Classifications

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  • 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
  • A61K31/495—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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • C07D401/02—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 two hetero rings
  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
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  • 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
  • C07D491/02—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
  • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-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
• • 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
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • 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

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 cytotoxic 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.
• PARP 1 and PARP2 are the most extensively studied PARPs for their role in DNA damage repair.
• PARPl is activated by DNA damage breaks and functions to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins.
• PARylation This post-translational modification, known as 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.
• Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways.
• 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.
• a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• a method of treating cancer in a subject in need thereof 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.
• 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-l-pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l- 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-buty
• 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, -NH2, or -NO2.
• alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, 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.
• a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, 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.
• 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.
• 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.
• the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0022] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined.
• 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.
• the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
• the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe.
• 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 - C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 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-decabn, 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, -NH2, or -NO2.
• 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 C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
• heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or - CH2CH2N(CH3)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, -CF3, -OH, -OMe, -NH2, or -NO2.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
• “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.
• 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. In some embodiments, 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 7 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, tetrahydropyr
• 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, -CF3, -OH, -OMe, -NH2, or -NO2.
• the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -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. In some embodiments, 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. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, 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. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, 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]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• 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, -CF3, -OH, -OMe, -NH2, or -NO2.
• the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
• the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above.
• 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., -CH2CHF2, -CH2CF3, -CF2CH3, - 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, “a PARP1- 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.
• R 1 is halogen or cycloalkyl.
• R 1 is cycloalkyl.
• R 1 is C 1 -C 6 alkyl.
• X is N and Y is CR 5 .
• R 5 is hydrogen, deuterium, 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, C1-C6heteroalkyl, or cycloalkyl.
• R 5 is hydrogen, deuterium, halogen, or C1-C6alkyl.
• R 5 is hydrogen.
• X is CR 2 and Y is N.
• R 2 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 2 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (I’), R 2 is hydrogen. In some embodiments of a compound of Formula (I) or (I’), R 2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (I’), R 2 is C1-C6alkyl. [0051] In some embodiments of a compound of Formula (I) or (I’), X is N and Y is N. In some embodiments of a compound of Formula (I) or (I’), Z is N.
• Z is CR 4 .
• R 4 is hydrogen, deuterium, 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, or cycloalkyl.
• R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (I’), R 4 is hydrogen. [0053] In some embodiments of a compound of Formula (I) or (I’), R 6 is hydrogen, deuterium, 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, C1-C6heteroalkyl, or cycloalkyl.
• R 6 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (I’), R 6 is hydrogen. [0054] In some embodiments of a compound of Formula (I) or (I’), each R 7 is independently hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (I’), each R 7 is hydrogen. In some embodiments of a compound of Formula (I) or (I’), two R 7 are taken together to form a cycloalkyl.
• each R 8 is C1-C6alkyl; or two R 8 on the same carbon are taken together to form an oxo.
• two R 8 on opposite carbons are taken together to form a cycloalkyl.
• two R 8 on the same carbon are taken together to form a cycloalkyl.
• two R 8 on adjacent carbons are taken together to form a cycloalkyl.
• n is 0. In some embodiments of a compound of Formula (I) or (I’), n is 1. In some embodiments of a compound of Formula (I) or (I’), n is 2. In some embodiments of a compound of Formula (I) or (I’), n is 3. In some embodiments of a compound of Formula (I) or (I’), n is 4. In some embodiments of a compound of Formula (I) or (I’), n is 5. In some embodiments of a compound of Formula (I) or (I’), n is 6. In some embodiments of a compound of Formula (I) or (I’), n is 0-3.
• n is 1-3. In some embodiments of a compound of Formula (I) or (I’), n is 1 or 2. In some embodiments of a compound of Formula (I) or (I’), n is 1-4. In some embodiments of a compound of Formula (I) or (I’), n is 2-4. [0057] In some embodiments of a compound of Formula (I), Ring A is 3- to 7-membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S. [0058] In some embodiments of a compound of Formula (I), Ring A is phenyl.
• Ring A is 5- to 6-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 5-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 6-membered heteroaryl, comprising 1 to 3 heteroatoms that are N.
• Ring A is pyridinyl.
• Ring A is not pyridinyl.
• Ring A is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 6- to 12-membered bicyclic heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring A is 6- to 12-membered bicyclic partially saturated ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• each R Aa is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl; or two R Aa on the same atom are taken together to form an oxo.
• m is 0-4. In some embodiments of a compound of Formula (I), m is 0 or 1.
• m is 2 or 3. In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I), m is 0. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4. In some embodiments of a compound of Formula (I), m is 5. In some embodiments of a compound of Formula (I), m is 6. [0075] In some embodiments of a compound of Formula ( .
• each R 11 is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I’), each R 11 is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (I’), each R 11 is independently halogen. [0077] In some embodiments of a compound of Formula (I’), q is 0 or 1. In some embodiments of a compound of Formula (I’), q is 1 or 2. In some embodiments of a compound of Formula (I’), q is 0.
• q is 1. In some embodiments of a compound of Formula (I’), q is 2. In some embodiments of a compound of Formula (I’), q is 3. [0078] In some embodiments of a compound of Formula (I’), R 12 is cycloalkyl. In some embodiments of a compound of Formula (I’), R 12 is cycloalkyl.
• the compound is a compound of formula: wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Y is N, CH, or CF; each A 1 is independently CH, CD, CMe, CCF 3 , CCl, CF, or N; each R A is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, NHMe, or NHCD 3 .
• the compound is a compound of formula: wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Y is N, CH, or CF; each A 1 is independently CH, CD, CMe, CCF 3 , CCl, CF, or N; each R A is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, NHMe, or NHCD 3 .
• the compound is a compound of formula: wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Y is N, CH, or CF; each A 1 is independently CH, CD, CMe, CCF 3 , CCl, CF, or N; each R A is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, NHMe, or NHCD 3 ; A 2 is O, NH, NMe, or NCD 3 ; and A 3 is N, CH, CF, or CD.
• the compound is a compound of formula: wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Y is N, CH, or CF; each A 1 is independently CH, CD, CMe, CCF 3 , CCl, CF, or N; each R A is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, NHMe, or NHCD 3 ; A 2 is O, NH, NMe, or NCD 3 ; and A 3 is N, CH, CF, or CD.
• the compound is a compound of formula: wherein R 1 is C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; W is CH2, CF2, CD2, CHF, CHD; each R 11 is independently hydrogen, deuterium, or halogen; and R 12 is C1-C6alkyl or C1-C6deuteroalkyl.
• R 1 is 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R 1 is C 1 -C 6 alkyl.
• X is CR 2 and Y is CR 5 .
• X is N and Y is CR 5 .
• R 5 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 5 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II), R 5 is hydrogen. [0089] In some embodiments of a compound of Formula (II), X is CR 2 and Y is N.
• R 2 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 2 is hydrogen, deuterium, halogen, or C1-C6alkyl.
• R 2 is hydrogen.
• X is N and Y is N.
• Z is N.
• Z is CR 4 .
• R 4 is hydrogen, deuterium, 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, or cycloalkyl.
• R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 4 is hydrogen.
• R 6 is hydrogen, deuterium, 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, or cycloalkyl.
• R 6 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 6 is hydrogen.
• W 1 is -C(R 7 )2-, -NR W1 -, -C(R 7 )2C(R 7 )2-, - C(R 7 )2NR W1 -, or -NR W1 C(R 7 )2-.
• W 1 is -C(R 7 )2-, - NR W1 -, or -C(R 7 )2NR W1 -.
• W 1 is -C(R 7 )2-.
• each R 7 is independently hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R 7 is hydrogen. In some embodiments of a compound of Formula (II), two R 7 are taken together to form a cycloalkyl.
• R W1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), R W1 is hydrogen.
• W 2 is absent, -C(R 9 )2-, -NR W2 -, - C(R 9 )2C(R 9 )2-, -C(R 9 )2NR W2 -, or -NR W2 C(R 9 )2-.
• W 1 is absent or -NR W2 -.
• W 2 is absent.
• W 2 is -O-.
• each R 9 is independently hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R 9 is hydrogen. In some embodiments of a compound of Formula (II), two R 799 are taken together to form a cycloalkyl.
• R W2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), R W2 is hydrogen.
• Ring B is 3- to 7-membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring B is 3- to 7-membered cycloalkyl.
• Ring B is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring B is piperazinyl. [00106] In some embodiments of a compound of Formula (II), Ring B is not piperazinyl. [00107] In some embodiments of a compound of Formula (II), Ring B is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S. [00108] In some embodiments of a compound of Formula (II), Ring B is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring B is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms that are N.
• Ring B is 6- to 16-membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring B is 6- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring B is 6- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms that are N.
• each R B is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , 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, heterocycloalkyl; or two R B on the same atom are taken together to form an oxo.
• each R B is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R B on the same atom are taken together to form an oxo.
• p is 0-4. In some embodiments of a compound of Formula (II), p is 0 or 1. In some embodiments of a compound of Formula (II), p is 1 or 2. In some embodiments of a compound of Formula (II), p is 1. In some embodiments of a compound of Formula (II), p is 2.
• each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), each R 11 is independently halogen or C 1 -C 6 alkyl. [00119] In some embodiments of a compound of Formula (II), q is 0 or 1. In some embodiments of a compound of Formula (II), q is 1 or 2. In some embodiments of a compound of Formula (II), q is 1. In some embodiments of a compound of Formula (II), q is 0.
• R C1 is deuterium, halogen, -CN, -OH, - OR a , -NR c R d , C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R Ca .
• R C1 is halogen, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), R C1 is halogen, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), R C1 is halogen or cycloalkyl. In some embodiments of a compound of Formula (III”), R C1 is halogen. In some embodiments of a compound of Formula (III”), R C1 is cycloalkyl.
• each R Ca is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R C2 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R C2 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III”), R C2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III”), R C2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III”), R C2 is hydrogen. In some embodiments of a compound of Formula (III”), R C2 is C 1 -C 6 alkyl.
• R C3 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R C3 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R C3 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
• R C3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III”), R C3 is hydrogen. In some embodiments of a compound of Formula (III”), R C3 is C 1 -C 6 alkyl. [00125] In some embodiments of a compound of Formula (III”), R C3 is hydrogen or C 1 -C 6 alkyl.
• each R 7 is independently hydrogen, deuterium, halogen, Ci-G, alkyl or Ci-G,haloalkyl. In some embodiments of a compound of Formula (III”), each R 7 is hydrogen. In some embodiments of a compound of Formula (III”), two R 7 are taken together to form a cycloalkyl. [00128] In some embodiments of a compound of Formula (III”), each R 8 is C1-C6alkyl; or two R 8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (III”), two R 8 on opposite carbons are taken together to form a cycloalkyl.
• n is 0. In some embodiments of a compound of Formula (III”), n is 1. In some embodiments of a compound of Formula (III”), n is 2. In some embodiments of a compound of Formula (III”), n is 3. In some embodiments of a compound of Formula (III”), n is 4. In some embodiments of a compound of Formula (III”), n is 5.
• n is 6. In some embodiments of a compound of Formula (III”), n is 0-3. In some embodiments of a compound of Formula (III”), n is 1-3. In some embodiments of a compound of Formula (III”), n is 1 or 2. In some embodiments of a compound of Formula (III”), n is 1-4. In some embodiments of a compound of Formula (III”), n is 2-4.
• each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III”), each R 11 is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (III”), each R 11 is independently halogen. [00131] In some embodiments of a compound of Formula (III”), q is 0 or 1. In some embodiments of a compound of Formula (III”), q is 1 or 2. In some embodiments of a compound of Formula (III”), q is 0.
• q is 1. In some embodiments of a compound of Formula (III”), q is 2. In some embodiments of a compound of Formula (III”), q is 3. [00132] In some embodiments of a compound of Formula (III”), R 12 is C 1 -C 6 alkyl or cycloalkyl. In some embodiments of a compound of Formula (III”), R 12 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III”), R 12 is cycloalkyl.
• Ring C is phenyl.
• Ring C is 5- to 6-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 5-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 6-membered heteroaryl, comprising 1 to 3 heteroatoms that are N.
• Ring C is 3- to 7-membered cycloalkyl.
• Ring C is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 6- to 12-membered bicyclic heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 8- to 16-membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• Ring C is 8- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.
• each R C is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two R C on the same atom are taken together to form an oxo.
• each R C is independently deuterium, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R C on the same atom are taken together to form an oxo.
• each R C is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, C2-C6alkynyl, or cycloalkyl.
• each R C is independently C1-C6alkyl.
• R C is not C1-C6alkyl.
• R C is not C1-C6haloalkyl.
• r is 0-4. In some embodiments of a compound of Formula (III) or (III’), r is 1-3. In some embodiments of a compound of Formula (III) or (III’), r is 0 or 1. In some embodiments of a compound of Formula (III) or (III’), r is 0-3. In some embodiments of a compound of Formula (III) or (III’), r is 1 or 2. In some embodiments of a compound of Formula (III) or (III’), r is 1 or 2.
• r is 1. In some embodiments of a compound of Formula (III) or (IIF), r is 2. In some embodiments of a compound of Formula (III) or (IIF), r is 3. In some embodiments of a compound of Formula (III) or (IIF), r is 4. . [00151] In some embodiments of a compound of Formula (III) or (III’), W 3 is absent. In some embodiments of a compound of Formula (III) or (III’), W 3 is C2 alkynylene. In some embodiments of a compound of Formula (III) or (III’), W 3 is -C(R 7 )2-.
• each R 7 is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (III’), each R 7 is hydrogen. In some embodiments of a compound of Formula (III) or (III’), two R 7 are taken together to form a cycloalkyl. [00153] In some embodiments of a compound of Formula (III) or (III’), each R 8 is C 1 -C 6 alkyl; or two R 8 on the same carbon are taken together to form an oxo.
• n is 0. In some embodiments of a compound of Formula (III) or (III’), n is 1. In some embodiments of a compound of Formula (III) or (III’), n is 2.
• n is 3. In some embodiments of a compound of Formula (III) or (III’), n is 4. In some embodiments of a compound of Formula (III) or (III’), n is 5. In some embodiments of a compound of Formula (III) or (III’), n is 6. In some embodiments of a compound of Formula (III) or (III’), n is 0-3. In some embodiments of a compound of Formula (III) or (III’), n is 1-3. In some embodiments of a compound of Formula (III) or (III’), n is 1 or 2. In some embodiments of a compound of Formula (III) or (III’), n is 1-4.
• n is 2-4.
• each R 11 is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III) or (III’), each R 11 is independently halogen or C1-C6alkyl. [00156] In some embodiments of a compound of Formula (III) or (III’), q is 0 or 1. In some embodiments of a compound of Formula (III) or (III’), q is 1 or 2. In some embodiments of a compound of Formula (III) or (III’), q is 0.
• q is 1. In some embodiments of a compound of Formula (III) or (III’), q is 2. In some embodiments of a compound of Formula (III) or (III’), q is 3. [00157] In some embodiments of a compound of Formula (III) or (III’), the compound is a compound of formula: wherein Y is N, CH, or CF; A 1 is CH2, CF2, CHF, CHCH3, C(CH 3 ) 2 ; B 1 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; and C 1 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 2 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; B 2 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; and C 2 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; and D 2 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl optionally substituted with halogen; B 3 is O or S; and C 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; B 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; and C 4 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 5 is O or S; B 5 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and C 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 6 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and B 6 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 7 is O or S; B 7 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; and C 7 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 8 is O or S; B 8 is CH2, CF2, CHF, CHCH 3 , C(CH 3 ) 2 ; C 7 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; and D 8 is CH 2 , CF 2 , CHF, CHCH 3 , C(CH 3 ) 2 ; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A 9 is O or S; B 9 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl optionally substituted with halogen; and C 9 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is a compound of formula: wherein Y is N, CH, or CF; A is CH, CMe, CCF 3 , CCl, CF, or N; R 12 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl; each R 11 is independently hydrogen, deuterium, or halogen; A 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 1 is 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R 1 is C 1 -C 6 alkyl. [00169] In some embodiments of a compound of Formula (IV), X is CR 2 and Y is CR 5 .
• X is N and Y is CR 5 .
• R 5 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl.
• R 5 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 5 is hydrogen.
• X is CR 2 and Y is N.
• R 2 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 2 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IV), R 2 is hydrogen. [00174] In some embodiments of a compound of Formula (IV), X is N and Y is N. [00175] In some embodiments of a compound of Formula (IV), Z is N. In some embodiments of a compound of Formula (IV), Z is CR 4 .
• R 4 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 4 is hydrogen.
• R 6 is hydrogen, deuterium, 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, or cycloalkyl.
• R 6 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 6 is hydrogen.
• R 7a is deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 7a is deuterium or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), R 7a is deuterium. [00179] In some embodiments of a compound of Formula (IV), R 7b is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 7b is hydrogen, deuterium, or C 1 -C 6 alkyl.
• R 7a and R 7b are taken together to form a cycloalkyl.
• R 7a and R 7b are deuterium.
• each R 8 is C1-C6alkyl; or two R 8 on the same carbon are taken together to form an oxo.
• two R 8 on opposite carbons are taken together to form a cycloalkyl.
• n is 0. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), n is 2. In some embodiments of a compound of Formula (IV), n is 3. In some embodiments of a compound of Formula (IV), n is 4. In some embodiments of a compound of Formula (IV), n is 5. In some embodiments of a compound of Formula (IV), n is 6.
• n is 0-3. In some embodiments of a compound of Formula (IV), n is 1-3. In some embodiments of a compound of Formula (IV), n is 1 or 2. In some embodiments of a compound of Formula (IV), n is 1-4. In some embodiments of a compound of Formula (IV), n is 2-4.
• each R 11 is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IV), each R 11 is independently halogen or C1-C6alkyl. [00184] In some embodiments of a compound of Formula (IV), q is 0 or 1. In some embodiments of a compound of Formula (IV), q is 1 or 2. In some embodiments of a compound of Formula (IV), q is 0. In some embodiments of a compound of Formula (IV), q is 1. In some embodiments of a compound of Formula (IV), q is 2.
• q is 3.
• R 1 is 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, C 2 -C 6 alkynyl, or cycloalkyl.
• R 1 is C1-C6alkyl.
• X is N and Y is CR 5 .
• R 5 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6heteroalkyl, or cycloalkyl.
• R 5 is hydrogen, deuterium, halogen, or C1-C6alkyl.
• R 5 is hydrogen.
• X is CR 2 and Y is N.
• R 2 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl.
• R 2 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 2 is hydrogen.
• X is N and Y is N.
• Z is N.
• Z is CR 4 .
• R 4 is hydrogen, deuterium, 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, or cycloalkyl.
• R 4 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• R 4 is hydrogen.
• R 6 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl.
• R 6 is hydrogen, deuterium, halogen, or C1-C6alkyl.
• R 6 is hydrogen.
• each R 7 is independently hydrogen, deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V), each R 7 is hydrogen. In some embodiments of a compound of Formula (V), two R 7 are taken together to form a cycloalkyl. [00196] In some embodiments of a compound of Formula (V), each R 8 is C1-C6alkyl; or two R 8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (V), two R 8 on opposite carbons are taken together to form a cycloalkyl.
• n is 0. In some embodiments of a compound of Formula (V), n is 1. In some embodiments of a compound of Formula (V), n is 2. In some embodiments of a compound of Formula (V), n is 3. In some embodiments of a compound of Formula (V), n is 4. In some embodiments of a compound of Formula (V), n is 5. In some embodiments of a compound of Formula (V), n is 6.
• n is 0-3. In some embodiments of a compound of Formula (V), n is 1-3. In some embodiments of a compound of Formula (V), n is 1 or 2. In some embodiments of a compound of Formula (V), n is 1-4. In some embodiments of a compound of Formula (V), n is 2-4.
• each R 11 is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (V), each R 11 is independently halogen or C1-C6alkyl.
• one A is CR 11 and one is N. In some embodiments of a compound of Formula (V), both A are CR 11 . In some embodiments of a compound of Formula (V), both A are N.
• R 12 is C1-C6alkyl.
• R 12 is C1-C6deuteroalkyl.
• one R 11 and one R 8 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, - CN, -OH, -OR a , -NR c R d , 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, or C 1 -C 6 heteroalkyl.
• one R 11 and one R 8 are taken together to form a heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -OR a , - NR c R d , 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, or C 1 -C 6 heteroalkyl.
• one R 11 and one R 8 are taken together to form a 5- or 6-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , 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, or C 1 -C 6 heteroalkyl.
• one R 11 and one R 8 are taken together to form a 6-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
• one R 11 and one R 8 are taken together to form a 5-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
• the compound has the following formula: CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; B 1 is O, S, NH, NMe, NCD3, CH2, CHF, CD2, or CDH; R is hydrogen, deuterium, or halogen; and R 12 is C1-C6alkyl or C1-C6deuteroalkyl.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl.
• each R c and R d are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C1-C6alkyl.
• each R A , R B , R C , R a , R b , R c , R d , the cycloalkyl or heterocycloalkyl formed when 2 R 7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is independently substituted with one, two, three, or four substituents as defined herein.
• each R A , R B , R C , R a , R b , R c , R d , the cycloalkyl or heterocycloalkyl formed when 2 R 7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is independently substituted with one, two, or three substituents as defined herein.
• each R A , R B , R C , R a , R b , R c , R d , the cycloalkyl or heterocycloalkyl formed when 2 R 7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is independently substituted with one or two substituents as defined herein.
• each R A , R B , R C , R a , R b , R c , R d , the cycloalkyl or heterocycloalkyl formed when 2 R 7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R 8 are taken together, and the heterocycloalkyl formed when R c and R d are taken together, is independently substituted with one substituent as defined herein.
• Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
• the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is selected from a compound of Table 1. TABLE 1
• the compound is selected from the group consisting of: eptable salt, solvate, or stereoisomer thereof.
• the compound is selected from the group consisting of:
• the compound is selected from the group consisting of:
• the compound is selected from the group consisting of: pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• the compound is selected from the group consisting of: pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
• 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. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• Labeled compounds [00220] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
• 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, l5 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. [00221] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent 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-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dio
• 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, fiimaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethane sulfonic acid
• 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 I-4 alkyl)4, and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
• 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 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 LI (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), MRE1 1 A (NM_005590) and NBS 1 (NM_002485).
• ATM NM_000051
• RAD51 NM_002875
• RAD51 LI NM_002877
• RAD51 C NM_002876
• RAD51 L3 NM_002878
• DMC1
• 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. [00237] To minimize the risks of off-target effects, it is desirable for drug molecules to possess selectivity for a specific target.
• PARP5A Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. PNAS, January 26, 2011, 108 (7) 2783-2788 ).
• PARP5A also known as Tankyrase 1, plays key roles in Wnt signaling and telomere length (Kulak, O., Chen, H., Holohan B. et al. Disruption of Wnt/ ⁇ -Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol.2015 Jul; 35(14), 2425–2435).
• PARP6 is an essential microtubule-regulatory gene in mice, germline mutations in PARP6 that abrogate the catalytic activity has negative effects on neuronal function in humans (Vermenten-Schmaedick, A., Huang J.Y., Levinson, M. et al. Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay. Cells, 2021 Jun; 10(6), 1289).
• PARP7 catalytic inhibition causes hyper stimulatory effects on type one interferon producing an autoimmune phenotype (Gozgit, J.M., Vasbinder, M.M., Abo, R.P. et al.
• PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Volume 39, Issue 9, 13 September 2021, Pages 1214-1226). While the exact function of PARP8 has not been established, its knockout has been shown to induce mitotic and nuclear morphology defects and a decrease in cellular viability (Vyas, S., Chesarone-Cataldo, M., Todorova, T., et al. A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat. Commun.2013, 4 (1), 2240). PARP10 has been described as a MYC interacting protein with tumor suppressor activities (Yu, M., Schreek, S., Cerni, C.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are PARP1 selective over other members of the PARP family including PARP2, PARP3, PARP6, PARP7, PARP8, PARP10, PARP11, PARP14, PARP15, TNKS1 (PARP5A), and TNKS2 (PARP5B).
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP7.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have selective for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP14.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are selective for PARP1 over PARP15. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over TNKS2 (PARP5B). [00240] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 10000-fold more PARP1 selective over PARP2.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 9000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 8000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 7000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 6000-fold more PARP1 selective over PARP2.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 5000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 4000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 3000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 2000-fold more PARP1 selective over PARP2.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 1000-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 100-fold more PARP1 selective over PARP2. In some embodiments, the compounds disclosed herein has at least a 400- to 600-fold selectivity for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 400-fold selectivity for PARP1 over PARP2.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 500-fold selectivity for PARP1 over PARP2.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 100-fold more PARP1 selective over PARP3.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 200-fold more PARP1 selective over PARP3.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 200- to 700-fold selectivity for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 200-fold selectivity for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 650-fold selectivity for PARP1 over PARP3.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have more than 1000-fold more PARP1 selective over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2000- to 3000-fold selectivity for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2400-fold selectivity for PARP1 over PARP6.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 3000-fold selectivity for PARP1 over PARP6.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have more than 500-fold more PARP1 selective over PARP7.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 600- to 900-fold selectivity for PARP1 over PARP7.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 600-fold selectivity for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 800-fold selectivity for PARP1 over PARP7. [00245] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 3000-fold more PARP1 selective over PARP8.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 5000- to 9000-fold selectivity for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 8000-fold selectivity for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 5000-fold selectivity for PARP1 over PARP8.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have more than 200-fold more PARP1 selective over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 300- to 400-fold selectivity for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 350-fold selectivity for PARP1 over PARP10.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 300-fold selectivity for PARP1 over PARP10. [00247] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 5-fold more PARP1 selective over PARP11. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 5- to 270-fold selectivity for PARP1 over PARP11.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 6-fold selectivity for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 270-fold selectivity for PARP1 over PARP11. [00248] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 2000-fold more PARP1 selective over PARP14.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 1400- to 2600-fold selectivity for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 1400-fold selectivity for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2600-fold selectivity for PARP1 over PARP14.
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have more than 1000-fold more PARP1 selective over PARP15. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 1600-fold selectivity for PARP1 over PARP15. [00250] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 100-fold more PARP1 selective over TNKS1 (PARP5A).
• PARP5A TNKS1
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 100- to 250-fold selectivity for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 100-fold selectivity for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 230-fold selectivity for PARP1 over TNKS1 (PARP5A).
• the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have more than 100-fold more PARP1 selective over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 100- to 150-fold selectivity for PARP1 over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 140-fold selectivity for PARP1 over TNKS2 (PARP5B).
• 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.”
• prophylactically effective amount or dose the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, 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.
• 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.
• 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.
• 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 LDio 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.
• 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.
• compositions/Formulations [00266]
• 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, fdling 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.
• 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.
• the active compounds are dissolved or suspended in 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 2 Preparation of 6-cyano-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt: [00278] To a stirred solution of tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1- carboxylate (260 mg, 0.75 mmol, 1.00 equiv.) in dioxane (2 ml) was added HCl (gas) in 1,4-dioxane (2 mL, 4M in 1,4-dioxane) dropwise at ice bath. The resulting mixture was stirred for 1h at room temperature. The reaction was monitored by LCMS.
• Step 3 Preparation of 6-cyano-5- ⁇ 4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl ⁇ - N-methylpyridine-2-carboxamide:
• Step 2 Preparation of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-l- carboxylate:
• Step 4 Preparation of 5-[(2R)-4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2-methylpiperazin- l-yl]-N-methylpyridine- 2-carboxamide:
• the reaction was monitored by LCMS.
• the resulting mixture was diluted with water (40 mL).
• the mixture was acidified to pH 6 with saturated NH4Cl (aq.).
• the resulting mixture was extracted with CH2Cl2 (3 x 100 mL).
• the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]- 2,5-diazabicyclo[4.1.0] heptane-2-carboxylate (1.2 g, crude) as a yellow crude oil.
• Step 5 Preparation of rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5- diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine- 2-carboxamide (Example 3A) and rel-5-[(lR,6S)-5- [(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N- methylpyridine-2-carboxamide (Example 3B) :
• Step 1 Preparation of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3- methylpiperazine-1-carboxylate: [00290] To a stirred solution of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine- 1-carboxylate (2.20 g, 6.58 mmol, 1.00 equiv) in DMF (30 mL) was added NBS (1.29 g, 7.24 mmol, 1.10 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere.
• Desired product could be detected by LCMS.
• the reaction was quenched by the addition of sat.NaHCO3(aq) (30 mL) at 0°C.
• the resulting mixture was poured into water (100 mL), extracted with EtOAc (3 x 200 mL).
• the combined organic layers were washed with brine (3x150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
• Step 2 Preparation of tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3- methylpiperazine-1-carboxylate: [00291] A mixture of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1- carboxylate (500 mg, 1.21 mmol, 1.00 equiv), Zn(CN)2 (156 mg, 1.33 mmol, 1.10 equiv) and Pd(PPh3)4 (140 mg, 0.12 mmol, 0.10 equiv) in DMF (8 mL) was stirred overnight at 120°C under nitrogen atmosphere.
• Desired product could be detected by LCMS.
• the mixture was allowed to cool down to room temperature.
• the resulting mixture was poured into water (100 mL), extracted with EtOAc (3 x 150 mL).
• the combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na 2 SO 4 .
• the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel chromatography to afford tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (428 mg, 98%) as a yellow solid.
• Step 4 Preparation of 6-cyano-5-[(2R)-4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2- methylpiperazin-l-yl]-N-methylpyridine-2-carboxamide:
• Step 1 Preparation of tert-butyl 4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate: [00294] A mixture of methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.84 g, 4.48 mmol, 1.05 equiv), RuPhos Palladacycle Gen.3 (0.36 g, 0.43 mmol, 0.10 equiv) and Cs2CO3 (2.78 g, 8.55 mmol, 2.00 equiv) in 1,4-dioxane (16 mL) was stirred overnight at 110°C under nitrogen atmosphere.
• Step 2 Preparation of tert-butyl 4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1- carboxylate: [00295] To a stirred solution of ethyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1- carboxylate (1.20 g, 3.86 mmol, 1.00 equiv) in methanol (8 mL) was added CH3NH2 (8 mL, 25%-30% in water) at room temperature. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat.
• Step 3 Preparation of 3-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide: [00296] To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (1.22 g, 5.12 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added HCl (gas) in 1,4-dioxane (10 mL, 4M) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 4 Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-fluoro-N-methylpicolinamide: [00297] To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (80 mg, assumed 100% yield, 0.34 mmol, 1.50 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (50 mg, 0.22 mmol, 1.00 equiv) in ACN (5 mL) was added KI (7 mg, 0.04 mmol, 0.20 equiv) and DIEA (145 mg, 1.12 mmol, 5.00 equiv) at room temperature.
• Step 2 Preparation of tert-butyl 4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1- carboxylate: [00299] A mixture of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.20 g, 3.00 mmol, 1.00 equiv), Pd(dppf)Cl 2 (0.22 g, 0.30 mmol, 0.10 equiv), Cs 2 CO 3 (1.96 g, 6.01 mmol, 2.00 equiv) and cyclopropylboronic acid (0.26 g, 3.00 mmol, 1.00 equiv) in Toluene/H2O (10 mL/1 mL) was stirred for 1.5h at 100°C under nitrogen atmosphere.
• Step 3 Preparation of 6-cyclopropyl-N-methyl-5-(piperazin-1-yl)picolinamide, HCl salt: [00300] To a stirred solution of tert-butyl 4-[2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1- carboxylate (900 mg, 2.50 mmol, 1.00 equiv) in 1,4-dioxane (3 ml) were added HCl(gas)in 1,4-dioxane (10.00 mL, 4 M) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 4 Preparation of 6-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)-N-methylpicolinamide: [00301] To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv) and 6-cyclopropyl-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (200 mg, 0.67 mmol, 1.50 equiv) in MeCN (10 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (290 mg, 2.25 mmol, 5.00 equiv) at room temperature.
• Example 7 Step 1 Preparation of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: [00302] To a stirred mixture of methyl 4-bromo-2-fluorobenzoate (1.00 g, 4.29 mmol, 1.00 equiv) and tert- butyl piperazine-1-carboxylate (0.84 g, 4.51 mmol, 1.05 equiv) in dioxane (100 mL) were added Cs2CO3 (2.80 g, 8.58 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (0.18 g, 0.22 mmol, 0.05 equiv) at room temperature.
• Step 2 Preparation of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate: [00303] A mixture of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1.3 g, 3.84 mmol, 1.00 equiv) in MeOH (5 mL) was added Methylamine (3.5 mL, 25-30%wt in water) dropwise. And the mixture was stirred overnight at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt: [00304] To a stirred mixture of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-1- carboxylate (500 mg, 1.48 mmol, 1.00 equiv) in DCM (4 mL) was added HCl(gas)in 1,4-dioxane (2 mL, 4M) dropwise at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 4 Preparation of 4- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ -2-fluoro- N-methylbenzamide: [00305] To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one, HCl salt (100 mg, 0.45 mmol, 1.00 equiv) and 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (123 mg, 0.45 mmol, 1.00 equiv) in MeCN (5 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (290 mg, 2.24 mmol, 5.00 equiv).
• Example 8 Step 1 Preparation of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate: [00306] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1-carboxylate (859 mg, 2.78 mmol, 1.20 equiv), methyl 5-bromopyridine-2-carboxylate (500 mg, 2.31 mmol, 1.00 equiv), K2CO3 (640 mg, 4.63 mmol, 2.00 equiv) and Pd(dppf)Cl2 (339 mg, 0.46 mmol, 0.2 equiv) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred overnight at 80°C under nitrogen atmosphere.
• Step 2 Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate: [00307] To a stirred solution of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)- dicarboxylate (210 mg, 0.66 mmol, 1.00 equiv) in methanol (3 mL) was added CH3NH2 (3 mL, 25-30%wt in water) at room temperature. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere.
• Step 3 Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, TFA salt: [00308] To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'- carboxylate (170 mg, 0.54 mmol, 1 equiv) in DCM (5 mL) was added TFA (1 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Example 9 Step 1 Preparation of 7-(chloromethyl)-3-ethyl-1H-quinolin-2-one: [00310] To a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-quinolin-2-one (1.00 g, 4.92 mmol, 1.00 equiv) and DMF (18 mg, 0.25 mmol, 0.05 equiv) in DCM (20 mL) was added SOCl 2 (1.76 g, 14.76 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Example 10 Step 1 Preparation of N-(3-bromophenyl)-2-oxocyclopentane-1-carboxamide: [00312] A solution of 4-(cyclopent-1-en-1-yl) morpholine (3.60 g, 23.49 mmol, 1.00 equiv.) and 1-bromo- 3-isocyanatobenzene (5.58 g, 28.19 mmol, 1.20 equiv.) in CHCl3 (100 mL) was stirred for 4h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum.
• Step 2 Preparation of 7-bromo-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one: [00313] To a stirred solution of H2SO4 (10 mL) was added N-(3-bromophenyl)-2-oxocyclopentane-1- carboxamide (3.3 g, 11.69 mmol, 1.00 equiv.) slowly at 0°C.The resulting mixture was stirred for 4h at room temperature. The reaction was monitored by LCMS. The mixture was basified with aq.Na2CO3 (200 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 200 mL).
• Step 3 Preparation of ethyl 4-oxo-1H,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate: [00314] To a solution of 7-bromo-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (1.50 g, 5.67 mmol, 1.00 equiv.) and Et3N (1.15 g, 11.35 mmol, 2.00 equiv.) in EtOH (20 mL) was added Pd(PPh3)2Cl2 (797 mg, 1.13 mmol, 0.20 equiv.) in pressure tank.
• Step 5 Preparation of 7-(chloromethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one: [00316] To a stirred solution of 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (350 mg, 1.62 mmol, 1.00 equiv.) and DMF (12 mg, 0.16 mmol, 0.10 equiv.) in DCM (2 mL) was added SOCl 2 (967 mg, 8.13 mmol, 5.00 equiv.) dropwise at 0°C.The resulting mixture was stirred for 2h at room temperature. The reaction was monitored by LCMS.
• Example 11 Step 1 Preparation of methyl 3-(furan-3-amido)-4-iodobenzoate: [00318] A mixture of methyl 3-amino-4-iodobenzoate (10.00 g, 36.09 mmol, 1.00 equiv), 3-furoic acid (8.09 g, 72.18 mmol, 2.00 equiv), T 3 P (114.84 g, 180.46 mmol, 5.00 equiv, 50%wt in EA) and DIEA (23.32 g, 180.46 mmol, 5.00 equiv) in DCM (100 mL) was stirred overnight at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature.
• Step 2 Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate: [00319] A solution of methyl 3-(furan-3-amido)-4-iodobenzoate (6.00 g, 16.167 mmol, 1.00 equiv), (Boc)2O (7.06 g, 32.34 mmol, 2.00 equiv) and DMAP (1.98 g, 16.17 mmol, 1.00 equiv) in DCE (100 mL) was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate: [00320] To a mixture of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (400 mg, 0.85 mmol, 1.00 equiv) and PCy3 (48 mg, 0.17 mmol, 0.20 equiv) in DMF (12 mL) were added Pd(OAc)2 (38 mg, 0.17 mmol, 0.20 equiv) and K2CO3 (235 mg, 1.70 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere.
• Pd(OAc)2 38 mg, 0.17 mmol, 0.20 equiv
• K2CO3 235 mg, 1.70 mmol, 2.00 equiv
• the final reaction mixture was irradiated with microwave radiation for 2 h at 100 °C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (2 x 25 mL). The combined organic layers were washed with brine (2x25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (120 mg, 58.13%) as a yellow solid.
• Step 5 Preparation of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one: [00322] To a stirred mixture of 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (300 mg, 1.39 mmol, 1.00 equiv) and DMF (10 mg, 0.14 mmol, 0.10 equiv) in DCM (5 mL) was added SOCl 2 (995 mg, 8.36 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 6 Preparation of N-methyl-5-[4-( ⁇ 4-oxo-5H-furo[3,2-c]quinolin-7-yl ⁇ methyl)piperazin-1- yl]pyridine-2-carboxamide: [00323] A mixture of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.43 mmol, 1.00 equiv), N- methyl-5-(piperazin-1-yl)picolinamide, HCl salt (110 mg, 0.43 mmol, 1.00 equiv), KI (14 mg, 0.09 mmol, 0.20 equiv) and DIEA (276 mg, 2.14 mmol, 5.00 equiv) in MeCN (10 mL) was stirred for 2 h at 80°C under nitrogen atmosphere.
• Example 12 Step 1 Preparation of 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ pyridine- 2-carboxylic acid: [00324] To a stirred solution of methyl 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin- 1-yl ⁇ pyridine-2-carboxylate (120 mg, 0.29 mmol, 1.00 equiv) in EtOH/THF (1:1, 5 mL) was added aqueous NaOH (3.0 mL, 1N) at room temperature under nitrogen atmosphere.
• Step 2 Preparation of N-cyclopropyl-5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin- 1-yl ⁇ pyridine-2-carboxamide: [00325] To a stirred solution of 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- yl ⁇ pyridine-2-carboxylic acid (120 mg, 0.30 mmol, 1.00 equiv) and DIEA (158 mg, 1.22 mmol, 4.00 equiv) in DMF (4 mL) was added HATU (174 mg, 0.46 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere.
• DIEA 158 mg, 1.22 mmol, 4.00 equiv
• Example 13 Step 1 Preparation of methyl 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- yl ⁇ pyridine-2-carboxylate: [00326] To a stirred mixture of methyl 5-(piperazin-1-yl)pyridine-2-carboxylate (280 mg, 1.26 mmol, 1.00 equiv) and DIEA (818 mg, 6.32 mmol, 5.00 equiv) in MeCN (6 mL) were added 7-(chloromethyl)-3-ethyl- 1H-1,5-naphthyridin-2-one (282 mg, 1.26 mmol, 1.00 equiv) and KI (42 mg, 0.25 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere.
• Step 2 Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1- yl)picolinic acid: [00327] To a stirred solution of methyl 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin- 1-yl ⁇ pyridine-2-carboxylate (200 mg, 0.49 mmol, 1.00 equiv) in EtOH/THF (5 mL/5 mL) was added 5.0 mL 1(N) aqueous NaOH at room temperature under nitrogen atmosphere.
• Step 3 Preparation of N-(2,2-difluoroethyl)-5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) methyl] piperazin-1-yl ⁇ pyridine-2-carboxamide: [00328] To a stirred solution of 5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl) methyl]piperazin-1- yl ⁇ pyridine-2-carboxylic acid (220 mg, 0.56 mmol, 1.00 equiv) and DIEA (361 mg, 2.80 mmol, 5.00 equiv) in DMF (5 mL) ware added EDCI (536 mg, 2.80 mmol, 5.00 equiv) and HOBT (227 mg, 1.68 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere.
• the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (80 mg, 94% purity) as a white solid.
• Example 14 1 Preparation of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: [00329] To a stirred solution of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1- carboxylate (1.73 g, 4.33 mmol, 1.00 equiv) and TMEDA (604 mg, 5.20 mmol, 1.20 equiv) in toluene (60 ml) were added bis(adamantan-1-yl)(butyl)phosphane (311 mg, 0.87 mmol, 0.20 equiv) and Pd(OAc) 2 (97 mg, 0.43 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere.
• Step 2 Preparation of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1- carboxylate: [00330] To a stirred solution of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1- carboxylate (1.50 g, 4.29 mmol, 1.00 equiv) in DCM (8 mL) was added BAST (1.20 mL, 6.44 mmol, 1.50 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 4h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 4 Preparation of 6-(difluoromethyl)-5- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl ⁇ -N-methylpyridine-2-carboxamide: [00332] To a stirred solution of 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (250 mg, 0.82 mmol, 1.40 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (130 mg, 0.58 mmol, 1.00 equiv) in MeCN (5 mL) were added DIEA (377 mg, 2.92 mmol, 5.00 equiv) and KI (2 mg, 0.01 mmol, 0.02 equiv) at room temperature under nitrogen atmosphere.
• DIEA 377 mg,
• the reaction was cooled to - 78 °C and NBS (15.28 g, 85.82 mmol, 1.10 equiv) in 50 mL THF added dropwise. The reaction was then stirred for 2 hours and allowed to warm to room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH 4 CI (aq.) (50 mL) at 0°C. The resulting mixture was extracted with Et 2 0 (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure.
• Step 3 Preparation of methyl 6-[(lZ)-2-cyclopropyl-3-ethoxy-3-oxoprop-l-en-l-yl]-5-nitropyridine-3- carboxylate:
• Step 4 Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: [00336] To a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5- nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL) was added CaCl2 (1.24 g, 11.24 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere.
• the resulting mixture was stirred overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was added 50 mL water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
• Step 5 Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: [00337] To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv) was added LiAlH 4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 6 Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one: [00338] To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv) and DMF (3 mg, 0.04 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl 2 (264 mg, 2.22 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 7 Preparation of 5- ⁇ 4-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ -N- methylpyridine-2-carboxamide: [00339] A mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (80 mg, 0.34 mmol, 1.00 equiv), N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (75 mg, 0.34 mmol, 1.00 equiv), KI (11 mg, 0.07 mmol, 0.20 equiv) and DIEA (220 mg, 1.71 mmol, 5.00 equiv) in MeCN (10 mL) was stirred for 2 hours at 80°C under nitrogen atmosphere.
• Example 16 Step 1 Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate: [00340] To a stirred mixture of 5-bromo-N-methylpyridine-2-carboxamide (300 mg, 1.40 mmol, 1.00 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (518 mg, 1.67 mmol, 1.20 equiv) in 1,4-dioxane/H 2 O (4/1, 5 mL) were added Pd(dppf)Cl 2 (102 mg, 0.14 mmol, 0.10 equiv) and K 2 CO 3 (386 mg, 2.79 mmol, 2.00 equiv) at room temperature.
• Step 2 Preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate: [00341] To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate (330 mg, 1.04 mmol, 1.00 equiv) in methanol (20 mL) was added Pd/C (33 mg, 10%wt) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of N-methyl-5-(piperidin-4-yl)picolinamide, TFA salt: [00342] To a stirred solution of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate (310 mg, 0.97 mmol, 1.00 equiv) in DCM (5 mL) was added TFA (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 4 Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)- N-methylpicolinamide: [00343] To a stirred mixture of N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide, TFA salt (294 mg, assumed 50% yield, 1.35 mmol, 2.00 eq) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in MeCN (3 mL) were added KI (112 mg, 0.67 mmol, 1.00 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere.
• TFA salt 294 mg, assumed 50% yield, 1.35 mmol, 2.00 eq
• Step 2 Preparation of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate: [00345] To a stirred solution of tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-1- carboxylate (1.00 g, 2.90 mmol, 1.00 equiv) and methylamine (5 mL, 25%-30%wt in water) in methanol (5 mL). The resulting mixture was stirred overnight at 50°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.
• Step 3 Preparation of 3-cyano-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt: [00346] To a stirred solution of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-1- carboxylate (900 mg, 2.61 mmol, 1.00 equiv) in Dichloromethane (3 mL) was added HCl(gas)in 1,4-dioxane (7 mL) dropwise at 0 °C. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 4 Preparation of 3-cyano-4- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ - N-methylbenzamide: [00347] To a stirred solution of 3-cyano-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt (150 mg, crude) and 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (128 mg, 0.61 mmol, 1.00 equiv) in acetonitrile (8 mL) was added DIEA (238 mg, 1.84 mmol, 3.00 equiv) and KI (20 mg, 0.12 mmol, 0.20 equiv) under nitrogen atmosphere.
• the resulting mixture was stirred for 1.5h 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.
• the residue was purified by trituration with MeOH (3 mL).
• the resulting mixture was stirred for 1h at 50°C under nitrogen atmosphere.
• the precipitated solids were collected by filtration and washed with MeOH (2x1 mL).
• Example 18 Step 1 Preparation of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate: [00348] To a solution of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (480 mg, 1.97 mmol, 1.00 equiv) in MeOH/DCM (80 mL/20 mL) was added Pd/C (200 mg, 10%wt) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 days under hydrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure.
• Step 2 Preparation of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one: [00349] To a stirred solution of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (170 mg, 0.69 mmol, 1.00 equiv) in THF (8 mL) was added LiAlH4 (0.55 mL, 1.39 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one: [00350] To a stirred solution of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (170 mg, 0.78 mmol, 1.00 equiv) and DMF (29 mg, 0.39 mmol, 0.50 equiv) in DCM (6 mL) was added thionyl chloride (744 mg, 6.26 mmol, 8.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum.
• Step 4 Preparation of N-methyl-5-[4-( ⁇ 4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl ⁇ methyl)piperazin-1- yl]pyridine-2-carboxamide: [00351] To a stirred solution of N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (200 mg, crude) and DIEA (351 mg, 2.72 mmol, 4.00 equiv) in MeCN (6 mL) were added 7-(chloromethyl)-2H,3H,5H-furo[3,2- c]quinolin-4-one (160 mg, 0.68 mmol, 1.00 equiv) and KI (22 mg, 0.14 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere.
• Example 19 1 Preparation of 5-bromo-2-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridine: [00352] A solution of 5-bromo-2-(1H-imidazol-2-yl)pyridine (1.00 g, 4.46 mmol, 1.00 equiv) and NaH (0.23 g, 5.80 mmol, 1.30 equiv, 60%wt) in DMF (10 mL) was stirred for 0.5h at 0 °C, and then to the above solution was added SEMCl (0.97 g, 5.80 mmol, 1.30 equiv) dropwise at room temperature. And the mixture was stirred for 2h.
• Step 2 Preparation of tert-butyl 4-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridin-3- yl]piperazine-1-carboxylate: [00353] To a stirred solution of 5-bromo-2-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridine (900 mg, 2.54 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (426 mg, 2.29 mmol, 1.00 equiv) in dioxane (10 mL) was added RuPhos Palladacycle Gen.3 (118 mg, 0.25 mmol, 0.10 equiv) and Cs2CO3 (1.66 g, 5.08 mmol, 2.00 equiv) at room temperature.
• Step 3 Preparation of 1-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridin-3-yl]piperazine: [00354] To a stirred solution of tert-butyl 4-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2- yl)pyridin-3-yl]piperazine-1-carboxylate (1.00 g, 2.17 mmol, 1.00 equiv) and DIEA (5.62 g, 43.50 mmol, 20.00 equiv) in dioxane (20 mL) was added TMSOTf (4.84 g, 21.75 mmol, 10.00 equiv) dropwise at 0°C.
• Step 4 Preparation of 3-ethyl-7-( ⁇ 4-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridin-3- yl]piperazin-1-yl ⁇ methyl)-1H-1,5-naphthyridin-2-one: [00355] To a stirred solution of 1-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2-yl)pyridin-3- yl]piperazine (160 mg, 0.44 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.44 mmol, 1.00 equiv) in acetonitrile (8 mL) were added DIEA (172 mg, 1.34 mmol, 3.00 equiv) and potassium iodide (15 mg, 0.09
• Step 5 Preparation of 3-ethyl-7-( ⁇ 4-[6-(1H-imidazol-2-yl)pyridin-3-yl]piperazin-1-yl ⁇ methyl)-1H-1,5- naphthyridin-2-one: [00356] To a stirred solution of 3-ethyl-7-( ⁇ 4-[6-(1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazol-2- yl)pyridin-3-yl]piperazin-1-yl ⁇ methyl)-1H-1,5-naphthyridin-2-one (300 mg, 0.55 mmol, 1.00 equiv) in DCM (7 mL) was added TFA (3 mL) dropwise at 0°C under nitrogen atmosphere.
• Step 1 Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid: [00357] To a solution of methyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.15 g, 4.95 mmol, 1.00 equiv) in MeOH (15 mL) and H 2 O (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL).
• Step 2 Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide: [00358] To a solution of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800 mg, crude) and N,O- dimethylhydroxylamine (336 mg, 5.50 mmol, 1.50 equiv) in DMF (8 mL) was added EDCI (2.10 g, 11.00 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one: [00359] To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide (540 mg, 2.07 mmol, 1.00 equiv) in THF (5 mL) was added CH3MgBr (1.4 mL, 4.13 mmol, 2.00 equiv, 3M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 4 Preparation of 3-ethyl-7-(1-hydroxyethyl)-1H-1,5-naphthyridin-2-one: [00360] To a solution of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (398 mg, 1.84 mmol, 1.00 equiv) in MeOH (5 mL) was added NaBH4 (174 mg, 4.59 mmol, 2.50 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0°C.
• Step 5 Preparation of 7-(1-chloroethyl)-3-ethyl-1H-1,5-naphthyridin-2-one: [00361] To a solution of 3-ethyl-7-(1-hydroxyethyl)-1H-1,5-naphthyridin-2-one (335 mg, 1.54 mmol, 1.00 equiv) in DCM (10 mL) was added SOCl2 (457 mg, 3.84 mmol, 2.50 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step.
• Step 7 Preparation of rel-5- ⁇ 4-[(1R)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl ⁇ - N-methylpyridine-2-carboxamide (Example 20) & rel-5- ⁇ 4-[(1R)-1-(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)ethyl]piperazin-1-yl ⁇ -N-methylpyridine-2-carboxamide (Example 21): [00363] 5- ⁇ 4-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl ⁇ -N-methylpyridine-2- carboxamide (300 mg, 0.71 mmol, 1.00 equiv) was isolated by prep-Chiral HPLC.
• Step 2 Preparation of 4-benzyl 1-(tert-butyl) (R)-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2- yl)oxy)methyl)piperazine-1,4-dicarboxylate: [00367] A mixture of PPh3 (19.76 g, 75.34 mmol, 6.00 equiv) and DEAD (10.93 g, 62.78 mmol, 5.00 equiv) in THF (200 mL) was stirred for 1h at 0°C under nitrogen atmosphere.
• Step 3 Preparation of benzyl (R)-3-(((3-bromo-6-(methoxycarbonyl)pyridin-2- yl)oxy)methyl)piperazine-1-carboxylate: [00368] To a stirred mixture of 4-benzyl 1-tert-butyl 2-( ⁇ [3-bromo-6-(methoxycarbonyl)pyridin-2- yl]oxy ⁇ methyl)piperazine-1,4-dicarboxylate (5.60 g, 9.62 mmol, 1.00 equiv) in DCM (100 mL) was added HCl(gas)in 1,4-dioxane (50 mL, 4M) in portions at room temperature under nitrogen atmosphere.
• the resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane/diethyl ether (1/1, 3 x 50 mL). The precipitated solids were collected by filtration and washed with hexane (3x50 mL). The residue was basified to pH 8 ⁇ 9 with saturated Na2CO3 (aq.) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 4 Preparation of 3-benzyl 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-3,8(4H)-dicarboxylate: [00369] To a stirred mixture of benzyl 3-( ⁇ [3-bromo-6-(methoxycarbonyl)pyridin-2- yl]oxy ⁇ methyl)piperazine-1-carboxylate (1.20 g, 2.58 mmol, 1.00 equiv) and Cs 2 CO 3 (2.53 g, 7.75 mmol, 3.00 equiv) in THF (60 mL) was added dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (740 mg, 1.03 mmol, 0.40 equiv) at room temperature under nitrogen atmosphere.
• Step 5 Preparation of benzyl (R)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-3(4H)-carboxylate: [00370] To a stirred mixture of 3-benzyl 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-3,8(4H)-dicarboxylate (560 mg, 1.46 mmol, 1.00 equiv) in MeOH (15 mL) was added methylamine (10 mL, 25-30%wt in water) dropwise at room temperature under nitrogen atmosphere.
• the resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was added saturated NH 4 Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
• Step 6 Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine- 8-carboxamide: [00371] To a stirred mixture of benzyl 5-(methylcarbamoyl)-8-oxa-1,6,12- triazatricyclo[8.4.0.0 ⁇ 2,7 ⁇ ]tetradeca-2,4,6-triene-12-carboxylate (500 mg, 1.30 mmol, 1.00 equiv) and NH3.H2O (3 mL) in i-PrOH (15 mL) was added Pd/C (100 mg, 10%wt) at room temperature under hydrogen atmosphere.
• Step 7 Preparation of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl- 1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide: [00372] To a stirred mixture of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-8-carboxamide (123 mg, 0.49 mmol, 1.10 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5- naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv) in ACN (4 mL) were added DIEA (290 mg, 2.
• the resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was cooled down to room temperature. The reaction mixture was poured into Water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 2 Preparation of 4-benzyl 1-tert-butyl (2S)-2-( ⁇ [3-bromo-6-(methoxycarbonyl)pyridin-2- yl]oxy ⁇ methyl)piperazine-1,4-dicarboxylate: [00374] A mixture of PPh3 (11.23 g, 42.80 mmol, 6.00 equiv) and DEAD (6.21 g, 35.67 mmol, 5.00 equiv) in THF (100 mL) was stirred for 1h at 0°C under nitrogen atmosphere.
• the resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane/diethyl ether (1/1, 3 X 20 mL). The precipitated solids were collected by filtration and washed with hexane (3x5 mL). The residue was basified to pH 8 ⁇ 9 with saturated Na2CO3 (aq.). The resulting mixture was added 200 mL water and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
• Step 4 Preparation of 3-benzyl 8-methyl (S)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-3,8(4H)-dicarboxylate: [00376] To a stirred mixture of benzyl (3S)-3-( ⁇ [3-bromo-6-(methoxycarbonyl)pyridin-2- yl]oxy ⁇ methyl)piperazine-1-carboxylate (2.00 g, 4.31 mmol, 1.00 equiv) and Cs2CO3 (4.21 g, 12.92 mmol, 3.00 equiv) in THF (100 mL) was added (II)/Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (308 mg, 0.43 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere.
• Step 5 Preparation of benzyl (S)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-3(4H)-carboxylate: [00377] A mixture of 3-benzyl 8-methyl (S)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine- 3,8(4H)-dicarboxylate (500 mg, 1.30 mmol, 1.00 equiv) and methylamine water solution (5 mL, 25-30%wt in water) in MeOH (5 mL) was stirred overnight at room temperature under nitrogen atmosphere.
• methylamine water solution 5 mL, 25-30%wt in water
• Step 6 Preparation of (10S)-N-methyl-8-oxa-1,6,12-triazatricyclo[8.4.0.0 ⁇ 2,7 ⁇ ]tetradeca-2,4,6-triene- 5-carboxamide: [00378] To a stirred mixture of benzyl (10S)-5-(methylcarbamoyl)-8-oxa-1,6,12- triazatricyclo[8.4.0.0 ⁇ 2,7 ⁇ ]tetradeca-2,4,6-triene-12-carboxylate (400 mg, 1.05 mmol, 1.00 equiv) in MeOH (10 mL) and HOAc (2 mL) was added Pd/C (40 mg) at room temperature under nitrogen atmosphere.
• Step 7 Preparation of (10S)-12-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-N-methyl-8-oxa- 1,6,12-triazatricyclo[8.4.0.0 ⁇ 2,7 ⁇ ]tetradeca-2,4,6-triene-5-carboxamide : [00379] To a stirred mixture of (10S)-N-methyl-8-oxa-1,6,12-triazatricyclo[8.4.0.0 ⁇ 2,7 ⁇ ]tetradeca-2,4,6- triene-5-carboxamide (200 mg, 0.81 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin- 2-one (215 mg, 0.97 mmol, 1.20equiv) in MeCN (10 mL) were added KI (27 mg, 0.16 mmol, 0.20 equiv) and DIEA (0.
• Step 1 Preparation of 1'-tert-butyl 6-methyl 5-fluoro-3',6'-dihydro-2'H-[3,4'-bipyridine]-1',6- dicarboxylate: [00380] A mixture of methyl 5-bromo-3-fluoropyridine-2-carboxylate (550 mg, 2.35 mmol, 1.00 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (872 mg, 2.82 mmol, 1.20 equiv) and Pd(dppf)Cl2 (171 mg, 0.23 mmol, 0.10 equiv) and K2CO3 (975 mg, 7.05 mmol, 3.00 equiv) in 1,4-dioxane (10 mL) and water (0.5 mL) was stirred for 2 h at 80°C
• Step 2 Preparation of methyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-fluoropyridine-2- carboxylate: [00381] A solution of 1'-tert-butyl 6-methyl 5-fluoro-3',6'-dihydro-2'H-[3,4'-bipyridine]-1',6-dicarboxylate (530 mg, 1.57 mmol, 1.00 equiv) in EtOAc (10 ml) was add Pd/C (100 mg, 10%wt) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS.
• Step 3 Preparation of tert-butyl 4-[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]piperidine-1- carboxylate: [00382] To a stirred solution of methyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-fluoropyridine-2- carboxylate (500 mg, 1.48 mmol, 1.00 equiv) in MeOH (5 ml) was added CH 3 NH 2 (10 mL, 25-30%wt in water) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was monitored by LCMS.
• Step 4 Preparation of 3-fluoro-N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide, TFA salt: [00383] To a stirred solution of tert-butyl 4-[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]piperidine-1- carboxylate (460 mg, 1.36 mmol, 1.00 equiv) in DCM (10 ml) was added TFA (3 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 5 Preparation of 5- ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperidin-4-yl ⁇ -3-fluoro- N-methylpyridine-2-carboxamide: [00384] To a stirred mixture of 3-fluoro-N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide, TFA salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) and KI (23 mg, 0.14 mmol, 0.20 equiv) in acetonitrile (5 ml) was added DIEA (435 mg, 3.37 mmol, 5.00 equiv) dropwise at room temperature under nitrogen atmosphere.
• Step 1 Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one: [00385] To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (1.00 g, 4.62 mmol, 1.00 equiv) and DMF (30 mg, 0.46 mmol, 0.10 equiv) in DCM (10 mL) were added SOCl2 (3.30 g, 27.74 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 2 Preparation of N-cyclopropyl-5- ⁇ 4-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl ⁇ pyridine-2-carboxamide: [00386] To a stirred mixture of N-cyclopropyl-5-(piperazin-1-yl) pyridine-2-carboxamide (115 mg, 0.47 mmol, 1.10 equiv) and DIEA (275 mg, 2.13 mmol, 5.00 equiv) in acetonitrile (5 mL) were added KI (14.15 mg, 0.09 mmol, 0.20 equiv) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (100 mg, 0.43 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere.
• Step 1 Preparation of methyl 5- ⁇ [1-(tert-butoxycarbonyl)azetidin-3-yl]oxy ⁇ pyridine-2-carboxylate: [00387] A mixture of DEAD (5.69 g, 32.65 mmol, 5.00 equiv) and PPh3 (10.90 g, 39.18 mmol, 6.00 equiv) in THF (100 ml) was stirred for 1h at 0 °C under nitrogen atmosphere.
• Step 2 Preparation of tert-butyl 3- ⁇ [6-(methylcarbamoyl)pyridin-3-yl]oxy ⁇ azetidine-1-carboxylate: [00388] A mixture of methyl 5- ⁇ [1-(tert-butoxycarbonyl)azetidin-3-yl]oxy ⁇ pyridine-2-carboxylate (3.50 g, crude, contained TPPO) and CH3NH2 (20 mL, 25-30%wt in water) in MeOH (20 mL) was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 4 Preparation of 5-( ⁇ 1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl ⁇ oxy)-N- methylpyridine-2-carboxamide: [00390] To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.90 mmol, 1.00 equiv) and 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt (280 mg, crude) in MeCN (5 mL) were added KI (30 mg, 0.18 mmol, 0.20 equiv) and DIEA (580 mg, 4.49 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere.
• Example 26 Step 1 Preparation of methyl 5- ⁇ [1-(tert-butoxycarbonyl) azetidin-3-yl] (methyl)amino ⁇ pyridine-2- carboxylate: [00391] To a solution of methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol, 1.00 equiv) and tert- butyl 3-(methylamino) azetidine-1-carboxylate (2.07 g, 11.11 mmol, 1.20 equiv) in 1,4-dioxane (20 mL) were added Cs 2 CO 3 (9.05 g, 27.77 mmol, 3.00 equiv) and RuPhos Palladacycle Gen.3 (0.77 g, 0.93 mmol, 0.10 equiv) at room temperature.
• Step 2 Preparation of tert-butyl 3- ⁇ methyl[6-(methylcarbamoyl)pyridin-3-yl]amino ⁇ azetidine-1- carboxylate: [00392] A solution of methyl 5- ⁇ [1-(tert-butoxycarbonyl) azetidin-3-yl] (methyl)amino ⁇ pyridine-2- carboxylate (1.00 g, 3.11 mmol, 1.00 equiv) and CH 3 NH 2 (5 mL, 25-30%wt in water) in MeOH (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 3 Preparation of 5-[azetidin-3-yl(methyl)amino]-N-methylpyridine-2-carboxamide, TFA salt: [00393] A solution of tert-butyl 3- ⁇ methyl[6-(methylcarbamoyl)pyridin-3-yl]amino ⁇ azetidine-1- carboxylate (800 mg, 2.50 mmol, 1.00 equiv) and TFA (10 mL) in DCM (10 mL) was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• the resulting mixture was stirred for 2h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 1 Preparation of tert-butyl 4-(pyridin-2-yl)piperazine-1-carboxylate: [00395] A mixture of 2-bromopyridine (500 mg, 3.16 mmol, 1.00 equiv), tert-butyl piperazine-1- carboxylate (589 mg, 3.16 mmol, 1.00 equiv), Cs 2 CO 3 (2.06 g, 6.33 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (132 mg, 0.16 mmol, 0.05 equiv) in 1,4-dioxane (10 mL) was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 2 Preparation of pyridinylpiperazine, HCl salt: [00396] A mixture of tert-butyl 4-(pyridin-2-yl)piperazine-1-carboxylate (450 mg, 1.71 mmol, 1.00 equiv) in HCl(gas)in 1,4-dioxane (5 mL, 4M) was stirred for 30 min at room temperature.
• Step 3 Preparation of 3-ethyl-7- ⁇ [4-(pyridin-2-yl)piperazin-1-yl]methyl ⁇ -1H-1,5-naphthyridin-2-one: [00397] To a stirred mixture of pyridinylpiperazine, HCl salt (150 mg, crude), 7-(chloromethyl)-3-ethyl- 1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) and KI (22 mg, 0.14 mmol, 0.20 equiv) in ACN (5 mL) was added DIEA (261 mg, 2.02 mmol, 3.00 equiv) dropwise at room temperature under nitrogen atmosphere.
• DIEA 261 mg, 2.02 mmol, 3.00 equiv
• Step 2 Preparation of 5-bromo-3-nitropicolinaldehyde: [00400] A solution of NaIO4 (540 g, 2.52 mol, 2.50 equiv) in EtOH (1 L) and H2O (1.85 L) was treated for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was added [(E)-2-(5-bromo- 3-nitropyridin-2-yl)ethenyl]dimethylamine (200 g, 735.018 mmol, 1 equiv) in NMP (1 L) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC.
• Step 3 Preparation of ethyl (Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylacrylate: [00401] A solution of LiCl (23.49 g, 554.10 mmol, 1.60 equiv) in Toluene (350 mL) and Pyridine (50 mL) was stirred for 1 h at 50°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added TEA (38.55 g, 380.94 mmol, 1.10 equiv). The resulting mixture was stirred for additional 15 min at 50°C.
• Step 4 Preparation of 7-bromo-3-methyl-1,5-naphthyridin-2(1H)-one: [00402] To a stirred solution of Fe (70.89 g, 1269.34 mmol, 5.00 equiv) in AcOH (500 mL) was added ethyl (2E)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate (55 g, 174.54 mmol, 1.00 equiv, crude) dropwise at 80°C under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at 75°C. The reaction was monitored by LCMS.
• the resulting mixture was filtered at 75°C, and the filter cake was washed with AcOH (3x 200 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with ice/water (800 mL). The precipitated solids were collected by filtration and washed with water (3x 100 mL). The residue was purified by trituration with MTBE (500 mL). The precipitated solids were collected by filtration and washed with MTBE (3x 100 mL). This resulted in 7-bromo-3-methyl- 1H-1,5-naphthyridin-2-one (26g, 62.83%, two steps) as a brown solid.
• Step 5 Preparation of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one: [00403] To a stirred mixture of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (3.00 g, 12.54 mmol, 1.00 equiv) and tributyl(1-ethoxyethenyl)stannane (13.60 g, 37.64 mmol, 3.00 equiv) in 1,4-dioxane (20 mL) were added Pd(PPh 3 ) 2 Cl 2 (0.44 g, 0.62 mmol, 0.05 equiv) at room temperature.
• Step 7 Preparation of N-methyl-5- ⁇ 4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1- yl ⁇ pyridine-2-carboxamide: [00405] A mixture of N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (743 mg, 2.23 mmol, 1.50 equiv) and 7-acetyl-3-methyl-1H-1,5-naphthyridin-2-one (300 mg, 1.48 mmol, 1.00 equiv) in DCM (2 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
• Step 8 Preparation of rel-N-methyl-5- ⁇ 4-[(1R)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3- yl)ethyl]piperazin-1-yl ⁇ pyridine-2-carboxamide and rel-N-methyl-5- ⁇ 4-[(1R)-1-(7-methyl-6-oxo-5H- 1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl ⁇ pyridine-2-carboxamide: [00406] The racemate N-methyl-5- ⁇ 4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1- yl ⁇ pyridine-2-carboxamide (240 mg) was separated by Prep-Chiral HPLC to afford rel-N-methyl-5- ⁇ 4- [(1R)-1-(7-methyl-6-oxo-5H-1,5
• 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ 11.84 (s, 1H), 8.42 (d, 2H), 8.25 (d, 1H), 7.82 (d, 2H), 7.62 (d, 1H), 7.37 (dd, 1H), 3.65 (d, 1H), 3.33 – 3.28 (m, 4H), 2.78 (d, 3H), 2.64– 2.57 (m, 2H), 2.50 – 2.43 (m, 2H), 2.14 (d, 3H), 1.38 (d, 3H).
• 1 H NMR 300 MHz, DMSO-d6) ⁇ 11.84 (s, 1H), 8.41 (d, 2H), 8.24 (d, 1H), 7.82 (d, 2H), 7.62 (s, 1H), 7.37 (dd, 1H), 3.65 (d, 1H), 3.34 – 3.31 (m, 4H), 2.78 (d, 3H), 2.67 – 2.57 (m, 2H), 2.49 – 2.41 (m, 2H), 2.14 (s, 3H), 1.37 (d, 3H). [00409] The following examples were made using similar procedures shown for example 124 and 125.
• Step 2 Preparation of 3- ⁇ 4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ pyridine- 2-carbonitrile: [00411] To a stirred solution of 3-(piperazin-1-yl)pyridine-2-carbonitrile (150 mg, 0.79 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (266 mg, 1.19 mmol, 1.50 equiv) in MeCN (6 mL) were added DIEA (309 mg, 2.39 mmol, 3.00 equiv) and KI (26 mg, 0.15 mmol, 0.20 equiv) in portions at room temperature.
• 3-(piperazin-1-yl)pyridine-2-carbonitrile 150 mg, 0.79 mmol, 1.00 equiv
• Step 1 Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: [00413] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) was added NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30%wt) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3x100 mL).
• Step 2 Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine: [00414] A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.
• Step 3 Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: [00415] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by TLC. The reaction was quenched by the addition of sat.
• Step 4 Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: [00416] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) were added SnCl2 (26.25 g, 134.09 mmol, 5.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 5 Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate: [00417] To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120°C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature.
• Step 6 Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate: [00418] To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH3CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50°C.The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature.
• Step 7 Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: [00419] To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added LiAlH 4 (2.5 mL, 5.85 mmol, 2.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 0°C. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M HCl.
• Step 8 Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: [00420] To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv) in CH2Cl2 (5 mL) was added SOCl2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
• Step 9 5- ⁇ 4-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl ⁇ -N-methylpyridine-2- carboxamide: [00421] A solution of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (100 mg, 0.43 mmol, 1.00 equiv), KI (7 mg, 0.04 mmol, 0.10 equiv) and DIEA (225 mg, 1.74 mmol, 4.00 equiv) in acetonitrile (3 mL) was stirred for 1 h at 50°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature.
• the reaction was monitored by LCMS. The mixture was allowed to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtoAc (3x300 mL). The combined organic layers were washed with sat. NaCl (aq.) (3x100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 48.74%) as a light yellow oil.
• Step 2 Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: [00423] To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) were added NH4Cl (25 mL, sat. aq.) and Fe (5.03 g, 90.01 mmol, 4.00 equiv). The reaction was stirred at 80°C for 4h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to room temperature then concentrated under reduced pressure.
• Step 3 Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: [00424] A solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to the solution of methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 60°C under nitrogen.
• the reaction was monitored by LCMS.
• the reaction was quenched with MeOH (30 mL) at 0°C.
• the resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2/2-Propanol (5:1, 3x200 mL).
• the combined organic layers were washed with water (3x100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography to afford methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3- carboxylate (1.80 g, 40.66%) as a light yellow solid.
• Step 4 Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: [00425] To a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH 3 COOH (7 mL) was added 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 5 Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: [00426] To a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was added LiAlH4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
• Step 6 Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: [00427] To a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv) and DMF (7 mg, 0.09 mmol, 0.10 equiv) in DCM (10 mL) were added SOCl2 (318 mg, 2.67 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 10 h at room temperature. The reaction was monitored by LCMS.
• Step 7 Preparation of 5- ⁇ 4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- yl ⁇ -N-methylpyridine-2-carboxamide: [00428] To a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (120 mg, 0.49 mmol, 1.00 equiv), KI (16 mg, 0.09 mmol, 0.20 equiv) and N-methyl-5-(piperazin-1-yl)pyridine-2- carboxamide (97 mg, 0.44 mmol, 0.90 equiv) in MeCN (5 mL) was added DIEA (319 mg, 2.47 mmol, 5.00 equiv) dropwise at room temperature under nitrogen atmosphere.
• Example A Cell Growth Inhibition Assay [00431] The objective of this study is to evaluate the effect of invention compounds on cell proliferation through the cell viability assay in DLD-1 BRCA2(-/-) and parental isogenic pair and MDA-MB-436 (mutated BRCA1) cell lines.
• the CellTiter-Glo (CTG) based cell viability assay is designed to determine the number of viable cells in the culture because of compound effect, by quantifying ATP, which indicates the presence of metabolically active cells.
• DLD-1 BRCA2(-/-) and parental isogenic pair were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both are culture at 37°C with 5% CO2.
• Invention compounds were distributed to the 384 well plate (Coming, 3764) using Echo acoustic liquid handler to form a 1:3 serially diluted final concentration with top dose of 10 or 30 mM. The cells were seeded into the plate in the density of 50 cells/well (DLD-1 parental), 200 cells/well (DLD-1 BRCA2-/-), or 500 cells/well (MDA-MB-436).
• the cells were cultured in a well moisturized incubator at 37°C with 5% CO2 for 7 days without disturbance.
• the cell viability was measured by CellTiter Glo 2.0 assay kit (Promega, G9243), and growth inhibition rate was calculated and plotted against final compound concentration, and the data were fitted in Xfit to generate IC50 .
• PARPl and PARP2 protein were expressed, purified and diluted in assay buffer containing 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCL. 150 mM NaCI to a final concentration of 20nM. The PARPi-FL was then added at a final concentration of 3nM.
• the assay plate is centrifuged at lOOOrpm for lmin and incubated for 4h at room temperature.
• the fluorescent polarization is read using an Envision plate reader using the following settings:
• the inhibition rate is calculated using the percentage of permuted Mahalanobis distances greater than the control samples (mP value) following the equation below:
• XLFit (equation 201) is used to calculate a reported IC50 for each compound.
• Example C In vitro human hepatic clearance in cellular relay format: [00441] Working stocks of individual test articles were prepared at concentrations of 100 ⁇ M by diluting 10 mM stocks prepared in DMSO 100-fold (v:v) into ACN/H 2 O (50/50, v:v). Human cryopreserved hepatocytes were thawed in a 37°C water bath in ⁇ 2 min., suspended in thawing media, and then centrifuged at 100 x g for 10 min. Thawing media was aspirated, and pelleted hepatocytes were resuspended into incubation media at 1.5E+06 cells/mL.
• hepatocytes were removed from the incubations via centrifugation, and supernatants were stored frozen until the following day at which point incubations were reinitiated by diluting thawed supernatants with freshly thawed hepatocytes in incubation media, again to a final concentration of 0.5E+06 viable cells /mL. These steps were repeated for a total of 5 incubations of 4 hrs. each covering 20 total hours of incubation. Incubational losses due to cellular uptake, nonspecific binding, and dilution at each relay step were corrected for. Supernatants of all incubation aliquots were diluted into ultrapure water prior to analysis via LC/MS/MS.
• In vitro intrinsic clearances (CLint) in ⁇ L/min/1E+06 cells were determined for each incubation from calculated in vitro half-lives determined using a standard log- linear regression approach.
• In vitro CL int values were scaled up using the following physiological scaling factors: 99E+06 cells / g human liver and 25.7 g human liver / kg body weight.
• Scaled intrinsic clearance values were finally introduced to the well-stirred liver model for the purpose of calculating predicted human hepatic clearance (CL hep,pred ) in mL/min/kg assuming a human liver blood flow of 20.7 mL/min/kg and making no corrections for test article binding to red blood cells, plasma proteins, or components of the incubation system.
• Example D PAPR and TNKS broader panel of selectivity by FP
• All assays were carried out by following the BPS PARP and TNKS assay kit protocols with a few modifications.
• the enzymatic reactions were conducted in duplicate at room temperature in 96 well plates coated with histone substrate. The incubation times were one hour for PARPs 3, 8, 10, 15 and TNKSs, and two hours for PARPs 6, 7, 11 and 14, respectively.
• the luminescence (Lt) in each data set was defined as 100% activity. In the absence of the enzyme, the luminescence (Lb) in each data set was defined as 0% activity.

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