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WO2024074128A1 - Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof - Google Patents

Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof Download PDF

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WO2024074128A1
WO2024074128A1 PCT/CN2023/123133 CN2023123133W WO2024074128A1 WO 2024074128 A1 WO2024074128 A1 WO 2024074128A1 CN 2023123133 W CN2023123133 W CN 2023123133W WO 2024074128 A1 WO2024074128 A1 WO 2024074128A1
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compound
alkyl
pharmaceutically acceptable
stereoisomer
acceptable salt
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Xin Cheng
Luoheng QIN
Feng Ren
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes.
  • ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other nucleoside monophosphates as well as pyrophosphate (PPi) .
  • the enzyme can also hydrolyze other nucleoside monophosphate esters.
  • ENPP1 has been identified as the dominant 2’-3’-cGAMP hydrolase in cultured cells, tissue extracts and blood. Tissues and blood from ENPP1 knockout mice lack 2’-3’-cGAMP hydrolase activity.
  • ENPP1 Elevated levels of ENPP1 have been associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease, an inflammatory disease resulting from CPPD crystal deposits in the joint and surrounding tissues.
  • CAVD calcific aortic valve disease
  • CPPD calcium pyrophosphate dihydrate
  • ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid, and breast cancers and has been associated with resistance to chemotherapy.
  • ENPP1 upregulation and variants of ENPP1 are also associated with insulin resistance and type 2 diabetes and enzyme activity of ENPP1 was reported to be required for the inhibition of insulin receptor signaling.
  • Cyclic GMP-AMP synthase is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA derived from viruses, bacteria, damaged mitochondria, or cancer cells.
  • the cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, which initiates a signaling response that activates innate immunity and results in the production of type I interferon, antiviral, and immune-stimulatory cytokines.
  • STING interferon genes
  • the cGAS enzyme, cGAMP messenger and STING are also involved in host defense against RNA viruses and the immune control of tumor development.
  • ENPP1 has been identified as the enzyme that naturally hydrolyzes cGAMP and therefore counteracts the innate immune response against infectious agents, damaged cells, and cancer cells.
  • the efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of natural, hydrolysable cGAMP.
  • Virus infection has been demonstrated to be facilitated by ENPP1 overexpression and is attenuated by silencing of ENPP1.
  • Inhibitors of cGAMP hydrolysis may therefore be used to increase the effectiveness of immune responses against cancer cells and tumors and against infections by RNA or DNA viruses or bacteria.
  • Inhibitors of ENPP1 and of cGAMP or nucleoside triphosphate hydrolysis may also be used for the treatment of inflammatory diseases that are associated with elevated nucleotidase levels, reduced nucleoside triphosphate, reduced cGAMP or reduced nucleoside monophosphate ester levels or diseases associated with elevated nucleoside or nucleoside monophosphate levels.
  • ENPP1 is an attractive therapeutic target for the treatment of diseases, such as cancers and viral infections.
  • the cancer is a solid tumor.
  • the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, or sarcoma.
  • the cancer is a hematologic malignancy.
  • the hematologic malignancy is a leukemia, a lymphoma, or a myeloma.
  • the hematologic malignancy is a B-cell malignancy. In some embodiments, the hematologic malignancy is multiple myeloma. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer.
  • Also disclosed herein is a method of treating an infection in a subject in need thereof comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
  • the infection is a viral infection.
  • the viral infection is due to a DNA virus.
  • the viral infection is due to a herpesvirus.
  • the herpesvirus is selected from herpes simplex viruses 1 (HSV-l) , herpes simplex viruses 2 (HSV-2) , varicella-zoster virus (VZV) , Epstein-Barr virus (EBV) , human cytomegalovirus (HCMV) , human herpesvirus 6A (HHV-6A) , human herpesvirus 6B (HHV-6B) , human herpesvirus 7 (HHV-7) , and Kaposi's sarcoma-associated herpesvirus (KSHV) .
  • the herpesvirus is herpes simplex viruses 1 (HSV-l) .
  • the viral infection is due to a retrovirus.
  • the retrovirus is human immunodeficiency virus (HIV) .
  • the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV) .
  • the viral infection is due to a hepatitis virus.
  • the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV) .
  • the viral infection is due to vaccinia virus (VACV) , adenovirus, or human papillomaviruses (HPV) .
  • the viral infection is due to a RNA virus.
  • the viral infection is due to dengue fever virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1- butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, 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 (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated 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, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, 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 (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • 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, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • 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) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • 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.
  • a “disease or disorder associated with ENPP1” or, alternatively, “a ENPP1-mediated disease or disorder” means any disease or other deleterious condition in which ENPP1, or a mutant thereof, is known or suspected to play a role.
  • Described herein are compounds, or a pharmaceutically acceptable salt or stereoisomer thereof useful in the treatment of a disease or disorder associated with ENPP1.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • L is a bond, -NH-, or -O-;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • R 3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • X is N or CR X and Y is N or CR Y ;
  • R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
  • R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
  • R Y1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
  • each R Y2 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, or 4;
  • R 8 is -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • the compound is of Formula (Ia) :
  • the compound is of Formula (Ia-1) :
  • the compound is of Formula (Ia-2) :
  • X is N and Y is N.
  • X is CR X and Y is N.
  • X is N and Y is CR Y .
  • X is CR X and Y is CR Y .
  • R X is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • R X is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • R X is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , R X is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , R X is methyl.
  • R X is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , R X is CF 3 . In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , R X is cycloalkyl.
  • R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.
  • R Y is hydrogen or C 1 -C 6 alkyl.
  • R Y is hydrogen.
  • R Y is C 1 -C 6 alkyl.
  • the compound is of Formula (Ib) :
  • the compound is of Formula (Ib-1) :
  • the compound is of Formula (Ib-2) :
  • Y is NR Y1 . In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , Y is C (R Y2 ) 2 .
  • R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , R Y1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , R Y1 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , R Y1 is methyl.
  • each R Y2 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , each R Y2 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • Ring A is aryl or heteroaryl.
  • Ring A is aryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is phenyl.
  • Ring A is heteroaryl.
  • Ring A is 5-or 6-membered heteroaryl.
  • Ring A is 6-membered heteroaryl.
  • Ring A is pyridinyl, pyrimidinyl, or pyrazinyl.
  • Ring A is pyridinyl or pyrimidinyl.
  • Ring A is pyridinyl.
  • L is a bond. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , L is a -O-. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , L is a -NH-.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen.
  • n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0, 1, or 2.
  • n is 0 or 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1, 2, or 3.
  • n is 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 2 or 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1 or 2.
  • n is 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 3.
  • R 2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 2 is hydrogen.
  • R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 3 is hydrogen.
  • Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is cycloalkyl.
  • Ring B is heterocycloalkyl.
  • Ring B is aryl or heteroaryl.
  • Ring B is aryl.
  • Ring B is phenyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is heteroaryl.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R 4 is independently C 1 -C 6 alkyl.
  • m is 0, 1, or 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 0 or 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 0.
  • m is 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 2.
  • R 5 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 5 is hydrogen, -CN, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 5 is -OR a or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 5 is -OR a .
  • R 5 is -C 1 -C 6 alkoxyl. In some embodiments, R 5 is -OCH 3 . In some embodiments, the -OCH 3 is -OCD 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 5 is C 1 -C 6 alkyl.
  • R 6 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 6 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 6 is hydrogen.
  • R 7 is hydrogen, -CN, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 7 is hydrogen or -CN.
  • R 7 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 7 is -CN. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 7 is C 1 -C 6 alkyl.
  • R 8 is -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • R 8 is -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 8 is cycloalkyl.
  • R 8 is heteroaryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 8 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 8 is aryl.
  • R 8 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 8 is C 2 -C 6 alkenyl.
  • R 8 is -NR c R d .
  • R 8 is -NHCH 3 , -N (CH 3 ) 2 or -NH 2 .
  • R 8 is -OR a .
  • R 8 is C 1 -C 6 alkoxyl.
  • R 8 is heterocycloalkyl.
  • R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 8 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R 8 is methyl.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • two R a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein the alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R b is independently hydrogen or C 1 -C 6 alkyl.
  • each R b is hydrogen.
  • each R b is independently C 1 -C 6 alkyl.
  • two R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycl
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein the alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R c and R d are each independently hydrogen or C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen.
  • R c and R d are each independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl.
  • each R is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl.
  • two R on the same atom form an oxo.
  • one or more of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more hydrogens of Ring A or Ring B are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof is one of the compounds in Table 1.
  • the absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.
  • OR label denotes a pure substance, but the absolute configuration of the stereochemical center is unknown.
  • OR indicates purity with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown) .
  • the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof is one of the compounds in Table 2.
  • 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.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium) , 2 H (deuterium) , and 3 H (tritium) .
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • 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 stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • 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.
  • methods of regulating the STING pathway in a subject in need thereof by hydrolyzing cGAMP and/or generating immune suppressor adenosine the method comprising administering to the subject an amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the subject has cancer.
  • the cancer is a solid tumor.
  • the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, or sarcoma.
  • the cancer is a hematologic malignancy.
  • the hematologic malignancy is a leukemia, a lymphoma, or a myeloma.
  • the hematologic malignancy is a B-cell malignancy.
  • the hematologic malignancy is multiple myeloma.
  • the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer.
  • the cancer is hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid, or breast cancer.
  • the cancer is basal cell carcinoma, biliary tract cancer, bone cancer, brain cancer (e.g., glioblastoma multiforme, glioma, medulloblastoma, primitive neuroectodermal tumor (PNET) , acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, cho
  • lip, tongue, mouth, and pharynx ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, rhabdomyosarcoma, sarcoma, skin cancer, stomach cancer, testicular cancer, or uterine cancer.
  • the infection is a viral infection.
  • the viral infection is due to a DNA virus.
  • the viral infection is due to a herpesvirus.
  • the herpesvirus is selected from herpes simplex viruses 1 (HSV-l) , herpes simplex viruses 2 (HSV-2) , varicella-zoster virus (VZV) , Epstein-Barr virus (EBV) , human cytomegalovirus (HCMV) , human herpesvirus 6A (HHV-6A) , human herpesvirus 6B (HHV-6B) , human herpesvirus 7 (HHV-7) , and Kaposi's sarcoma-associated herpesvirus (KSHV) .
  • the herpesvirus is herpes simplex viruses 1 (HSV-l) .
  • the viral infection is due to a retrovirus.
  • the retrovirus is human immunodeficiency virus (HIV) .
  • the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV) .
  • the viral infection is due to a hepatitis virus.
  • the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV) .
  • the viral infection is due to vaccinia virus (VACV) , adenovirus, or human papillomaviruses (HPV) .
  • the viral infection is due to a RNA virus.
  • the viral infection is due to dengue fever virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
  • compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
  • a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition is defined to be a “prophylactically effective amount or dose. ”
  • the precise amounts also depend on the patient’s state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday” ) .
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 10 and the ED 90 .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds disclosed herein 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 or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular) , intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including compounds described herein, or a pharmaceutically acceptable salt or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
  • compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
  • compositions for parental use are formulated as infusions or injections.
  • the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt 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.
  • 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.
  • the additional therapeutic agent is an anti-cancer agent.
  • the additional therapeutic agent is an ALK inhibitor: e.g. crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, or lorlatinib; an androgen receptor inhibitor: e.g. enzalutamide, apalutamide, abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, or flutamide; an antineoplastic agent: e.g.
  • oxaliplatin carboplatin, or cisplatin
  • an aromatase inhibitor exemestane, letrozole, anastrozole, fulvestrant, or tamoxifen
  • a BCL-2 inhibitor e.g. venetoclax
  • a BCR-ABL inhibitor e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, or PF03814735
  • a BRAF inhibitor e.g.
  • vemurafenib or dabrafenib a CD20 antibody: e.g. rituximab, tositumomab, or ofatumumab; a CDK4/6 inhibitor: e.g. alvocidib, palbociclib, ribociclib, trilaciclib, or abemaciclib; a CTLA-4 inhibitor: e.g. tremelimumab or ipilimumab; a DNA synthesis inhibitor: e.g. capecitabine, gemcitabine, nelarabine, or hydroxycarbamide; an epidermal growth factor receptor (EGFR) inhibitor: e.g.
  • EGFR epidermal growth factor receptor
  • HSP Heat Shock Protein
  • a Heat Shock Protein (HSP) inhibitor e.g. tanespimycin
  • a Hedgehog antagonist e.g. vismodegib
  • an HER2 receptor inhibitor e.g. trastuzumab, pertuzumab, neratinib, lapatinib, or lapatinib
  • a Histone deacetylase inhibitor (HDI) e.g. vorinostat
  • Immunomodulators e.g.
  • afutuzumab lenalidomide, thalidomide, or pomalidomide
  • a CD40 inhibitor e.g. dacetuzumab
  • a MEK inhibitor e.g. trametinib, cobimetinib, binimetinib, or selumetinib
  • a MET inhibitor e.g. crizotinib or cabozantinib
  • an mTOR inhibitor e.g. temsirolimus, ridaforolimus, everolimus, or sirolimus
  • a PD1 inhibitor e.g. nivolumab, or pembrolizumab
  • a PDL1 inhibitor e.g.
  • PARAs Pro-apoptotic receptor agonists
  • Examples xA are the enantiomers with the shorter retention time.
  • Examples xB are the enantiomers with the longer retention time.
  • the absolute configurations of the stereochemical centers are unknown.
  • Examples 1, 1A, and 1B Synthesis of (R) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 3-bromo-N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methyl-5-nitropyridin-4-amine (Compound 1_3) .
  • Step 2 General procedure for preparation of N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methyl-5-nitro-3-phenylpyridin-4-amine (Compound 1_4) .
  • Step 3 General procedure for preparation of N 4 - (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-5-phenylpyridine-3, 4-diamine (Compound 1_5) .
  • Step 4 General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 1_6) .
  • Step 5 General procedure for preparation of (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 1) .
  • Step 6 General procedure for preparation of Synthesis of (R) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 1 (70 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 1A (21 mg, 30.1%yield) and Example 1B (19 mg, 27.1%yield) .
  • Example 1A SFC: Retention time: 5.314 min.
  • LCMS: [M+H] + 427.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.78 (s, 1 H) , 7.42 –7.35 (m, 3H) , 7.33 –7.26 (m, 2H) , 7.06 (d, J 7.2 Hz, 2H) , 5.11 (s, 2H) , 4.49 (s, 1H) , 3.12 (s, 3 H) , 2.49 (s, 3H) , 2.17 (s, 3H) .
  • Example 1B SFC: Retention time: 5.727 min.
  • LCMS: [M+H] + 427.1.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.75 (s, 1H) , 7.42 –7.35 (m, 3H) , 7.33 –7.26 (m, 2H) , 7.06 (d, J 7.2 Hz, 2H) , 5.11 (s, 2H) , 4.49 (s, 1H) , 3.12 (s, 3H) , 2.49 (s, 3H) , 2.16 (s, 3H) .
  • Examples 2A and 2B Synthesis of (R) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 3-bromo-N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methoxy-5-nitropyridin-4-amine (Compound 2_2) .
  • Step 2 General procedure for preparation of N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methoxy-5-nitro-3-phenylpyridin-4-amine (Compound 2_3) .
  • Step 3 General procedure for preparation of N 4 - (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-5-phenylpyridine-3, 4-diamine (Compound 2_4)
  • Step 4 General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 2_5)
  • Step 5 General procedure for (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 2) .
  • Step 6 General procedure for preparation of (R) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 2A 50 mg, 41.7%yield
  • Example 2B 50 mg, 41.7%yield
  • Example 2A SFC: Retention time: 2.752 min.
  • LCMS: [M+H] + 443.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.46 (s, 1H) , 7.38 –7.18 (m, 5H) , 7.05 (d, J 7.6 Hz, 2H) , 5.14 (s, 2H) , 4.47 (s, 1H) , 3.74 (s, 3H) , 3.11 (s, 3H) , 2.48 (s, 3H) .
  • Example 2B SFC: Retention time: 3.085 min.
  • LCMS: [M+H] + 443.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.46 (s, 1H) , 7.38 –7.18 (m, 5H) , 7.05 (d, J 7.2 Hz, 2H) , 5.14 (s, 2H) , 4.47 (s, 1H) , 3.74 (s, 3H) , 3.11 (s, 3H) , 2.48 (s, 3H) .
  • Examples 3A and 3B Synthesis of (R) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 2-cyclopropyl-1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 3_1) .
  • Step 2 General procedure for preparation of (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 3) .
  • Step 3 General procedure for preparation of (R) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 3 (60 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 3A (15.37 mg, 25.6%yield) and Example 3B (15.98 mg, 25.8%yield) .
  • Example 3A SFC: Retention time: 1.416 min.
  • LCMS: [M+H] + 453.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.70 (s, 1H) , 7.41 –7.35 (m, 3H) , 7.35 –7.27 (m, 2H) , 7.11 (d, J 7.3 Hz, 2H) , 5.23 (s, 2H) , 4.50 (s, 1H) , 3.12 (s, 3H) , 2.19 –2.12 (m, 1H) , 2.16 (s, 3H) , 1.14 –0.73 (m, 4H) .
  • Example 3B SFC: Retention time: 2.072 min.
  • LCMS: [M+H] + 453.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.70 (s, 1H) , 7.41 –7.35 (m, 3H) , 7.35 –7.27 (m, 2H) , 7.11 (d, J 7.6 Hz, 2H) , 5.23 (s, 2H) , 4.50 (s, 1H) , 3.12 (s, 3H) , 2.19 –2.12 (m, 1H) , 2.16 (s, 3H) , 1.14 –0.73 (m, 4H) .
  • Examples 4A and 4B Synthesis of (R) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -2- ( (difluoro-l3-methyl) -l2-fluoraneyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 4_1)
  • Step 2 General procedure for preparation of (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 4) .
  • Step 3 General procedure for preparation of (R) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6-sulfanone and (S) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 4 (70 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 4A (15 mg, 21.4%yield) and Example 4B (18 mg, 25.7%yield) .
  • Example 4A SFC: Retention time: 1.837 min.
  • LCMS: [M+H] + 481.2.
  • Example 4B SFC: Retention time: 2.252 min.
  • LCMS: [M+H] + 481.2.
  • Examples 5A and 5B Synthesis of (R) - (3, 5-difluoro-4- ( (7- (3-fluorophenyl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 5 was synthesized as described in example 1. Compound 5 (80 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 5A (12 mg, 15.0%yield) and Example 5B (14 mg, 17.5%yield) .
  • Example 5A SFC: Retention time: 2.439 min.
  • LCMS: [M+H] + 445.2.
  • Example 5B SFC: Retention time: 2.673 min.
  • LCMS: [M+H] + 445.2.
  • Examples 6A and 6B Synthesis of (R) - (4- ( (7- (cyclopent-1-en-1-yl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone and (S) - (4- ( (7- (cyclopent-1-en-1-yl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 6 was synthesized as described in example 1. Compound 6 (60 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 6A (8 mg, 13.3%yield) and Example 6B (9 mg, 15.0%yield) .
  • Example 6A SFC: Retention time: 2.513 min.
  • LCMS: [M+H] + 417.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.62 (s, 1H) , 7.61 (d, J 7.6 Hz, 2H) , 5.75 –5.65 (m, 1H) , 5.55 –5.43 (m, 2H) , 4.54 (s, 1H) , 3.12 (s, 3H) , 2.47 (s, 3H) , 2.37 (s, 3H) , 2.48 –2.28 (m, 3H) , 2.20 –1.80 (m, 3H) .
  • Example 6B SFC: Retention time: 2.865 min.
  • LCMS: [M+H] + 417.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.62 (s, 1H) , 7.61 (d, J 8.0 Hz, 2H) , 5.75 –5.65 (m, 1H) , 5.55 –5.43 (m, 2H) , 4.54 (s, 1H) , 3.11 (s, 3H) , 2.47 (s, 3H) , 2.37 (s, 3H) , 2.48 –2.28 (m, 3H) , 2.20 –1.80 (m, 3H) .
  • Examples 7A and 7B Synthesis of (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
  • Step 1 General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7_1)
  • Step 2 General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7_2)
  • Step 3 General procedure for preparation of 1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7)
  • Step 4 General procedure for preparation of (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
  • Example 7 (70 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 7A (11 mg, 15.7%yield) and Example 7B (12 mg, 17.1%yield) .
  • Example 7A SFC: Retention time: 3.661 min.
  • LCMS: [M+H] + 443.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.34 (s, 1H) , 7.46 –7.26 (m, 5H) , 7.11 (d, J 6.9 Hz, 2H) , 4.69 (s, 2H) , 4.49 (s, 1H) , 3.43 (s, 3H) , 3.12 (s, 3H) , 2.10 (s, 3H) .
  • Example 7B SFC: Retention time: 5.089 min.
  • LCMS: [M+H] + 443.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.34 (s, 1H) , 7.46 –7.26 (m, 5H) , 7.11 (d, J 6.9 Hz, 2H) , 4.69 (s, 2H) , 4.48 (s, 1H) , 3.43 (s, 3H) , 3.12 (s, 3H) , 2.10 (s, 3H) .
  • Examples 8A and 8B Synthesis of (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
  • Compound 8 was synthesized from Compound 2_4 as described in example 7.
  • Compound 8 (90 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A:Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 8A (27.8 mg, 30.9%yield) and Example 8B (27.91 mg, 31.0%yield) .
  • Example 8A SFC: Retention time: 2.574 min.
  • LCMS: [M+H] + 459.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.00 (s, 1H) , 7.40 –7.17 (m, 5H) , 7.09 (d, J 7.0 Hz, 2H) , 4.76 (s, 2H) , 4.47 (s, 1H) , 3.70 (s, 3H) , 3.40 (s, 3H) , 3.11 (s, 3H) .
  • Example 8B SFC: Retention time: 3.180 min.
  • LCMS: [M+H] + 459.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.00 (s, 1H) , 7.40 –7.17 (m, 5H) , 7.09 (d, J 7.0 Hz, 2H) , 4.76 (s, 2H) , 4.47 (s, 1H) , 3.70 (s, 3H) , 3.40 (s, 3H) , 3.10 (s, 3H) .
  • Examples 9A and 9B Synthesis of (S) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
  • Step 1 General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9_2) .
  • Step 4 General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9_3) .
  • Step 5 General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9) .
  • Step 6 General procedure for preparation of (S) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
  • Example 9 (58 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 9A (21 mg, 36.2%yield) and Example 9B (23 mg, 39.6%yield) .
  • Example 9A SFC: Retention time: 4.500 min.
  • LCMS: [M+H] + 449.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 7.88 (s, 1H) , 7.58 (d, J 7.6 Hz, 2H) , 5.64 (s, 1H) , 5.23 (s, 2H) , 4.53 (s, 1H) , 3.77 (s, 3H) , 3.35 (s, 3H) , 3.10 (s, 3H) , 2.56 –2.48 (m, 2H) , 2.44 –2.36 (m, 2H) , 1.85 –1.78 (m, 2H) .
  • Example 9B SFC: Retention time: 4.673 min.
  • LCMS: [M+H] + 449.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 7.88 (s, 1H) , 7.58 (d, J 7.6 Hz, 2H) , 5.64 (s, 1H) , 5.23 (s, 2H) , 4.53 (s, 1H) , 3.77 (s, 3H) , 3.35 (s, 3H) , 3.10 (s, 3H) , 2.56 –2.48 (m, 2H) , 2.44 –2.36 (m, 2H) , 1.85 –1.78 (m, 2H) .
  • Examples 11A and 11B Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 2-methyl-5-nitro-3-phenylpyridin-4-ol (Compound 11_2) .
  • Step 2 General procedure for preparation of 4-chloro-2-methyl-5-nitro-3-phenylpyridine (Compound 11_3) .
  • Step 3 General procedure for preparation of 2-methyl-N- ( (5- (methylthio) pyridin-2-yl) methyl) -5-nitro-3-phenylpyridin-4-amine (Compound 11_5) .
  • Step 4 General procedure for preparation of 6-methyl-N4- ( (5- (methylthio) pyridin-2-yl) methyl) -5-phenylpyridine-3, 4-diamine (Compound 11_6) .
  • Step 5 General procedure for preparation of 2, 6-dimethyl-1- ( (5- (methylthio) pyridin-2-yl) methyl) -7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 11_7) .
  • Step 6 General procedure for preparation of (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 11) .
  • Step 7 General procedure for preparation of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 11 (30 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 11A (3 mg, 10.0%yield) and Example 11B (3 mg, 10.0%yield) .
  • Example 11A SFC: Retention time: 5.512 min.
  • LCMS: [M+H] + 392.2.
  • Example 11B SFC: Retention time: 6.862 min.
  • LCMS: [M+H] + 392.2.
  • Examples 12A and 12B Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 3-bromo-N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methyl-5-nitropyridin-4-amine (Compound 12_2) .
  • Step 2 General procedure for preparation of N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methyl-5-nitro-3-phenylpyridin-4-amine (Compound 12_3) .
  • Step 3 General procedure for preparation of N 4 - ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methyl-5-phenylpyridine-3, 4-diamine (Compound 12_4) .
  • Step 4 General procedure for preparation of 1- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 12_5) .
  • Step 5 General procedure for preparation of (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 12) .
  • Step 6 General procedure for preparation of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 12 (60 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 12A (5 mg, 8.3%yield) and Example 12B (5 mg, 8.3%yield) .
  • Example 12A SFC: Retention time: 2.833 min.
  • LCMS: [M+H] + 410.2.
  • Example 12B SFC: Retention time: 3.448 min.
  • LCMS: [M+H] + 410.2.
  • Examples 13A and 13B Synthesis of (S) - (6- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Compound 13 was synthesized from Compound 11_6 as described in example 3.
  • Compound 13 43 mg was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A:n-Hexane; mobile phase B: EtOH (+0.1%7.0mol/l Ammonia in MEOH) ) mobile phase: (MEOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 13A (9 mg, 20.9%yield) and Example 13B (9mg, 20.9%yield) .
  • Examples 14A and 14B Synthesis of (S) -imino (methyl) (6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) - ⁇ 6 -sulfanone and (R) -imino (methyl) (6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) - ⁇ 6 -sulfanone
  • Compound 14 was synthesized from Compound 11_6 as described in example 4. Compound 14 (60 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A:Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 14A (15 mg, 25.0%yield) and Example 14B (15 mg, 25.0%yield) .
  • Example 14A SFC: Retention time: 1.445 min.
  • LCMS: [M+H] + 446.2.
  • Example 14B SFC: Retention time: 1.920 min.
  • LCMS: [M+H] + 446.2.
  • Examples 15A and 15B Synthesis of (R) - (5-fluoro-6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanoneand (S) - (5-fluoro-6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Compound 15 was synthesized from Compound 12_4 as described in example 4.
  • Compound 15 (40 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 15A (5 mg, 12.5%yield) and Example 15B (5 mg, 12.5%yield) .
  • Example 15A SFC: Retention time: 2.125 min.
  • LCMS: [M+H] + 464.2.
  • Example 15B SFC: Retention time: 2.428 min.
  • LCMS: [M+H] + 464.2.
  • Examples 16A and 16B Synthesis of (S) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone and (R) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of 2-methoxy-N- ( (5- (methylthio) pyridin-2-yl) methyl) -5-nitro-3-phenylpyridin-4-amine (Compound 16_2) .
  • Step 2 General procedure for preparation of 6-methoxy-N 4 - ( (5- (methylthio) pyridin-2-yl) methyl) -5-phenylpyridine-3, 4-diamine (Compound 16_3) .
  • Step 3 General procedure for preparation of 6-methoxy-1- ( (5- (methylthio) pyridin-2-yl) methyl) -7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridine (Compound 16_4) .
  • Step 5 General procedure for imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone (Compound 16) .
  • Step 6 General procedure for preparation of (S) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone and (R) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone
  • Example 16 (100 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 16A (15 mg, 15.0%yield) and Example 16B (12 mg, 12.0%yield) .
  • Example 16A SFC: Retention time: 3.579 min.
  • LCMS: [M+H] + 462.2.
  • Example 16B SFC: Retention time: 3.923 min.
  • LCMS: [M+H] + 443.2.
  • Examples 17A and 17B Synthesis of (S) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Step 1 General procedure for preparation of N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methoxy-5-nitro-3-phenylpyridin-4-amine (Compound 17_2) .
  • Step 2 General procedure for preparation of N 4 - ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methoxy-5-phenylpyridine-3, 4-diamine (Compound 17_3) .
  • Step 3 General procedure for preparation of 1- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridine (Compound 17_4) .
  • Step 4 General procedure for preparation of (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone (Compound 17) .
  • Step 5 General procedure for preparation of (S) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Example 17 (25 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 17A (4 mg, 16.0%yield) and Example 17B (4 mg, 16.0%yield) .
  • Example 17A SFC: Retention time: 3.789 min.
  • LCMS: [M+H] + 480.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.90 (s, 1H) , 8.56 (s, 1H) , 7.93 –7.86 (m, 1H) , 7.32 (t, J 7.5 Hz, 1H) , 7.27 –7.12 (m, 2H) , 6.98-6.88 (m, 2H) , 5.36 (s, 2H) , 4.62 (s, 1H) , 3.79 (s, 3H) , 3.18 (s, 3H) .
  • Example 17B SFC: Retention time: 4.020 min.
  • LCMS: [M+H] + 480.2.
  • 1 H NMR: (400 MHz, DMSO-d 6 ) ⁇ 8.90 (s, 1H) , 8.56 (s, 1H) , 7.93 –7.86 (m, 1H) , 7.32 (t, J 7.5 Hz, 1H) , 7.27 –7.12 (m, 2H) , 6.98-6.88 (m, 2H) , 5.36 (s, 2H) , 4.62 (s, 1H) , 3.79 (s, 3H) , 3.18 (s, 3H) .
  • Examples 18A and 18B Synthesis of (S) - (6- ( (2- (difluoromethyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2- (difluoromethyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Compound 18 was synthesized from Compound 12_4 as described in example 4.
  • Compound 18 (58 mg) was separated by SFC (column: (250*25 mm 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 18A (6 mg, 10.3%yield) and Example 18B (6 mg, 10.3%yield) .
  • Example 18A SFC: Retention time: 5.199 min.
  • LCMS: [M+H] + 446.2.
  • Example 18B SFC: Retention time: 5.583 min.
  • LCMS: [M+H] + 446.2.
  • Examples 19A and 19B Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Compound 19 was synthesized from Compound 11_6 as described in example 4.
  • Compound 19 (45 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 19A (7 mg, 15.6%yield) and Example 19B (7 mg, 15.6%yield) .
  • Example 19A SFC: Retention time: 2.237 min.
  • LCMS: [M+H] + 428.2.
  • Example 19B SFC: Retention time: 2.898 min.
  • LCMS: [M+H] + 428.2.
  • Examples 20A and 20B Synthesis of (S) -imino (6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone and (R) -imino (6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) - ⁇ 6 -sulfanone
  • Compound 20 was synthesized from Compound 16_3 as described in example 2.
  • Compound 20 (45 mg) was separated by SFC (column: (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 20A (6 mg, 13.3%yield) and Example 20B (6 mg, 13.3%yield) .
  • Example 20A SFC: Retention time: 3.910 min.
  • LCMS: [M+H] + 408.3.
  • Example 20B SFC: Retention time: 3.967 min.
  • LCMS: [M+H] + 408.3.
  • Examples 21A and 21B Synthesis of (S) - (6- ( (2- (difluoromethyl) -6-methoxy-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone and (R) - (6- ( (2- (difluoromethyl) -6-methoxy-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) - ⁇ 6 -sulfanone
  • Compound 21 was synthesized from Compound 16_3 as described in example 4.
  • Compound 21 (50 mg) was separated by SFC (column: REGIS (S, S) WHELK-O1 (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 21A (9 mg, 18.0%yield) and Example 21B (8 mg, 16.0%yield) .
  • Example 21A SFC: Retention time: 3.354 min.
  • LCMS: [M+H] + 444.3.
  • Example 21B SFC: Retention time: 3.837 min.
  • LCMS: [M+H] + 444.3.
  • Examples 22A and 22B Synthesis of (S) -imino (4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (methyl) - ⁇ 6 -sulfanone and (R) -imino (4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (methyl) - ⁇ 6 -sulfanone
  • Compound 22 was synthesized from Compound 2_1 as described in example 2.
  • Compound 22 (200 mg) was separated by SFC (column: column: REGIS (S, S) WHELK-O1 (250*25 mm, 10 ⁇ m) ; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 22A (41 mg, 20.5%yield) and Example 22B (41 mg, 20.5%yield) .
  • Example 22A SFC: Retention time: 4.951 min.
  • LCMS: [M+H] + 407.3.
  • Example 22B SFC: Retention time: 5.848 min.
  • LCMS: [M+H] + 407.3.
  • the final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl and 0.1%BSA
  • the final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl and 0.1%BSA
  • IC 50 (nM) 0 ⁇ A ⁇ 1 nM; 1 nM ⁇ B ⁇ 10 nM; 10 nM ⁇ C ⁇ 100 nM; 100 nM ⁇ D.

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Abstract

Described herein are ENPP1 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with ENPP1.

Description

ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE 1 (ENPP1) INHIBITORS AND USES THEREOF
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2022/123810, filed October 8, 2022; which is incorporated herein by reference in its entirety.
BACKGROUND
Ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other nucleoside monophosphates as well as pyrophosphate (PPi) . The enzyme can also hydrolyze other nucleoside monophosphate esters. ENPP1 has been identified as the dominant 2’-3’-cGAMP hydrolase in cultured cells, tissue extracts and blood. Tissues and blood from ENPP1 knockout mice lack 2’-3’-cGAMP hydrolase activity. Elevated levels of ENPP1 have been associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease, an inflammatory disease resulting from CPPD crystal deposits in the joint and surrounding tissues. ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid, and breast cancers and has been associated with resistance to chemotherapy. ENPP1 upregulation and variants of ENPP1 are also associated with insulin resistance and type 2 diabetes and enzyme activity of ENPP1 was reported to be required for the inhibition of insulin receptor signaling.
Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA derived from viruses, bacteria, damaged mitochondria, or cancer cells. The cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, which initiates a signaling response that activates innate immunity and results in the production of type I interferon, antiviral, and immune-stimulatory cytokines. The cGAS enzyme, cGAMP messenger and STING are also involved in host defense against RNA viruses and the immune control of tumor development. ENPP1 has been identified as the enzyme that naturally hydrolyzes cGAMP and therefore counteracts the innate immune response against infectious agents, damaged cells, and cancer cells. The efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of natural, hydrolysable cGAMP. Virus infection has been demonstrated to be facilitated by ENPP1 overexpression and is attenuated by silencing of ENPP1.
Inhibitors of cGAMP hydrolysis may therefore be used to increase the effectiveness of immune responses against cancer cells and tumors and against infections by RNA or DNA viruses or bacteria. Inhibitors of ENPP1 and of cGAMP or nucleoside triphosphate hydrolysis may also be used for the treatment of inflammatory diseases that are associated with elevated nucleotidase levels, reduced nucleoside triphosphate, reduced cGAMP or reduced nucleoside monophosphate ester levels or diseases  associated with elevated nucleoside or nucleoside monophosphate levels. For these reasons, ENPP1 is an attractive therapeutic target for the treatment of diseases, such as cancers and viral infections.
SUMMARY
Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt or stereoisomer thereof:
Also disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, or sarcoma. In some embodiments, the cancer is a hematologic malignancy. In some embodiments, the hematologic malignancy is a leukemia, a lymphoma, or a myeloma. In some embodiments, the hematologic malignancy is a B-cell malignancy. In some embodiments, the hematologic malignancy is multiple myeloma. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer.
Also disclosed herein is a method of treating an infection in a subject in need thereof comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the infection is a viral infection. In some embodiments, the viral infection is due to a DNA virus. In some embodiments, the viral infection is due to a herpesvirus. In some embodiments, the herpesvirus is selected from herpes simplex viruses 1 (HSV-l) , herpes simplex viruses 2 (HSV-2) , varicella-zoster virus (VZV) , Epstein-Barr virus (EBV) , human cytomegalovirus (HCMV) , human herpesvirus 6A (HHV-6A) , human herpesvirus 6B (HHV-6B) , human herpesvirus 7 (HHV-7) , and Kaposi's sarcoma-associated herpesvirus (KSHV) . In some embodiments, the herpesvirus is herpes simplex viruses 1 (HSV-l) . In some embodiments, the viral infection is due to a retrovirus. In some embodiments, the retrovirus is human immunodeficiency virus (HIV) . In some embodiments, the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV) . In some embodiments, the viral infection is due to a hepatitis virus. In some embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV) . In some  embodiments, the viral infection is due to vaccinia virus (VACV) , adenovirus, or human papillomaviruses (HPV) . In some embodiments, the viral infection is due to a RNA virus. In some embodiments, the viral infection is due to dengue fever virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
Definitions
In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed subject matter.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“oxo” refers to =O.
“Carboxyl” refers to -COOH.
“Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1- butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , 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. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the 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. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl” , 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally  substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -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.
“Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, 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. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -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) , spiro, 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 (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl) , from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl) , from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl) , from three to six carbon atoms (e.g.,  C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl) , from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl) , or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated 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, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more 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.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the  rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“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, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl) , from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl) , or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl) . Examples of such 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, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term  heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . Unless stated otherwise specifically in the specification, a heteroaryl 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. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, 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. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, 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.
The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
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. In some embodiments,  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.
As used herein, a “disease or disorder associated with ENPP1” or, alternatively, “a ENPP1-mediated disease or disorder” means any disease or other deleterious condition in which ENPP1, or a mutant thereof, is known or suspected to play a role.
Compounds
Described herein are compounds, or a pharmaceutically acceptable salt or stereoisomer thereof useful in the treatment of a disease or disorder associated with ENPP1.
Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L is a bond, -NH-, or -O-;
each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R1 on the same atom are taken together to form an oxo;
n is 0, 1, 2, 3, 4, 5, or 6;
R2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
R3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
is a single bond or a double bond; wherein:
whenis a double bond, X is N or CRX and Y is N or CRY;
whenis a single bond, X is C (=O) and Y is NRY1 or C (RY2) 2;
RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
RY1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
each RY2 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R4 on the same atom are taken together to form an oxo;
m is 0, 1, 2, 3, or 4;
R5 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R6 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R7 is hydrogen, halogen, -CN, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or  C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two Ra are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two Rb are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo.
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ia) :
In some embodiments of a compound of Formula (I) or (Ia) , the compound is of Formula (Ia-1) :
In some embodiments of a compound of Formula (I) or (Ia) , the compound is of Formula (Ia-2) :
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , X is N and Y is N.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , X is CRX and Y is N.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , X is N and Y is CRY.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , X is CRX and Y is CRY.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is methyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is CF3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RX is cycloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RY is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RY is hydrogen. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , or (Ia-2) , RY is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ib) :
In some embodiments of a compound of Formula (I) or (Ib) , the compound is of Formula (Ib-1) :
In some embodiments of a compound of Formula (I) or (Ib) , the compound is of Formula (Ib-2) :

In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , Y is NRY1. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , Y is C (RY2) 2.
In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , RY1 is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , RY1 is C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , RY1 is methyl.
In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , each RY2 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ib) , (Ib-1) , or (Ib-2) , each RY2 is independently hydrogen, halogen, or C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is aryl or heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is aryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is phenyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is 5-or 6-membered heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is 6-membered heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is pyridinyl, pyrimidinyl, or pyrazinyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is pyridinyl or pyrimidinyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring A is pyridinyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , L is a bond. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , L is a -O-. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , L is a -NH-.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R1 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R1 is independently halogen.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0, 1, or 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 0 or 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1, 2, or 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 2, 3, or 4. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 2 or 3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1 or 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , n is 3.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R2 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R2 is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R3 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R3 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R3 is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is aryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is phenyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , Ring B is heteroaryl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd,  C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R4 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , each R4 is independently C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 0, 1, or 2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 0 or 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 0. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 1. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , m is 2.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is hydrogen, -CN, -ORa, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is -ORa or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is -ORa. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is -C1-C6alkoxyl. In some embodiments, R5 is -OCH3. In some embodiments, the -OCH3 is -OCD3. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R5 is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R6 is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R6 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R6 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R6 is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R7 is hydrogen, -CN, or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R7 is hydrogen or -CN. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R7 is hydrogen. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R7 is -CN. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R7 is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or  (Ib-2) , R8 is cycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is heteroaryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is aryl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C2-C6alkynyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C2-C6alkenyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is -NRcRd. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is -NHCH3, -N (CH3) 2 or -NH2. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is -ORa. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C1-C6alkoxyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ia-1) , (Ia-2) (Ib) , (Ib-1) , or (Ib-2) , R8 is methyl.
In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed  herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, two Ra are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, two Rb are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with  one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene (cycloalkyl) , or C1-C6alkylene (heterocycloalkyl) , wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl, wherein the alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen. In some embodiments of a compound disclosed herein, Rc and Rd are each independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl, C1-C3alkoxy, or C1-C3haloalkyl.
In some embodiments of a compound disclosed herein, two R on the same atom form an oxo.
In some embodiments of a compound disclosed herein, one or more of R, R1, R2, R3, R4, R5, R6, R7, R8, RX, RY, RY1, RY2, Ra, Rb, Rc, and Rd groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
In some embodiments of a compound disclosed herein, one or more hydrogens are replaced with one or more deuteriums in one or more of the following groups R, R1, R2, R3, R4, R5, R6, R7, R8, RX, RY, RY1, RY2, Ra, Rb, Rc, and Rd.
In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R1, R2, R3, R4, R5, R6, R7, R8, RX, RY, RY1, RY2, Ra, Rb, Rc, and Rd is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments of a compound disclosed herein, one or more hydrogens of Ring A or Ring B are replaced with one or more deuteriums.
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.
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 1.
TABLE 1



The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.
The OR label (or) denotes a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with pure structures isolated, multiple OR labels (OR indicates purity) with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown) .
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 2.
TABLE 2




Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Isotopically enriched compounds
Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium) , 2H (deuterium) , and 3H (tritium) . Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H) , tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms.
The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate,  succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’-methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, 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 or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
In some embodiments, 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. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Method of Treatment
Disclosed herein are methods of treating a disease modulated at least in part by ENPP1 in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, disclosed herein.
Disclosed herein are methods of treating cancer in a subject, the method comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, disclosed herein.
Disclosed herein are methods of inhibiting ENPP1 in a subject in need thereof, the method comprising administering to the subject an amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof. Disclosed herein are methods of regulating the STING pathway in a subject in need thereof by hydrolyzing cGAMP and/or generating immune suppressor adenosine, the method comprising administering to the subject an amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the subject has cancer.
In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, or sarcoma.
In some embodiments, the cancer is a hematologic malignancy. In some embodiments, the hematologic malignancy is a leukemia, a lymphoma, or a myeloma. In some embodiments, the hematologic malignancy is a B-cell malignancy. In some embodiments, the hematologic malignancy is multiple myeloma.
In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer.
In some embodiment, the cancer is hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid, or breast cancer. In some embodiments, the cancer is basal cell carcinoma, biliary tract cancer, bone cancer, brain cancer (e.g., glioblastoma multiforme, glioma, medulloblastoma, primitive neuroectodermal tumor (PNET) , acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, hemangiopercytoma, metastatic brain tumor, ependymoma, astrocytoma, oligodendroglioma, oligoastrocytoma, juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytom, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri, multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma, ganglioglioma) , breast cancer, cancer of the head and neck, cancer of the respiratory system, cancer of the urinary system, choriocarcinoma, colon cancer, connective tissue cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer,  gastrointestinal tract cancer, genitourinary tract cancer, hematological cancer (e.g., acute myeloid leukemia (AML) , acute lymphoblastic leukemia (ALL) , chronic myeloid leukemia (CML) , chronic lymphocytic leukemia (CLL) , hairy cell leukemia, chronic myelomonocytic leukemia (CMML) , juvenile myelomonocytic leukemia (JMML) , Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, solitary myeloma, localized myeloma, extramedullary myeloma, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma) , intra-epithelial neoplasm, kidney cancer, larynx cancer, lung cancer, lymphatic system cancer, melanoma, myeloma, neuroblastoma, oral cavity cancer (e.g. lip, tongue, mouth, and pharynx) , ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, rhabdomyosarcoma, sarcoma, skin cancer, stomach cancer, testicular cancer, or uterine cancer.
Disclosed herein are methods of treating an infection in a subject in need thereof comprising administering a therapeutically affective amount of a compound disclosed herein. In some embodiments, the infection is a viral infection. In some embodiments, the viral infection is due to a DNA virus. In some embodiments, the viral infection is due to a herpesvirus. In some embodiments, the herpesvirus is selected from herpes simplex viruses 1 (HSV-l) , herpes simplex viruses 2 (HSV-2) , varicella-zoster virus (VZV) , Epstein-Barr virus (EBV) , human cytomegalovirus (HCMV) , human herpesvirus 6A (HHV-6A) , human herpesvirus 6B (HHV-6B) , human herpesvirus 7 (HHV-7) , and Kaposi's sarcoma-associated herpesvirus (KSHV) . In some embodiments, the herpesvirus is herpes simplex viruses 1 (HSV-l) . In some embodiments, the viral infection is due to a retrovirus. In some embodiments, the retrovirus is human immunodeficiency virus (HIV) . In some embodiments, the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV) . In some embodiments, the viral infection is due to a hepatitis virus. In some embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV) . In some embodiments, the viral infection is due to vaccinia virus (VACV) , adenovirus, or human papillomaviruses (HPV) . In some embodiments, the viral infection is due to a RNA virus. In some embodiments, the viral infection is due to dengue fever virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
Dosing
In certain embodiments, the compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
In prophylactic applications, 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. ” In this use, 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.
In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion 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.
In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday” ) . In specific embodiments, 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%.
Once improvement of the patient’s conditions has occurred, 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.
In general, however, 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.
In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the  mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD10 and the ED90. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, 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. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, 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.
In any of the aforementioned aspects are further embodiments in which 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.
In 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.
In 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. In further or alternative embodiments, 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. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, 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. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, 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. In yet other embodiments, the compound described herein is administered topically.
Pharmaceutical Compositions/Formulations
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. In one embodiment, the compounds disclosed herein 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.
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt 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. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
The pharmaceutical 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. The  pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt 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.
Pharmaceutical 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. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical 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. In soft capsules, 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.
Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, 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 or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, 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. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
Combination
Disclosed herein are methods of treating a disease or disorder associated with ENPP1 using a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with an additional therapeutic agent.
In some embodiments, 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.
In some embodiments, the additional therapeutic agent is an anti-cancer agent.
In some embodiments, the additional therapeutic agent is an ALK inhibitor: e.g. crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, or lorlatinib; an androgen receptor inhibitor: e.g. enzalutamide, apalutamide, abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, or flutamide; an antineoplastic agent: e.g. oxaliplatin, carboplatin, or cisplatin; an aromatase inhibitor: exemestane, letrozole, anastrozole, fulvestrant, or tamoxifen; a BCL-2 inhibitor: e.g. venetoclax; a BCR-ABL inhibitor: e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, or PF03814735; a BRAF inhibitor: e.g. vemurafenib or dabrafenib; a CD20 antibody: e.g. rituximab, tositumomab, or ofatumumab; a CDK4/6 inhibitor: e.g. alvocidib, palbociclib, ribociclib, trilaciclib, or abemaciclib; a CTLA-4 inhibitor: e.g. tremelimumab or ipilimumab; a DNA synthesis inhibitor: e.g. capecitabine, gemcitabine, nelarabine, or hydroxycarbamide; an epidermal growth factor receptor (EGFR) inhibitor: e.g. gefitinib, osimertinib, cetuximab, or panitumumab; an ERK inhibitor: e.g. ulixertinib, MK 8353, or LY 3214996; a KRAS inhibitor: e.g. AMG-510, MRTX849, or ARS-3248; an FGFR inhibitor: e.g. infigratinib, dovitinib, erdafitinib, TAS-120, pemigatinib, BLU-554, or AZD4547; an FLT3 inhibitor: e.g. sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, or crenolanib; a Heat Shock Protein (HSP) inhibitor: e.g. tanespimycin; a Hedgehog antagonist: e.g. vismodegib; an HER2 receptor inhibitor: e.g. trastuzumab, pertuzumab, neratinib, lapatinib, or lapatinib; a Histone deacetylase inhibitor (HDI) : e.g. vorinostat; Immunomodulators: e.g. afutuzumab, lenalidomide, thalidomide, or pomalidomide; a CD40 inhibitor: e.g. dacetuzumab; a MEK inhibitor: e.g. trametinib, cobimetinib, binimetinib, or selumetinib; a MET inhibitor: e.g. crizotinib or cabozantinib; an mTOR inhibitor: e.g. temsirolimus, ridaforolimus, everolimus, or sirolimus; a PD1 inhibitor: e.g. nivolumab, or pembrolizumab; a PDL1 inhibitor: e.g. MSB0010718C; YW243.55. S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105; a PI3K inhibitor: e.g. pictilisib, dactolisib, alpelisib, buparlisib, taselisib, idelalisib, duvelisib, or umbralisib; a PIK3CA inhibitor; a Pro-apoptotic receptor agonists (PARAs) : e.g. dulanermin; a proteasome inhibitor: e.g. bortezomib; a SHP2 inhibitor; or a Tyrosine kinase inhibitor: e.g. erlotinib, linifanib, sunitinib, or pazopanib.
Examples
Examples xA are the enantiomers with the shorter retention time. Examples xB are the enantiomers with the longer retention time. The absolute configurations of the stereochemical centers are unknown.
Examples 1, 1A, and 1B: Synthesis of (R) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 3-bromo-N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methyl-5-nitropyridin-4-amine (Compound 1_3) .
To a solution of Compound 1_1 (1.3 g, 6.87 mmol) in acetonitrile (12 mL) were added Compound 1_2 (1.9 g, 7.56 mmol) and DIPEA (5.68 mL, 34.35 mmol) . This reaction mixture was stirred at 60℃ for 2 h. Solvent was removed under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 1_3 (2.5 g, 90.0%yield) . LCMS: [M+H] + = 404.0.
Step 2: General procedure for preparation of N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methyl-5-nitro-3-phenylpyridin-4-amine (Compound 1_4) .
To a solution of Compound 1_3 (339 mg, 0.84 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added XPhos (80 mg, 0.17 mmol) , Pd2 (dba) 3 (77 mg, 0.08 mmol) , K2CO3 (348 mg, 2.52 mmol) and phenylboronic acid (205 mg, 1.68 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was removed under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 1_4 (264 mg, 78.4%yield) . LCMS: [M+H] + = 402.1.
Step 3: General procedure for preparation of N4- (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-5-phenylpyridine-3, 4-diamine (Compound 1_5) .
To a solution of Compound 1_4 (255 mg, 0.64 mmol) in MeOH (3 mL) and DCM (3 mL) was added Pd/C (50 mg, 10%wt) , and the reaction mixture was stirred at room temperature for 16 h under H2 atmosphere. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with MeOH (3×15 mL) . The combined filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide the corresponding Compound 1_5 (180 mg, 76.3%yield) . LCMS: [M+H] + = 372.1.
Step 4: General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 1_6) .
To a solution of Compound 1_5 (170 mg, 0.46 mmol) in ethanol (10 mL) were added triethyl orthoacetate (530 mg, 4.60 mmol) and Py-HCl (26 mg, 0.23 mmol) . The reaction mixture was stirred at 80℃ for 2 h. Solvent was removed under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 1_6 (160 mg, 88.4%yield) . LCMS: [M+H] + = 396.1.
Step 5: General procedure for preparation of (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone (Compound 1) .
To a solution of Compound 1_6 (80 mg, 0.20 mmol) in ethanol (8 mL) were added iodobenzene diacetate (393 mg, 1.21 mmol) and ammonium acetate (62 mg, 0.81 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was removed under reduced pressure and the obtained residue was purified by Prep-HPLC to provide the corresponding Compound 1 (70 mg, 81.1%yield) . LCMS: [M+H] + = 427.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.42 –7.35 (m, 3H) , 7.33 –7.26 (m, 2H) , 7.06 (d, J = 7.2 Hz, 2H) , 5.11 (s, 2 H) , 4.49 (s, 1H) , 3.12 (s, 3 H) , 2.49 (s, 3H) , 2.16 (s, 3H) .
Step 6: General procedure for preparation of Synthesis of (R) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Compound 1 (70 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 1A (21 mg, 30.1%yield) and Example 1B (19 mg, 27.1%yield) .
Example 1A: SFC: Retention time: 5.314 min. LCMS: [M+H] + = 427.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.78 (s, 1 H) , 7.42 –7.35 (m, 3H) , 7.33 –7.26 (m, 2H) , 7.06 (d, J = 7.2 Hz, 2H) , 5.11 (s, 2H) , 4.49 (s, 1H) , 3.12 (s, 3 H) , 2.49 (s, 3H) , 2.17 (s, 3H) .
Example 1B: SFC: Retention time: 5.727 min. LCMS: [M+H] + = 427.1. 1H NMR: (400 MHz, DMSO-d6) δ 8.75 (s, 1H) , 7.42 –7.35 (m, 3H) , 7.33 –7.26 (m, 2H) , 7.06 (d, J = 7.2 Hz, 2H) , 5.11 (s, 2H) , 4.49 (s, 1H) , 3.12 (s, 3H) , 2.49 (s, 3H) , 2.16 (s, 3H) .
Examples 2A and 2B: Synthesis of (R) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone and (S) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 3-bromo-N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methoxy-5-nitropyridin-4-amine (Compound 2_2) .
To a solution of Compound 2_1 (1.0 g, 3.76 mmol) in acetonitrile (10 mL) was added Compound 1_2 (846 mg, 3.76 mmol) and DIPEA (970 mg 7.52 mmol) . This reaction mixture was stirred at 60℃ for 2 h. Solvent was removed under reduced pressure and the obtained residue was  purified by flash silica gel chromatography to provide the corresponding Compound 2_2 (730 mg, 46.0%yield) . LCMS: [M+H] + = 419.9.
Step 2: General procedure for preparation of N- (2, 6-difluoro-4- (methylthio) benzyl) -2-methoxy-5-nitro-3-phenylpyridin-4-amine (Compound 2_3) .
To a solution of Compound 2_2 (730 mg, 1.74 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (720 mg, 5.22 mmol) , XPhos-Pd-G2 (137 mg, 0.17 mmol) and phenylboronic acid (424 mg, 3.48 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was removed under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 2_3 (600 mg, 83%yield) . LCMS: [M+H] + =418.1.
Step 3: General procedure for preparation of N4- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-5-phenylpyridine-3, 4-diamine (Compound 2_4)
To a solution of Compound 2_3 (600 mg, 1.44 mmol) in MeOH/DCM (10 mL/10 mL) was added Pd/C (120 mg, 10%wt) . The mixture was stirred at room temperature for 2 h under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a light yellow solid. The obtained solid was purified by flash silica gel chromatography to provide the corresponding Compound 2_4 (320 mg, 57.5%yield) . LCMS: [M+H] + = 388.1.
Step 4: General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 2_5)
To a solution of Compound 2_4 (320 mg, 0.83 mmol) in ethanol (10 mL) were added triethyl orthoacetate (1.35 g, 8.27 mmol) and Py-HCl (48 mg, 0.41 mmol) . The reaction mixture was stirred at 80℃ for 2 h. Solvent was removed under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 2_5 (150 mg, 44%yield) . LCMS: [M+H] + = 412.1.
Step 5: General procedure for (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone (Compound 2) .
To a solution of Compound 2_5 (320 mg, 0.78 mmol) in ethanol (3 mL) were added iodobenzene diacetate (1.5 g, 4.67 mmol) and ammonium acetate (240 mg, 3.12 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was removed under reduced pressure and the obtained residue was purified by Prep-HPLC to provide the corresponding Compound 2 (120 mg, 34.9%yield) . LCMS: [M+H] + = 443.2.
Step 6: General procedure for preparation of (R) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone and (S) - (3, 5-difluoro-4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone
Compound 2 (120 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 2A (50 mg, 41.7%yield) and Example 2B (50 mg, 41.7%yield) .
Example 2A: SFC: Retention time: 2.752 min. LCMS: [M+H] + = 443.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.46 (s, 1H) , 7.38 –7.18 (m, 5H) , 7.05 (d, J = 7.6 Hz, 2H) , 5.14 (s, 2H) , 4.47 (s, 1H) , 3.74 (s, 3H) , 3.11 (s, 3H) , 2.48 (s, 3H) .
Example 2B: SFC: Retention time: 3.085 min. LCMS: [M+H] + = 443.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.46 (s, 1H) , 7.38 –7.18 (m, 5H) , 7.05 (d, J = 7.2 Hz, 2H) , 5.14 (s, 2H) , 4.47 (s, 1H) , 3.74 (s, 3H) , 3.11 (s, 3H) , 2.48 (s, 3H) .
Examples 3A and 3B: Synthesis of (R) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 2-cyclopropyl-1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 3_1) .
To a mixture of Compound 1_5 (100 mg, 0.27 mmol) in EtOH/AcOH (5 mL/0.5 mL) was added cyclopropanecarbaldehyde (94 mg, 1.35 mmol) . The mixture was stirred at 100℃ for 3 h. After the reaction mixture was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 3_1 (80 mg, 70.5%yield) . LCMS: [M+H] + =422.2.
Step 2: General procedure for preparation of (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone (Compound 3) .
To a solution of Compound 3_1 (80 mg, 0.19 mmol) in ethanol (8 mL) were added iodobenzene diacetate (92 mg, 0.29 mmol) and ammonium acetate (30 mg, 0.38 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was concentrated under reduced pressure and the obtained residue was purified by Prep-HPLC to provide the corresponding Compound 3 (60 mg, 69.9%yield) . LCMS: [M+H] + = 453.2.
Step 3: General procedure for preparation of (R) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Compound 3 (60 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 3A (15.37 mg, 25.6%yield) and Example 3B (15.98 mg, 25.8%yield) .
Example 3A: SFC: Retention time: 1.416 min. LCMS: [M+H] + = 453.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.41 –7.35 (m, 3H) , 7.35 –7.27 (m, 2H) , 7.11 (d, J = 7.3 Hz, 2H) , 5.23 (s, 2H) , 4.50 (s, 1H) , 3.12 (s, 3H) , 2.19 –2.12 (m, 1H) , 2.16 (s, 3H) , 1.14 –0.73 (m, 4H) .
Example 3B: SFC: Retention time: 2.072 min. LCMS: [M+H] + = 453.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.41 –7.35 (m, 3H) , 7.35 –7.27 (m, 2H) , 7.11 (d, J = 7.6 Hz, 2H) , 5.23 (s, 2H) , 4.50 (s, 1H) , 3.12 (s, 3H) , 2.19 –2.12 (m, 1H) , 2.16 (s, 3H) , 1.14 –0.73 (m, 4H) .
Examples 4A and 4B: Synthesis of (R) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone and (S) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -2- ( (difluoro-l3-methyl) -l2-fluoraneyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 4_1) 
A mixture of Compound 1_5 (100 mg, 0.27 mmol) in TFA (5 mL) was stirred at 70℃ for 1 h. After the solvent was concentrated under reduced pressure, Et3N (5 mL) was added. The mixture was stirred at 70℃ for 1 h. The mixture was concentrated to dryness and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 4_1 (90 mg, 74.1%yield) . LCMS: [M+H] + = 450.1.
Step 2: General procedure for preparation of (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone (Compound 4) .
To a solution of Compound 4_1 (90 mg, 0.20 mmol) in EtOH (2 mL) were added ammonium acetate (61 mg, 0.797 mmol) and iodobenzene diacetate (367 mg, 1.13 mmol. The reaction mixture was stirred at 40℃ for 1 h. After the solvent was concentrated under reduced pressure, the obtained residue was purified by Prep-HPLC to provide the corresponding Compound 4 (70 mg, 81.9%yield) . LCMS: [M+H] + = 481.2.
Step 3: General procedure for preparation of (R) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone and (S) - (3, 5-difluoro-4- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone
Compound 4 (70 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 4A (15 mg, 21.4%yield) and Example 4B (18 mg, 25.7%yield) .
Example 4A: SFC: Retention time: 1.837 min. LCMS: [M+H] + = 481.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 7.43 -7.35 (m, 3H) , 7.33 -7.26 (m, 2H) , 7.18 -7.08 (m, 2H) , 5.31 (s, 2H) , 4.52 (s, 1H) , 3.14 (s, 3H) , 2.23 (s, 3H) .
Example 4B: SFC: Retention time: 2.252 min. LCMS: [M+H] + = 481.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 7.43 -7.36 (m, 3H) , 7.33 -7.26 (m, 2H) , 7.18 -7.08 (m, 2H) , 5.31 (s, 2H) , 4.52 (s, 1H) , 3.13 (s, 3H) , 2.23 (s, 3H) .
Examples 5A and 5B: Synthesis of (R) - (3, 5-difluoro-4- ( (7- (3-fluorophenyl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Compound 5 was synthesized as described in example 1. Compound 5 (80 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 5A (12 mg, 15.0%yield) and Example 5B (14 mg, 17.5%yield) .
Example 5A: SFC: Retention time: 2.439 min. LCMS: [M+H] + = 445.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.75 (s, 1H) , 7.45 –7.29 (m, 3H) , 7.27 –7.18 (m, 1H) , 6.99 –6.93 (m, 1H) , 6.89 (d, J = 7.5 Hz, 1H) , 5.18 (s, 2H) , 4.46 (d, J = 11.3 Hz, 1H) , 3.11 (s, 3H) , 2.53 (s, 3H) , 2.16 (s, 3H) .
Example 5B: SFC: Retention time: 2.673 min. LCMS: [M+H] + = 445.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.75 (s, 1H) , 7.45 –7.29 (m, 3H) , 7.27 –7.18 (m, 1H) , 6.99 –6.93 (m, 1H) , 6.89 (d, J = 7.5 Hz, 1H) , 5.18 (s, 2H) , 4.46 (d, J = 11.3 Hz, 1H) , 3.11 (s, 3H) , 2.53 (s, 3H) , 2.16 (s, 3H) .
Examples 6A and 6B: Synthesis of (R) - (4- ( (7- (cyclopent-1-en-1-yl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone and (S) - (4- ( (7- (cyclopent-1-en-1-yl) -2, 6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (imino) (methyl) -λ6-sulfanone
Compound 6 was synthesized as described in example 1. Compound 6 (60 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 6A (8 mg, 13.3%yield) and Example 6B (9 mg, 15.0%yield) .
Example 6A: SFC: Retention time: 2.513 min. LCMS: [M+H] + = 417.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.62 (s, 1H) , 7.61 (d, J = 7.6 Hz, 2H) , 5.75 –5.65 (m, 1H) , 5.55 –5.43 (m, 2H) , 4.54 (s, 1H) , 3.12 (s, 3H) , 2.47 (s, 3H) , 2.37 (s, 3H) , 2.48 –2.28 (m, 3H) , 2.20 –1.80 (m, 3H) .
Example 6B: SFC: Retention time: 2.865 min. LCMS: [M+H] + = 417.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.62 (s, 1H) , 7.61 (d, J = 8.0 Hz, 2H) , 5.75 –5.65 (m, 1H) , 5.55 –5.43 (m, 2H) , 4.54 (s, 1H) , 3.11 (s, 3H) , 2.47 (s, 3H) , 2.37 (s, 3H) , 2.48 –2.28 (m, 3H) , 2.20 –1.80 (m, 3H) .
Examples 7A and 7B: Synthesis of (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one

Step 1: General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7_1)
A mixture of Compound 1_5 (200 mg, 0.54 mmol) and urea (324 mg, 5.4 mmol) was heated at 150℃ for 3 h. Then the reaction mixture was diluted with water (10 mL) and stirred for 1 h at room temperature. The precipitate is filtered off and dried to give the crude product Compound 7_1 (140 mg, 65.4%yield) . LCMS: [M+H] + = 398.1.
Step 2: General procedure for preparation of 1- (2, 6-difluoro-4- (methylthio) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7_2)
To a solution of Compound 7_1 (140 mg, 0.35 mmol) in DMF (5 mL) under an ice bath was added NaH (28.8 mg, 0.72 mmol, 60%in oil) . The mixture was stirred at this temperature for 30 min. Methyl iodide (50 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was diluted with water (20 mL) . The aqueous phase was extracted with ethyl acetate (20 mL x 2) . The combined organic phase was washed by brine (20 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 7_2 (98 mg, 67.6%yield) . LCMS: [M+H] + =412.1.
Step 3: General procedure for preparation of 1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 7) 
To a solution of Compound 7_2 (98 mg, 0.24 mmol) in EtOH (5 mL) were added iodobenzene diacetate (111 mg, 0.35 mmol) and ammonium acetate (35 mg, 0.46 mmol) . The mixture was stirred at 40℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by Prep-HPLC to provide the corresponding Compound 7 (70 mg, 66.4%yield) . LCMS: [M+H] += 443.2.
Step 4: General procedure for preparation of (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -3, 6-dimethyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
Compound 7 (70 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 7A (11 mg, 15.7%yield) and Example 7B (12 mg, 17.1%yield) .
Example 7A: SFC: Retention time: 3.661 min. LCMS: [M+H] + = 443.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.34 (s, 1H) , 7.46 –7.26 (m, 5H) , 7.11 (d, J = 6.9 Hz, 2H) , 4.69 (s, 2H) , 4.49 (s, 1H) , 3.43 (s, 3H) , 3.12 (s, 3H) , 2.10 (s, 3H) .
Example 7B: SFC: Retention time: 5.089 min. LCMS: [M+H] + = 443.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.34 (s, 1H) , 7.46 –7.26 (m, 5H) , 7.11 (d, J = 6.9 Hz, 2H) , 4.69 (s, 2H) , 4.48 (s, 1H) , 3.43 (s, 3H) , 3.12 (s, 3H) , 2.10 (s, 3H) .
Examples 8A and 8B: Synthesis of (S) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-7-phenyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
Compound 8 was synthesized from Compound 2_4 as described in example 7. Compound 8 (90 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A:Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 8A (27.8 mg, 30.9%yield) and Example 8B (27.91 mg, 31.0%yield) .
Example 8A: SFC: Retention time: 2.574 min. LCMS: [M+H] + = 459.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.00 (s, 1H) , 7.40 –7.17 (m, 5H) , 7.09 (d, J = 7.0 Hz, 2H) , 4.76 (s, 2H) , 4.47 (s, 1H) , 3.70 (s, 3H) , 3.40 (s, 3H) , 3.11 (s, 3H) .
Example 8B: SFC: Retention time: 3.180 min. LCMS: [M+H] + = 459.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.00 (s, 1H) , 7.40 –7.17 (m, 5H) , 7.09 (d, J = 7.0 Hz, 2H) , 4.76 (s, 2H) , 4.47 (s, 1H) , 3.70 (s, 3H) , 3.40 (s, 3H) , 3.10 (s, 3H) .
Examples 9A and 9B: Synthesis of (S) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one

Step 1: General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9_2) .
A mixture of Compound 9_1 (140 mg, 0.37 mmol) and urea (222 mg, 3.7 mmol) was heated at 150℃ for 3 h. Then the reaction mixture was diluted with water (10 mL) and stirred for 1 h at room temperature. The precipitate is filtered off and dried to give the crude product Compound 9_2 (80 mg, 53.4%yield) . LCMS: [M+H] + = 404.1.
Step 4: General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (methylthio) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9_3) .
To a solution of Compound 9_2 (80 mg, 0.20 mmol) in DMF (5 mL) under an ice bath were added NaH (18 mg, 0.46 mmol, 60%in oil) . The mixture was stirred at this temperature for 30 min. Methyl iodide (33 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was diluted with water (20 mL) . The aqueous phase was extracted with ethyl acetate (20 mL x 2) . The combined organic phase was washed by brine (20 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 9_3 (70 mg, 84.6%yield) . LCMS: [M+H] + =418.1.
Step 5: General procedure for preparation of 7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one (Compound 9) .
To a solution of Compound 9_3 (70 mg, 0.17 mmol) in EtOH (5 mL) were added iodobenzene diacetate (111 mg, 0.35 mmol) and ammonium acetate (35 mg, 0.46 mmol) . The mixture was stirred at 40℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by Prep-HPLC to provide the corresponding Compound 9 (58 mg, 77.1%yield) . LCMS: [M+H] += 449.2.
Step 6: General procedure for preparation of (S) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one and (R) -7- (cyclopent-1-en-1-yl) -1- (2, 6-difluoro-4- (S-methylsulfonimidoyl) benzyl) -6-methoxy-3-methyl-1, 3-dihydro-2H-imidazo [4, 5-c] pyridin-2-one
Compound 9 (58 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 9A (21 mg, 36.2%yield) and Example 9B (23 mg, 39.6%yield) .
Example 9A: SFC: Retention time: 4.500 min. LCMS: [M+H] + = 449.2. 1H NMR: (400 MHz, DMSO-d6) δ 7.88 (s, 1H) , 7.58 (d, J = 7.6 Hz, 2H) , 5.64 (s, 1H) , 5.23 (s, 2H) , 4.53 (s, 1H) , 3.77 (s, 3H) , 3.35 (s, 3H) , 3.10 (s, 3H) , 2.56 –2.48 (m, 2H) , 2.44 –2.36 (m, 2H) , 1.85 –1.78 (m, 2H) .
Example 9B: SFC: Retention time: 4.673 min. LCMS: [M+H] + = 449.2. 1H NMR: (400 MHz, DMSO-d6) δ 7.88 (s, 1H) , 7.58 (d, J = 7.6 Hz, 2H) , 5.64 (s, 1H) , 5.23 (s, 2H) , 4.53 (s, 1H) , 3.77 (s, 3H) , 3.35 (s, 3H) , 3.10 (s, 3H) , 2.56 –2.48 (m, 2H) , 2.44 –2.36 (m, 2H) , 1.85 –1.78 (m, 2H) .
Example 10: Synthesis of N- ( (4- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -3, 5-difluorophenyl) (methyl) (oxo) -l6-sulfaneylidene) cyanamide
To a solution of Compound 1 (200 mg, 0.47 mmol) in DCM (10 mL) were added cyanogen bromide (149 mg, 1.41 mmol) and 4-dimethylaminopyridine (11 mg, 0.094 mmol) . This reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. Solvent was removed under reduced pressure and the obtained residue was purified by Prep-HPLC to provide the corresponding Example 10 (5 mg, 2.4%yield) . LCMS: [M+H] + = 452.2.
Examples 11A and 11B: Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone

Step 1: General procedure for preparation of 2-methyl-5-nitro-3-phenylpyridin-4-ol (Compound 11_2) .
To a solution of Compound 11_1 (2.50 g, 10.78 mmol) in dioxane (10 mL) and H2O (1 mL) were added XPhos (1 g, 2.16 mmol) , Pd2 (dba) 3 (874 mg, 1.08 mmol) , K2CO3 (4.46 g, 32.34 mmol) , and phenylboronic acid (2.63 g, 21.56 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 11_2 (1.10 g, 41.7%yield) . LCMS: [M+H] + = 231.1.
Step 2: General procedure for preparation of 4-chloro-2-methyl-5-nitro-3-phenylpyridine (Compound 11_3) .
To a solution of Compound 11_2 (1.10 g, 4.78 mmol) in POCl3 (4 mL) was added N, N-dimethylaniline (2.10 g, 9.57 mmol) at 0℃. This reaction mixture was stirred at 80℃ for 1.5 h. Solvent was removed in vacuum to give the crude product which was purified by flash silica gel chromatography to afford Compound 11_3 (620 mg, 52.1%yield) . LCMS: [M+H] + = 249.0.
Step 3: General procedure for preparation of 2-methyl-N- ( (5- (methylthio) pyridin-2-yl) methyl) -5-nitro-3-phenylpyridin-4-amine (Compound 11_5) .
To a solution of Compound 11_3 (620 mg, 2.5 mmol) in acetonitrile (5 mL) were added Compound 11_4 (461 mg, 3 mmol) and DIPEA (645 mg, 5 mmol) . The mixture was stirred at 60℃ for 2 h.After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 11_5 (300 mg, 32.9%yield) . LCMS: [M+H] += 367.2.
Step 4: General procedure for preparation of 6-methyl-N4- ( (5- (methylthio) pyridin-2-yl) methyl) -5-phenylpyridine-3, 4-diamine (Compound 11_6) .
To a solution of Compound 11_5 (300 mg, 0.89 mmol) in ethanol (5 mL) were added nickel (II) chloride hexahydrate (21.4 mg, 0.09 mmol) and NaBH4 (67.3 mg, 1.78 mmol) at 0℃. The mixture was stirred at room temperature for 1 h. The mixture was filtered, and the filtrate was concentrated under vacuum to give a light yellow solid. The obtained solid was purified by flash silica gel chromatography to provide the corresponding Compound 11_6 (170 mg, 61.8%yield) . LCMS: [M+H] + = 337.1.
Step 5: General procedure for preparation of 2, 6-dimethyl-1- ( (5- (methylthio) pyridin-2-yl) methyl) -7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 11_7) .
To a solution of Compound 11_6 (170 mg, 0.51 mmol) in ethanol (3 mL) were added 1, 1, 1-trimethoxyethane (827 mg, 5.1 mmol) and pyridine hydrochloride (6 mg, 0.05 mmol) . The reaction mixture was stirred at 80℃ for 2 h. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide Compound 11_7 (100 mg, 55%yield) . LCMS: [M+H] +=361.1.
Step 6: General procedure for preparation of (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone (Compound 11) .
To a solution of Compound 11_7 (100 mg, 0.278 mmol) in ethanol (2 mL) were added iodobenzene diacetate (540 mg, 1.67 mmol) and ammonium acetate (86 mg, 1.11 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography to provide the corresponding Compound 11 (30 mg, 29.1%yield) . LCMS: [M+H] + = 392.2.
Step 7: General procedure for preparation of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 11 (30 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 11A (3 mg, 10.0%yield) and Example 11B (3 mg, 10.0%yield) .
Example 11A: SFC: Retention time: 5.512 min. LCMS: [M+H] + = 392.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.81 –8.71 (m, 2H) , 8.09 –8.02 (m, 1H) , 7.40-7.31 (m, 1H) , 7.30-7.20 (m, 2H) , 6.97 (d, J =7.2 Hz, 2H) , 6.66 (d, J = 8.0 Hz, 1H) , 5.03 (s, 2H) , 4.47 (s, 1H) , 3.13 (s, 3H) , 2.45 (s, 3H) , 2.17 (s, 3H) .
Example 11B: SFC: Retention time: 6.862 min. LCMS: [M+H] + = 392.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.81 –8.71 (m, 2H) , 8.09 –8.02 (m, 1H) , 7.40-7.31 (m, 1H) , 7.30-7.20 (m, 2H) , 6.97 (d, J =7.2 Hz, 2H) , 6.65 (d, J = 8.0 Hz, 1H) , 5.03 (s, 2H) , 4.47 (s, 1H) , 3.13 (s, 3H) , 2.44 (s, 3H) , 2.16 (s, 3H) .
Examples 12A and 12B: Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 3-bromo-N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methyl-5-nitropyridin-4-amine (Compound 12_2) .
To a solution of Compound 1_1 (200 mg, 0.80 mmol) in acetonitrile (5 mL) were added Compound 12_1 (164 mg, 0.96 mmol) and DIPEA (206 mg, 1.60 mmol) . The mixture was stirred at 60℃for 2 h. After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 12_2 (200 mg, 64.9%yield) . LCMS: [M+H] + = 387.0.
Step 2: General procedure for preparation of N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methyl-5-nitro-3-phenylpyridin-4-amine (Compound 12_3) .
To a solution of Compound 12_2 (200 mg, 0.52 mmol) in dioxane (10 mL) and H2O (1 mL) were added XPhos (29 mg, 0.06 mmol) , K2CO3 (211 mg, 1.53 mmol) and Pd2 (dba) 3 (27 mg, 0.03 mmol) , and phenylboronic acid (126 mg, 1.03 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 12_3 (160 mg, 80.6%) . LCMS: [M+H] + = 385.1.
Step 3: General procedure for preparation of N4- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methyl-5-phenylpyridine-3, 4-diamine (Compound 12_4) .
To a solution of Compound 12_3 (160 mg, 0.42mmol) in MeOH/DCM (6 mL/6 mL) were added Pd/C (30 mg, 10%wt) . The mixture was stirred at room temperature for 2 h under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to provide the corresponding Compound 12_4 (110 mg, 74.6%yield) . LCMS: [M+H] + = 355.1.
Step 4: General procedure for preparation of 1- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridine (Compound 12_5) .
To a solution of Compound 12_4 (110 mg, 0.31 mmol) in EtOH (2 mL) were added 1, 1, 1-trimethoxyethane (373 mg, 3.10 mmol) and pyridine hydrochloride (6 mg, 0.05 mmol) . The reaction mixture was stirred at 80℃ for 2 h. The reaction was concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography to provide Compound 12_5 (90 mg, 76.6%yield) . LCMS: [M+H] += 379.2.
Step 5: General procedure for preparation of (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone (Compound 12) .
To a solution of Compound 12_5 (90 mg, 0.24 mmol) in EtOH (3 mL) were added iodobenzene diacetate (393 mg, 1.21 mmol) and ammonium acetate (62 mg, 0.81 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was concentrated under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 12 (60 mg, 61.2%yield) . LCMS: [M+H] += 410.2.
Step 6: General procedure for preparation of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 12 (60 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 12A (5 mg, 8.3%yield) and Example 12B (5 mg, 8.3%yield) .
Example 12A: SFC: Retention time: 2.833 min. LCMS: [M+H] + = 410.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.74 (s, 1H) , 8.58 (s, 1H) , 7.93 (dd, J = 9.1, 1.6 Hz, 1H) , 7.36 (t, J = 7.5 Hz, 1H) , 7.26 –7.19 (m, 2H) , 6.88 (d, J = 7.6 Hz, 2H) , 5.14 (s, 2H) , 4.62 (s, 1H) , 3.18 (s, 3H) , 2.46 (s, 3H) , 2.14 (s, 3H) .
Example 12B: SFC: Retention time: 3.448 min. LCMS: [M+H] + = 410.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.74 (s, 1H) , 8.58 (s, 1H) , 7.93 (dd, J = 9.1, 1.6 Hz, 1H) , 7.36 (t, J = 7.5 Hz, 1H) , 7.26 –7.19 (m, 2H) , 6.88 (d, J = 7.6 Hz, 2H) , 5.14 (s, 2H) , 4.62 (s, 1H) , 3.18 (s, 3H) , 2.46 (s, 3H) , 2.14 (s, 3H) .
Examples 13A and 13B: Synthesis of (S) - (6- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 13 was synthesized from Compound 11_6 as described in example 3. Compound 13 (43 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A:n-Hexane; mobile phase B: EtOH (+0.1%7.0mol/l Ammonia in MEOH) ) mobile phase: (MEOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 13A (9 mg, 20.9%yield) and Example 13B (9mg, 20.9%yield) .
Compound 13A: SFC: Retention time: 13.036 min. LCMS: [M+H] + = 418.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.79 –8.69 (m, 2H) , 8.10 –8.02 (m, 1H) , 7.37-7.22 (m, 1H) , 7.27-7.19 (m, 2H) , 6.98 (d, J = 7.6 Hz, 2H) , 6.69 (d, J = 8.0 Hz, 1H) , 5.18 (s, 2H) , 4.47 (s, 1H) , 3.13 (s, 3H) , 2.16 (s, 3H) , 2.10-2.00 (m, 1H) , 1.08-0.98 (m, 2H) , 0.97-0.90 (m, 2H) .
Compound 13B: SFC: Retention time: 20.465 min. LCMS: [M+H] + = 418.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.79 –8.69 (m, 2H) , 8.10 –8.02 (m, 1H) , 7.37-7.22 (m, 1H) , 7.27-7.19 (m, 2H) , 6.98 (d, J = 7.6 Hz, 2H) , 6.69 (d, J = 8.0 Hz, 1H) , 5.18 (s, 2H) , 4.45 (s, 1H) , 3.13 (s, 3H) , 2.15 (s, 3H) , 2.10-2.00 (m, 1H) , 1.08-0.98 (m, 2H) , 0.97-0.90 (m, 2H) .
Examples 14A and 14B: Synthesis of (S) -imino (methyl) (6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) -λ6-sulfanone and (R) -imino (methyl) (6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) -λ6-sulfanone
Compound 14 was synthesized from Compound 11_6 as described in example 4. Compound 14 (60 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A:Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 14A (15 mg, 25.0%yield) and Example 14B (15 mg, 25.0%yield) .
Example 14A: SFC: Retention time: 1.445 min. LCMS: [M+H] + = 446.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.13 (s, 1H) , 8.70 (d, J = 2.0 Hz, 1H) , 8.04 (dd, J = 8.3, 2.3 Hz, 1H) , 7.34 (t, J = 7.5 Hz, 1H) , 7.25 –7.18 (m, 2H) , 6.98 (d, J = 6.5 Hz, 2H) , 6.84 (d, J = 8.3 Hz, 1H) , 5.25 (s, 2H) , 4.48 (s, 1H) , 3.14 (s, 3H) , 2.22 (s, 3H) .
Example 14B: SFC: Retention time: 1.920 min. LCMS: [M+H] + = 446.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.13 (s, 1H) , 8.70 (d, J = 2.0 Hz, 1H) , 8.04 (dd, J = 8.3, 2.3 Hz, 1H) , 7.34 (t, J = 7.5 Hz, 1H) , 7.25 –7.18 (m, 2H) , 6.98 (d, J = 6.5 Hz, 2H) , 6.84 (d, J = 8.3 Hz, 1H) , 5.25 (s, 2H) , 4.48 (s, 1H) , 3.14 (s, 3H) , 2.22 (s, 3H) .
Examples 15A and 15B: Synthesis of (R) - (5-fluoro-6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanoneand (S) - (5-fluoro-6- ( (6-methyl-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 15 was synthesized from Compound 12_4 as described in example 4. Compound 15 (40 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 15A (5 mg, 12.5%yield) and Example 15B (5 mg, 12.5%yield) .
Example 15A: SFC: Retention time: 2.125 min. LCMS: [M+H] + = 464.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 8.57 (s, 1H) , 7.94 (dd, J = 9.0, 1.7 Hz, 1H) , 7.38 (t, J = 7.6 Hz, 1H) , 7.30 –7.20 (m, 2H) , 6.99 –6.88 (m, 2H) , 5.34 (s, 2H) , 4.64 (s, 1H) , 3.20 (s, 3H) , 2.20 (s, 3H) .
Example 15B: SFC: Retention time: 2.428 min. LCMS: [M+H] + = 464.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 8.57 (s, 1H) , 7.94 (dd, J = 9.0, 1.7 Hz, 1H) , 7.38 (t, J = 7.6 Hz, 1H) , 7.30 –7.20 (m, 2H) , 6.99 –6.88 (m, 2H) , 5.34 (s, 2H) , 4.64 (s, 1H) , 3.20 (s, 3H) , 2.20 (s, 3H) .
Examples 16A and 16B: Synthesis of (S) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone and (R) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of 2-methoxy-N- ( (5- (methylthio) pyridin-2-yl) methyl) -5-nitro-3-phenylpyridin-4-amine (Compound 16_2) .
To a solution of Compound 16_1 (300 mg, 0.78 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (323 mg, 2.34 mmol) , XPhos-Pd-G2 (63 mg, 0.08 mmol) and phenylboronic acid (190 mg, 1.56 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 16_2 (230 mg, 77.2%yield) . LCMS: [M+H] +=383.1.
Step 2: General procedure for preparation of 6-methoxy-N4- ( (5- (methylthio) pyridin-2-yl) methyl) -5-phenylpyridine-3, 4-diamine (Compound 16_3) .
To a solution of Compound 16_2 (600 mg, 1.44 mmol) in MeOH/DCM (8 mL/8 mL) was added Pd/C (120 mg, 10%wt) . The mixture was stirred at room temperature for 2 h under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to provide the corresponding Compound 16_3 (420 mg, 76.0%yield) . LCMS: [M+H] += 353.1.
Step 3: General procedure for preparation of 6-methoxy-1- ( (5- (methylthio) pyridin-2-yl) methyl) -7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridine (Compound 16_4) .
A solution of Compound 16_3 (200 mg, 0.57 mmol) in TFA (10 mL) was stirred at 70℃ for 3 h.After the solvent was concentrated under reduced pressure, Et3N (10 mL) was added. The mixture was stirred at 70℃ for 1 h. The mixture was concentrated to dryness and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 16_4 (160 mg, 65.5%) . LCMS: [M+H] + = 431.1.
Step 5: General procedure for imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone (Compound 16) .
To a solution of Compound 16_4 (160 mg, 0.37 mmol) in EtOH (5 mL) were added iodobenzene diacetate (715 mg, 2.22 mmol) and ammonium acetate (114 mg, 1.48 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was removed under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 16 (100 mg, 58.3%yield) . LCMS: [M+H] + = 462.2.
Step 6: General procedure for preparation of (S) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone and (R) -imino (6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone
Compound 16 (100 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 16A (15 mg, 15.0%yield) and Example 16B (12 mg, 12.0%yield) .
Example 16A: SFC: Retention time: 3.579 min. LCMS: [M+H] + = 462.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.90 (s, 1H) , 8.68 (d, J = 1.8 Hz, 1H) , 8.01 (dd, J = 8.3, 2.3 Hz, 1H) , 7.29 (t, J = 7.4 Hz, 1H) , 7.24 –7.16 (m, 2H) , 7.02 –6.92 (m, 2H) , 6.78 (d, J = 8.2 Hz, 1H) , 5.26 (s, 2H) , 4.45 (s, 1H) , 3.80 (s, 3H) , 3.12 (s, 3H) .
Example 16B: SFC: Retention time: 3.923 min. LCMS: [M+H] + = 443.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.90 (s, 1H) , 8.68 (d, J = 1.8 Hz, 1H) , 8.01 (dd, J = 8.3, 2.3 Hz, 1H) , 7.29 (t, J = 7.4 Hz, 1H) , 7.24 –7.16 (m, 2H) , 7.02 –6.92 (m, 2H) , 6.78 (d, J = 8.2 Hz, 1H) , 5.26 (s, 2H) , 4.45 (s, 1H) , 3.80 (s, 3H) , 3.12 (s, 3H) .
Examples 17A and 17B: Synthesis of (S) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Step 1: General procedure for preparation of N- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -2-methoxy-5-nitro-3-phenylpyridin-4-amine (Compound 17_2) .
To a solution of Compound 17_1 (270 mg, 0.67 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (277 mg, 2.01 mmol) , XPhos-Pd-G2 (105 mg, 0.13 mmol) and phenylboronic acid (163 mg, 1.34 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2 atmosphere. After the solvent was concentrated under reduced pressure, the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 17_2 (270 mg, 77.9%) . LCMS: [M+H] +=401.1.
Step 2: General procedure for preparation of N4- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methoxy-5-phenylpyridine-3, 4-diamine (Compound 17_3) .
To a solution of Compound 17_2 (120 mg, 0.30 mmol) in MeOH (10 mL) was added Pd/C (24 mg, 10%wt) , and the reaction mixture was stirred at room temperature for 1 h under H2 atmosphere. The mixture was filtered, and the filter cake was washed with MeOH (3×10 mL) . The combined filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to provide the corresponding Compound 17_3 (65 mg, 58.6%) . LCMS: [M+H] +=371.1.
Step 3: General procedure for preparation of 1- ( (3-fluoro-5- (methylthio) pyridin-2-yl) methyl) -6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridine (Compound 17_4) .
A solution of Compound 17_3 (60 mg, 0.16 mmol) in TFA (5 mL) was stirred at 70℃ for 1 h. After the solvent was concentrated under reduced pressure, Et3N (5 mL) was added. The mixture was stirred at 70℃ for 1 h. The mixture was concentrated to dryness and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 17_4 (33 mg, 45.4%) . LCMS: [M+H] += 449.1.
Step 4: General procedure for preparation of (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone (Compound 17) .
To a solution of Compound 17_4 (33 mg, 0.07 mmol) in EtOH (3 mL) were added iodobenzene diacetate (143 mg, 0.44 mmol) and ammonium acetate (23 mg, 0.29 mmol) . The reaction mixture was stirred at 40℃ for 1 h. Solvent was concentrated under reduced pressure and the obtained residue was purified by flash silica gel chromatography to provide the corresponding Compound 17 (25 mg, 70.9%yield) . LCMS: [M+H] + = 480.2.
Step 5: General procedure for preparation of (S) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (5-fluoro-6- ( (6-methoxy-7-phenyl-2- (trifluoromethyl) -1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 17 (25 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: EtOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 17A (4 mg, 16.0%yield) and Example 17B (4 mg, 16.0%yield) .
Example 17A: SFC: Retention time: 3.789 min. LCMS: [M+H] + = 480.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.90 (s, 1H) , 8.56 (s, 1H) , 7.93 –7.86 (m, 1H) , 7.32 (t, J = 7.5 Hz, 1H) , 7.27 –7.12 (m, 2H) , 6.98-6.88 (m, 2H) , 5.36 (s, 2H) , 4.62 (s, 1H) , 3.79 (s, 3H) , 3.18 (s, 3H) .
Example 17B: SFC: Retention time: 4.020 min. LCMS: [M+H] + = 480.2. 1H NMR: (400 MHz, DMSO-d6) δ 8.90 (s, 1H) , 8.56 (s, 1H) , 7.93 –7.86 (m, 1H) , 7.32 (t, J = 7.5 Hz, 1H) , 7.27 –7.12 (m, 2H) , 6.98-6.88 (m, 2H) , 5.36 (s, 2H) , 4.62 (s, 1H) , 3.79 (s, 3H) , 3.18 (s, 3H) .
Examples 18A and 18B: Synthesis of (S) - (6- ( (2- (difluoromethyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2- (difluoromethyl) -6-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) -5-fluoropyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 18 was synthesized from Compound 12_4 as described in example 4. Compound 18 (58 mg) was separated by SFC (column:  (250*25 mm 10 μm) ; mobile phase A: Supercritical CO2; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 18A (6 mg, 10.3%yield) and Example 18B (6 mg, 10.3%yield) .
Example 18A: SFC: Retention time: 5.199 min. LCMS: [M+H] + = 446.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.03 (s, 1H) , 8.57 (s, 1H) , 7.93 (d, J = 8.7 Hz, 1H) , 7.54 –7.18 (m, 4H) , 6.93 (d, J = 7.6 Hz, 2H) , 5.32 (s, 2H) , 4.65 (s, 1H) , 3.19 (s, 3H) , 2.20 (s, 3H) .
Example 18B: SFC: Retention time: 5.583 min. LCMS: [M+H] + = 446.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.03 (s, 1H) , 8.56 (s, 1H) , 7.93 (d, J = 8.7 Hz, 1H) , 7.54 –7.18 (m, 4H) , 6.93 (d, J = 7.6 Hz, 2H) , 5.32 (s, 2H) , 4.65 (s, 1H) , 3.19 (s, 3H) , 2.20 (s, 3H) .
Examples 19A and 19B: Synthesis of (S) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2, 6-dimethyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 19 was synthesized from Compound 11_6 as described in example 4. Compound 19 (45 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 19A (7 mg, 15.6%yield) and Example 19B (7 mg, 15.6%yield) .
Example 19A: SFC: Retention time: 2.237 min. LCMS: [M+H] + = 428.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.04 (s, 1H) , 8.71 (s, 1H) , 8.04 (d, J = 7.7 Hz, 1H) , 7.58 –7.12 (m, 4H) , 6.97 (d, J = 6.9 Hz, 2H) , 6.72 (d, J = 8.2 Hz, 1H) , 5.24 (s, 2H) , 4.48 (s, 1H) , 3.14 (s, 3H) , 2.21 (s, 3H) .
Example 19B: SFC: Retention time: 2.898 min. LCMS: [M+H] + = 428.2. 1H NMR: (400 MHz, DMSO-d6) δ 9.04 (s, 1H) , 8.70 (s, 1H) , 8.03 (d, J = 7.7 Hz, 1H) , 7.58 –7.12 (m, 4H) , 6.97 (d, J = 6.9 Hz, 2H) , 6.72 (d, J = 8.2 Hz, 1H) , 5.24 (s, 2H) , 4.47 (s, 1H) , 3.13 (s, 3H) , 2.20 (s, 3H) .
Examples 20A and 20B: Synthesis of (S) -imino (6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone and (R) -imino (6- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (methyl) -λ6-sulfanone
Compound 20 was synthesized from Compound 16_3 as described in example 2. Compound 20 (45 mg) was separated by SFC (column:  (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: IPA (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 20A (6 mg, 13.3%yield) and Example 20B (6 mg, 13.3%yield) .
Example 20A: SFC: Retention time: 3.910 min. LCMS: [M+H] + = 408.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.3 Hz, 1H) , 8.49 (s, 1H) , 8.03 (dd, J = 8.2, 2.1 Hz, 1H) , 7.30 (t, J = 7.2 Hz, 1H) , 7.23 –7.15 (m, 2H) , 6.97 (d, J = 7.8 Hz, 2H) , 6.62 (d, J = 8.2 Hz, 1H) , 5.06 (s, 2H) , 4.45 (s, 1H) , 3.74 (s, 3H) , 3.12 (s, 3H) , 2.43 (s, 3H) .
Example 20B: SFC: Retention time: 3.967 min. LCMS: [M+H] + = 408.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.3 Hz, 1H) , 8.49 (s, 1H) , 8.03 (dd, J = 8.2, 2.1 Hz, 1H) , 7.30 (t, J = 7.2 Hz, 1H) , 7.23 –7.15 (m, 2H) , 6.97 (d, J = 7.8 Hz, 2H) , 6.62 (d, J = 8.2 Hz, 1H) , 5.06 (s, 2H) , 4.45 (s, 1H) , 3.74 (s, 3H) , 3.12 (s, 3H) , 2.43 (s, 3H) .
Examples 21A and 21B: Synthesis of (S) - (6- ( (2- (difluoromethyl) -6-methoxy-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone and (R) - (6- ( (2- (difluoromethyl) -6-methoxy-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) pyridin-3-yl) (imino) (methyl) -λ6-sulfanone
Compound 21 was synthesized from Compound 16_3 as described in example 4. Compound 21 (50 mg) was separated by SFC (column: REGIS (S, S) WHELK-O1 (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 21A (9 mg, 18.0%yield) and Example 21B (8 mg, 16.0%yield) .
Example 21A: SFC: Retention time: 3.354 min. LCMS: [M+H] + = 444.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.80 (s, 1H) , 8.68 (d, J = 2.1 Hz, 1H) , 8.00 (dd, J = 8.2, 2.3 Hz, 1H) , 7.39 (t, J = 51.6 Hz, 1H) , 7.28 (t, J = 7.6 Hz, 1H) , 7.21 –7.12 (m, 2H) , 6.96 (d, J = 7.6 Hz, 2H) , 6.67 (d, J = 8.3 Hz, 1H) , 5.25 (s, 2H) , 4.45 (s, 1H) , 3.78 (s, 3H) , 3.12 (s, 3H) .
Example 21B: SFC: Retention time: 3.837 min. LCMS: [M+H] + = 444.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.80 (s, 1H) , 8.68 (d, J = 2.1 Hz, 1H) , 8.00 (dd, J = 8.2, 2.3 Hz, 1H) , 7.39 (t, J = 51.6 Hz, 1H) , 7.28 (t, J = 7.6 Hz, 1H) , 7.21 –7.12 (m, 2H) , 6.96 (d, J = 7.6 Hz, 2H) , 6.67 (d, J = 8.3 Hz, 1H) , 5.25 (s, 2H) , 4.45 (s, 1H) , 3.78 (s, 3H) , 3.12 (s, 3H) .
Examples 22A and 22B: Synthesis of (S) -imino (4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (methyl) -λ6-sulfanone and (R) -imino (4- ( (6-methoxy-2-methyl-7-phenyl-1H-imidazo [4, 5-c] pyridin-1-yl) methyl) phenyl) (methyl) -λ6-sulfanone
Compound 22 was synthesized from Compound 2_1 as described in example 2. Compound 22 (200 mg) was separated by SFC (column: column: REGIS (S, S) WHELK-O1 (250*25 mm, 10μm) ; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1%7.0mol/L Ammonia in MeOH) ) to afford Example 22A (41 mg, 20.5%yield) and Example 22B (41 mg, 20.5%yield) .
Example 22A: SFC: Retention time: 4.951 min. LCMS: [M+H] + = 407.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.51 (s, 1H) , 7.69 (d, J = 8.2 Hz, 2H) , 7.34 -7.28 (m, 1H) , 7.24 -7.18 (m, 2H) , 7.05 (d, J =7.4 Hz, 2H) , 6.65 (d, J = 8.3 Hz, 2H) , 4.97 (s, 2H) , 4.14 (s, 1H) , 3.76 (s, 3H) , 3.01 (s, 3H) , 2.39 (s, 3H) .
Example 22B: SFC: Retention time: 5.848 min. LCMS: [M+H] + = 407.3. 1H NMR: (400 MHz, DMSO-d6) δ 8.52 (s, 1H) , 7.69 (d, J = 8.1 Hz, 2H) , 7.34 -7.28 (m, 1H) , 7.24 -7.18 (m, 2H) , 7.05 (d, J =7.4 Hz, 2H) , 6.66 (d, J = 8.2 Hz, 2H) , 4.97 (s, 2H) , 4.14 (s, 1H) , 3.76 (s, 3H) , 3.01 (s, 3H) , 2.39 (s, 3H) .
Example A: Enzymatic assay
ATP-Glo assay:
1. Diluted compounds in DMSO by hand for 11 points, 3 folds dilution. Then transferred 0.02 μL compounds to 384 assay plate by ECHO.
2. Added 2 μL specified concentration of ENPP1 to 384 assay plate. Centrifuged 1000 RPM for 1 min.
3. Added 2 μL specified concentration of ATP to the assay plate. Centrifuged 1000 RPM for 1 min.
4. Incubated at 25℃ for 60 min.
5. Added 4 μL AMP-Glo Reagent to the assay plates.
6. Centrifuged 1000 RPM for 1 min, incubate at 25℃ for 1 hours.
7. Added 8 μL Kinase Detection Reagent to the assay plates.
8. Centrifuged 1000 RPM for 1 min, incubated at 25℃ for 1 hours. The final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl and 0.1%BSA
9. Read on Envision for US LUM as RLU.
10. Analyzed the raw data using the equation (V. Data analysis) .
cGAMP-Glo assay:
1. Diluted compounds in DMSO by hand for 11 points, 3 folds dilution. Then transferred 0.02 μL compounds to 384 assay plate by ECHO.
2. Added 2 μL specified concentration of ENPP1 to 384 assay plate, centrifuged 1000 RPM for 1 min.
3. Added 2 μL specified concentration of 2'3'-cGAMP to the assay plate, centrifuged 1000 RPM for 1 min.
4. Incubated at 25℃ for 60 min.
5. Added 4 μL AMP-Glo Reagent to the assay plates.
6. Centrifuged 1000 RPM for 1 min, incubated at 25℃ for 1 hours.
7. Added 8 μL Kinase Detection Reagent to the assay plates.
8. Centrifuged 1000 RPM for 1 min, incubate at 25℃ for 1 hours. The final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl and 0.1%BSA
9. Read on Envision for US LUM as RLU.
10. Analyzed the raw data using the equation (V. Data analysis) .
The data is shown in Table 3.
TABLE 3

IC50 (nM) : 0 < A ≤ 1 nM; 1 nM < B ≤ 10 nM; 10 nM < C ≤ 100 nM; 100 nM < D.

Claims (86)

  1. A compound of Formula (I) , or a pharmaceutically acceptable salt or stereoisomer thereof:
    wherein:
    Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    L is a bond, -NH-, or -O-;
    each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    or two R1 on the same atom are taken together to form an oxo;
    n is 0, 1, 2, 3, 4, 5, or 6;
    R2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
    R3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
    is a single bond or a double bond; wherein:
    whenis a double bond, X is N or CRX and Y is N or CRY;
    whenis a single bond, X is C (=O) and Y is NRY1 or C (RY2) 2;
    RX is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
    RY is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
    RY1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R;
    each RY2 is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;
    Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    or two R4 on the same atom are taken together to form an oxo;
    m is 0, 1, 2, 3, or 4;
    R5 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    R6 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    R7 is hydrogen, halogen, -CN, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or two Ra are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
    each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or two Rb are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
    Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
    each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;
    or two R on the same atom form an oxo.
  2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ia) :
  3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ia-1) :

  4. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ia-2) :
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N and Y is N.
  6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CRX and Y is N.
  7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is N and Y is CRY.
  8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CRX and Y is CRY.
  9. The compound of any one of claims 1-4, 6, or 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RX is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  10. The compound of claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RX is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  11. The compound of any one of claims 1-4 or 7-10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RY is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl.
  12. The compound of claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RY is hydrogen or C1-C6alkyl.
  13. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ib) :
  14. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ib-1) :
  15. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of Formula (Ib-2) :
  16. The compound of any one of claims 1 or 13-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is NRY1.
  17. The compound of claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
  18. The compound of any one of claims 1 or 13-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is C (RY2) 2.
  19. The compound of claim 18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each RY2 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.
  20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.
  21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is aryl.
  22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is heteroaryl.
  23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is a bond.
  24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R1 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.
  27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R1 is independently halogen.
  28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0, 1, or 2.
  29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0 or 1.
  30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 or 2.
  31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.
  32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is hydrogen or C1-C6alkyl.
  33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is hydrogen.
  34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.
  35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is hydrogen or C1-C6alkyl.
  36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is hydrogen.
  37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is cycloalkyl or heterocycloalkyl.
  38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is cycloalkyl.
  39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is heterocycloalkyl.
  40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is aryl or heteroaryl.
  41. The compound of any one of claims 1-36 or 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is aryl.
  42. The compound of any one of claims 1-36 or 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is heteroaryl.
  43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R4 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.
  46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R4 is independently C1-C6alkyl.
  47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0, 1, or 2.
  48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0 or 1.
  49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is hydrogen, -CN, -ORa, C1-C6alkyl, or C1-C6haloalkyl.
  51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is -ORa or C1-C6alkyl.
  52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
  53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.
  54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 is hydrogen or C1-C6alkyl.
  55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is hydrogen, -CN, or C1-C6alkyl.
  56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is hydrogen or -CN.
  57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is hydrogen.
  58. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is -CN.
  59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R8 is -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.
  61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R8 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.
  62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R8 is C1-C6alkyl.
  63. A compound selected from table 1 or table 2, or a pharmaceutically acceptable salt or stereoisomer thereof.
  64. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  65. A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of claims 1-63, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 64.
  66. The method of claim 65, wherein the cancer is a solid tumor.
  67. The method of claim 66, wherein the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, or sarcoma.
  68. The method of claim 66, wherein the cancer is a hematologic malignancy.
  69. The method of claim 68, wherein the hematologic malignancy is a leukemia, a lymphoma, or a myeloma.
  70. The method of claim 68, wherein the hematologic malignancy is a B-cell malignancy.
  71. The method of claim 68, wherein the hematologic malignancy is multiple myeloma.
  72. The method of any one of the claims 65-71, wherein the cancer is a relapsed or refractory cancer.
  73. The method of any one of the claims 65-71, wherein the cancer is a metastatic cancer.
  74. A method of treating an infection in a subject in need thereof comprising administering a compound of any one of claims 1-63, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 64.
  75. The method of claim 74, wherein the infection is a viral infection.
  76. The method of claim 75, wherein the viral infection is due to a DNA virus.
  77. The method of claim 75 or 76, wherein the viral infection is due to a herpesvirus.
  78. The method of claim 77, wherein the herpesvirus is selected from herpes simplex viruses 1 (HSV-l) , herpes simplex viruses 2 (HSV-2) , varicella-zoster virus (VZV) , Epstein-Barr virus (EBV) , human cytomegalovirus (HCMV) , human herpesvirus 6A (HHV-6A) , human herpesvirus 6B (HHV-6B) , human herpesvirus 7 (HHV-7) , and Kaposi's sarcoma-associated herpesvirus (KSHV) .
  79. The method of claim 77 or 78, wherein the herpesvirus is herpes simplex viruses 1 (HSV-l) .
  80. The method of claim 76 or 77, wherein the viral infection is due to a retrovirus.
  81. The method of claim 80, wherein the retrovirus is human immunodeficiency virus (HIV) .
  82. The method of claim 76 or 77, wherein the viral infection is due to a hepatitis virus.
  83. The method of claim 82, wherein the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV) .
  84. The method of claim 76 or 77, wherein the viral infection is due to vaccinia virus (VACV) , adenovirus, or human papillomaviruses (HPV) .
  85. The method of claim 84, wherein the viral infection is due to a RNA virus.
  86. The method of claim 76 or 77, wherein the viral infection is due to dengue fever virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
PCT/CN2023/123133 2022-10-08 2023-10-07 Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof Ceased WO2024074128A1 (en)

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WO2025007955A1 (en) * 2023-07-06 2025-01-09 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase/phosphodiesterase 1 (enpp1) inhibitor combinations and uses thereof
WO2025026377A1 (en) * 2023-08-02 2025-02-06 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof
WO2025233863A1 (en) * 2024-05-07 2025-11-13 Re Ventures I, Llc Enpp1 inhibitors

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WO2020028724A1 (en) * 2018-08-01 2020-02-06 Stingray Therapeutics, Inc. Substituted-3h-imidazo[4,5-c]pyridine and 1h-pyrrolo[2,3-c]pyridine series of novel ectonucleotide pyrophosphatase/phosphodiesterase-1 (enpp1) and stimulator for interferon genes (sting) modulators as cancer immunotherapeutics
WO2021061803A1 (en) * 2019-09-23 2021-04-01 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Phosphodiesterase inhibitors and use
WO2023076866A1 (en) * 2021-10-25 2023-05-04 Volastra Therapeutics, Inc. Tricyclic sulfoximine inhibitors of enpp1
WO2023143520A1 (en) * 2022-01-28 2023-08-03 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof

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WO2019177971A1 (en) * 2018-03-12 2019-09-19 Mavupharma, Inc. Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp-1) inhibitors and uses thereof
WO2020028724A1 (en) * 2018-08-01 2020-02-06 Stingray Therapeutics, Inc. Substituted-3h-imidazo[4,5-c]pyridine and 1h-pyrrolo[2,3-c]pyridine series of novel ectonucleotide pyrophosphatase/phosphodiesterase-1 (enpp1) and stimulator for interferon genes (sting) modulators as cancer immunotherapeutics
WO2021061803A1 (en) * 2019-09-23 2021-04-01 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Phosphodiesterase inhibitors and use
WO2023076866A1 (en) * 2021-10-25 2023-05-04 Volastra Therapeutics, Inc. Tricyclic sulfoximine inhibitors of enpp1
WO2023143520A1 (en) * 2022-01-28 2023-08-03 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof

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* Cited by examiner, † Cited by third party
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WO2025007955A1 (en) * 2023-07-06 2025-01-09 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase/phosphodiesterase 1 (enpp1) inhibitor combinations and uses thereof
WO2025026377A1 (en) * 2023-08-02 2025-02-06 Insilico Medicine Ip Limited Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof
WO2025233863A1 (en) * 2024-05-07 2025-11-13 Re Ventures I, Llc Enpp1 inhibitors

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