memebered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is tetrahydropyran.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6 alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —C(═S)NRcRd, —C(═O)NRbORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C2-C6alkenyl, cycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6heteroalkyl; wherein the alkyl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RA is independently hydrogen, deuterium, halogen, —OH, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; wherein the alkyl is optionally and independently substituted with one or more RAa.
In some embodiments of a compound of Formula (I), each RA is independently halogen, —OH, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.
In some embodiments of a compound of Formula (I), each RAa is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (I), each RAa is independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —OC(═O)Ra, —NRcRd, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; wherein the alkyl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, or —NRcRd.
In some embodiments of a compound of Formula (I), each RAa is independently hydrogen, deuterium, halogen, —CN, —OH, -OR', —NRcRd, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.
In some embodiments of a compound of Formula (I), each RAa is independently hydrogen, deuterium, halogen, —OH, —C(═O)ORb, —C(═O)NRcRd, or C1-C6alkyl.
In some embodiments of a compound of Formula (I), each RAa is independently OH, —C(═O)ORb, —C(═O)NRcRd, or C1-C6alkyl.
In some embodiments of a compound of Formula (I), each RAa is independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —OC(═O)Ra, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; wherein the alkyl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, or —NRcRd.
In some embodiments of a compound of Formula (I), n is 0-4. In some embodiments of a compound of Formula (I), n is 2-4. In some embodiments of a compound of Formula (I), n is 1-3. In some embodiments of a compound of Formula (I), n is 2-4. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3. In some embodiments of a compound of Formula (I), n is 4.
In some embodiments of a compound of Formula (I),
In some embodiments of a compound of Formula (I), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I), Ring B is phenyl. In some embodiments of a compound of Formula (I), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I), Ring B is 5- or 6-membered heteroaryl.
In some embodiments of a compound of Formula (I), each RB is independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RBa; or two RB on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (I), each RB is independently hydrogen, deuterium, halogen, —CN, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RBa.
In some embodiments of a compound of Formula (I), each RB is independently halogen or C1-C6alkyl.
In some embodiments of a compound of Formula (I), each RBa is independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (I), each RBa is independently hydrogen, deuterium, halogen, —ORa, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more of deuterium, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
In some embodiments of a compound of Formula (I), m is 1-3. In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I), m is 0-3. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4.
In some embodiments of a compound of Formula (I),
In some embodiments of a compound of Formula (I),
In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl). In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Ra is independently C1-C6alkyl. In some embodiments of a compound of Formula (I), each Ra is independently C1-C6haloalkyl.
In some embodiments of a compound of Formula (I), each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl). In some embodiments of a compound of Formula (I), each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), each Rb is independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rb is independently C1-C6alkyl. In some embodiments of a compound of Formula (I), each Rb is independently C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rb is hydrogen.
In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl). In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently C1-C6alkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are independently C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each Rc and Rd are hydrogen.
In some embodiments of a compound of Formula (I), Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, -N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, —OH, —OCH3, —NH2, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.
In some embodiments of a compound of Formula (I), each RA, RAa, RB, RBa, Rb, Rc, Rd, and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of a compound of Formula (I), each RA, RAa, RB, RBa, Ra, Rb, Rc, Rd, and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with one, two, or three substituents as defined herein. In some embodiments of a compound of
Formula (I), each RA, RAa, RB, RBa, Ra, Rb, Rc, Rd, and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with one or two substituents as defined herein. In some embodiments of a compound of Formula (I), each RA, RAa, RB, RBa, Ra, Rb, Rc, Rd, and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with one substituent as defined herein. In some embodiments of a compound of Formula (I), each RA, RAa, RB, RBa, Ra, Rb, Rc, Rd, and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with two substituents as defined herein. In some embodiments of a compound of Formula (I), each RA, RAa, RB, RBa, Ra, Rb, Rc, Rd , and the heterocycloalkyl formed when Rc and Rd are taken together is independently substituted with three substituents as defined herein.
In some embodiments of a compound of Formula (I), the compound is selected from a compound of Table 1:
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 all 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 all 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.
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, tautomer, 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 particularly preferred 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, tautomer, 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 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 therefor 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, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfate, 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, tosylateundeconate, 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 salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like of the tetrazole.
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. The disclosure provides for methods of treating diseases by administering such solvates. The 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, 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.
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the tetrazole of Formula (I) exists as either of its tautomers:
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, WI, 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, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), 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 through 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 compound described herein is administered as a pure chemical. In some embodiments, the 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)).
Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
In certain embodiments, the compound provided herein 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.
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 patient, the type and severity of the patient'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, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, 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 patient.
In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.
Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involve the administration of about 0.1 μg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 μg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject's physiological response.
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 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
Disclosed herein are methods for treating cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Disclosed herein are methods for treating a RNR-related cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
In some embodiments, the RNR-related cancer includes malignant tumors whose incidence can be decreased or whose symptom is in remission or alleviated and/or completely cured by deleting or suppressing and/or inhibiting functions of RNR. Malignant tumors of interest is, but not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumor and the like.
In some embodiments, the term cancer is used in accordance with its plain ordinary meaning in light of the present disclosure and refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, pharmaceutical compositions include lymphoma (e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zona lymphoma, Burkitt's lymphoma), sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin (trastuzumab) resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's Disease of the Nipple, Phyllodes Tumors, lobular carcinoma, ductal carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer. In embodiments, the cancer is selected from ovarian cancer, prostate cancer, esophageal cancer, salivary gland cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, lung cancer, bladder cancer, colon cancer, and uterine cancer. In embodiments, the cancer is selected from muscle cancer, brain cancer, lymph node cancer, thyroid cancer, kidney cancer, and adrenal gland cancer.
In certain instances, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with a second therapeutic agent.
In some embodiment, the second therapeutic includes antimetabolites, platinum drugs, plant alkaloid drugs, and molecular targeting drugs.
In some embodiments, the antimetabolites include 5-fluorouracil, 5-fluoro-2′-deoxyuridine, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil, pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors (decitabine, guadecitabine, azacitidine, etc.).
In some embodiments, the platinum drugs include cisplatin, oxaliplatin, carboplatin, and nedaplatin.
In some embodiments, the plant alkaloid drugs include microtube inhibiting drugs such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibiting drugs such as irinotecan (or an active metabolite SN-38), nogitecan, and etoposide.
In some embodiments, the molecular targeting drugs include ATR (ataxia telangiectasia and Rad3 related protein) inhibitors, Chk1 (checkpoint kinase 1) inhibitors, HSP (heat shock protein) 90 inhibitors, PARP (poly ADP ribose polymerase) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, Her2 inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MET inhibitors, AXL inhibitors, RET inhibitors, FLT3 (fins-related tyrosine kinase 3) inhibitors, KIT inhibitors, CSF1R (colony-stimulating factor 1 receptor) inhibitors, TIE2 (tunica interna endothelial cell kinase 2) inhibitors, TRKB inhibitors, and CDK4/6 inhibitors. In some embodiments, the ATR inhibitors include AZD6738, berzosertib, BAY1895344, and VX-803. In some embodiments, the Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737. In some embodiments, the HSP90 inhibitors include luminespib, ganetespib, and onalespib. In some embodiments, the PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib. In some embodiments, the EGFR inhibitors include small molecule inhibitors such as lapatinib, gefitinib, erlotinib, afatinib, and vandetanib, and anti-EGFR antibodies such as cetuximab and panitumumab. In some embodiments, the Her2 inhibitors include small molecule inhibitors such as lapatinib, and anti-Her2 antibodies such as trastuzumab, pertuzumab, and trastuzumab emtansine. In some embodiments, the VEGFR inhibitors are inhibitors of at least one of VEGFR1, VEGFR2, and VEGFR3 and include small molecule inhibitors such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and anti-VEGFR antibodies such as ramucirumab. In some embodiments, the PDGFR inhibitors are PDGFRα and/or PDGFREβ inhibitors and include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. In some embodiments, the MET inhibitors include cabozantinib, crizotinib, and tepotinib. In some embodiments, the AXL inhibitors include cabozantinib and gilteritinib. In some embodiments, the RET inhibitors include sunitinib, cabozantinib, sorafenib, lenvatinib, and vandetanib. In some embodiments, the FLT3 inhibitors include sunitinib, cabozantinib, midostaurin, gilteritinib, and sorafenib. In some embodiments, the KIT inhibitors include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. In some embodiments, the CSF1R inhibitors include sunitinib, BLZ-945, and ARRY-382. In some embodiments, the TIE2 inhibitors include cabozantinib. In some embodiments, the TRKB inhibitors include cabozantinib and entrectinib. In some embodiments, the CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib.
In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.
In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
The compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
In some embodiments, the compound of described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
A solution of (2S) -2-{[(tert-butoxy)carbonyl]amino}-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.0 g, 3.073 mmol, 1.0 eq), triethylamine (471 μL, 3.379 mmol, 1.1 eq) and ethyl chloroformate (323 μL, 3.378 mmol, 1.099 eq) in THF (50 mL) was cooled to −10° C. After 1 h, ammonia solution (25% in H2O, 25 mL) was added dropwise and the reaction was continued overnight. Solvents were removed in vacuo and the residue was taken up in EtOAc. Organic layer was washed with 1M Na2HPO4, water and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by FCC (30% AcOEt in hexanes) to afford tert-butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate as a single diastereoisomer (550 mg, 1.695 mmol, yield 52%) as a white solid. LC-MS: m/z=325.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 7.02-6.91 (m, 3H), 6.80 (dd, J=11.6, 8.3 Hz, 1H), 6.70 (s, 1H), 4.32 (t, J=9.9 Hz, 1H), 3.42 (t, J=8.5 Hz, 1H), 2.18 (s, 6H), 1.40 (s, 9H), 1.22-1.14 (m, 3H).
Trifluoroacetic anhydride (354 μL, 2.547 mmol, 1.502 eq) was added dropwise at 0° C. to a solution of tert-butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (550 mg, 1.695 mmol, 1.0 eq) in pyridine (16.5 mL). The reaction was continued at rt overnight. Solvent was removed in vacuo. The residue was purified by FCC to afford tert-butyl N-[(1S,2R)-1-cyano-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (400 mg, 1.306 mmol, yield 76%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 7.94 (d, J=8.8 Hz, 1H), 7.14 (dd, J=8.4, 5.9 Hz, 1H), 6.95 (dd, J=12.0, 8.4 Hz, 1H), 4.78 (t, J=10.1 Hz, 1H), 3.63 (dd, J=11.7, 7.0 Hz, 1H), 2.25 (s, 6H), 1.44 (s, 9H), 1.21 (d, J=6.9 Hz, 3H).
To a solution of tert-butyl N-[(1S2R)-1-cyano-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (400 mg, 1.306 mmol, 1.0 eq) in DMF (20.0 mL) sodium azide (127 mg, 1.954 mmol, 4 eq) was added followed by NH4Cl (279 mg, 5.216 mmol, 4 eq). The reaction was carried out at 110° C. overnight. The mixture was cooled down, diluted with EtOAc and washed twice with water, 10% sol. of NaH2PO4, brine, dried, filtered and concentrated to afford tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H -1,2,3,4-tetrazol-5-yl)propyl]carbamate (360 mg, 1.03 mmol, yield 75%) as a yellow oil. LC-MS: m/z=349.95 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 7.79 (d, J=8.6 Hz, 1H), 6.91 (dd, J=8.4, 5.8 Hz, 1H), 6.75 (dd, J=11.8, 8.4 Hz, 1H), 5.41 (t, J=9.9 Hz, 1H), 3.82 (q, J=8.1, 6.6 Hz, 1H), 2.09 (d, J=5.5 Hz, 6H), 1.36 (d, J=9.2 Hz, 12H).
A mixture of tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]carbamate (360 mg, 1.03 mmol, 1.0 eq) and 4M HCl in dioxane (5.152 mL, 20.608 mmol, 20 eq) was stirred at rt for 2 h until full conversion was observed. Solvents were removed in vacuo, then the residue was co-evaporated twice with toluene and dried under high vacuum to afford (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine as a hydrochloride (290 mg, 1.02 mmol, yield 100%). LC-MS: m/z=349.95 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 9.16 (s, 3H), 6.97 (dd, J=8.4, 5.9 Hz, 1H), 6.82 (dd, J=11.8, 8.4 Hz, 1H), 5.06 (d, J=10.8 Hz, 1H), 3.99 (d, J=18.4 Hz, 1H), 2.05 (d, J=10.5 Hz, 6H), 1.55-1.42 (m, 3H).
To a mixture of (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine hydrochloride (50 mg, 0.175 mmol, 1.0 eq) in pyridine (1.5 mL,) 4-chloro-2-methoxybenzenesulfonyl chloride (44 mg, 0.183 mmol, 1.043 eq) was added portionwise at 0° C. and the resulting mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by pHPLC to afford 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]-2-methoxybenzene-1-sulfonamide (16 mg, 0.035 mmol, yield 20%) as a white solid. LC-MS: m/z=452.36 [M−H]−, 454.17 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.46 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.07 (dq, J=3.7, 1.9 Hz, 2H), 6.88 (dd, J=8.4, 5.8 Hz, 1H), 6.71 (dd, J=12.0, 8.5 Hz, 1H), 5.06 (dd, J=11.3, 9.2 Hz, 1H), 3.83 (dd, J=11.6, 6.7 Hz, 1H), 3.77 (s, 3H), 2.03 (d, J=2.2 Hz, 6H), 1.33 (d, J=6.8 Hz, 3H).
To a mixture of (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine hydrochloride (150 mg, 0.52 mmol, 1.0 eq) in pyridine (4.5 mL) cooled to 0° C., 4-chloro-2-cyanobenzene-1-sulfonyl chloride (130 mg, 0.55 mmol, 1.043 eq) was added portionwise and the resulting mixture was stirred at rt overnight. Solvent was removed in vacuo. The residue was purified by FCC to afford 4-chloro-2-cyano-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]benzene-1-sulfonamide (150 mg, 0.334 mmol, yield 57%) as a yellow foam. LC-MS: m/z=447.05 [M−H]−, 449.55 [M+H]+. 1H NMR (300 MHz, Chloroform-d) 8.02 (d, J=9.0 Hz, 1H), 7.71-7.64 (m, 2H), 6.90 (dd, J=8.4, 5.8 Hz, 1H), 6.67 (dd, J=11.9, 8.3 Hz, 2H), 5.54-5.45 (m, 1H), 3.79 (t, J=8.7 Hz, 1H), 2.11 (s, 3H), 2.07 (d, J=3.9 Hz, 3H), 1.51-1.47 (m, 3H).
To a cooled solution of 4-chloro-2-cyano-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H -1,2,3,4-tetrazol-5-yl)propyl]benzene-1-sulfonamide (150 mg, 0.334 mmol, 1.0 eq) in DMSO (1.34 mL), 30% H2O2 solution (100 μL, 3.34 mmol, 10.0 eq) was added dropwise, followed by 3M NaOH (1.1 mL, 3.34 mmol, 10.0 eq) and the mixture was stirred at rt for 1 h. The mixture was washed with DCM and acidified with 1M HCl. Aqueous layer was extracted twice with DCM. Organic layers combined, washed with brine, dried, filtered and concentrated to dryness. The residue was purified by FCC to afford 5-chloro -2-{[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]sulfamoyl}benzamide (24 mg, 0.0514 mmol, yield 15%) as a white solid. LC-MS: m/z=465.20 [M−H]−, 467.18 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.98 (s, 1H), 7.94 (d, J=9.8 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61 (dd, J=8.5, 2.1 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 6.89 (dd, J=8.4, 5.8 Hz, 1H), 6.73 (dd, J=11.8, 8.4 Hz, 1H), 5.22 (dd, J=11.1, 8.6 Hz, 1H), 3.75-3.63 (m, 1H), 2.05-1.98 (m, 6H), 1.31 (d, J=6.8 Hz, 3H).
A solution of 5-chloro-8-(chlorosulfonyl)-4-methyl-3,4-dihydro-2H-1-benzopyran-4-yl acetate (47 mg, 0.140 mmol, 1.0 eq) in DCM (400 μL) was added to a cooled solution of (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine hydrochloride (40 mg, 0.140 mmol, 1.0 eq) in Pyridine (1.2 mL) at 0° C. The reaction was continued at rt overnight. The mixture was diluted with AcOEt, washed with 1M HCl and sat. NaHCO3. Organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by pTLC (10% MeOH in DCM) to afford the product as a mixture of diastereoisomers (23 mg, 0.042 mmol, yield 30%). LC-MS: m/z=552.6 [M+H]+.
To a solution of 5-chloro-8-{[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5yl)propyl]sulfamoyl}-4-methyl-3,4-dihydro-2H-1-benzopyran-4-yl acetate (23 mg, 0.042 mmol, 1.0 eq) in THF (690 μL), a solution of NaOH (4 mg, 0.095 mmol, 2.2 eq) in water (600 μL) was added. The reaction was continued at 70° C. for 3 days. The mixture was diluted with water and extracted with AcOEt. Organic layer was dried, filtered and concentrated in vacuo. The residue was purified by pHPLC. Earlier eluting compound was assigned as Compound A and later eluting compound as Compound B.
Compound A: LC-MS: m/z=508.16 [M−H]−. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.5 Hz, 1H), 7.21 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.81 (dd, J=8.4, 5.7 Hz, 1H), 6.68-6.61 (m, 1H), 5.04 (s, 1H), 4.91-4.83 (m, 1H), 4.14-4.06 (m, 1H), 3.78-3.70 (m, 1H), 3.69-3.59 (m, 1H), 2.02 (d, J=2.7 Hz, 6H), 2.00-1.91 (m, 1H), 1.81-1.73 (m, 1H), 1.49 (s, 3H), 1.41 (d, J=6.9 Hz, 3H).
Compound B: LC-MS: m/z=508.36 [M−H]−. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.88 (dd, J=8.4, 5.8 Hz, 1H), 6.77-6.67 (m, 1H), 5.16 (s, 1H), 5.12 (dd, J=11.3, 8.5 Hz, 1H), 4.30-4.20 (m, 1H), 4.16-4.06 (m, 1H), 3.85-3.73 (m, 1H), 2.09-2.04 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.93-1.86 (m, 1H), 1.59 (s, 3H), 1.27 (d, J=6.8 Hz, 3H).
Examples 5-80 were synthesized as described for example 1-4.
1H NMR
1H NMR (300 MHz, Chloroform-d) 8.02 (d, J = 9.0 Hz, 1H),
1H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.48 (d, J = 8.5
1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 6.91-6.86 (m,
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.75 (d, J = 8.4
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.51 (d, J = 8.4
1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.62 (d, J = 8.5 Hz,
1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.62 (d, J = 8.5 Hz,
1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.50 (d, J = 8.5
1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.40 (d, J = 2.2
1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.54 (d, J = 8.6
1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.54 (d, J = 8.6 Hz,
1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.58 (t, J = 8.2 Hz,
1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.43 (d, J = 8.5 Hz,
1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.92 (d, J = 1.8
1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.62 (d, J = 8.6
1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.56 (d, J = 8.3
1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.65 (d, J = 8.5
1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.68 (d, J = 8.3
1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.67 (d, J = 8.6
1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.75 (d, J = 8.5 Hz,
1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.08 (s, 1H), 6.86
1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.28 (d, J = 8.6 Hz,
1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.55 (d, J = 8.4
1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.57 (s, 1H), 7.28
1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.58 (d, J = 2.1
1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.61-7.54 (m,
1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.0 Hz, 1H), 7.72
1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.59 (d, J = 8.9
1H NMR(300 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.61-7.42 (m,
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.77-7.72 (m,
1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.72 (s,
1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.85 (d, J = 8.5
1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.81 (d, J = 9.4 Hz,
1H NMR (300 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.51 (d, J = 8.4
1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.40 (d, J = 9.8 Hz,
1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J = 8.8 Hz, 1H), 7.86
1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.64 (ddd, J = 8.8,
1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.79 (d, J = 2.6
1H NMR (300 MHz, DMSO-d6) δ 7.62 (d, J = 7.4 Hz, 1H), 7.56
1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.71 (s, 1H), 7.92
1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.39-7.31 (m,
1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.56 (dd, J = 8.7, 7.3
1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.66-7.36 (m,
1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.97 (s, 1H), 7.78
1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.50 (d, J = 2.4
1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.63 (d, J = 8.2
1H NMR (400 MHz, DMSO-d6) δ 16.02 (s, 1H), 9.05 (s, 1H),
1H NMR (400 MHz, DMSO-d6) δ 16.28 (s, 1H), 9.42 (s, 1H),
1H NMR (400 MHz, DMSO-d6) δ 16.20 (s, 1H), 8.84 (s, 1H), 7.82
1H NMR (400 MHz, DMSO-d6) δ 16.20 (s, 1H), 8.84 (s, 1H), 7.81
1H NMR (300 MHz, Methanol-d4) δ 8.28 (dd, J = 5.6, 2.3 Hz, 1H),
1H NMR (400 MHz, DMSO-d6) δ 15.96 (s, 1H), 8.92 (s, 1H), 7.59
1H NMR (400 MHz, DMSO-d6) δ 16.00 (s, 1H), 8.97 (s, 1H),
1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, J = 7.9 Hz, 1H), 7.37 (s,
1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 8.5 Hz, 1H), 7.50
1H NMR (300 MHz, Methanol-d4) δ 8.23 (s, 1H), 7.86 (d, J = 8.0
1H NMR (400 MHz, DMSO-d6) δ 16.08 (s, 1H), 9.01 (s, 1H),
1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.25 (s, 1H), 7.66
1H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.72 (s, 1H), 7.64
1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 124.6 Hz, 1H),
1H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 8.1 Hz, 1H), 7.52
1H NMR (400 MHz, Methanol-d4) δ 7.62 (dd, J = 8.3, 1.5 Hz, 1H),
1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.68 (d, J = 9.0
1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.85 (d, J = 2.0 Hz,
1H NMR (400 MHz, Methanol-d4) δ 7.48 (dd, J = 8.7, 1.9 Hz, 1H),
1H NMR (300 MHz, DMSO-d6) δ 15.79 (s, 1H), 8.31 (s, 1H),
1H NMR (300 MHz, Methanol-d4) δ 7.55 (d, J = 8.5 Hz, 1H), 6.86
1H NMR (300 MHz, Methanol-d4) δ 7.66 (dt, J = 8.5, 0.9 Hz, 1H),
1H NMR (300 MHz, Methanol-d4) δ 7.52 (d, J = 8.5 Hz, 1H), 7.20
1H NMR (400 MHz, Methanol-d4) δ 7.83 (d, J = 8.5 Hz, 1H), 7.21
1H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 8.5 Hz, 1H), 7.30
1H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.16
A rapid-fire mass spectrometry (RFMS) assay was used to assess RNR enzyme activity using a 384 well plate and a robotic platform.
The plate layout included two validated reference compounds (Triapine (3-AP) and Hydroxyurea (HU)):
First, the multidrop pipes were saturated for 30 minutes with enzymatic solution. Then 30 μL of Stop solution was distributed in column 24. Next, 15 μL of enzyme was distributed in column 1 to 24. Next, a pre-incubation step of 15 minutes at room temperature occurred, followed by distribution of 15 μL of substrate solution (column 1 to 24). Next, the plate was incubated for 45 minutes at 37° C. 30 μL of Stop solution was distributed to columns 1 to 23.
The final parameters for the enzyme reactions were:
The compounds were screened at concentrations from 10 nM to 30 μM.
Phospho-CHK1 cellular activity was measured as a marker of replication stress which is a consequence of RNR inhibition.
Colo320 DM cells (ATCC #CCL-220, derived from human colorectal adenocarcinoma, Dukes' type C) were seeded on a 96-well cell culture treated assay plate at a density of 50,000 cells/well in 200 μL of RPMI-1640 media supplemented with 10% Fetal Bovine Serum and incubated at 37 degrees Celsius overnight. The following day, test compound dilutions were added directly to the plated cells by a Tecan digital dispenser to a final DMSO concentration of <0.5% and incubated at 37 degrees Celsius overnight (approximately 16 hours). The following day all culture media is removed from the cells. 75 μL of 1× AlphaLisa lysis buffer is added to each well and plates are agitated on a shaker for 30 minutes at room temperature. The lysis of cells and detection of pCHK1 (S345) are performed with reagents contained within the AlphaLisa Sure Fire assay kit (Perkin Elmer #ALSU-PCHK1-A) according to the manufacturer's instructions. 10 μL of each lysate was then transferred to a white, 384-well assay plate (Perkin Elmer #6008280). 5 μL of Acceptor mix was then added to each well of lysate in the white, 384-well assay plate and incubated in the dark at room temperature for 60 minutes. 5 μL of Donor mix was then added to each well of the white, 384-well assay plate in subdued light and incubated at room temperature for 60 minutes. Plates are read on an Alpha Technology-compatible plate reader using standard AlphaLisa settings.
The results of examples A and B are shown in table 2.
To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound described herein, with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.
The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.
This application claims the benefit of U.S. Provisional Application Ser. No. 63/155,441 filed Mar. 2, 2021 which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/018279 | 3/1/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63155441 | Mar 2021 | US |
