Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
  • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• PARP inhibitors Target for a broad spectrum of disorders. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia reperfusion injury, inflammatory disease, degenerative diseases, protection from adverse effects of cytoxic compounds, and the potentiation of cytotoxic cancer therapy. PARP has also been indicated in retroviral infection and thus inhibitors may have use in antiretroviral therapy.
• PARP inhibitors have been efficacious in preventing ischemia reperfusion injury in models of myocardial infarction, stroke, other neural trauma, organ transplantation, as well as reperfusion of the eye, kidney, gut, and skeletal muscle. Inhibitors have been efficacious in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefit in several models of degenerative disease including diabetes (as well as complications) and Parkinson’s disease.
• PARP inhibitors can ameliorate the liver toxicity following acetaminophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, as well as skin damage secondary to sulfur mustards.
• PARP inhibitors have been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing animals.
• PARP1 and PARP2 are the most extensively studied PARPs for their role in DNA damage repair.
• PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins.
• PAR poly (ADP-ribose)
• PARylation mediates the recruitment of additional DNA repair factors to DNA lesions.
• PARP auto-PARylation triggers the release of bound PARP from DNA to allow access to other DNA repair proteins to complete repair.
• the binding of PARP to damaged sites, its catalytic activity, and its eventual release from DNA are all important steps for a cancer cell to respond to DNA damage caused by chemotherapeutic agents and radiation therapy.
• PARP inhibitors having improved selectivity for PARP1 may possess improved efficacy and reduced toxicity compared to other clinical PARP1 /2 inhibitors. It is believed also that selective strong inhibition of PARP1 would lead to trapping of PARP1 on DNA, resulting in DNA double strand breaks (DSBs) through collapse of replication forks in S-phase. It is believed also that PARP1 - DNA trapping is an effective mechanism for selectively killing tumor cells having HRD. An unmet medical need therefore exists for effective and safe PARP inhibitors. Especially PARP inhibitors having selectivity for PARP1.
• composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer.
• the cancer is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer.
• oxo refers to ⁇ O.
• Carboxyl refers to —COOH.
• Cyano refers to —CN.
• Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably 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, isopen
• a numerical range such as “C 1 -C 6 alkyl” or “C 1 - 6 alkyl”, means that the alkyl group may consist 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.
• the alkyl is a C 1 - 10 alkyl.
• the alkyl is a C 1 - 6 alkyl.
• the alkyl is a C 1 - 5 alkyl.
• the alkyl is a C 1 - 4 alkyl.
• the alkyl is a C 1 - 3 alkyl.
• an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH 2 , or —NO 2 .
• the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe.
• the alkyl is optionally substituted with halogen.
• Alkenyl refers to a straight-chain, or 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 ⁇ CH 2 ), 1-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl [—C(CH 3 ) ⁇ CH 2 ], butenyl, 1,3-butadienyl and the like.
• a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 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.
• an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkenyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH 2 , or-NO 2 .
• the alkenyl is optionally substituted with halogen, —CN, —OH, or —OMe.
• the alkenyl is optionally substituted with halogen.
• Alkynyl refers to a straight-chain or 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.
• a numerical range such as “C 2 -C 6 alkynyl” or “C 2 - 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
• an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH 2 , or —NO 2 .
• the alkynyl is optionally substituted with halogen, —CN, —OH, or —OMe.
• the alkynyl is optionally substituted with halogen.
• Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen.
• Alkoxy refers to a radical of the formula —OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
• Aryl refers to a radical derived from a hydrocarbon ring system comprising 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.
• the aryl is a 6- to 10-membered aryl.
• the aryl is a 6-membered aryl (phenyl).
• 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.
• an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the aryl is optionally substituted with halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
• the aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen.
• 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. In some embodiments, the cycloalkyl is fully saturated.
• Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl or C 3 -C 15 cycloalkenyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl or C 3 -C 5 cycloalkenyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl or C 3 -C 4 cycloalkenyl).
• the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl.
• Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, 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.
• a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF 3 , —OH, —OMe, —NH 2 , or—NO 2 .
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe.
• the cycloalkyl is optionally substituted with halogen.
• Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
• “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.
• 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.
• Cyanoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more cyano group. In some embodiments, the alkyl is substituted with one cyano. In some embodiments, the alkyl is substituted with one or two cyanos. Cyanoalkyls include, for example, cyanomethyl.
• Deuteroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .
• 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.
• a heteroalkyl is a C 1 -C 6 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.
• heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• heteroalkyl are, for example, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH(CH 3 )OCH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 3 , or —CH 2 CH 2 N(CH 3 ) 2 .
• 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.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
• Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
• the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
• the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 -C 6 heterocycloalkenyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 heterocycloalkenyl), or two to four carbon atoms (C 2 -C
• heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, 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, tetrahydropyrany
• heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. 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). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
• the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
• the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
• a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
• the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
• Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
• the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
• the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
• the heteroaryl comprises one to three nitrogens.
• the heteroaryl comprises one or two nitrogens.
• the heteroaryl comprises one nitrogen.
• the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• the heteroaryl is a 5- to 10-membered heteroaryl.
• the heteroaryl is a 5- to 6-membered heteroaryl.
• the heteroaryl is a 6-membered heteroaryl.
• the heteroaryl is a 5-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]pyridirryl, carbazolyl, cinnolinyl,
• a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
• the heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
• an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., —CH 2 CHF 2 , —CH 2 CF 3 , —CF 2 CH 3 , —CFHCHF 2 , etc.).
• any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
• an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
• Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
• treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
• “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.
• a “disease or disorder associated with PARP” or, alternatively, “a PARP-mediated disease or disorder” means any disease or other deleterious condition in which PARP, or a mutant thereof, is known or suspected to play a role.
• a “disease or disorder associated with PARP1” or, alternatively, “aPARP1-mediated disease or disorder” means any disease or other deleterious condition in which PARP, or a mutant thereof, is known or suspected to play a role.
• Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of cancer.
• the compound is of Formula (Ia):
• the compound is of Formula (Ib):
• the compound is of Formula (Ic):
• R 1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl.
• R 1 is halogen, —CN, —OH, —OR a , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl.
• R 1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 alkyl, C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl.
• R 1 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl.
• R 1 is C 1 -C 6 alkyl or cycloalkyl.
• R 1 is C 1 alkyl or C 3 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cyclopropyl.
• R 1 is methyl or ethyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is ethyl.
• R 1 is deuterium, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
• R 1 is deuterium, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
• R 1 is halogen, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is halogen, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
• R 1 is halogen or cycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is halogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cyclopropyl.
• R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
• R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl.
• R 1 is halogen, C 1 -C 6 alkyl, or cycloalkyl.
• X is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is CR 2 .
• R 2 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 2 is hydrogen, halogen, or C 1 -C 6 alkyl.
• R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.
• R 1 and R 2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
• R 1 and R 2 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
• R 1 and R 2 are taken together to form an aryl or heteroaryl; each optionally substituted with one or more R.
• Ring B taken with X 1 and X 2 is a 5-membered heterocycloalkyl.
• Ring B taken with X 1 and X 2 is pyrrolidinyl or furanyl.
• Ring B taken with X 1 and X 2 is a 5-membered heteroaryl.
• Ring B taken with X 1 and X 2 is pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.
• Ring B taken with X 1 and X 2 is pyrazolyl or imidazolyl.
• Ring B taken with X 1 and X 2 is pyrazolyl.
• Ring B taken with X 1 and X 2 is pyrazolyl.
• Ring B taken with X 1 and X 2 is furanyl.
• X 1 is C. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is CH. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is N. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 2 is C.
• X 2 is CH. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 2 is N.
• Z is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is CR 4 .
• R 4 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 4 is hydrogen, halogen, or C 1 -C 6 alkyl.
• R 4 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.
• Y is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is CR 5 .
• R 5 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 5 is hydrogen, halogen, or C 1 -C 6 alkyl.
• R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is hydrogen.
• R 6 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 6 is hydrogen, halogen, or C 1 -C 6 alkyl.
• R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 6 is hydrogen.
• each R 7 is independently hydrogen, deuterium, fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 7 is independently hydrogen, deuterium, fluoro, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 is independently hydrogen, fluoro, or C 1 -C 6 alkyl.
• each R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 is independently hydrogen or fluoro. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 is hydrogen.
• one R 7 is hydrogen and the other R 7 is C 1 -C 6 alkyl.
• two R 7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
• two R 7 are taken together to form a cycloalkyl or a heterocycloalkyl.
• two R 7 are taken together to form a cycloalkyl.
• n is 1. In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2.
• each R 8 is independently deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 8 is independently deuterium, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 8 is independently deuterium, halogen, —CN, or C 1 -C 6 alkyl.
• each R 8 is independently —CN or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 8 is independently C 1 -C 6 alkyl.
• two R 8 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
• two R 8 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl.
• two R 8 on adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
• two R 8 on adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl.
• p is 0-3. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0-2. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0 or 1.
• p is 2-4. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2 or 3. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1-4.
• p is 1-3. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0.
• p is 1. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 3.
• p′ is 0-2. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 0 or 1. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 2 or 3. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 1-3.
• p′ is 1 or 2. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 0. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 1. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 2. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p′ is 3.
• R 8a is deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 8a is deuterium, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloa.lkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8a is deuterium, halogen, —CN, or C 1 -C 6 alkyl.
• R 8a is —CN or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8a is C 1 -C 6 alkyl.
• W is —C(R 9 ) 2 —, —O—, —S—, —S( ⁇ O)—, —S( ⁇ O) 2 —, —S( ⁇ O)( ⁇ NR W )—, or —NR W —.
• W is absent, —C(R 9 ) 2 —, —O—, or —NR W —.
• W is —C(R 9 ) 2 —, —O—, or —NR W —.
• W is —O— or —NR W —.
• W is —S—, —S( ⁇ O)—, —S( ⁇ O) 2 —, or —S( ⁇ O)( ⁇ NR W )—.
• W is —S—, —S( ⁇ O)—, or —S( ⁇ O) 2 —.
• W is —O—.
• W is —NR W2 —.
• W is absent.
• each R 9 is independently hydrogen, deuterium, fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 9 is independently hydrogen, deuterium, fluoro, or C 1 -C 6 alkyl.
• each R 9 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 is independently hydrogen, fluoro, or C 1 -C 6 alkyl.
• each R 9 is independently hydrogen or fluoro. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one R 9 is hydrogen and the other R 9 is C 1 -C 6 alkyl.
• two R 9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R.
• two R 9 are taken together to form a cycloalkyl or a heterocycloalkyl.
• two R 9 are taken together to form a cycloalkyl.
• R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R W is hydrogen.
• Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is cycloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is heterocycloalkyl.
• Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is phenyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is heteroaryl.
• Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 6-membered heteroaryl.
• Ring A is not pyridinyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is not
• each R 10 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR b , —OC( ⁇ O)NR c R d , —SH, —SR a , —S( ⁇ O)R a , —S( ⁇ O) 2 R a , —S( ⁇ O) 2 NR c R d , —NR c R d , —NR b C( ⁇ O)NR c R d , —NR b C( ⁇ O)R a , —NR b C( ⁇ O)OR b , —NR b S( ⁇ O) 2 R a , —C( ⁇ O)
• each R 10 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR b , —OC( ⁇ O)NR c R d , —SH, —SR a , —S( ⁇ O)R a , —S( ⁇ O) 2 R a , —S( ⁇ O) 2 NR c R d , —NR c R d , —NR b C( ⁇ O)NR c R d , —NR b C( ⁇ O)R a , —NR b C( ⁇ O)OR b , —NR b S( ⁇ O) 2 R a , —C( ⁇ O)
• each R 10 is independently deuterium, halogen, —CN, —OH, —OR a , —OC( ⁇ O)R a , —OC( ⁇ O)OR b , —OC( ⁇ O)NR c R d , —NR c R d , —NR b C( ⁇ O)NR c R d , —NR b C( ⁇ O)R a , —NR b C( ⁇ O)OR b , —C( ⁇ O)R a , —C( ⁇ O)OR b , —C( ⁇ O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6
• each R 10 is independently deuterium, halogen, —CN, —OC( ⁇ O)NR c R d , —NR b C( ⁇ O)NR c R d , —NR b C( ⁇ O)R a , —NR b C( ⁇ O)OR b , —C( ⁇ O)R a , —C( ⁇ O)OR b , —C( ⁇ O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 10 is independently deuterium, halogen, —CN, —C( ⁇ O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• each R 10 is independently —C( ⁇ O)NR c R d .
• q is 0-3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 0-2. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 0 or 1.
• q is 1-4. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 1-3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 2-4.
• q is 2 or 3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 1 or 2. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 1.
• q is 2. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 3.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
• each R b is independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R.
• each R c and R d are independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R.
• R c is cycloalkyl and R d hydrogen.
• R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
• R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl.
• each R is independently deuterium, halogen, —CN, —OH, -OC 1 -C 6 alkyl, —NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , —C( ⁇ O)C 1 -C 6 alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 6 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)N(C 1 -C 6 alkyl) 2 , —C( ⁇ O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R on the same
• each R is independently deuterium, halogen, —CN, —OH, -OC 1 -C 6 alkyl, —NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R on the same atom form an oxo.
• each R is independently deuterium, halogen, —CN, —OH, -OC 1 -C 6 alkyl, - C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R on the same atom form an oxo.
• the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.
• OR label denotes a pure substance, but the absolute configuration of the stereochemical center is unknown.
• OR indicates purity with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).
• 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,
• 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.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
• 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.
• dissociable complexes are preferred.
• the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
• the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
• the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• the compounds described herein exist in their isotopically-labeled forms.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
• 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.
• isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, 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 invention.
• isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
• 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.
• the compounds described herein exist as their pharmaceutically acceptable salts.
• the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
• the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
• the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, 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, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzo
• 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-ethaned
• other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
• those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• a suitable base such as the hydroxide, carbonate, bicarbonate, 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.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
• 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.
• the compounds described herein exist as solvates.
• the invention provides for methods of treating diseases by administering such solvates.
• the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
• 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.
• 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.
• the disease is cancer.
• the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer.
• the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
• the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.
• the cancer comprises a BRCA1 and/or a BRCA2 mutation.
• the cancer comprising a BRCA1 and/or a BRCA2 mutation is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer.
• the cancer is a cancer deficient in Flomologous Recombination (FIR) dependent DNA DSB repair activity.
• FIR Flomologous Recombination
• the FIR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix.
• the components of the FIR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485).
• ATM NM_000051
• RAD51 NM_002875
• RAD51 L1 NM_002877
• RAD51 C NM_002876
• RAD51 L3 NM_002878
• DMC1 NM
• the cancer which is deficient in FIR dependent DNA DSB repair comprises one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway, relative to normal cells i. e. the activity of the FIR dependent DNA DSB repair pathway may be reduced or abolished in the one or more cancer cells.
• the activity of one or more components of the FIR dependent DNA DSB repair pathway is abolished in the one or more cancer cells of an individual having a cancer which is deficient in FIR dependent DNA DSB repair.
• the cancer cells have a BRCA1 and/or a BRCA2 deficient phenotype i. e. BRCA1 and/or BRCA2 activity is reduced or abolished in the cancer cells.
• Cancer cells with this phenotype may be deficient in BRCA1 and/or BRCA2, i.e. expression and/or activity of BRCA1 and/or BRCA2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA2 regulatory factor.
• BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and/or BRCA2 are also at elevated risk of certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, and lung cancer.
• compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
• Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
• a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition is defined to be a “prophylactically effective amount or dose.”
• dose a pharmaceutically effective amount or dose.
• the precise amounts also depend on the patient’s state of health, weight, and the like.
• effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
• prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
• the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
• the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
• a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
• Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 10 and the ED 90 .
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
• the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
• the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
• the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
• the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours.
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 2 days to 1 year.
• Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
• parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
• a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
• long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
• the liposomes are targeted to and taken up selectively by the organ.
• the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
• the compound described herein is administered topically.
• the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds of this invention may be administered to animals.
• the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
• compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
• Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
• the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
• compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
• parenteral e.g., intravenous, subcutaneous, intramuscular
• intranasal e.g., buccal
• topical e.g., rectal, or transdermal administration routes.
• the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
• compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
• compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
• disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
• compositions for parental use are formulated as infusions or injections.
• the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the pharmaceutical composition comprises a liquid carrier.
• the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof
• the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
• Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
• the additional therapeutic agent is an anticancer agent.
• the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
• Step 1 Preparation of Methyl 5- ⁇ [(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl] Oxy ⁇ Pyridine-2-carboxylate
• Step 4 Preparation of 5- ⁇ [(3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) Methyl] Pyrrolidin-3-yl] oxy ⁇ -N-methylpyridine-2-carboxamide
• Step 1 Preparation of Methyl 5- ⁇ [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy ⁇ pyridine-2-carboxylate
• Step 4 Preparation of 5- ⁇ [(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide
• Step 3 Preparation of Methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate:
• Step 7 Preparation of 5- ⁇ [(3R)-1-[ (7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of 5- ⁇ [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy ⁇ pyridine-2-carboxylic acid
• Step 4 Preparation of N-cyclopropyl-5- ⁇ [(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl] pyrrolidin-3-yl] oxy ⁇ pyridine-2-carboxamide
• Step 1 Preparation of Methyl 5-1[(3R,4R)-1-(tert-butoxycarbonyl)4-fluoropyrrolidin-3-yl] Oxy ⁇ pyridine-2-carboxylate
• Step 2 Preparation of Tert-butyl (3R,4R)-3-fluoro-4- ⁇ [6-(methylcarbamoyl) Pyridin-3-yl] Oxy ⁇ pyrrolidine-1-carboxylate
• Step 3 Preparation of 5- ⁇ [(3R,4R)-4-fluoropyrrolidin-3-yl] oxy ⁇ -N-methylpyridine-2-carboxamide, HCl salt
• Step 4 Preparation of 5- ⁇ [(3R,4R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) Methyl]-4-fluoropyrrolidin-3-yl] oxy ⁇ -N-methylpyridine-2-carboxamide
• Step 1 Preparation of Methyl 5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)picolinate
• Step 2 Preparation of Tert-butyl (3S,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate
• Step 4 Preparation of 5-(((3S,4S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide
• Step 7 Preparation of N-cyclopropyl-5- ⁇ [(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl] pyrrolidin-3-yl] oxy ⁇ pyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (3S,4R)-3-fluoro-4- ⁇ [6-(methylcarbamoyl)pyridin-3-yl]oxy ⁇ pyrrolidine-1-carboxylate:
• Step 4 Preparation of 5- ⁇ [(3R,4S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl] oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate:
• Step 4 Preparation of 5-(((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide:
• the mixture was allowed to cool down to room temperature.
• the reaction mixture was poured into water (50 mL) at room temperature.
• the resulting mixture was extracted with CH 2 Cl 2 /i-PrOH (3/1, 3 ⁇ 50 mL).
• the combined organic layers were washed with brine (1 ⁇ 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 1 Preparation of Tert-butyl (3R)-3-( ⁇ 6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl ⁇ oxy)pyrrolidine-1-carboxylate:
• Step 3 Preparation of N-(2,2-difluoroethyl)-5- ⁇ [(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthytidin-3-yl)methyl] pyrrolidin-3-yl] oxy ⁇ pyridine-2-carboxamide:
• Step 4 Preparation of 5- ⁇ [(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl](methyl)amino ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (3R)-3-methyl-3-1[6-(methylcarbamoyl)pyridin-3-yl]oxylpyrrolidine-1-carboxylate:
• Step 4 Preparation of 5- ⁇ [(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylpyrrolidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide:
• the nickel mixture was added to a mixture of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate (300 mg, 1.14 mmol, 1.00 equiv.), methyl 5-bromopyridine-2-carboxylate (245 mg, 1.14 mmol, 1.00 equiv.), tris(trimethylsilyl)silane (282 mg, 1.14 mmol, 1.00 equiv.), Cs 2 CO 3 (740 mg, 2.27 mmol, 2.00 equiv.) and Ir[dF(CF 3 )ppy] 2 (dtpby)PF 6 (38 mg, 0.03 mmol, 0.03 equiv.) at room temperature under nitrogen atmosphere.
• Step 5 Preparation of 5- ⁇ [(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]methyl ⁇ -N-methylpyridine-2-carboxamide:
• Step 4 Preparation of 5-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl ⁇ amino)-N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl 3-methyl-3- ⁇ [6-(methylcarbamoyl)pyridin-3-yl]oxy ⁇ azetidine-1-carboxylate:
• Step 4 Preparation of 5-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylazetidin-3-yl ⁇ oxy)-N-methylpyridine-2-carboxamide:
• Desired product could be detected by LCMS.
• the mixture was allowed to cool down to room temperature.
• the resulting mixture was filtered, the filter cake was washed with CH 2 Cl 2 /MeOH(10:1) (150 mL).
• the filtrate was concentrated under reduced pressure.
• the crude product 300 mg was purified by Prep-HPLC, the pure fraction was concentrated then lyophilized to afford 5-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylazetidin-3-yl ⁇ oxy)-N-methylpyridine-2-carboxamide (90.8 mg, 24.65%).
• Step 4 Preparation of 5-( ⁇ 1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthytidin-3-yl)methyl] azetidin-3-yl ⁇ oxy)-N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (2R,3S)-2-methyl-3- ⁇ [6-(methylcarbamoyl)pyridin-3-yl]oxy ⁇ azetidine-1-carboxylate:
• Step 4 Preparation of 5- ⁇ [(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] Oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (2S,3R)-2-methyl-3- ⁇ [6-(methylcarbamoyl) Pyridin-3-yl] Oxy ⁇ azetidine-1-carboxylate:
• Step 3 Preparation of N-methyl-5- ⁇ [(2S,3R)-2-methylazetidin-3-yl] Oxy ⁇ Pyridine-2-carboxamide, HCl salt:
• Step 4 Preparation of 5- ⁇ [(2S,3R)-1- [(7-e1hyl-6-oxo-5H-1,5-naphthyridin-3-yl) Methyl]-2-methylazetidin-3-yl] oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5- ⁇ [(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl] oxy ⁇ pyridine-2-carboxylate:
• Step 2 Preparation of Tert-butyl (2R,3R)-2-methyl-3- ⁇ [6-(methylcarbamoyl)pyridin-3-yl] oxy ⁇ azetidine-1-carboxylate:
• Step 3 Preparation of N-methyl-5- ⁇ [(2R,3R)-2-methylazetidin-3-yl]oxy ⁇ pyridine-2-carboxainide, TFA salt:
• Step 4 Preparation of 5- ⁇ [(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 1 Preparation of Methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate:
• Step 2 Preparation of Tert-butyl (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate:
• Step 4 Preparation of 5-(((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide:
• the reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 ⁇ 50 mL). The combined organic layers were washed with brine (3 ⁇ 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC.
• Desired product could be detected by LCMS.
• the mixture was allowed to cool down to room temperature.
• the resulting mixture was poured into water (400 mL), extracted with EtOAc (3 ⁇ 200 mL). The combined organic layers were washed with brine (2 ⁇ 100 mL), dried over anhydrous Na 2 SO 4 .
• the resulting mixture was concentrated under reduced pressure to afford methyl 5- ⁇ [1-(tert-butoxycarbonyl)azetidin-3-yl]oxy ⁇ pyridine-2-carboxylate (45 g, crude) as a grey oil.
• Step 3 Preparation of Tert-butyl 3- ⁇ [6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy ⁇ azetidine-1-carboxylate:
• Step 5 Preparation of N-cyclopropyl-5-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl ⁇ oxy)pyridine-2-carboxamide:
• Step 3 Preparation of 4-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl ⁇ oxy) benzonitrile:
• Step 1 Preparation of Tert-butyl (2R,3S)-3-((6-cyanopyridin-3-yl)oay)-2-methylazetidine-1-carboxylate:
• Step 3 Preparation of Tert-butyl (2R,3S)-3- ⁇ [6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy ⁇ -2-methylazetidine-1-carboxylate:
• Step 4 Preparation of N-cyclopropyl-5- ⁇ [(2R,3S)-2-methylazetidin-3-yl]oxy ⁇ pyridine-2-carboxamide HCl salt:
• Step 5 Preparation of N-cyclopropyl-5- ⁇ [(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl] oxy ⁇ pyridine-2-carboxamide:
• Step 2 Preparation of Methyl 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinate:
• Step 3 Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinic acid:
• Step 4 Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-(oxetan-3-yl)picolinamide:
• the resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 ⁇ 20 mL). The combined organic layers were washed with water (1 ⁇ 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 4 Preparation of 5- ⁇ [(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide:
• Step 5 Preparation of 5- ⁇ [(2R,3S)-1-[(1R*)-1-(7-e1hyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxamide and 5- ⁇ [(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy ⁇ -N-methylpyridine-2-carboxaniide
• 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ 11.81 (s, 1H), 8.55 (d, 1H), 8.39 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.41-7.35 (m, 1H), 4.55 (d, 1H), 3.72-3.40 (m, 4H), 2.77 (d, 3H), 2.56 (m, 2H), 1.43 (d, 3H), 1.28 (d, 3H), 1.17 (t, 3H).
• 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ 11.89 (s, 1H), 8.58 (q, 1H), 8.45 (d, 1H), 8.24 (d, 1H), 7.96 (d, 1H), 7.74 (s, 1H), 7.63 (d, 1H), 7.45 (dd, 1H), 4.55 (q, 1H), 4.02 (t, 1H), 3.60-3.49 (m, 1H), 3.25 (t, 1H), 2.92-2.73 (m, 4H), 2.60-2.52 (m, 2H), 1.19 (q, 6H), 0.70 (d, 3H).
• Step 1 Preparation of Tert-butyl (2R,3R)-2-methyl-3- ⁇ [4-(trifluoromethyl)benzenesulfonyl]oxy ⁇ azetidine-1-carboxylate:
• Step 2 Preparation of Tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylate:
• Step 3 Preparation of Tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylate:
• Step 4 Preparation of N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride:
• Step 5 Preparation of 1-[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthytidin-3-yl)methyl]-2-methylazetidin-3-yl]-N-methylpyrrolo[3,2-b]pyridine-5-carboxamide:
• the resulting mixture was stirred for 2 h at 80° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford crude product. The residue was dissolved in DMSO (3 mL). The residue was purified by Prep-HPLC.
• Step 1 Preparation of Methyl 5- ⁇ [(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy ⁇ -3-fluoropyridine-2-carboxylate:
• Step 2 Preparation of 5- ⁇ [(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy ⁇ -3-fluoropyridine-2-carboxylic Acid
• Step 3 Preparation of Tert-butyl (2R,3S)-3- ⁇ [6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy ⁇ -2-methylazetidine-1-carboxylate
• Step 4 Preparation of N-cyclopropyl-3-fluoro-5- ⁇ [(2R,3S)-2-methylazetidin-3-yl] Oxy ⁇ Pyridine-2-carboxamide hydrochloride
• Step 5 Preparation of N-cyclopropyl-5- ⁇ [(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) Methyl]-2-methylazetidin-3-yl] oxy ⁇ -3-fluoropyridine-2-carboxamide
• the resulting mixture was stirred for additional 2 h at 80° C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 ⁇ 40 mL). The combined organic layers were washed with brine (1 ⁇ 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography. The resulting mixture was concentrated under reduced pressure.
• Step 5 Preparation of N-cyclopropyl-5- ⁇ [(2R,3S)-1- ⁇ [7-(difluoromethyl)-6-oxo-SH-1,5-naphthyridin-3-yl] Methyl ⁇ -2-methylazetidin-3-yl] Oxy ⁇ pyridine-2-carboxamide

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