WO2023250439A1 - Inhibiteurs de trex1 et leurs utilisations - Google Patents

Inhibiteurs de trex1 et leurs utilisations Download PDF

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WO2023250439A1
WO2023250439A1 PCT/US2023/068909 US2023068909W WO2023250439A1 WO 2023250439 A1 WO2023250439 A1 WO 2023250439A1 US 2023068909 W US2023068909 W US 2023068909W WO 2023250439 A1 WO2023250439 A1 WO 2023250439A1
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compound
cycloalkyl
heterocycloalkyl
heteroaryl
aryl
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PCT/US2023/068909
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Ryan C. Clark
Henry William Beecroft Johnson
Thomas Walter. DUBENSKY Jr.
Biswajit Kalita
Athisayamani Jeyaraj DURAISWAMY
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Tempest Therapeutics, Inc.
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Publication of WO2023250439A1 publication Critical patent/WO2023250439A1/fr

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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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Definitions

  • TILs tumor infiltrating T cells
  • TME tumor microenvironment
  • Transcriptional profiling analyses of melanoma patients has revealed that tumors containing infiltrating activated T cells are characterized by a type I IFN transcriptional signature (Harlin et al., Cancer Res.2009, 69, 3077-3085). Studies in mice have demonstrated that type I IFN signaling plays a critical role in tumor-initiated T cell priming (Diamond et al., J. Exp. Med.2011, 208, 1989-2003; and Fuertes et al., J. Exp. Med.2011, 208, 2005-2016).
  • mice lacking the IFN- ⁇ / ⁇ receptor in dendritic cells (“DCs”) cannot reject immunogenic tumors and CD8 ⁇ + DCs from these mice are defective in antigen cross-presentation to CD8 + T cells.
  • DCs dendritic cells
  • Baft3 -/- mice that lack the CD8 ⁇ + DC lineage lose the capacity to spontaneously prime tumor-specific CD8 + T cells (Fuertes et al., J. Exp. Med.2011, 208, 2005-2016; and Hildner et al., Science 2008, 322, 1097-1100).
  • PAMPs Pathogen-Associated Molecular Patterns
  • PRRs germ-line encoded host cell Pattern Recognition Receptors
  • DAMPs Danger Associated Molecular Patterns
  • innate immune activators One objective in the design of innate immune activators is to select defined PAMPs, DAMPS, or synthetic molecules which activate designated PRRs and initiate a desired response.
  • Innate immune ligands (agonists) such as monophosphoryl lipid A (“MPL”) and CpG are microbial-derived PAMPs recognized by Toll-like receptors (“TLRs”), a class of PRRs that signal through MyD88 and TRIF adaptor molecules and mediate induction of NF-kB dependent proinflammatory cytokines (Kawai and Akira, Nat. Immunol.2010, 11, 373-384).
  • TLRs present on the cell surface e.g., TLR-4
  • endosomes e.g., TLR-9
  • TLRs present on the cell surface e.g., TLR-4
  • TLR-9 e.g., TLR-9
  • TLRs present on the cell surface e.g., TLR-4
  • endosomes e.g., TLR-9
  • TLRs present on the cell surface e.g., TLR-4
  • TLR-9 endosomes
  • the productive growth cycle of multiple pathogens including viruses and intracellular bacteria occurs in the cytosol.
  • the compartmentalization of extracellular, vacuolar, and cytosolic PRRs has led to the hypothesis that the innate immune system can sense particular productively replicating pathogenic microbes by monitoring the cytosol (Vance et al., Science 2009, 323, 1208-1211).
  • This provides a rationale for the use of agonists that activate PRRs comprising the cytosolic
  • Nucleic acids from bacterial, viral, protozoan, and fungal pathogens are sensed by several distinct cytosolic signaling pathways. When activated, these individual pathways induce a characteristic cytokine profile, which in turn shapes the antigen (“Ag”)-specific immune response.
  • Ag antigen
  • the nucleotide binding oligomerization domain (“NOD”)-like receptor (“NLR”) family such as “absent in melanoma 2” (“AIM2”), senses cytosolic double-stranded (“ds”) DNA, triggering activation of the inflammasome and caspase-1 dependent production of IL-1 ⁇ (Strowig et al., Nature 2012, 481, 278-286).
  • Type I interferons are the signature cytokines induced by two distinct TLR- independent cytosolic signaling pathways.
  • RNA helicases including retinoic acid-inducible gene I (“RIG-I”) and melanoma differentiation-associated gene 5 (“MDA-5”), and through the IFN- ⁇ promoter stimulator 1 (“IPS-1”) adaptor protein mediate phosphorylation of the IRF-3 transcription factor, leading to induction of IFN- ⁇ (Ireton and Gale, Viruses 2011, 3, 906-919).
  • IPS-1 -/- deficient mice have increased susceptibility to infection with RNA viruses.
  • Synthetic dsRNA such as polyinosinic:polycytidylic acid (“poly (I:C)”) and poly ICLC, an analog that is formulated with poly L lysine to resist RNase digestion, is an agonist for both TLR3 and MDA5 pathways, is a powerful inducer of IFN- ⁇ , and is currently being evaluated in several diverse clinical settings (Caskey et al., J. Exp. Med. 2011, 208, 2357-2366).
  • Stimulator of Interferon Genes is the central mediator for the second cytosolic pathway that triggers type I interferon in response to sensing cytosolic double-stranded (“ds”) DNA from infectious pathogens or aberrant host cells (DAMPS) (Motwani, Nat. Rev. Genet.2019, 20, 657-674, and Barber, Curr. Opin. Immunol.2011, 23, 10-20).
  • DAMPS cytosolic double-stranded
  • TMEM173, MITA, ERIS, and MPYS STING was discovered by Glen Barber and colleagues using cDNA expression cloning methods as a MyD88-independent host cell defense factor expressed in macrophages, dendritic cells, and fibroblasts, and was found to induce expression of IFN- ⁇ and NF- ⁇ B dependent pro-inflammatory cytokines in response to sensing cytoplasmic DNA (Ishikawa and Barber, Nature 2008, 455, 674-678).
  • STING is a transmembrane protein localized to the endoplasmic reticulum that undergoes a conformational change in response to direct binding of cyclic dinucleotides (“CDNs”), resulting in a downstream signaling cascade involving TBK1 activation, IRF-3 phosphorylation, and production of IFN- ⁇ and other cytokines (Burdette et al., Nature 2011, 478, 515- 518; Burdette and Vance, Nat. Immunol.2013, 14, 19-26; and Ishikawa and Barber, Nature 2008, 455, 674-678). After CDN binding by STING, canonical NF- ⁇ B dependent cytokines are also induced (Chen et al., Nat.
  • IFN- ⁇ is the signature cytokine induced in response to STING activation, by either exogenous CDNs produced by bacterial infection, or through binding of a structurally distinct endogenous CDN produced by a host cyclic GMP-AMP synthetase (“cGAS”) in response to sensing cytosolic double-stranded DNA (“dsDNA”) (Ablasser et al., Nature 2013, 498, 380- 384; Diner et al., Cell Rep.2013, 3, 1355-1361; McWhirter et al., J. Exp.
  • IFNs stimulate expression of interferon-stimulated genes (“ISGs”), a key event that links host innate immunity to the initiation of adaptive immunity.
  • ISGs interferon-stimulated genes
  • IT intratumoral
  • cytokine storm or cytokine release syndrome due to expression of high levels of pro-inflammatory cytokines such as IL-6 and TNF- ⁇ resulting from broad activation of STING with the systemic administration of potent ligands/agonists.
  • IT injection of CDNs demonstrates potent anti-tumor effects in multiple syngeneic mouse tumor models without significant local or systemic toxicity.
  • MHC major histocompatibility complex
  • the immunoediting process is constant due to the genetic instability of tumor cells, such that the antigens presented by a given metastatic tumor in an individual with advanced cancer can be distinct from those presented by a distinct metastatic tumor lesion.
  • the genetic heterogeneity in evolving progressing tumors means that a CD8+ T cell with specificity for a designated antigen expressed on one tumor cell, with said CD8 + T cell able to kill that tumor cell, may not recognize a separate and distinct tumor because its cognate antigen is not presented on that tumor cell.
  • Implanted mouse tumor models in comparison, lack genetic heterogeneity because these models are based on homogenous tumor cell lines that grow to lethality before immune selection.
  • tumor-specific CD8 + T cells primed locally in the draining lymph node serving an injected tumor can traffic to and eradicate distal non-injected tumors.
  • mice which has been referred to as an abscopal effect, is an artificial model of human cancer because the identical tumor cell line, e.g., CT26 colorectal tumor cells, is implanted on opposite flanks of the mouse.
  • tumor antigen-specific CD4 + and CD8 + T cells are implanted on opposite flanks of the mouse.
  • Such selective targeting of designated innate immune receptors in the TME is anticipated to induce desired IRF3- and NF- ⁇ B-dependent pro-inflammatory cytokines and chemokines that are required to recruit, activate, and initiate innate and adaptive immune cell populations, resulting in priming of tumor-specific T cell immunity.
  • STING has been shown in mice to be a critical innate immune receptor for development of antigen-specific T cell immunity, and genetic mutations in STING result in a significant inflammatory disease in humans known as STING-associated vasculopathy with onset in infancy (“SAVI”), providing scientific rationale for targeting the STING pathway to initiate tumor- specific immunity (Fuertes et al., J. Exp. Med.2011, 208, 2005-2016).
  • SAVI STING-associated vasculopathy with onset in infancy
  • TREX1 three prime repair exonuclease 1
  • TREX1 three prime repair exonuclease 1
  • TREX1 is a 3’-5’ DNA exonuclease that maintains immune homeostasis by limiting activation of cGAS-STING in normal cells.
  • TREX1 is induced by cytosolic DNA resulting from inflammation, DNA repair deficiency, chemotherapy, or radiotherapy.
  • Severe human inflammatory diseases including Aicardi-Goutines syndrome (“AGS”) and chilblain lupus are interferonopathies resulting from inactivating genetic mutations in TREX1, lead to increased levels of cytosolic dsDNA and chronic activation of the STING pathway.
  • TREX1 is an upstream regulatory mediator of radiation- induced anti-tumor immunity, and the immunity induced by radiation is STING-dependent (Deng et al., Immunity 2014, 41, 843-852). Radiation dose is reversibly correlated with the induced level of IFN- ⁇ , the signature cytokine of activated STING.
  • TREX1 is significantly induced at levels which substantially degrades cytosolic DNA, leading to lower levels of production of cGAMP by cGAS and correspondingly decreased activation of STING and induction of IFN- ⁇ .
  • hyperfractionated radiation lower dose levels of radiation delivered over multiple doses
  • TREX-1 inhibitor an effective anti-tumor immunity and tumor regression
  • TREX-1 inhibitor an effective TREX-1 inhibitor.
  • Genotoxic stress-mediated induction of TREX1 can also be achieved by DNA-modifying chemotherapeutic agents, including dsDNA crosslinking alkylating agents such as nimustine, carmustine, fotemustine, and topotecan (Tomicic et al., Biochimica et Biophysica Acta 2013, 1835, 11-27).
  • Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: Formula (I) as disclosed herein.
  • a compound of Formula (Ia) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: Formula (Ia) as disclosed herein.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof Formula (Ic) as disclosed herein.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer in a subject in need thereof comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the cancer is characterized a DNA repair deficiency in one or more DNA repair pathways.
  • the DNA repair deficiency is a deficiency in the base excision repair (“BER”) pathway, the Fanconi anaemia-mediated repair (“FA”) pathway, the homologous recombination (“HR”) pathway, the nucleotide excision repair (“NER”) pathway, the non-homologous end joining (“NHEJ”) pathway, the mismatch repair (“MMR”) pathway, the RecQ-mediated repair (“RecQ”) pathway, or the double-stranded breaks (“DSB”) pathway.
  • the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway.
  • the DNA repair deficiency is a BRCA1 mutation.
  • the method further comprises administering a DNA repair inhibitor.
  • the DNA repair inhibitor is a poly ADP ribose polymerase (“PARP”) inhibitor.
  • PARP poly ADP ribose polymerase
  • the method further comprises administering an alkylating agent.
  • the alkylating agent is cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, nimustine, fotemustine, streptozocin, or busulfan.
  • the method further comprises administering a DNA damaging agent.
  • the DNA damaging agent is camptothecin, etoposide, oxaliplatin, cisplatin, or doxorubicin.
  • the compound is administered in conjunction with high-dose radiotherapy.
  • the high-dose radiotherapy is administered as a single dose and/or hypofractionated.
  • the compound is administered in conjunction with Stereotactic Body Radiation Therapy (SBRT).
  • SBRT Stereotactic Body Radiation Therapy
  • 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
  • a numerical range such as “C 1 -C 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 C1-C10 alkyl.
  • the alkyl is a C1- C 6 alkyl.
  • the alkyl is a C 1 -C 5 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C1-C3 alkyl.
  • an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • alkyl is optionally substituted with one or more 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 or Z or E conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 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 one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkenyl is optionally substituted with one or more 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.
  • C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one or more 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 one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with one or more halogen, - CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0029] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above.
  • an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2.
  • the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • 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 anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the aryl is optionally substituted with one or more 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, and/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., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 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
  • 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]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with one or more 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, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to -O-haloalkyl, with haloalkyl as defined above.
  • “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 includes, 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 includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. [0038] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium.
  • the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [0039] “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, 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, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples are, for example, - Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - NO 2 .
  • a heteroalkyl is optionally substituted with one or more 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 is C-linked.
  • the heterocycloalkyl is N-linked. 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.
  • 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., 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-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • 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 is optionally substituted, for example, with one or more 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 one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked.
  • 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. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]
  • a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the terms “treat,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, amelioration, or inhibition. Rather, there are varying degrees of treatment, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • the treatment, amelioration, or inhibition provided by the methods disclosed herein can include treatment, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.
  • “treatment,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • 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. Compounds [0045] Described herein are compounds that are useful in treating diseases associated with TREX1 and STING dysfunction.
  • the compounds disclosed herein are TREX1 inhibitors. In some embodiments, the compounds disclosed herein are reversible TREX1 inhibitors. In some embodiments, the compounds disclosed herein are reversible, non-competitive TREX1 inhibitors.
  • the compound is of Formula (Ia): Formula (Ia).
  • Ring B is a bicyclic heteroaryl or bicyclic heterocycloalkyl.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to two heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is a bicyclic heteroaryl.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is benzimidazole, benzoxazole, or benzothiazole.
  • Ring B is benzimidazole.
  • Ring B is a bicyclic heterocycloalkyl.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is isoindolinyl, tetrahydroisoquinolinyl, or tetrahydrobenzoazepinyl.
  • Ring B is tetrahydroisoquinolinyl.
  • each R 5 is independently halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl or heterocycloalkyl.
  • each R 5 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R5 is independently aryl or heteroaryl.
  • each R 5a is independently halogen, -CN, -OH, -OR a , - NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 - C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 5a is independently halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C 1- C6alkyl, or C1-C6haloalkyl.
  • each R 5a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.
  • each R 5a is independently halogen or C 1 -C 6 alkyl.
  • each R 5a is independently halogen, -CN, -OR a , or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia), each R 5a is independently halogen, -OR a , or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia), each R 5a is independently halogen. [0070] In some embodiments of a compound of Formula (I) or (Ia), each R 5 is independently , , [0071] In some embodiments of a compound of Formula (I) or (Ia), m is 0, 1, 2, or 3.
  • m is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia), m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia), m is 0. In some embodiments of a compound of Formula (I) or (Ia), m is 1. In some embodiments of a compound of Formula (I) or (Ia), m is 2. In some embodiments of a compound of Formula (I) or (Ia), m is 3.
  • each R 10 is independently halogen, - CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.
  • each R 10 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently phenyl independently optionally substituted with one or more R 10a .
  • each R 10a is independently halogen.
  • each R 10 is independently , , , , , . In some embodiments of a compound of Formula (Ia- 1), each R 10 is independently . In some embodiments of a compound of Formula (Ia-1), each R 10 is independently , , , . In some embodiments of a compound of Formula (Ia- 1), each R 10 is independently . In some embodiments of a compound of Formula (Ia-1), each R 10 is independently .
  • each R 10 is In some embodiments of a compound of Formula (Ia-1), each R 10 is [0085] In some embodiments of a compound of Formula (Ia-1), s is 0 or 1. In some embodiments of a compound of Formula (Ia-1), s is 1 or 2. In some embodiments of a compound of Formula (Ia-1), s is 0. In some embodiments of a compound of Formula (Ia-1), s is 1. In some embodiments of a compound of Formula (Ia-1), s is 2.
  • t is 0 or 1. In some embodiments of a compound of Formula (Ia-1), t is 1 or 2. In some embodiments of a compound of Formula (Ia-1), t is 0. In some embodiments of a compound of Formula (Ia-1), t is 1. In some embodiments of a compound of Formula (Ia-1), t is 2. [0094] In some embodiments of a compound of Formula (Ia-1), each R 11 is independently , independently .
  • each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently .
  • each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . In some embodiments of a compound of Formula (Ia-1), each R 11 is independently . [0095] In some embodiments of a compound of Formula (Ia-1), the compound has the following formula: some embodiments of a compound of Formula (Ia-1), the some embodiments of a compound of Formula (Ia-1), the compound has the following formula:
  • R 6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(cycloalkyl) or C 1 -C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(aryl); wherein the alkylene and aryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally substituted with one or more R 6a .
  • Ring C is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (Ic), Ring C is aryl or heteroaryl. In some embodiments of a compound of Formula (Ic), Ring C is cycloalkyl or aryl. In some embodiments of a compound of Formula (Ic), Ring C is cycloalkyl. In some embodiments of a compound of Formula (Ic), Ring C is aryl. In some embodiments of a compound of Formula (Ic), Ring C is phenyl.
  • each R 8 is independently halogen, -CN, -OH, -NH2, - 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 - C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.
  • each R 8 is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy.
  • each R 8 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, or C 1 - C3haloalkyl.
  • each R 8 is independently halogen, C1- C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound of Formula (Ic), each R 8 is independently halogen or C 1 -C 3 alkyl. [00106] In some embodiments of a compound of Formula (Ic), p is 0, 1, or 2. In some embodiments of a compound of Formula (Ic), p is 0 or 1. In some embodiments of a compound of Formula (Ic), p is 1 or 2. In some embodiments of a compound of Formula (Ic), p is 0. In some embodiments of a compound of Formula (Ic), p is 1.
  • p is 2. In some embodiments of a compound of Formula (Ic), p is 3. [00107] In some embodiments of a compound of Formula (Ic), Ring D is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (Ic), Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (Ic), Ring D is cycloalkyl or aryl. In some embodiments of a compound of Formula (Ic), Ring D is cycloalkyl. In some embodiments of a compound of Formula (Ic), Ring D is aryl. In some embodiments of a compound of Formula (Ic), Ring D is phenyl.
  • q is 0, 1, or 2. In some embodiments of a compound of Formula (Ic), q is 0 or 1. In some embodiments of a compound of Formula (Ic), q is 1 or 2. In some embodiments of a compound of Formula (Ic), q is 0. In some embodiments of a compound of Formula (Ic), q is 1. In some embodiments of a compound of Formula (Ic), q is 2. In some embodiments of a compound of Formula (Ic), q is 3. [00110] In some embodiments of a compound of Formula (Ic), the compound has the following formula: .
  • the compound is of Formula (IIa): Formula (IIa).
  • Ring B is phenyl or heteroaryl.
  • Ring B is phenyl.
  • Ring B is 5- or 6-membered heteroaryl.
  • Ring B is 6-membered heteroaryl.
  • Ring B is cycloalkyl or heterocycloalkyl.
  • Ring B is monocyclic cycloalkyl or monocyclic heterocycloalkyl.
  • Ring B is monocyclic heterocycloalkyl.
  • Ring B is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a bicyclic heteroaryl or bicyclic heterocycloalkyl.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to two heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl or a 8- to 12-membered bicyclic heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl comprises one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is a bicyclic heteroaryl.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is benzimidazole, benzoxazole, or benzothiazole.
  • Ring B is benzimidazole.
  • Ring B is a bicyclic heterocycloalkyl.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to three heteroatoms selected from the group consisting of O, S, and N.
  • Ring B is a 8- to 12-membered bicyclic heterocycloalkyl comprising one to two heteroatoms selected from the group consisting of O and N.
  • Ring B is isoindolinyl, tetrahydroisoquinolinyl, or tetrahydrobenzoazepinyl. In some embodiments of a compound of Formula (II) or (IIa), Ring B is tetrahydroisoquinolinyl.
  • each R 5 is independently C 1 - C6alkyl or aryl; wherein each alkyl and aryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a.
  • each R 5 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently cycloalkyl or heterocycloalkyl.
  • each R 5 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 5a .
  • each R 5 is independently aryl or heteroaryl.
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 5a is independently halogen, -CN, -OH, - OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 5a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R5a is independently halogen or C 1 -C 6 alkyl.
  • each R 5a is independently halogen, -CN, -OR a , or C 1 -C 6 alkyl.
  • each R 5a is independently halogen, -OR a , or C1-C6alkyl.
  • each R 5a is independently halogen.
  • m is 0, 1, 2, or 3.
  • m is 0, 1, or 2.
  • m is 1 or 2.
  • m is 0 or 1.
  • m is 0.
  • m is 1. In some embodiments of a compound of Formula (II) or (IIa), m is 2. In some embodiments of a compound of Formula (II) or (IIa), m is 3.
  • each R 10 is independently 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 - C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 10a .
  • each R 10 is independently phenyl independently optionally substituted with one or more R 10a .
  • each R 10a is independently halogen.
  • each R 10 is independently , , , , , . In some embodiments of a compound of Formula (IIa- , , , . In some embodiments of a compound of Formula (IIa- 1), each R 10 is independently . In some embodiments of a compound of Formula (IIa-1), each R 10 is independently . In some embodiments of a compound of Formula (IIa-1), each R 10 is independently . In some embodiments of a compound of Formula (IIa-1), each R 10 is independently . [00160] In some embodiments of a compound of Formula (IIa-1), s is 0 or 1.
  • s is 1 or 2. In some embodiments of a compound of Formula (IIa-1), s is 0. In some embodiments of a compound of Formula (IIa-1), s is 1. In some embodiments of a compound of Formula (IIa-1), s is 2.
  • t is 0 or 1. In some embodiments of a compound of Formula (IIa-1), t is 1 or 2. In some embodiments of a compound of Formula (IIa-1), t is 0. In some embodiments of a compound of Formula (IIa-1), t is 1. In some embodiments of a compound of Formula (IIa-1), t is 2. [00169] In some embodiments of a compound of Formula (IIa-1), each R 11 is independently , , or .
  • each R 11 is . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently .
  • each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently . In some embodiments of a compound of Formula (IIa-1), each R 11 is independently .
  • the compound has the following formula: some embodiments of a compound of Formula (IIa-1), some embodiments of a compound of Formula (IIa-1), the compound has the following formula: some embodiments of a compound of Formula (IIa-1), the some embodiments of a compound of Formula (IIa-1), the compound has the following formula:
  • R 6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 6a .
  • R 6 is C 1 -C 6 alkylene(cycloalkyl) or C1-C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is independently optionally substituted with one or more R 6a .
  • R 6 is C1-C6alkylene(aryl); wherein the alkylene and aryl is independently optionally substituted with one or more R 6a .
  • R 6 is C 1 -C 6 alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is independently optionally substituted with one or more R 6a .
  • Ring C is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (IIc), Ring C is aryl or heteroaryl. In some embodiments of a compound of Formula (IIc), Ring C is cycloalkyl or aryl. In some embodiments of a compound of Formula (IIc), Ring C is cycloalkyl. In some embodiments of a compound of Formula (IIc), Ring C is aryl. In some embodiments of a compound of Formula (IIc), Ring C is phenyl.
  • each R 8 is independently halogen, -CN, -OH, -NH2, - 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 - C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.
  • each R 8 is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy.
  • each R 8 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, or C 1 - C3haloalkyl.
  • each R 8 is independently halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound of Formula (IIc), each R 8 is independently halogen or C 1 -C 3 alkyl. [00181] In some embodiments of a compound of Formula (IIc), p is 0, 1, or 2. In some embodiments of a compound of Formula (IIc), p is 0 or 1. In some embodiments of a compound of Formula (IIc), p is 1 or 2. In some embodiments of a compound of Formula (IIc), p is 0. In some embodiments of a compound of Formula (IIc), p is 1.
  • p is 2. In some embodiments of a compound of Formula (IIc), p is 3. [00182] In some embodiments of a compound of Formula (IIc), Ring D is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (IIc), Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (IIc), Ring D is cycloalkyl or aryl. In some embodiments of a compound of Formula (IIc), Ring D is cycloalkyl. In some embodiments of a compound of Formula (IIc), Ring D is aryl.
  • Ring D is phenyl.
  • q is 0, 1, or 2. In some embodiments of a compound of Formula (IIc), q is 0 or 1. In some embodiments of a compound of Formula (IIc), q is 1 or 2. In some embodiments of a compound of Formula (IIc), q is 0. In some embodiments of a compound of Formula (IIc), q is 1. In some embodiments of a compound of Formula (IIc), q is 2. In some embodiments of a compound of Formula (IIc), q is 3. [00185] In some embodiments of a compound of Formula (IIc), the compound has the following formula: .
  • a compound of Formula (IIc) has the following formula: .
  • R 7 is hydrogen or C 1 -C 6 alkyl.
  • R 7 is C1-C6alkyl.
  • R 7 is hydrogen.
  • Ring A is cycloalkyl or heterocycloalkyl.
  • Ring A is cycloalkyl.
  • Ring A is phenyl or a 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), Ring A is a 6-membered heteroaryl.
  • Ring A is phenyl.
  • each R 1 is independently halogen, - CN, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 1 is independently halogen, C 1 - C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), each R 1 is independently halogen or C1-C6alkyl.
  • n is 0, 1, or 2. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), n is 1 or 2. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), n is 0 or 1.
  • n is 0. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), n is 1. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), n is 2.
  • n is 3.
  • X 1 is -O-.
  • X 1 is -S-. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), X 1 is -NR X1 -.
  • R X1 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, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R X1a .
  • R X1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R X1a .
  • R X1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), R X1 is hydrogen or C 1 -C 6 alkyl.
  • each R X1a is independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R X1a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.
  • each R X1a is independently halogen or C 1 - C6alkyl.
  • X 2 is -N-.
  • X 2 is -CR X2 -.
  • R X2 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , 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.
  • R X2 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R X2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R X2 is hydrogen, halogen, or C1-C6alkyl.
  • X 1 is -O- and X 2 is -N-.
  • X 1 is -NR X1 - and X 2 is -N-.
  • R 2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), (Ib), (Ic), (II), (IIa), (IIa-1), (IIb), or (IIc), R 2 is hydrogen.
  • R 3 is C 1 -C 6 alkyl.
  • R 3 is methyl.
  • R 3 is hydrogen or C1- C6alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ia-1), or (Ib), R 3 is hydrogen.
  • each R a is independently C1-C6alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl.
  • each R b is independently hydrogen, C1- 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, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; wherein each 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, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each 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, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen, C 1 - C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, R c and R d are each 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 independently optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1- C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , C1-C3alkyl, C1-C3alkoxy, or C1-C3haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH2, C1- C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -NH 2 , -NHC 1 - C 3 alkyl, or -N(C 1 -C 3 alkyl) 2 .
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is selected from a compound found in table 1: Table 1
  • the compound disclosed herein is selected from a racemic compound selected from the group consisting of:
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
  • Labeled compounds [00210] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32P, 35S, 18F, and 36Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the abundance of deuterium in each of the substituents disclosed herein 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% of a total number of hydrogen and deuterium.
  • one or more of the substituents disclosed herein 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 substituents disclosed herein.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [00214] In some embodiments, 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. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, 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, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne
  • 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,
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • 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 + (C1-C4 alkyl)4 hydroxide, 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.
  • Solvates [00220] In some embodiments, the compounds described herein exist as solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • 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.
  • Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for the inhibition of TREX1.
  • a method of treating cancer in a subject in need thereof comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the cancer is selected from non-Hodgkin lymphoma, Hodgkin lymphoma, squamous cell carcinoma, cancer of the head and neck, cholangiocarcinoma, hepatocellular carcinoma, bladder cancer, sarcoma, colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple myeloma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, and breast cancer.
  • the cancer is a solid tumor malignancy.
  • the solid tumor malignancy is bone cancer (for example, but not limited to, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma of bone/osteosarcoma, osteosarcoma, or rhabdomyosarcoma), heart cancer, brain and nervous system cancer (for example, but not limited to, astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, glioblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, or visual pathway and hypothalamic glioma), breast cancer (for example, but not limited to, invasive lobular carcinoma, tubular carcinoma
  • TREX1 is a component of the cellular DNA repair mechanism.
  • DNA repair inhibitors such as poly ADP ribose polymerase (“PARP”) inhibitors
  • PARP poly ADP ribose polymerase
  • TREX1 inhibitors also possess potential utility as effective synthetic lethality partners in patients with cancers characterized by defective DNA repair.
  • the DNA repair deficiency is a deficiency in the base excision repair (“BER”) pathway (such as a PolB mutation).
  • the DNA repair deficiency is a deficiency in the Fanconi anaemia-mediated repair (“FA”) pathway (such as an FANCA mutation).
  • the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway (such as a BRCA1 mutation).
  • the DNA repair deficiency is a deficiency in the nucleotide excision repair (“NER”) pathway (such as an XPA mutation).
  • NER nucleotide excision repair
  • NHEJ non-homologous end joining
  • the DNA repair deficiency is a deficiency in the mismatch repair (“MMR”) pathway (such as an hMSH2 mutation). In some embodiments, the DNA repair deficiency is a deficiency in the RecQ-mediated repair (“RecQ”) pathway (such as a BLM mutation). In some embodiments, the DNA repair deficiency is a deficiency in the double-stranded breaks (“DSB”) pathway (such as a POLQ mutation). [00238] In some embodiments, the cancer is characterized by a deficiency in one or more DNA repair pathways.
  • MMR mismatch repair
  • RecQ RecQ-mediated repair
  • DSB double-stranded breaks
  • the cancer is characterized by a deficiency in one or more DNA repair pathways.
  • the DNA repair deficiency is a deficiency in the base excision repair (“BER”) pathway, the Fanconi anaemia-mediated repair (“FA”) pathway, the homologous recombination (“HR”) pathway, the nucleotide excision repair (“NER”) pathway, the non-homologous end joining (“NHEJ”) pathway, the mismatch repair (“MMR”) pathway, the RecQ-mediated repair (“RecQ”) pathway, or the double-stranded breaks (“DSB”) pathway.
  • the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway.
  • the DNA repair deficiency is a BRCA1 mutation.
  • the cancer is a solid tumor malignancy.
  • the cancer is selected from non-Hodgkin lymphoma, Hodgkin lymphoma, squamous cell carcinoma, cancer of the head and neck, cholangiocarcinoma, hepatocellular carcinoma, bladder cancer, sarcoma, colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple myeloma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, and breast cancer.
  • a method of increasing type I interferon production in a subject in need thereof comprising administering a reversible, non-competitive TREX1 inhibitor.
  • the increase in type I interferon production occurs in the tumor microenvironment.
  • the TREX1 inhibitor is administered systemically.
  • the TREX1 inhibitor comprises a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • Productive infection of CD4+ T cells requires successful reverse transcription of the single-stranded viral RNA genome.
  • the resulting dsDNA undergoes 3’ processing before stable integration into the host genome. Only a small percentage of infectious particles complete reverse transcription successfully.
  • Abortive reverse transcription from the remaining viral particles results in accumulation of cDNA intermediates, yet chronic HIV infection does not induce an interferon response.
  • TREX1 The 3’ exonuclease activity of TREX1 prevents the accumulation of reverse transcribed HIV-1 DNA to avoid the interferon response.
  • TREX1 processing of the 3’end of HIV-1 DNA in the pre integration complex is critical for successful HIV-1 integration.
  • treatment strategies to reduce or inhibit TREX1 promote both antiviral immunity and have direct antiviral effects by reducing productive integration.
  • Combination Therapy [00243] In certain instances, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with a second therapeutic agent.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
  • different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent.
  • Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth.
  • the compound provided herein when co-administered with a second therapeutic agent, is administered either simultaneously with the second therapeutic agent, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with an adjuvant.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with a DNA repair inhibitor.
  • the DNA repair inhibitor is a poly ADP ribose polymerase (“PARP”) inhibitor.
  • PARP poly ADP ribose polymerase
  • the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, or E7016.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with an alkylating agent.
  • the alkylating agent is cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, nimustine, fotemustine, streptozocin, or busulfan.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in conjunction with radiation therapy.
  • the radiation therapy is administered on a standard fractionation, an accelerated fractionation, a hyperfractionation, or a hypofractionation schedule.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof increases anti-tumor immunity when combined with radiation therapy.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof modulates intratumoral immune infiltrate in tumors when combined with radiation therapy.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof improves tumor control when combined with radiation therapy.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, when combined with tumor-directed radiotherapy enhances systemic anti-tumor immune responses as measured by blood-based immune markers, modulation of intratumoral infiltrate in non-irradiated (abscopal) tumors and tumor control in non-irradiated tumors.
  • the radiation therapy is tumor-directed radiation therapy. In some embodiments, the radiation therapy is metastasis-directed radiation therapy.
  • the radiation therapy is external beam radiation therapy. External beam radiation therapy is a local treatment, which means it treats a specific part of the body.
  • the external beam radiation therapy is from a photon beam. In some embodiments, the external beam radiation therapy is from a proton beam. In some embodiments, the external beam radiation therapy is from an electron beam. [00262] In some embodiments, the external beam radiation therapy is 3-D conformal radiation therapy. 3-D conformal radiation therapy is a type of external beam radiation therapy. It uses images from CT, MRI, and PET scans to precisely plan the treatment area, a process called simulation. A computer program is used to analyze the images and to design radiation beams that conform to the shape of the tumor. [00263] In some embodiments, the external beam radiation therapy is intensity-modulated radiation therapy (IMRT). In some embodiments, the external beam radiation therapy is image-guided radiation therapy (IGRT).
  • IMRT intensity-modulated radiation therapy
  • IGRT image-guided radiation therapy
  • IGRT is a type of IMRT using imaging scans not only for treatment planning before radiation therapy sessions but also during radiation therapy sessions.
  • the external beam radiation therapy is tomotherapy®.
  • Tomotherapy® is a type of IMRT that uses a machine that is a combination of a CT scanner and an external-beam radiation machine.
  • the external beam radiation therapy is stereotactic radiosurgery: Stereotactic radiosurgery is the use of focused, high-energy beams to treat small tumors with well- defined edges in the brain and central nervous system.
  • GammaKnife is a type of stereotactic radiosurgery.
  • the external beam radiation therapy is stereotactic body radiation therapy (SBRT).
  • SBRT stereotactic body radiation therapy
  • Stereotactic body radiation therapy is similar to stereotactic radiosurgery, but it is used for small, isolated tumors outside the brain and spinal cord.
  • the radiation therapy is internal radiation therapy.
  • Internal radiation therapy is a treatment in which a source of radiation is put inside the body.
  • the radiation source can be solid or liquid.
  • Internal radiation therapy with a solid source is called brachytherapy.
  • seeds, ribbons, or capsules that contain a radiation source are placed in the body, in or near the tumor.
  • brachytherapy is a local treatment and treats only a specific part of your body.
  • the brachytherapy is low-dose rate (LDR) implants.
  • the brachytherapy is high-dose rate (HDR) implants.
  • the brachytherapy is permanent implants. After the radiation source is put in place, the catheter is removed. The implants remain in the body for the rest of the patient’s life, but the radiation gets weaker each day. As time goes on, almost all the radiation will go away.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in conjunction with high-dose radiotherapy administered as a single dose and/or hypofractionated.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in conjunction with Stereotactic Body Radiation Therapy (SBRT).
  • SBRT Stereotactic Body Radiation Therapy
  • Example 1 6-(benzo[d]oxazol-2-yl)-2-(1-cyclobutyl-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)- 5-hydroxy-3-methylpyrimidin-4(3H)-one
  • Step 1 To a stirred solution of ethyl 2-(diethoxymethyl)-5-ethoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (2 g, 6.09 mmol) in a mixture of THF (26.7 mL, 328 mmol) and water (13.3 mL, 740 mmol) was added lithiumhydroxide monohydrate (307 mg, 1.2 eq
  • Step 2 To a stirred solution of 2-(diethoxymethyl)-5-ethoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (1.8 g, 5.99 mmol) in DMF (2 mL) was added HATU (3.42 g, 1.5 eq., 8.99 mmol) , DIPEA (4.19 mL, 4 eq., 24 mmol) . The reaction mixture was stirred at ambient temperature for 1 h, the reaction mixture was poured into water and extracted with ethyl acetate.
  • Step 3 To a stirred solution of 2-(diethoxymethyl)-5-ethoxy-N-(2-hydroxyphenyl)-1-methyl- 6-oxo-1,6-dihydropyrimidine-4-carboxamide (1.2 g, 3.07 mmol) in THF (20 mL, 246 mmol) was added triphenylphosphane (2.01 g, 2.5 eq., 7.66 mmol) and N- ⁇ [(propan-2-yloxy)carbonyl]imino ⁇ (propan-2- yloxy)formamide (3.87 g, 2.5 eq., 7.66 mmol) . The reaction was stirred at 80 ° C 16 h.
  • Step 4 A solution of 6-(1,3-benzoxazol-2-yl)-2-(diethoxymethyl)-5-ethoxy-3-methyl-3,4- dihydropyrimidin-4-one (1 g, 2.68 mmol) in formic acid (13.3 mL, 351 mmol) was heated to 85 ° C for 3 h .
  • Step 5 To a stirred solution of N1-cyclobutyl-5-(2H-1,2,3,4-tetrazol-5-yl)benzene-1,2-diamine (0.1 g, 0.434 mmol) and 4-(1,3-benzoxazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-2- carbaldehyde (130 mg, 0.434 mmol) in a mixture of DMF (1 mL) and water (0.3 mL) was added oxone monopersulfate (133 mg, 0.434 mmol). The reaction was stirred for 1 h at ambient temperature. Progress of the reaction monitored by TLC and LCMS.
  • Step 6 A stirred solution of 6-(1,3-benzoxazol-2-yl)-2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5- yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-3-methyl-3,4-dihydropyrimidin-4-one (90 mg, 0.177 mmol) in DCM (418 ⁇ L, 6.53 mmol) was cooled to -40 °C. Tribromoborane (22.6 ⁇ L, 3 eq., 0.132 mmol) was added and the mixture was stirred at ambient temperature for 4 h, The reaction was monitored by TLC and LCMS .
  • Step 1 To a stirred solution of cyclobutanecarbaldehyde (1.7 g, 20.2 mmol) in dry THF (34 mL, 418 mmol), phenyllithium (1.7 g, 20.2 mmol) was added at -50 °C and the mixture was stirred at ambient temperature for 16 h.
  • reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate to provide the crude.
  • the crude compound was purified by CombiFlash chromatography (10 - 20% EtOAc in heptane) to provide cyclobutyl(phenyl)methanol (2.7 g, 74%).
  • Step 2 To a stirred solution of cyclobutyl(phenyl)methanol (2.7 g, 16.6 mmol) in DCM (67.5 mL, 1.05 mol) and 1,1-bis(acetyloxy)-3-oxo-3H-1 ⁇ 5,2-benziodaoxol-1-yl acetate (9.18 g, 1.3 eq., 21.6 mmol) was added under 0 °C and stirred at ambient temperature for 1 h.
  • Step 3 To a stirred solution of cyclobutyl(phenyl)methanone (2.4 g, 15 mmol) in formic acid (10 mL) and formamide (2.99 mL, 5 eq., 74.9 mmol) was added at 0 °C and the mixture was stirred at 185 °C for 16 h. The reaction was monitored by TLC & LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate to provide the crude N- [cyclobutyl(phenyl)methyl]formamide (2.5 g, 71%).
  • Step 5 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (2.5 g, 10.7 mmol), 1-cyclobutyl-1-phenylmethanamine (1.73 g, 10.7 mmol) in DMSO (1 mL) and DIPEA (3.75 mL, 2 eq., 21.5 mmol) was added and stirred at 110 °C for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 6 To a stirred solution of methyl 2- ⁇ [cyclobutyl(phenyl)methyl]amino ⁇ -5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3 g, 8.39 mmol) in DMF (22.5 mL, 291 mmol), cesium carbonate (8.2 g, 3 eq., 25.2 mmol) and iodomethane (1.05 mL, 2 eq., 16.8 mmol) was added and the mixture was stirred at ambient temperature for 1 h.
  • Step 7 To a stirred solution of methyl 2- ⁇ [cyclobutyl(phenyl)methyl] (methyl)amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (2.8 g, 7.54 mmol) in methanol (5mL), THF (32 mL) and water (3 mL) was added lithium hydroxide (1.58 g, 5 eq., 37.7 mmol) at ambient temperature and the mixture was stirred for 3 h. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step 8 To a stirred solution of 2- ⁇ [cyclobutyl(phenyl)methyl](methyl)amino ⁇ -5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (1.8 g, 5.04 mmol) in DMF (18 mL, 232 mmol), DIPEA (2.79 mL, 3 eq., 15.1 mmol), HATU (2.87 g, 1.5 eq., 7.55 mmol) and 2-iodoaniline (1.21 g, 1.1 eq., 5.54 mmol) was added and the mixture was stirred at ambient temperature for 3 h.
  • Step 9 To a stirred solution of 2- ⁇ [cyclobutyl(phenyl)methyl](methyl)amino ⁇ -N-(2- iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (1.8 g, 3.22 mmol) in acetonitrile (51.4 mL, 985 mmol), cesium carbonate (1.58 g, 1.5 eq., 4.84 mmol) was added and the mixture was purged with nitrogen for 5 minutes.
  • ⁇ 1-copper (1+) iodide (30.7 mg, 0.05 eq., 161 ⁇ mol) and 1,10-phenanthroline (58.1 mg, 0.1 eq., 322 ⁇ mol) was added and the mixture was purged again with nitrogen for 5 minutes. The reaction mixture was then stirred at 110 °C for 16 h.
  • Step 10 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [cyclobutyl(phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (150 mg, 348 ⁇ mol) in DMF (15 mL) was added lithium bromide (242 mg, 8 eq., 2.79 mmol) at ambient temperature. The mixture was heated at 110 °C for 16 h.
  • Step 11 To a stirred solution of (R)-6-(benzo[d]oxazol-2-yl)-2- ((cyclobutyl(phenyl)methyl)(methyl)amino)-5-methoxy-3-methylpyrimidin-4(3H)-one (0.1 g, 232 ⁇ mol) in DMF (2 mL, 25.8 mmol) was added lithium bromide (202 mg, 10 eq., 2.32 mmol) at ambient temperature. The mixture was heated at 110 °C for 16 h.
  • reaction mixture was diluted with saturated ammonium chloride and extracted with the DCM, dried over anhydrous sodium sulfate, and concentrated to provide the crude product which washed with pentane to provide 6-(1,3-benzoxazol-2-yl)-2- ⁇ [cyclobutyl(phenyl)methyl](methyl)amino ⁇ -5-hydroxy-3-methyl- 3,4-dihydropyrimidin-4-one (0.04 g, 41%).
  • Step 12 To a stirred solution of (S)-6-(benzo[d]oxazol-2-yl)-2- ((cyclobutyl(phenyl)methyl)(methyl)amino)-5-methoxy-3-methylpyrimidin-4(3H)-one (0.1 g, 232 ⁇ mol) in DMF (2 mL, 25.8 mmol) was added lithium bromide (202 mg, 10 eq., 2.32 mmol) at ambient temperature. The mixture was heated at 110 °C for 16 h. After completion of the reaction, reaction mixture was diluted with saturated ammonium chloride and extracted with the DCM, washed with brine, and dried over anhydrous sodium sulfate, concentrated.
  • Step 1 To a stirred solution of 2-chlorobenzaldehyde (2.5 mL, 21.3 mmol) in DCM (30 mL, 469 mmol) was added cesium carbonate (10.4 g, 1.5 eq., 32 mmol) and 2-methylpropane-2-sulfinamide (3.1 g, 1.2 eq., 25.6 mmol) and the mixture was stirred at 40 °C for 16 h.
  • Step 2 To a stirred solution of N-[(Z)-(2-chlorophenyl) methylidene]-2-methylpropane-2- sulfinamide (3 g, 12.3 mmol) in THF (35.5 mL, 436 mmol) at -78 °C was added phenyl lithium (1.24 g, 1.2 eq., 14.8 mmol) and the mixture was stirred at ambient temperature for 6 h. After completion, the reaction mixture was quenched with ammonium chloride solution and extracted with EtOAc.
  • Step 3 To a stirred solution of N-[(2-chlorophenyl)(phenyl)methyl]-2-methylpropane-2- sulfinamide (2 g, 6.21 mmol) in DCM (20 mL), hydrogen chloride (453 mg, 2 eq., 12.4 mmol) was added at 0 °C and the mixture was stirred for 16 h. The solvent was removed under pressure to provide the crude which washed with n-Pentane then dried to afford 1-(2-chlorophenyl)-1-phenylmethanamine hydrochloride (1.4 g, 89%).
  • Step 4 To a stirred solution of 1-(2-chlorophenyl)-1-phenylmethanamine hydrochloride (1.4 g, 5.51 mmol) and methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.28 g, 5.51 mmol) in DMSO (10 mL) was added ethylbis(propan-2-yl) amine (2.88 mL, 3 eq., 16.5 mmol) and stirred the mixture was stirred at 110 °C for 2 h in the microwave. After completion, the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 5 To a stirred solution of methyl 2- ⁇ [(2-chlorophenyl) (phenyl)methyl] amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.7 g, 4.11 mmol) in DMF (20 mL), cesium carbonate (2.01 g, 1.5 eq., 6.16 mmol) and iodomethane (0.256 mL, 4.11 mmol) were added and the mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate.
  • Step 6 To a stirred solution of methyl 2- ⁇ [(2-chlorophenyl) (phenyl)methyl] (methyl)amino ⁇ - 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.5 g, 1.17 mmol) in methanol (20 mL), THF (12 mL), water (8 mL) was added lithium hydrate hydroxide (981 mg, 5 eq., 23.4 mmol) at ambient temperature and the mixture was stirred for 1 h. After completion, the mixture was concentrated under reduced pressure. The crude was dissolved in water and acidified with 1N HCl solution up to pH ⁇ 2.
  • Step 7 To a stirred solution of 2- ⁇ [(2-chlorophenyl) (phenyl)methyl] (methyl)amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.7 g, 1.69 mmol) and 2-iodoaniline (445 mg, 1.2 eq., 2.03 mmol) in DMF (10 mL) was added DIPEA (0.937 mL, 3 eq., 5.07 mmol) and HATU (965 mg, 1.5 eq., 2.54 mmol). The resultant reaction mixture was allowed to stir at ambient temperature for 3 h.
  • Step 8 To a stirred solution of 2- ⁇ [(2-chlorophenyl)(phenyl)methyl](methyl)amino ⁇ -N-(2- iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (850 mg, 1.38 mmol) in acetonitrile (17 mL, 325 mmol), was added cesium carbonate (676 mg, 1.5 eq., 2.07 mmol), 1,10- phenanthroline (24.9 mg, 0.1 eq., 0.138 mmol) and copper iodide (26.3 mg, 0.1 eq., 0.138 mol).
  • Step 9 To a solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(2-chlorophenyl) (phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.5 g, 1.03 mmol) in DMF (3 mL, 38.7 mmol) was added lithium bromide (446 mg, 5 eq., 5.13 mmol) the mixture was stirred at 100 °C for 16 h.. After completion of the reaction, the mixture was diluted with saturated ammonium chloride and extracted with EtOAc.
  • Example 8 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)benzoic acid [00303] Step 1: To a stirred solution of 4-bromobenzaldehyde (3 g, 16.2 mmol) and 2-methylpropane- 2-sulfinamide (1.97 g, 16.2 mmol) in THF (60 mL) was added titanium tetraethanolate (10.2 mL, 3 eq., 48.6 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • Step 2 To a stirred solution of N-[(Z)-(4-bromophenyl) methylidene]-2-methylpropane-2- sulfinamide (2 g, 6.94 mmol) in THF (20 mL) was added phenyllithium (0.583 g, 6.94 mmol) at -78 °C and the mixture was stirred at ambient temperature for 6 h. After completion, the reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. Combined organic layers were washed with brine and dried over anhydrous sodium sulfate to provide the crude.
  • Step 3 To a stirred solution of N-[(4-bromophenyl) (phenyl)methyl]-2-methylpropane-2- sulfinamide (1.88 g, 5.13 mmol) in DCM (13.8 mL, 215 mmol), hydrogen chloride (0.374 g, 10.3 mmol) was added at 0 °C and stirred for 1 h. After completion, the reaction mixture was evaporated under reduced pressure to provide the crude. The crude compound washed with n-pentane for 3 times and dried to afford 1-(4-bromophenyl)-1-phenylmethanamine hydrochloride (1.8 g, 99%).
  • Step 4 To a stirred solution of 1-(4-bromophenyl)-1-phenylmethanamine hydrochloride (1.88 g, 6.3 mmol) and methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.76 g, 1.2 eq., 7.56 mmol) in DMSO (11.4 mL, 160 mmol) was added DIPEA (1.64 mL, 1.5 eq., 9.44 mmol) and the mixture was stirred at 120 °C for 2 h. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step 5 To a stirred solution of methyl 2- ⁇ [(4-bromophenyl) (phenyl)methyl] amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.73 g, 3.77 mmol) in DMF (60 mL), was added cesium carbonate (1.84 g, 5.66 mmol) and iodomethane (0.258 mL, 4.15 mmol) and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ice water and extracted with ethyl acetate.
  • Step 6 To a stirred solution of methyl 2- ⁇ [(4-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ - 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.65 g, 3.49 mmol) in a mixture of methanol (10 mL), THF (4 mL) and water (3 mL) was added lithium hydroxide (0.44 g, 10.5 mmol) at ambient temperature and the mixture was stirred for 1 h.
  • Step 7 To a stirred solution of 2- ⁇ [(4-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (1.3 g, 2.84 mmol) and 2-iodoaniline (0.746 g, 3.4 mmol) in DMF (20 mL) was added DIPEA (1.57 mL, 8.51 mmol) and 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (1.62 g, 4.25 mmol) and the mixture was stirred at ambient temperature for 3 h.
  • Step 8 To a stirred solution of 2- ⁇ [(4-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -N-(2- iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (1.15 g, 1.74 mmol) in acetonitrile (30 mL, 587 mmol) was added cesium carbonate (0.852 g, 2.62 mmol) copper iodide (0.016 g, 872 mmol), and 1,10-phenanthroline (0.031 g, 174 mmol).
  • Step 9 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.2 g, 376 mmol) in 1,2- dimethoxyethane (5 mL) and water (2 mL), sodium carbonate (59.8 mg, 565 mmol) was added to the reaction mixture, followed by the addition of tetrafluoroboranuide, tri-tert-butylphosphanium (10.9 mg, 3.76 mmol) and hexakis(methanidylidyneoxidanium) molybdenum (149 mg, 565 mmol).
  • Step 10 To a stirred solution of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzoic acid (0.1 g, 0.201 mmol) in DMF (15 mL) was added lithium bromide (105 mg, 1.21 mmol) at ambient temperature and the mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride and extracted with the DCM.
  • Step 1 A solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.1 g, 0.188 mol) in DMF (10 mL) was purged with nitrogen for 5 minutes then zinc cyanide (0.044 mg, 0.376 mmol) was added followed by [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.013 mg, 0.0188 mmol) and the mixture was heated at 150 °C for 4 h
  • Step 2 To a stirred solution of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzonitrile (0.065 g, 0.136 mmol) in DMSO (2 mL) was added 20% hydrogen peroxide (0.047 mL, 0.204 mmol) and potassium carbonate (0.094 g, 0.681 mmol) at 0 °C and the mixture was stirred at ambient temperature for 16 h.
  • Step 3 To a stirred solution of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzamide (0.055 g, 0.111 mmol) in DMF (2 mL) was added lithium bromide (0.096 g, 1.11 mmol) at ambient temperature. The mixture was heated at 110 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride and extracted with the DCM.
  • Example 11 Synthesis of 6-(1,3-benzoxazol-2-yl)-2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- hydroxy-3-methyl-3,4-dihydropyrimidin-4-one [00317]
  • Step 1 To a stirred solution of 1-fluoro-2-nitrobenzene (3.4 mL, 35.4 mmol) in 1- methylpyrrolidin-2-one (5 mL), DIPEA (18.5 mL, 106 mmol) and cyclobutanamine (3.64 mL, 42.5 mmol) was added and the mixture was stirred at 120 oC for 16 h.
  • Step 2 To a solution of N-cyclobutyl-2-nitroaniline (6.8 g, 35.4 mmol) in methanol (25 mL) 10% Pd/C (0.1 g, 0.940 mmol) was added and the mixture was stirred at ambient temperature under a hydrogen balloon for 3 h.
  • Step 3 To a stirred solution of N1-cyclobutylbenzene-1,2-diamine (1.6 g, 9.86 mmol) in dry DMF (24 mL), and pyridine (2.38 mL, 29.6 mmol) was added and dichloro-1 ⁇ 4,2,3-dithiazol-1-ylium chloride (2.26 g, 10.8 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • Step 4 & 5 To a stirred solution of 1-cyclobutyl-1H-1,3-benzodiazole-2-carbonitrile (1.2 g, 6.08 mmol) in methanol (10 mL) and water (6 mL) was added disodium carbonate (0.387 g, 3.65 mmol) and hydrogen N-methylhydroxylamine chloride (0.610 g, 7.3 mmol) and the mixture was stirred at ambient temperature for 2 h. At this time 1,4-dimethyl but-2-ynedioate (0.963 mL, 7.86 mmol) was added and the mixture was stirred at ambient temperature for 5 h.
  • Step 7 To a stirred solution of methyl 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.750 g, 2.12 mmol) in THF (5 mL), methanol (5 mL) and sodium hydroxide (0.254 g, 6.35 mmol) in water (5 mL) was added at ambient temperature. The reaction mixture was heated to 50 °C for 3 h. The reaction mixture was concentrated and acidified with 1N HCl (pH ⁇ 2), then extracted with ethyl acetate.
  • Step 8 To a stirred solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl- 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.150 g, 0.441 mmol) in DMF (1 mL), HATU (0.335 g, 0.881 mmol), DIPEA (0.11 mL, 0.661 mmol) and 2-aminophenol (0.062 g, 0.573 mmol) was added and the mixture was stirred at 100 °C for 24 h.
  • Step 9 To a solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-N-(2- hydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.050 g, 0.116 mmol) in 1,4- xylene (1 mL) was added 4-methylbenzene-1-sulfonic acid (0.025 mg, 0.145 mmol) and the mixture was refluxed for 3 h. After completion, the reaction mixture was concentrated under the reduced pressure.
  • Step 1 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (2.5 g, 10.7 mmol) in DMSO (15.00 mL), 1-(3-bromophenyl)-1- phenylmethanamine (2.82 g, 10.7 mmol) and DIPEA (1.88 mL, 10.7 mmol) were added and the reaction mixture was stirred at 110°C for 6 h. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate.
  • Step 2 To a stirred solution of methyl 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxylate (3 g, 6.55 mmol) in THF (15 mL) and water (6 mL), lithium hydroxide (0.78 g, 5 eq., 32.7 mmol) was added at ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 16 h. After completion, the reaction mixture was concentrated. The residue was diluted with water and washed by ethyl acetate. The aqueous layer was acidified with 2 N HCl solution and extracted with 10% methanol in DCM.
  • Step 3 To a solution of 2- ⁇ [(3-bromophenyl)(phenyl)methyl]amino ⁇ -5-methoxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylic acid (2.8 g, 6.3 mmol) and iodoaniline (1.66 g, 7.56 mmol) in DMF (20 mL), was added DIPEA (3.3 mL, 3 eq., 18.9 mmol) and HATU (3.60 g, 1.5 eq., 9.45 mmol) and the mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step 4 To a stirred solution of 2- ⁇ [(3-bromophenyl)(phenyl)methyl]amino ⁇ -N-(2- iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (3.5 g, 5.42 mmol) in toluene (15.00 mL), was added potassium carbonate (2.25 g, 3 eq., 16.3 mmol) and then methyl[2- (methylamino)ethyl]amine (584 ⁇ L, 5.42 mmol) was added for 20 min.
  • Step 5 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3- bromophenyl)(phenyl)methyl]amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (1.5 g, 2.9 mmol) in DMF (5 mL) sodium hydride (174 mg, 1.5 eq., 4.35 mmol) and iodomethane (217 ⁇ L, 1.2 eq., 3.48 mmol) were added at 0°C. The mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 6 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3- bromophenyl)(phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.50 g, 941 ⁇ mol) in DMF (5.00 mL), zinc cyanide (0.16 g, 1.5 eq., 1.41 mmol) and the mixture was degassed.
  • Step 7 To a stirred solution of 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)benzonitrile (0.40 g, 838 ⁇ mol) in DMF (5 mL), ammonium chloride (0.22 mg, 5 eq., 4.19 mmol) and sodium azide (0.27 mg, 5 eq., 4.19 mmol) were added and the mixture was stirred at 120 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature and 1N HCl solution was added.
  • Step 8 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-5-methoxy-3-methyl-2- [methyl( ⁇ phenyl[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methyl ⁇ )amino]-3,4-dihydropyrimidin-4-one (0.1 g, 192 ⁇ mol) in DMF (1 mL), lithium bromide (83.4 mg, 5 eq., 961 ⁇ mol) was added and the mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressured to provide a residue which was dissolved with water and extracted with ethyl acetate.
  • Step 1 To a stirred solution of 2-chloro-5-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20 g, 97.8 mmol) in DMF (260.0 mL), dipotassium carbonate (40.5 g, 3 eq., 293 mmol) and iodomethane (12.8 mL, 2.1 eq., 205 mmol) were added and the reaction mixture was stirred at ambient temperature for 16 h .
  • Step 2 To a stirred solution of methyl 5-methoxy-1-methyl-2-(methylamino)-6-oxo-1,6- dihydropyrimidine-4-carboxylate (1 g, 4.4 mmol) and 2-aminophenol (480 mg, 4.4 mmol) in toluene (10 mL) was added triethylamine (675 ⁇ L, 1.1 eq., 4.84 mmol) and the mixture was cooled to 0 °C. Trimethylalumane (635 mg, 2 eq., 8.8 mmol) was added and the mixture was stirred at 80 °C for 1 h in the microwave.
  • Step 3 A stirred solution of N-(2-hydroxyphenyl)-5-methoxy-1-methyl-2-(methylamino)-6- oxo-1,6-dihydropyrimidine-4-carboxamide (0.2 g, 657 ⁇ mol) in acetic acid (2.0 mL) was irradiated at 180 °C for 2 h in microwave. After completion, the reaction mixture was quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product which was purified by flash chromatography.
  • Step 4 To a solution of 6-(1,3-benzoxazol-2-yl)-5-methoxy-3-methyl-2-(methylamino)-3,4- dihydropyrimidin-4-one (140 mg, 489 ⁇ mol) in DMF (5.0 mL) was added lithium bromide (212 mg, 5 eq., 2.45 mmol) and the mixture was stirred for 16 h at 100 °C.
  • Example 14 2-(benzhydryl(methyl)amino)-6-(benzo[d]thiazol-2-yl)-5-hydroxy-3-methylpyrimidin- 4(3H)-one [00337]
  • Step 1 To a solution of 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carbaldehyde (0.2 g, 550 ⁇ mol) and benzene-1,2-diamine (71.4 mg, 1.2 eq., 660 ⁇ mol) was added in DMSO (9.61 mL, 134 mmol), disodium sulfinatosulfonate (126 mg, 1.2 eq., 660 ⁇ mol) and the solution was stirred at 110°C for 16 h.
  • Step 2 To a solution of 6-(1H-1,3-benzodiazol-2-yl)-2-[(diphenylmethyl)(methyl)amino]-5- methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.2 g, 443 ⁇ mol) in DMF (10 mL, 129 mmol) was added lithium bromide (192 mg, 5 eq., 2.21 mmol) and the mixture was stirred for 16 h at 100 °C.
  • Step 1 To a solution of 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (1.0 g, 2.74 mmol) in toluene (10 mL, 84.5 mmol) & 2- aminophenol (0.299 g, 2.74 mmol), DIPEA (956 ⁇ L, 2 eq., 5.47 mmol) and tripropyl-1,3,5,2 ⁇ 5,4 ⁇ 5,6 ⁇ 5- trioxatriphosphinane-2,4,6-trione (5.22 g, 3 eq., 8.21 mmol) was added and the solution was heated in the microwave at 190°C for 1 h.
  • 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid 1.0 g, 2.74 mmol
  • 2- aminophenol 0.299 g,
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • organic layer dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product which was purified by flash chromatography and the desired fractions were concentrated to obtain 6-(1,3-benzoxazol-2-yl)-2-[(diphenylmethyl)amino]-5-methoxy-3-methyl-3,4- dihydropyrimidin-4-one (0.320 g, 13%).
  • Step 2 To a solution of 6-(1,3-benzoxazol-2-yl)-2-[(diphenylmethyl)amino]-5-methoxy-3- methyl-3,4-dihydropyrimidin-4-one (190 mg, 433 ⁇ mol) in DMF (2 mL) was added lithium bromide (54.4 ⁇ L, 5 eq., 2.17 mmol) and the mixture was stirred for 2 days at 100 °C.
  • Step 1 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (5.9 g, 25.3 mmol) in DMSO (15 mL) and (diphenylmethyl)(methyl)amine (5.0 g, 25.3 mmol), DIPEA (4.43 mL, 25.3 mmol) was added and the solution was stirred at 110 °C for 6 h. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 2 To a stirred solution of methyl 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.8 g, 2.03 mmol) in THF (2 ml, 24.6 mmol) and water (0.5 mL), lithium hydroxide (0.417 g, 5 eq., 10.2 mmol) was added and the mixture was stirred at ambient temperature for 16 h. Upon completion, the reaction mixture was diluted with aqueous 6 N HCl and extracted with ethyl acetate.
  • Step 3 To a stirred solution of 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.5 g, 1.32 mmol) in DMF (2.59 mL, 33.4 mmol) and 2- iodoaniline (0.346 g, 1.2 eq., 1.58 mmol) was added DIPEA (689 ⁇ L, 3 eq., 3.95 mmol) and HATU (0.752 g, 1.5 eq., 1.98 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • DIPEA 689 ⁇ L, 3 eq., 3.95 mmol
  • HATU 0.752 g, 1.5 eq., 1.98 mmol
  • Step 4 To a solution of 2-[(diphenylmethyl)(methyl)amino]-N-(2-iodophenyl)-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.320 g, 551 ⁇ mol) in acetonitrile (3 mL) was added cesium carbonate (0.269 g, 1.5 eq., 827 ⁇ mol) and the mixture was stirred at ambient temperature and the reaction mixture was degassed with nitrogen for 5 min.
  • cesium carbonate 0.269 g, 1.5 eq., 827 ⁇ mol
  • Iodocopper (5.25 mg, 0.05 eq., 27.6 ⁇ mol) and 1,10-phenanthroline (9.9 mg, 0.1 eq., 55.1 ⁇ mol) were added and degassing continued for 5 min. The mixture was heated at 110 °C for 16 h. Upon completion of the reaction, water was added and the mixture was extracted with ethyl acetate.
  • Step 5 To a solution of 6-(1,3-benzoxazol-2-yl)-2-[(diphenylmethyl)(methyl)amino]-5- methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.050 mg, 110 ⁇ mol) in DMF (2 mL) was added lithium bromide (13.9 ⁇ L, 5 eq., 552 ⁇ mol) and the mixture was stirred for 16 h at 100 °C. Upon completion the reaction mixture was concentrated, water was added, and the obtained solid was filtered and dried to provide crude product which was purified by reverse phase HPLC.
  • Example 17 2-[(diphenylmethyl)(methyl)amino]-5-hydroxy-3-methyl-6-(1-methyl-1H-1,3- benzodiazol-2-yl)-3,4-dihydropyrimidin-4-one [00346]
  • Step 1 To a solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (5.9 g, 25.3 mmol) in DMSO (15 mL) (diphenylmethyl)(methyl)amine (5.0 g, 25.3 mmol) and DIPEA (4.43 mL, 25.3 mmol) were added and the solution was stirred at 110 °C for 6 h.
  • reaction mixture Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product which was purified by flash chromatography and desired fractions were concentrated to provide methyl 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3.8 g, 32%).
  • Step 2 To a stirred solution of methyl 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxylate (2.0 g, 1 eq., 5.27 mmol) in THF (30 mL, 369 mmol), sodium borane (0.936 g, 5 eq., 25.4 mmol) was added and reaction mixture was heated at 65 °C for 15 min then methanol (8 mL, 197 mmol) was added drop-wise and the reaction mixture heated at 65 °C for 4h.
  • Step 3 To a stirred solution of 2-[(diphenylmethyl)amino]-6-(hydroxymethyl)-5-methoxy-3- methyl-3,4-dihydropyrimidin-4-one (0.7 g, 1.99 mmol) in toluene (7 mL, 59.2 mmol) dioxomanganese (0.866 g, 5 eq., 9.96 mmol) was added and the mixture was heated at 60 °C for 4 h. Upon completion of the reaction, the reaction mixture passed through celite.
  • Step 4 To a stirred solution of N1-methylbenzene-1,2-diamine (0.087 g, 716 ⁇ mol) and 2- [(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carbaldehyde (0.250 g, 716 ⁇ mol) in DMSO (5 mL) disodium sulfinatosulfonate (0.204 g, 1.5 eq., 1.07 mmol) was added and the resultant mixture was heated at 90 °C for 13 h. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 5 To a stirred solution of 2-[(diphenylmethyl)amino]-5-methoxy-3-methyl-6-(1-methyl- 1H-1,3-benzodiazol-2-yl)-3,4-dihydropyrimidin-4-one (0.2 g, 443 ⁇ mol) in DMF (1 mL) cesium carbonate (0.130 g, 0.9 eq., 399 ⁇ mol) & iodomethane (24.8 ⁇ L, 0.9 eq., 399 ⁇ mol) were added to the solution it was stirred at ambient temperature for 16 h. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 6 To a solution of 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-3-methyl-6-(1-methyl- 1H-1,3-benzodiazol-2-yl)-3,4-dihydropyrimidin-4-one (0.450 g, 967 ⁇ mol) in DMF (3 mL) was added lithium bromide (121 ⁇ L, 5 eq., 4.83 mmol) and the mixture was stirred for 16 h at 100 °C . Upon completion of the reaction, the reaction mixture was concentrated and water was added.
  • Example 18 6-(1H-1,3-benzodiazol-2-yl)-2-[(diphenylmethyl)(methyl)amino]-5-hydroxy-3-methyl- 3,4-dihydropyrimidin-4-one [00352]
  • Step 1 To a stirred solution of 2-[(diphenylmethyl)(methyl)amino]-5-methoxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carbaldehyde (0.2 g, 550 ⁇ mol) and benzene-1,2-diamine (71.4 mg, 1.2 eq., 660 ⁇ mol) was added DMSO (9.61 mL, 134 mmol) and disodium sulfinatosulfonate (126 mg, 1.2 eq., 660 ⁇ mol) and the solution was stirred at 110°C for 16 h.
  • Step 2 To a solution of 6-(1H-1,3-benzodiazol-2-yl)-2-[(diphenylmethyl)(methyl)amino]-5- methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.2 g, 443 ⁇ mol) in DMF (10 mL, 129 mmol) was added lithium bromide (192 mg, 5 eq., 2.21 mmol) and the mixture was stirred for 16
  • Example 21 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4-chlorophenyl) (
  • Example 26 6-(benzo[d]oxazol-2-yl)-5-hydroxy-2-(1-phenyl-3,4-dihydroisoquinolin-2(1
  • Step 1 To stirred solution of methyl 2,6-dichloro-5-methoxypyrimidine-4-carboxylate (5 g, 21.1 mmol) in DMF (5 mL), dipotassium carbonate (3.5 g, 1.2 eq., 25.3 mmol) and phenylmethanol (2.85 mL, 1.3 eq., 27.4 mmol) was added. The resulting mixture was heated to 70 °C for 16 h. After completion, reaction mixture was extracted with ethyl acetate, the organic layer was then dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography.
  • Step 2 To a stirred solution of methyl 6-(benzyloxy)-2-chloro-5-methoxypyrimidine-4- carboxylate (0.7 g, 2.27 mmol) in DMSO (5 mL) was added 1-phenyl-1,2,3,4-tetrahydroisoquinoline (475 mg, 2.27 mmol) and DMF (436 ⁇ L, 1.1 eq., 2.49 mmol) and the solution was stirred at 110 °C for 16 h.
  • Step 3 To a stirred solution of methyl 6-(benzyloxy)-5-methoxy-2-(1-phenyl-1,2,3,4- tetrahydroisoquinolin-2-yl) pyrimidine-4-carboxylate (2.5 g, 5.19 mmol) in THF (5.11 mL, 62.7 mmol) and water (0.5 mL), lithium hydroxide (1.06 g, 5 eq., 26 mmol) was added and stirred at ambient temperature for 16 h. After completion, the mixture was diluted with aqueous 6 N HCl and extracted with ethyl acetate.
  • Step 4 To a stirred solution of 6-(benzyloxy)-5-methoxy-2-(1-phenyl-1,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine-4-carboxylic acid (0.8 g, 1.71 mmol) in THF (6.78 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (416 mg, 1.5 eq., 2.57 mmol) and the reaction was stirred at ambient temperature for 30 min. Then 2-aminophenol (205 mg, 1.1 eq., 1.88 mmol) was added and stirred at 60 °C for 16 h.
  • Step 5 The solution of 6-(benzyloxy)-N-(2-hydroxyphenyl)-5-methoxy-2-(1-phenyl-1,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine-4-carboxamide (350 mg, 627 ⁇ mol) in acetic acid (5 mL) was stirred at 140 °C for 4 h.
  • Step 6 To a solution of 2-[4-(1,3-benzoxazol-2-yl)-6-(benzyloxy)-5-methoxy-1,6- dihydropyrimidin-2-yl]-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.2 g, 369 ⁇ mol) in DMF (16.9 mL, 219 mmol), lithium bromide (320 mg, 10 eq., 3.69 mmol) was added to the reaction mixture at 0 °C then it was stirred at 80 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature, concentrated, and diluted with water. The obtained solid was filtered and dried under reduced pressure.
  • Step 1 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (2.22 g, 9.56 mmol) in DMSO (20.0 mL) was added 1-phenyl-1,2,3,4- tetrahydroisoquinoline (2 g, 9.56 mmol) and DIPEA (1.84 mL, 1.1 eq., 10.5 mmol) and the solution was stirred at 110°C for 16 h. After completion of the reaction, it was diluted with water and extracted with ethyl acetate.
  • Step 2 To a stirred solution of methyl 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxylate (2.5 g, 6.17 mmol) in THF (18.0 mL) and water (6.0 mL) was added lithium hydroxide (738 mg, 5 eq., 30.8 mmol) and the mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was acidified with HCl and extracted with ethyl acetate.
  • Step 3 To a stirred solution of 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxylic acid (2.47 g, 6.31 mmol) in THF (25.0 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (1.53 g, 1.5 eq., 9.47 mmol) and the reaction was stirred at ambient temperature for 30 minutes then 2-aminophenol (757 mg, 1.1 eq., 6.94 mmol) was added and reaction was stirred for 16 h at 60 °C.
  • Step 4 A solution of N-(2-hydroxyphenyl)-5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxamide (1.2 g, 1.24 mmol) in acetic acid (20.0 mL) was heated at 180 °C for 2 h in microwave. After completion, the reaction mixture was concentrated to obtain crude product which was purified by CombiFlash.
  • Step 5 To a stirred solution of 5-methoxy-3-methyl-6-(oxazolo[5,4-c]pyridin-2-yl)-2-(1- phenyl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4(3H)-one (0.7 g, 1.51 mmol) in DMF (7.0 mL) was added lithium bromide (654 mg, 5 eq., 7.53 mmol) and the solution was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated and then ice cold water was added in it to obtain a solid which was filtered.
  • Step 1 To a stirred solution of 2,3-dihydro-1H-isoindole-1,3-dione (5 g, 34 mmol) in THF (0.1 L, 1.23 mol), was added phenyllithium (4.28 g, 1.5 eq., 51 mmol) at -78 °C. The resultant reaction mixture was allowed to stir at -78 °C for 16 h. After completion of the reaction quenched with saturated of ammonium chloride solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 To a stirred solution of 3-hydroxy-3-phenyl-2,3-dihydro-1H-isoindol-1-one (5 g, 22.2 mmol) in trifluoroacetic acid (10 mL) was added triethylsilane (7.68 g, 3 eq., 66.6 mmol). The resultant reaction mixture was allowed to stir at ambient temperature for 5 min. After completion of the reaction it was concentrated under reduced pressure.
  • Step 3 To a stirred solution of 3-phenyl-2,3-dihydro-1H-isoindol-1-one (350 mg, 1.67 mmol) in THF (5 mL) was added boron dimethyl sulfate (0.952 mL, 6 eq., 10 mmol) at 0 °C and the mixture was stirred at 75 °C for 16 h. Upon completion, the reaction mixture was cooled to 0 °C and was diluted with 1N HCl and extracted with EtOAc.
  • Step 4 To a stirred solution of 1-phenyl-2,3-dihydro-1H-isoindole (195 mg, 0.999 mmol) and methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (279 mg, 1.2 eq., 1.2 mmol) in DMF(6 mL) was added DIPEA (0.330 mL, 2 eq., 2 mmol) and the mixture was stirred at 110 °C for 16 h. After completion, the reaction mixture was diluted with water and the compound was extracted using EtOAc.
  • Step 5 To a stirred solution of methyl 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-2,3-dihydro- 1H-isoindol-2-yl)-1,6-dihydropyrimidine-4-carboxylate (218 mg, 0.557 mmol) in THF (5 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide (40 mg, 3 eq., 1.67 mmol) and the mixture was stirred at ambient temperature for 2 h. After completion, the solvent was evaporated completely. The crude was diluted with water and pH adjusted to ⁇ 2 with 1N HCl.
  • Step 6 To a stirred solution of 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-2,3-dihydro-1H- isoindol-2-yl)-1,6-dihydropyrimidine-4-carboxylic acid (205 mg, 0.543 mmol) in DMF (5 mL), diisopropyl ethylamine (301 ⁇ L, 3 eq., 1.63 mmol), HATU (310 mg, 1.5 eq., 0.815 mmol) and 2- iodoaniline (131 mg, 1.1 eq., 0.598 mmol) were added and the mixture was stirred at ambient temperature for 2 h.
  • Step 7 To a stirred solution of N-(2-iodophenyl)-5-methoxy-1-methyl-6-oxo-2-(1-phenyl-2,3- dihydro-1H-isoindol-2-yl)-1,6-dihydropyrimidine-4-carboxamide (0.1 g, 0.173 mmol) in acetonitrile (5 mL), cesium carbonate (84.5 mg, 1.5 eq., 0.259 mmol) was added and the mixture was purged with nitrogen for 5 min.
  • Step 8 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-5-methoxy-3-methyl-2-(1-phenyl-2,3- dihydro-1H-isoindol-2-yl)-3,4-dihydropyrimidin-4-one (40 mg, 88.8 ⁇ mol) in DMF(15 mL) was added lithium bromide (38.6 mg, 5 eq., 0.444 mmol) at ambient temperature. The mixture was heated at 100 °C for 16 h.
  • Example 40 and 41 6-(1,3-benzoxazol-2-yl)-5-hydroxy-3-methyl-2-(1-phenyl-2,3-dihydro-1H- isoindol-2-yl)-3,4-dihydropyrimidin-4-one [00384]
  • Intermediate 8 was separated by chiral HPLC and the two isomers were carried forward through Step 8 of example 24 to provide: [00385]
  • Step 1 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (1.11 g, 4.78 mmol) in DMSO (10.0 mL) was added 1-phenyl-1,2,3,4- tetrahydroisoquinoline (1 g, 4.78 mmol) and DIPEA (918 ⁇ L, 1.1 eq., 5.26 mmol) and the solution was stirred at 110 °C for 16 h.
  • Step 2 To a stirred solution of methyl 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-1,2,3,4- tetrahydroisoquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxylate (0.6 g, 1.48 mmol) in THF (4.5 mL) and water (1.5 mL, 83.3 mmol) was added lithium hydroxide (177 mg, 5 eq., 7.4 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • Step 3 To a stirred solution of 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-1,2,3,4- tetrahydroisoquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxylic acid (1 g, 2.55 mmol) in toluene (20 mL) was added DIPEA (892 ⁇ L, 2 eq., 5.11 mmol) and the solution was cooled to 0 °C and 1- propanephosphonic anhydride (2.44 g, 3 eq., 7.66 mmol) was added and it was irradiated at 190 °C for 1 h in microwave.
  • DIPEA 892 ⁇ L, 2 eq., 5.11 mmol
  • Step 4 To a solution of 5-methoxy-3-methyl-6- ⁇ [1,3] oxazolo[4,5-c] pyridin-2-yl ⁇ -2-(1- phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-3,4-dihydropyrimidin-4-one (570 mg, 1.22 mmol) in DMF (15.0 mL) was added lithium bromide (532 mg, 5 eq., 6.12 mmol) and the mixture was stirred for 3 days at 100 °C. After completion, the reaction was cooled to ambient temperature, concentrated, diluted with water, and extracted with ethyl acetate.
  • Step 1 To a stirred solution of methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (3 g, 12.9 mmol) in DMSO (10 mL), was added 1,1- diphenylmethanamine (2.68 mL, 15.5 mmol) and DIPEA (3.38 mL, 19.3 mmol). The resultant reaction mixture was allowed to stir at 120 °C for 2 h. Reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound.
  • Step 2 To a stirred solution of methyl 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxylate (1.8 g, 4.74 mmol) in THF (9 mL), was added methanol (3.6 mL) followed by the addition of lithium hydroxide (0.341 g, 3 eq., 14.2 mmol) in water (3.6 mL). The resultant reaction mixture was allowed to stir at ambient temperature for 30 min. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure then partitioned between ethyl acetate (30 mL) and water (30 mL).
  • Step 3 To a stirred solution of 2-[(diphenylmethyl)amino]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (1.3 g, 3.56 mmol) in DMF (12.7 mL), was added DIPEA (1.86 mL, 10.7 mmol) followed by the addition of 2-iodoaniline (1.17 g, 5.34 mmol) and HATU (1.26 g, 5.34 mmol). The resultant reaction mixture was allowed to stir at ambient temperature for 16 h. Completion of the reaction was monitored by TLC.
  • Step 4 To a stirred solution of 2-[(diphenylmethyl)amino]-N-(2-iodophenyl)-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.5 g, 0.0883 mmol) in acetonitrile (2.98 mL), was added cesium carbonate (431 mg, 1.32 mmol) and the reaction mixture was degassed for 10 minutes, then 1,10-phenanthroline (15.9 mg, 0.883 mmol) and copper iodide (16.8 mg, 0.00883 mmol) were added. The resultant reaction mixture was allowed to stir at 110 °C for 16 h.
  • Step 5 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2-[(diphenylmethyl)(ethyl)amino]-5- methoxy-3-methyl-3,4-dihydropyrimidin-4-one (40 mg, 0.0857 mmol) in DMF (5 mL) was added lithium bromide (44.7 mg, 6 eq., 0.514 mmol) at ambient temperature. The mixture was heated at 100 °C for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with saturated ammonium chloride and extracted with the DCM.
  • Step 1 To a solution of 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-1,2,3,4-tetrahydroisoquinolin- 2-yl)-1,6-dihydropyrimidine-4-carboxylic acid (1 g, 2.55 mmol) and 2-chloropyridin-3-amine (361 mg, 1.1 eq., 2.81 mmol) in DMF, was added DIPEA (825 mg, 2.5 eq., 1.28 mmol) and HATU (1.45 g, 1.5 eq., 766 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • Step 2 To a stirred solution of N-(2-chloropyridin-3-yl)-5-methoxy-1-methyl-6-oxo-2-(1- phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxamide (0.3 g, 598 ⁇ mol) in toluene (15 mL) was added potassium carbonate (165 mg, 2 eq., 1.2 mmol), methyl[2- (methylamino)ethyl]amine (10.5 mg, 0.2 eq., 120 ⁇ mol).
  • the reaction mixture was purged with nitrogen for 10 minutes and copper iodide (22.8 mg, 0.2 eq., 120 ⁇ mol) was added under nitrogen.
  • the resulting mixture was stirred in the microwave at 110 °C for 4 h.
  • the reaction was monitored by TLC.
  • the mixture was concentrated under reduced pressure and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography.
  • Step 3 To a stirred solution of 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)benzonitrile (80 mg, 168 ⁇ mol) in DMF (2 mL) was added bromolithium (87 mg, 6 eq., 1.01 mmol) under nitrogen. The reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (2 x 15 mL).
  • Step 1 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3-bromophenyl) (phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (250 mg, 0.00470 mmol) in toluene (5 mL) and water (1 mL) was added potassium dihydrogen phosphate (128 mg, 2 eq., 0.0941 mmol), cyclopropylboronic acid (48.5 mg, 1.2 eq., 0.0565 mmol), tricyclohexylphosphane (13.2 mg, 0.1 eq., 0.047 mmol) and the mixture was purged with nitrogen for 15 minutes.
  • Step 2 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3-cyclopropylphenyl) (phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (150 mg, 0.030 mmol) in DMF (5 mL) was added lithium bromide (212 mg, 8 eq., 2.44 mmol) and the mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride and extracted with the dichloromethane.
  • Example 37 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)-N, N-dimethylbenzamide [00407]
  • Step 1 To a stirred solution of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl) methyl) benzoic acid (0.180 g, 0363 mmol) and dimethyl amine HCl (0.059 g, 0.725 mmol) in DMF (2 mL) was added ethylbis(propan-2-yl) amine (0.095 mL, 0.544 mmol), [bis(dimethylamino)methylidene] ( ⁇ 3H-[1,2,3
  • Step 2 To a stirred solution of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl)-N, N-dimethylbenzamide (0.150 g, 0.286 mmol) in DMF (5 mL) was added lithium bromide (0.249 g, 2.86 mmol) at ambient temperature and the mixture was stirred at 110 °C for 16 h.
  • Example 38 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1- cyclobutyl-1H-1,3-benzodiazole-6-carboxamide [00411]
  • Step 1 To a stirred solution of 4-(1,3-benzoxazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-2-carbaldehyde (1 g, 3.34 mmol) and 4-amino-3-(cyclobutylamino)benzonitrile (501 mg, 0.8 eq., 2.67 mmol) in DMF (20 mL) and water (4 mL) was added oxone monopersulfate (1.03 g, 3.34 mmol) and stirred at ambient temperature for 16 h.
  • Step 2 To a stirred solution of 2-[4-(1,3-benzoxazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl]-1-cyclobutyl-1H-1,3-benzodiazole-6-carbonitrile (0.5 g, 1.07 mmol) in DMSO (4 mL), was added peroxol (108 ⁇ L, 1.5 eq., 1.61 mmol) followed by dipotassium carbonate (741 mg, 5 eq., 5.36 mmol) at 0 °C, after 5 minutes stirred at ambient temperature for 16 h.
  • Step 3 To a stirred solution of 2-[4-(1,3-benzoxazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl]-1-cyclobutyl-1H-1,3-benzodiazole-6-carboxamide (0.1 g, 206 ⁇ mol) in DMF (2 mL), was added lithium bromide (89.6 mg, 5 eq., 1.03 mmol) and stirred at 100 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was diluted with ice cold water, and the resulting mixture was filtered under vacuum.
  • Example 39 3-(2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-1-yl) benzoic acid [00414]
  • Step 1 To a stirred solution of methyl 2-phenylacetate (10 g, 66.6 mmol) in THF (100 mL) was added sodium borohydride (6.3 g, 2.5 eq., 166 mmol) at 0 °C.
  • Step 2 To a stirred solution of 2-phenylethan-1-ol (2 g, 16.4 mmol) in 1,2-dichloroethane (60 mL) was added 3-bromobenzonitrile (3.28 g, 1.1 eq., 18 mmol), 2-fluoropyridine (1.59 g, 16.4 mmol) & trifluoromethanesulfonyl (5.53 mL, 2 eq., 32.7 mmol) at 0 °C. The mixture was stirred at ambient temperature for 30 mins and then heated to 80 °C for 16 h. After completion of the reaction the mixture was concentrated then extracted with ethyl acetate.
  • Step 3 To a stirred solution of 1-(3-bromophenyl)-3,4-dihydroisoquinoline (1.9 g, 6.64 mmol) in methanol (30 mL, 741 mmol) was added sodium borohydride (754 mg, 3 eq., 19.9 mmol) at 0 °C.
  • Step 4 To a stirred solution of 1-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinoline (1.8 g, 6.25 mmol) in DMSO (50 mL) was added DIPEA (1.2 mL, 1.1 eq., 6.87 mmol) and methyl 2-chloro-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.45 g, 6.25 mmol) at ambient temperature. The mixture was heated at 110°C for 16 h. After completion of the reaction, it was diluted with water and extracted with ethyl acetate.
  • Step 5 To a stirred solution of methyl 2-[1-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-2- yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.9 g, 1.86 mmol) in THF (5 mL), methanol (5 mL,) and water (1 mL) was added lithium hydroxide (156 mg, 2 eq., 3.72 mmol) at ambient temperature. The reaction mixture was stirred at RT for 2 h. after completion solvent was removed under reduced pressure. The crude was dissolved in water and washed with diethyl ether (10 mL).
  • Step 6 To a stirred solution of 2-[1-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 0.213 mmol) and 2- aminophenol (25.5 mg, 1.1 eq., 0.234 mmol) in THF (10 mL) was added 1-(1H-imidazole-1-carbonyl)- 1H-imidazole (51.7 mg, 1.5 eq., 0.319 mmol) at 0 °C under N 2 atmosphere. The mixture was heated at 60 °C for 16 h.
  • Step 7 To a stirred solution of 2-[1-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-N- (2-hydroxyphenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (70 mg, 0.125 mmol) in acetic acid (2 mL) was irradiated in CEM microwave at 180 °C for 2 h. After completion of the reaction, it was concentrated.
  • Step 8 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2-[1-(3-bromophenyl)-1,2,3,4- tetrahydroisoquinolin-2-yl]-5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.5 g, 0.920 mmol) in a mixture of 1,2-dimethoxyethane (10 mL) and water (8 mL) was added sodium carbonate (146 mg, 1.5 eq., 1.38 mmol).
  • Tetrafluoroborohydride tri-tert-butylphosphanium (26.7 mg, 0.1 eq., 0.092 mmol), hexakis(methanidylidyneoxidanium) molybdenum (364 mg, 1.5 eq., 1.38 mmol) was then added and the mixture was purged with nitrogen gas for 10 minutes. Then palladium diacetate (20.7 mg, 0.1 eq., 0.092 mmol) was added and the mixture was stirred for 1 h at 120°C in microwave. After completion, the mixture was evaporated and the residue was diluted with water and washed with ethyl acetate.
  • aqueous layer was acidified with 1N HC1 solution (pH ⁇ 2), extracted with DCM, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 3- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinolin-1-yl ⁇ benzoic acid (150 mg, crude).
  • ES MS M/Z 509.2 [M+H] + .
  • Step 9 To a stirred solution of 3- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinolin-1-yl ⁇ benzoic acid (150 mg, 0.103 mmol) in DMF (5 mL) was added lithium bromide (26.9 mg, 3 eq., 0.310 mmol) at ambient temperature and the mixture was heated at 95 °C for 16 hours. After completion, the reaction mixture poured into wáter, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated.
  • Example 45 and 46 -3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin- 2-yl](methyl)amino ⁇ (phenyl)methyl)benzoic acid
  • Step 1 To a stirred solution of 3-bromobenzaldehyde (10 g, 54 mmol) in dichloromethane (70 mL) were added cesium carbonate (26.4 g, 1.5 eq., 81.1 mmol), 2-methylpropane-2-sulfinamide (7.86 g, 1.2 eq., 64.9 mmol) and stirred at 40 °C for 16 hours. After completion of the starting material, reaction mixture was diluted with water (15 mL) and the compound was extracted with dichloromethane.
  • Step 2 To a stirred solution of N-[(Z)-(3-bromophenyl) methylidene]-2-methylpropane-2- sulfinamide (15 g, 19.1 mmol) in tetrahydrofuran (50 mL), was added phenyllithium (1.92 g, 1.2 eq., 22.9 mmol) at -78 °C. The resultant reaction mixture was allowed to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL).
  • Step 3 To a stirred solution of N-[(3-bromophenyl) (phenyl)methyl]-2-methylpropane-2- sulfinamide (13.1 g, 35.9 mmol) in dichloromethane (55 mL) was added 4M hydrogen chloride in 1,4- dioxane (2.62 g, 2 eq., 71.7 mmol) at 0 °C. The resultant reaction mixture was allowed to stir at room temperature for 2 hours. After completion of reaction, reaction mixture was evaporated under reduced pressure.
  • Step 4 To a stirred solution of 1-(3-bromophenyl)-1-phenylmethanamine hydrochloride (10.4 g, 34.8 mmol) in dimethyl sulfoxide (100 mL) slowly added ethylbis(propan-2-yl) amine (18.2 mL, 3 eq., 104 mmol) after 10 min added methyl 2-chloro-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (8.1 g, 34.8 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 120 °C for 2 hours.
  • Step 5 To a stirred solution of methyl 2- ⁇ [(3-bromophenyl) (phenyl)methyl] amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (6.5 g, 14.2 mmol) in dimethylformamide (38 mL) were added cesium carbonate (13.9 g, 3 eq., 42.5 mmol) followed by iodo methane (1.3 mL, 22.3 mmol) and stirred at room temperature for 2 hours.
  • cesium carbonate (13.9 g, 3 eq., 42.5 mmol
  • iodo methane 1.3 mL, 22.3 mmol
  • Step 6 To a stirred solution of methyl 2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ - 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (6.5 g, 13.8 mmol) in mixture of tetrahydrofuran (35 mL), methanol (35 mL) and water (10 mL) was added lithium hydroxide (1.62 g, 5 eq., 67.6 mmol). The resulting reaction mixture was allowed to stir at room temperature for 2 hours. After completion of the reaction concentrated under reduced pressure.
  • Step 7 To a stirred solution of 2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (6 g, 13.1 mmol) and 2-iodoaniline (1.42 g, 1.1 eq., 6.48 mmol) in dimethylformamide (80 mL) were added ethylbis(propan-2-yl)amine (7.25 mL, 3 eq., 39.3 mmol), hexafluoro- ⁇ 5-phosphanuide 1-[bis(dimethylamino)methylidene]-1H-1 ⁇ 5- [1,2,3]triazolo[4,5-b]pyridin-3-ium-1-ylium-3-olate (7.47 g, 1.5 eq., 19.6 mmol) and stirred at room temperature for 4 h.
  • reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and evaporated to get the crude.
  • the crude compound was purified by combi flash chromatography 40-50% ethyl acetate in heptane to afford 2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -N-(2-iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4.77 g, 42%) as a pale yellow solid.
  • Step 8 To a stirred solution of 2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -N-(2- iodophenyl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4.77 g, 7.23 mmol) in acetonitrile (127 mL) were added cesium carbonate (3.54 g, 1.5 eq., 10.9 mmol), copper iodide (68.9 mg, 0.05 eq., 0.362 mmol) and 1,10-phenanthroline (130 mg, 0.1 eq., 0.723 mmol).
  • reaction mixture was diluted with water and extracted into ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and concentrated to get the crude.
  • the crude compound was purified by combi flash chromatography 30-40% ethyl acetate in heptane to get the crude compound.
  • Step 9a (Isomer-1): To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (0.4 g, 0.753 mmol) in mixture of 1,2-dimethoxyethane (10 mL) and water (6.67 mL) was added sodium carbonate (120 mg, 1.5 eq., 1.13 mmol).
  • aqueous layer was acidified by IN HC1 solution (pH ⁇ 2), extracted with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure to get crude.
  • the crude compound was purified by combi flash chromatography 30-40% EtOAc in Heptane to get the 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzoic acid (0.2 g, 53.51%) as a yellow solid.
  • ES MS M/Z 497.0 [M+H] + .
  • Step 9b (Isomer-2): To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(3-bromophenyl) (phenyl)methyl] (methyl)amino ⁇ -5-methoxy-3-methyl-3,4-dihydropyrimidin-4-one (370 mg, 0.696 mmol) in mixture of 1,2-dimethoxyethane (10 mL) and water (8 mL) was added sodium carbonate (111 mg, 1.5 eq., 1.04 mmol).
  • the aqueous layer was acidified by IN HC1 solution (pH ⁇ 2), extracted with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure to get the crude.
  • the crude compound was purified by combi flash chromatography 30-40% EtOAc in Heptane to get the 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzoic acid (170 mg, 49%) as a yellow solid.
  • ES MS M/Z 497.0 [M+H] + .
  • Step 10a (Isomer-1): To a stirred solution of 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzoic acid (0.2 g, 0.403 mmol) in dimethylformamide (8 mL) was added lithium bromide (350 mg, 10 eq., 4.03 mmol) at room temperature and stirred at 110 °C for 16 hours. After completion of the reaction, reaction mixture was diluted with saturated ammonium chloride and extracted with 10% methanol in DCM.
  • Step 10b (Isomer-2): To a stirred solution of 3-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl] (methyl)amino ⁇ (phenyl)methyl) benzoic acid (170 mg, 0.342 mmol) in dimethylformamide (5 mL) was added lithium bromide (297 mg, 10 eq., 3.42 mmol) at room temperature and stirred at 110 °C for 16 hours. After completion of the reaction, reaction mixture was diluted with saturated ammonium chloride and extracted with the dichloromethane.
  • Example 47 and 48 4-(((4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin- 2-yl) (methyl)amino) (phenyl)methyl) benzoic acid
  • Example 50 (1R)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-N,N-dimethyl- 1-(2-methylphenyl)-3,4-dihydro-1H-isoquinoline-7-carboxamide [00440] A solution of (1R)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1-(2- methylphenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylic acid (20 mg, 1 equiv), PyBOP (62 mg, 3 equiv), DIEA (21 mg, 4 equiv) and dimethylamine hydrochloride (5 mg, 1.5 equiv) in DMF (1.5 mL) was stirred for 3 h at 20 °C under N 2 atmosphere.
  • Example 54 (S)-2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)- 1-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide [00445] 1 H NMR (300 MHz, DMSO-d 6 ) ⁇ 8.36 - 8.35 (s, 2H), 8.28 - 8.26 (s, 1H), 7.86 (s, 1H), 7.66 - 7.63 (m, 1H), 7.50 - 7.46 (s, 1H), 7.42 - 7.20 (m, 4H), 7.02 - 6.97 (m, 2H), 6.17(s, 1H), 3.45 - 3.36 (s, 4H), 3.42 - 3.66 (m, 2H), 2.51 - 2.49 (m, 3H).
  • Example 65 (1R)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1-(2- chlorophenyl)-N,N-dimethyl-3,4-dihydro-1H-isoquinoline-6-carboxamide [00456]
  • Example 76 tert-butyl ((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(4-(((R)-2- hydroxypropyl)(methyl)carbamoyl)furan-2-yl)(oxo)-l6-sulfaneylidene)carbamate [00467]
  • Example 80 and 81 (R)-2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide and (S)-2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-(2- methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide [00473] 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1-(2-methoxyphenyl)- 3,4-dihydro-1H-isoquinoline-7-carboxamide (80 mg, 0.153 mmol, 1 equi
  • Example 92 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1-(2- cyanophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylic acid
  • Step 1 The mixture of methyl 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-1-(2-chlorophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate (300 mg, 0.539 mmol, 1 equiv), Zn (7 mg, 0.102 mmol, 0.19 equiv), Zn(CN)2 (35 mg, 0.302 mmol, 0.56 equiv), Pd(TFA)2 (35 mg, 0.108 mmol, 0.2 equiv), TRIXIEPHOS
  • the mixture was stirred at 100 °C for 16 h.
  • the mixture was diluted with H2O (30 mL) and extracted with DCM (20 mL x 3). The organic layer was combined, washed by brine, dried over sodium sulfate, filtered, and concentrated.
  • Step 2 To the mixture of methyl 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-1-(2-cyanophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate (200 mg, 0.365 mmol, 1 equiv) in DMF (5 mL) was added LiBr (190 mg, 2.19 mmol, 6 equiv). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with H 2 O (30 ml) and extracted with DCM/MeOH (10:1) (20 mL x 3).
  • Step 3 To the mixture of methyl (1S)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl]-1-(2-cyanophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate (100 mg, 0.187 mmol, 1 equiv) in THF (4 mL) and MeOH (2 mL) was added LiOH (27 mg, 1.122 mmol, 6 equiv) in H 2 O (2 mL). The mixture was stirred at ambient temperature for 48 h. The mixture was acidified to pH 3 with HCl (2 M). The mixture was concentrated to remove THF and MeOH.
  • Step 2 A solution of N-[2-(3-bromophenyl)ethyl]-2-methylbenzamide (12 g, 37.710 mmol, 1 equiv) in polyphosphoric acid (200 mL) was stirred for 4 h at 165 °C. The reaction was quenched with H 2 O at 0 °C. The mixture was basified to pH 8 with NaOH. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 3 A solution of 7-bromo-1-(2-methylphenyl)-3,4-dihydroisoquinoline (5.6 g, 18.654 mmol, 1 equiv) in MeOH (80 mL) was added NaBH4 (3.53 g, 93.270 mmol, 5 equiv) at 0 °C.
  • Step 4 A solution of 7-bromo-1-(2-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (2.91 g, 9.629 mmol, 1 equiv) in DCM (40 mL) was added Boc 2 O (3.15 g, 14.4 mmol, 1.5 equiv) and Et 3 N (4.38 g, 43.3 mmol, 4.5 equiv). The mixture was stirred for 2 h at 20 °C. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate.
  • Step 5 A solution of tert-butyl 7-bromo-1-(2-methylphenyl)-3,4-dihydro-1H-isoquinoline-2- carboxylate (3.5 g, 8.699 mmol, 1 equiv) in CH3OH (100 mL) was added Pd(dppf)Cl2 (0.95 g, 1.305 mmol, 0.15 equiv) and Et 3 N (4.40 g, 43.495 mmol, 5 equiv). The mixture was stirred for 16 h at 130 °C under CO (20 atm) atmosphere. The resulting mixture was filtered; the filter cake was washed with CH3OH (3 x 20 mL). The filtrate was concentrated under reduced pressure.
  • Step 6 The crude product was purified by PREP_SFC with the following conditions: Column: UnichiralOD-5H 4.6*100mm, 5 ⁇ m; Mobile Phase B: IPA (0.1%DEA); Flow rate: 4 mL/min; Gradient: isocratic% B. The resulting product was dried with a rotary evaporator, and gradient to afford 2-(tert- butyl) 7-methyl (S)-1-(o-tolyl)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (400 mg, 24%).
  • ES MS M/Z 382.5 [M+H] + .
  • Step 8 A solution of methyl (S)-1-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (245 mg, 0.871 mmol, 1 equiv), 6-(1,3-benzoxazol-2-yl)-2-chloro-5-methoxy-3-methylpyrimidin-4-one (330 mg, 1.132 mmol, 1.3 equiv) and CsF (145 mg, 0.958 mmol, 1.1 equiv) in DMSO (8 mL) was stirred for 16 h at 80 °C. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate.
  • Step 9 A solution of methyl (S)-2-(4-(benzo[d]oxazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (140 mg, 0.261 mmol, 1 equiv) in DMF (8 mL) was added LiBr (227 mg, 2.610 mmol, 10 equiv). The mixture was stirred for 16 h at 100 °C. The residue was purified by trituration with H2O (10 mL).
  • Step 10 A solution of methyl (S)-2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (130 mg, 0.249 mmol, 1 equiv) in MeOH (0.5 mL), THF (2 mL) and H2O (1.5 mL) was added LiOH (36 mg, 1.494 mmol, 6 equiv). The mixture was stirred for 5 h at 40 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 1 To a stirred solution of 6-(1,3-benzoxazol-2-yl)-2-(7-bromo-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-5-methoxy-3-methylpyrimidin-4-one (200 mg, 0.368 mmol, 1 equiv) and methyl carbamate (33 mg, 0.442 mmol, 1.2 equiv) in 1,4-dioxane (5 mL) were added Pd2(dba)3 (16 mg, 0.018 mmol, 0.05 equiv), Cs2CO3 (239 mg, 0.736 mmol,
  • Step 2 A solution of methyl N- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinolin-7-yl ⁇ carbamate (60 mg, 0.112 mmol, 1 equiv) and LiBr (58 mg, 0.672 mmol, 6 equiv) in DMF (1.00 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS.
  • Step 1 A solution of tert-butyl N-(2-oxocyclopentyl) carbamate (10 g, 50.188 mmol, 1 equiv) in HCl(gas) in 1,4-dioxane (100 mL) was stirred for 30 min at ambient temperature in an open flask. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure. This resulted in 2-aminocyclopentan-1-one (5 g, 101%) as a colorless solid. The crude product was used in the next step directly without further purification.
  • Step 2 To a stirred solution of 2-aminocyclopentan-1-one hydrochloride (5 g, 36.9 mmol, 1 equiv) and 2-chloro-5-methoxy-6-oxo-1H-pyrimidine-4-carboxylic acid (9.05 g, 44.3 mmol, 1.2 equiv) in DCM (60 mL) were added DIEA (28.60 g, 221.3 mmol, 6 equiv) and T 3 P (140.8 g, 221.3 mmol, 6 equiv, 50%) dropwise at ambient temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL).
  • Step 3 To a stirred solution 2-chloro-5-methoxy-6-oxo-N-(2-oxocyclopentyl)-1H-pyrimidine- 4-carboxamide (5 g, 17.502 mmol, 1 equiv) and MeI (2.7 mL, 43.755 mmol, 2.5 equiv) in DMF (50 mL, 646.1 mmol, 36.91 equiv) was added Cs2CO3 (17.1 g, 52.5 mmol, 3 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for 30 min at ambient temperature under air atmosphere.
  • Step 4 To a stirred solution of 2-chloro-5-methoxy-1-methyl-6-oxo-N-(2-oxocyclopentyl) pyrimidine-4-carboxamide (700 mg, 2.34 mmol, 1 equiv) and methyl (1R)-1-phenyl-1,2,3,4- tetrahydroisoquinoline-7-carboxylate (624 mg, 2.336 mmol, 1 equiv) in DMSO (5 mL, 84.39 equiv) was added CsF (390 mg, 2.570 mmol, 1.1 equiv) dropwise at ambient temperature under air atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere.
  • Step 5 To a stirred solution methyl (1R)-2- ⁇ 5-methoxy-1-methyl-6-oxo-4-[(2-oxocyclopentyl) carbamoyl] pyrimidin-2-yl ⁇ -1-phenyl-3,4-dihydro-1H-isoquinoline-7-carboxylate (300 mg, 0.565 mmol, 1 equiv) and hexachloroethane (334 mg, 1.412 mmol, 2.5 equiv) in DCM (5 mL) was added triethylamine (1.2 mL, 3.39 mmol, 6 equiv) and triphenylphosphine (444 mg, 1.70 mmol, 3 equiv) dropwise at ambient temperature under nitrogen atmosphere.
  • Step 6 A solution of methyl (1R)-2-(4- ⁇ 4H,5H,6H-cyclopenta[d] [1,3] oxazol-2-yl ⁇ -5- methoxy-1-methyl-6-oxopyrimidin-2-yl)-1-phenyl-3,4-dihydro-1H-isoquinoline-7-carboxylate (140 mg, 0.273 mmol, 1 equiv) and LiBr (142.3 mg, 1.64 mmol, 6 equiv) in DMF (2 mL) was stirred for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL).
  • Step 7 To a stirred mixture of methyl (1R)-2-(4- ⁇ 4H,5H,6H-cyclopenta[d] [1,3] oxazol-2-yl ⁇ - 5-hydroxy-1-methyl-6-oxopyrimidin-2-yl)-1-phenyl-3,4-dihydro-1H-isoquinoline-7-carboxylate (80 mg, 0.16 mmol, 1 equiv) in THF (2 mL) and MeOH (1 mL) was added LiOH (2M aq.) (0.80 mL, 1.60 mmol, 9.97 equiv) dropwise at ambient temperature under air atmosphere. The resulting mixture was stirred for 1 h at 40 °C under air atmosphere.
  • the reaction was monitored by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the mixture was acidified to pH 5 with HCl (aq.).
  • the aqueous layer was extracted with CH3Cl (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase, acetonitrile in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm).
  • Example 102 (1R,4S)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-4- methyl-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid
  • Step 1 To a solution of methyl isoquinoline-6-carboxylate (10 g, 53.419 mmol), NBS (14.26 g, 80.129 mmol) in AcOH (202 mL) giving a brown suspension, which was stirred at 80 °C overnight. After concentration, the obtained residue was extracted with ethyl acetate (10 mL x 3).
  • Step 2 To a solution of methyl 4-bromoisoquinoline-6-carboxylate (8 g, 30.065 mmol), methylboronic acid (3.60 g, 60.1 mmol), Pd(dppf)Cl 2 (2.20 g, 3.01 mmol), Cs 2 CO 3 (19.6 g, 60.1 mmol) in 1,4-dioxane/H2O (80/8 mL) was added giving a red suspension, which stirred at 110 °C under N2 for 2 h. After concentration, the resulting mixture was extracted with ethyl acetate (50 mL X 3).
  • Step 3 A solution of methyl 4-methylisoquinoline-6-carboxylate (5 g) in DCM (150 mL) was stirred at ambient temperature for 5 min. To this suspension, m-CPBA (8.2 g) was added and stirred at ambient temperature overnight.
  • Step 4 A solution of the N-oxide (4.5 g, 58.5 mL) in phosphorus(V) oxychloride (5.0 mL, 53.48 mmol) was stirred at 60 °C for 1 h. The excess of phosphorus(V) oxychloride was removed under reduced pressure. The residue was quenched with 2 N aqueous NaOH solution and then it was extracted three times with EA. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and evaporated to afford methyl 1-chloro-4-methylisoquinoline-6-carboxylate (3.8 g, 69.37% yield) as a yellow oil.
  • Step 5 To a solution of methyl 1-chloro-4-methylisoquinoline-6-carboxylate (3.7 g, 15.7mmol), phenyl boronic acid (3.83 g, 31.4mmol), Pd(dppf)Cl 2 DCM (1.28 g, 1.57mmol), Cs 2 CO 3 (10.23 g, 31.4mmol) in 1,4-dioxane/H2O (37/3.7 mL) was added giving a red suspension, which stirred at 110 °C under N2 for 2 h.
  • Step 6 To a 100 mL pressure tank reactor was added methyl 4-methyl-1-phenylisoquinoline- 6-carboxylate (3.7 g, 13.342 mmol) in AcOH (66.6 mL).
  • Step 7 A solution of E-methyl 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylate (200 mg, 0.711 mmol), 6-(benzo[d]oxazol-2-yl)-2-chloro-5-methoxy-3-methylpyrimidin- 4(3H)-one (249 mg, 0.853 mmol), CsF (130 mg, 0.853 mmol) in DMSO (3.6 mL) was stirred at 80 °C for overnight. The reaction mixture was quenched with water (10 mL), the resulting mixture was extracted with ethyl acetate (3 x 10 mL).
  • Step 8 A solution of methyl (1R,4S)-2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-4-methyl-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (330 mg, 0.615 mmol), LiBr (534 mg, 6.150 mmol) in DMF (6.6 mL) was stirred at 100 °C for overnight. After cooling to ambient temperature, the mixture was added H 2 O (20 mL). The mixture was extracted by EA (3 x 20 mL). The organic layers were concentrated under reduced pressure.
  • Step 9 To a solution of methyl (1R,4S)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl]-4-methyl-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (50 mg, 0.574 mmol) and lithium hydroxide (41 mg, 1.7 mmol) at ambient temperature in water (3 mL) was added giving a brown suspension. To this suspension, THF (3 mL) was added which was stirred giving a yellow solution, which stirred at ambient temperature overnight. After concentration, the pH was adjusted to 5-6 by addition of HCl (aq.2 M).
  • Step 1 A solution of 2-(4-bromophenyl)ethanol (5 g, 24.868 mmol, 1 equiv) in DCE (65 mL, 821.1 mmol, 33.02 equiv) was treated with 2-fluorobenzonitrile (4.5 g, 37.3 mmol, 1.5 equiv) and 2- fluoropyridine (2.4 g, 24.87 mmol, 1 equiv) at ambient temperature followed by the addition of Tf 2 O (14.03 g, 49.74 mmol, 2 equiv) dropwise at 0 °C.
  • 2-fluorobenzonitrile 4.5 g, 37.3 mmol, 1.5 equiv
  • 2- fluoropyridine 2.4 g, 24.87 mmol, 1 equiv
  • Step 2 To a stirred solution of 7-bromo-1-(2-fluorophenyl)-3,4-dihydroisoquinoline (10 g, 32.88 mmol, 1 equiv) in MeOH (100 mL) was added NaBH 4 (3.7 g, 98.63 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 2 h at ambient temperature.
  • Step 3 A solution of 7-bromo-1-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (4 g, 13.06 mmol, 1 equiv) in DCM (80 mL, 1258.4 mmol, 96.3 equiv) was treated with Et 3 N (3.97 g, 39.19 mmol, 3 equiv) for 5 min at 0 °C followed by the addition of Boc2O (4.28 g, 19.60 mmol, 1.5 equiv). The resulting mixture was stirred for 2 h at ambient temperature. The resulting mixture was extracted with DCM (2 x 20 ml).
  • Step 4 A solution of tert-butyl 7-bromo-1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinoline-2- carboxylate (3.38 g, 8.319 mmol, 1 equiv) in MeOH (170 mL) was treated with TEA (2.53 g, 24.96 mmol, 3 equiv) followed by the addition of Pd(dppf)Cl2 (913 mg, 1.248 mmol, 0.15 equiv). The resulting mixture was stirred overnight at 130 °C under CO (20atm). The resulting mixture was concentrated under vacuum. The residue was diluted with EA (50 mL) and water (50 mL).
  • Step 5 A solution of 2-tert-butyl 7-methyl 1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinoline- 2,7-dicarboxylate (1.9 g, 4.93 mmol, 1 equiv) in DCM (20 mL) was treated with 4 M HCl in dioxane (20 mL) for 1 h at ambient temperature. The resulting mixture was concentrated under vacuum. The residue was suspended in CHCl 3 /i-PrOH (20 mL, v/v, 3/1) and basified to pH ⁇ 10 with NaOH (aq., 1 M).
  • the first fraction provided (1R)-1-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate a light yellow oil.
  • ES MS M/Z 286.12 [M+H] + .
  • the second fraction provided methyl (1S)-1-(2- fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate as a light yellow oil.
  • ES MS M/Z 286.12 [M+H] + .
  • Step 7 A yellow solution of methyl (1S)-1-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-7- carboxylate (250 mg, 0.876 mmol, 1 equiv), 6-(1,3-benzoxazol-2-yl)-2-chloro-5-methoxy-3- methylpyrimidin-4-one (383 mg, 1.31 mmol, 1.5 equiv) and CsF (173 mg, 1.14 mmol, 1.3 equiv) in DMSO (5 mL) was stirred at 100 °C for 4 h. After cooling to ambient temperature, EtOAc (20 mL) and H2O (20 mL) were added.
  • Step 8 A yellow solution of methyl (1S)-2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate (330 mg, 0.610 mmol, 1 equiv), LiBr (265 mg, 3.050 mmol, 5 equiv) in DMF (3 mL) was stirred at 100 °C. After cooling to ambient temperature , EtOAc (20 mL) and H2O (20 mL) were added. The aqueous phase was extracted with EtOAc (20 mL x 2).
  • Step 9 To a solution of methyl (1S)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl]-1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate (300 mg, 0.570 mmol, 1 equiv) in THF (12 mL) and MeOH (4 mL), a solution of LiOH (41 mg, 1.710 mmol, 3 equiv) in H2O (4 mL) was added giving a white suspension, which stirred at ambient temperature for 2 h.
  • Step 1 A solution of methyl 2,6-dichloro-5-methoxypyrimidine-4-carboxylate (100 g, 422 mmol, 1 equiv) in H2O (800 mL) and THF (800 mL) was treated with lithium hydroxide (50.5 g, 2109 mmol, 5.00 equiv) in portions at ambient temperature. The resulting mixture was stirred for 12 h at 60 °C. The mixture was allowed to cool down to ambient temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 2 To a stirred solution of 2-iodoaniline (50.6 g, 231.217 mmol, 1.1 equiv) and 2-chloro- 6-hydroxy-5-methoxypyrimidine-4-carboxylic acid (43 g, 210.197 mmol, 1.00 equiv) in DCM (1000 mL) was added T3P (334.4 g, 1050.985 mmol, 5.00 equiv) and DIEA (135.8 g, 1050.985 mmol, 5.00 equiv) in portions at ambient temperature. The resulting mixture was stirred for 24 h at ambient temperature. The resulting mixture was diluted with water (1000 mL).
  • Step 3 A mixture of 1,10-phenanthroline (8.0 g, 44.381 mmol, 0.2 equiv) and CuCN (3.97 g, 44.381 mmol, 0.2 equiv) in DMF (1000 mL) was stirred for 30 min at ambient temperature under nitrogen atmosphere. To the above mixture was added 2-chloro-N-(2-iodophenyl)-5-methoxy-6-oxo-1H- pyrimidine-4-carboxamide (90 g, 221.904 mmol) and Cs2CO3 (217 g, 665.712 mmol) in portions at ambient temperature. The resulting mixture was stirred for additional 16 h at 100 °C. The crude product was used directly without purification.
  • Step 4 To the mixture of step 3 was added CH 3 I (63 g, 443.808 mmol, 2 equiv) dropwise over 10 min at ambient temperature. The resulting mixture was stirred for additional 12 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford 6-(1,3-benzoxazol-2-yl)-2-chloro-5- methoxy-3-methylpyrimidin-4-one (40 g, 62%). ES MS M/Z 292.05 [M+H] + .
  • Step 1 A solution of 6-bromo-2,3-dihydroisoindol-1-one (15 g, 70.74 mmol, 1 equiv) and Boc 2 O (18.5 g, 84.9 mmol) in THF (200 mL) was treated with DMAP (0.86 g, 7.07 mmol, 0.1 equiv) followed by the addition of Et 3 N (17.90 g, 176.85 mmol, 2.5 equiv) dropwise at ambient temperature. The resulting mixture was stirred overnight at 65 °C. The mixture was allowed to cool down to ambient temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 2 To a stirred solution/mixture of tert-butyl 6-bromo-1-oxo-3H-isoindole-2-carboxylate (14 g, 44.9 mmol, 1 equiv) in THF (150 mL) was added phenyllithium (28.3 mL 1.9 M in hexane, 53.8 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. Then the resulting mixture was stirred for 30 min at ambient temperature under a nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C.
  • Step 3 To a stirred solution/mixture of tert-butyl N-[(2-benzoyl-4- bromophenyl)methyl]carbamate (10 g, 25.623 mmol, 1 equiv) in MeOH (200 mL) was added NaBH 4 (2.9 g, 76.869 mmol, 3 equiv) in portions at 0 °C under. The resulting mixture was stirred for 1 h at ambient temperature. The mixture was allowed to cool down to 0 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (100 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 4 To a stirred solution of tert-butyl N-( ⁇ 4-bromo-2- [hydroxy(phenyl)methyl]phenyl ⁇ methyl)-carbamate (7 g, 17.844 mmol) in DCM (500 mL) was added TFAA (4 mL) dropwise at 0 °C. The resulting mixture was stirred for 30 min at ambient temperature. The reaction was quenched by the addition of NaHCO3(300 mL) at ambient temperature. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 5 To a 500 mL pressure tank reactor was added tert-butyl 6-bromo-1-phenyl-1,3- dihydroisoindole-2-carboxylate (6 g, 16.031 mmol) in MeOH (300 mL), TEA (8.11 g, 80.155 mmol) and Pd(dppf)Cl2 (1.74 g, 2.405 mmol) were added, and the reaction mixture was stirred under CO (30 atm) for 16 h at 130 °C.
  • Step 6 To a stirred solution of 2-tert-butyl 5-methyl 3-phenyl-1,3-dihydroisoindole-2,5- dicarboxylate (3 g, 8.489 mmol, 1 equiv) in 4M HCl in dioxane (20 mL). The resulting mixture was stirred for 2 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (50 mL) to afford methyl 3-phenyl-2,3-dihydro- 1H-isoindole-5-carboxylate (2 g, 93%) as a colorless solid.
  • Step 7 A mixture of ethyl 3-(3-phenylmorpholin-2-yl)propanoate (1 g, 3.797 mmol, 1 equiv) ,6-(1,3-benzoxazol-2-yl)-2-chloro-5-methoxy-3-methylpyrimidin-4-one (1.33 g, 4.556 mmol, 1.2 equiv) and cesium fluoride (0.69 g, 4.56 mmol, 1.2 equiv) in DMSO (10 mL) was stirred for 16 h at 80 °C.
  • Step 8 A solution of methyl 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin- 2-yl]-3-phenyl-1,3-dihydroisoindole-5-carboxylate (150 mg, 0.295 mmol), LiBr (256 mg, 2.950 mmol) in DMF (3 mL) was stirred overnight at 80 °C. The resulting mixture was diluted with water (30 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The residue was purified by trituration with diethyl ether (30 mL).
  • Example 116 and 117 (1R)-2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1- phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid and (1S)-2-[4-(1,3-benzoxazol-2-yl)-5- hydroxy-1-methyl-6-oxopyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid [00565] To a stirred solution of methyl (1S)-2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (1.6 g, 3.06 mmol, 1 equiv) in THF (4 mL),
  • Example 119 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)-N-methylbenzamide [00568]
  • Step 1 To a stirred mixture of 6-(1,3-benzoxazol-2-yl)-2-chloro-5-methoxy-3- methylpyrimidin-4-one (1 g, 3.43 mmol, 1 equiv) and 1-(4-bromophenyl)-1-phenylmethanamine (899 mg, 3.43 mmol, 1 equiv) in EtOH (10 mL) were added DIEA (1.3 g, 10.28 mmol, 3 equiv).
  • Step 2 To a stirred mixture of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4- bromophenyl)(phenyl)methyl]amino ⁇ -5-methoxy-3-methylpyrimidin-4-one (700 mg, 1.353 mmol, 1 equiv) in DMF (7 mL) was added MeI (384 mg, 2.71 mmol, 2 equiv) and Cs2CO3 (1.1 g, 3.38 mmol, 2.5 equiv). The reaction was stirred at ambient temperature for 2 h. The residue was purified by trituration with water (5 mL).
  • Step 3 To a stirred mixture of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4- bromophenyl)(phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methylpyrimidin-4-one (200 mg, 0.376 mmol, 1 equiv) and lithium(1+) formate (59 mg, 1.13 mmol, 3 equiv) in DMF (15 mL) was added Ac 2 O (76.8 mg, 0.752 mmol, 2 equiv) and Pd(OAc)2 (2.11 mg, 0.009 mmol, 0.025 equiv), DPPF (5.20 mg, 0.009 mmol, 0.025 equiv), and DIEA (97.29 mg, 0.752 mmol, 2 equiv).
  • Step 4 To a stirred mixture of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)benzoic acid (150 mg, 0.302 mmol, 1 equiv) and methylamine hydrochloride (24 mg, 0.362 mmol, 1.2 equiv) in DMF (1.5 mL) was added HATU (229 mg, 0.604 mmol, 2 equiv) and DIEA (117 mg, 0.906 mmol, 3 equiv). The reaction was stirred at ambient temperature for 2 h.
  • Step 5 To a stirred mixture of 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)-N-methylbenzamide (50 mg, 0.098 mmol, 1 equiv) in DMF (1 mL) was added dodecane-1-thiol (39 mg, 0.196 mmol, 2 equiv) and NaOMe (11 mg, 0.196 mmol, 2 equiv). The reaction was stirred at 110 °C for 12 h under nitrogen atmosphere.
  • the crude product was purified by Prep-HPLC (Column: XSelect CSH C18, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min mL/min; Gradient: 41% B to 71% B in7min; Wave Length: 254nm nm; RT (min): 6.78) to afford 4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy- 1-methyl-6-oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)-N-methylbenzamide (6.0 mg, 12%).
  • Example 120 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl) methyl)-2-methyl-3H-isoindol-1-one [00573]
  • Step 1 To the mixture of 3-oxo-1,2-dihydroisoindole-5-carbaldehyde (1 g, 6.205 mmol, 1 equiv) in THF (20 mL) was added titanium (IV) ethoxide (4.25 g, 18.62 mmol, 3 equiv) and tert- butanesulfinamide (0.75 g, 6.21 mmol, 1 equiv).
  • Step 2 To the mixture of 2-methyl-N-[(1E)-(3-oxo-1,2-dihydroisoindol-5- yl)methylidene]propane-2-sulfinamide (800 mg, 3.03 mmol, 1 equiv) in THF (20 mL) was added PhLi (1.99 mL, 3.78 mmol, 2 equiv) at -78°C under nitrogen atmosphere. The mixture was stirred for 2 h then warmed to ambient temperature and stirred for an additional 2 h. The mixture was quenched with sat. aq.
  • Step 3 A mixture of 2-methyl-N-[(3-oxo-1,2-dihydroisoindol-5-yl)(phenyl)methyl]propane-2- sulfinamide (140 mg, 0.409 mmol, 1 equiv) 1,4-dioxane (3 mL) with HCl (gas) was stirred at ambient temperature for 1 h. The mixture was concentrated under reduced pressure to afford 6- [amino(phenyl)methyl]-2,3-dihydroisoindol-1-one (80 mg, 82%) as a yellow solid.
  • Step 4 To the mixture of 6-[amino(phenyl)methyl]-2,3-dihydroisoindol-1-one (60 mg, 0.252 mmol, 1 equiv) and 6-(1,3-benzoxazol-2-yl)-2-chloro-5-methoxy-3-methylpyrimidin-4-one (73 mg, 0.252 mmol, 1 equiv) in DMSO (2 mL) was added DIEA (48 mg, 0.378 mmol, 1.5 equiv). The mixture was stirred at 120 °C for 1 h.
  • Step 5 To the mixture of 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin- 2-yl]amino ⁇ (phenyl)methyl)-2,3-dihydroisoindol-1-one (30 mg, 0.061 mmol, 1 equiv) in DMF (2 mL) was added CH 3 I (26 mg, 0.183 mmol, 3 equiv) and Cs 2 CO 3 (39 mg, 0.122 mmol, 2 equiv). The mixture was stirred at ambient temperature for 2 h then filtered.
  • the filtrate was purified by prep-HPLC (Column: Xselect CSH C18 OBD 30*150mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min mL/min; Gradient: 17% B to 42% B in 9 min; Wave Length: 254nm/220nm; RT(min): 8.9) to afford 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)-2-methyl-3H-isoindol-1-one (2.8 mg, 9%).
  • Example 121 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)-2,3-dihydroisoindol-1-one [00578] To the mixture of 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)-2,3-dihydroisoindol-1-one (50 mg, 0.10 mmol, 1 equiv) in DMF (2 mL) was added LiCl (63 mg).
  • the mixture was stirred at 100 °C for 16 h.
  • the mixture was purified by prep-HPLC (Column: XSelect CSH C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min mL/min; Gradient: 38% B to 68% B in7min; Wave Length: 254nm nm; RT(min): 6.58) to afford 6-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)-2,3-dihydroisoindol-1-one (1.9 mg, 3.50%) as an off- white solid.
  • Example 122 [4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2- yl](methyl)amino ⁇ (phenyl)methyl)phenyl]acetic acid [00579]
  • Step 1 To a stirred mixture of 6-(1,3-benzoxazol-2-yl)-2- ⁇ [(4- bromophenyl)(phenyl)methyl](methyl)amino ⁇ -5-methoxy-3-methylpyrimidin-4-one (200 mg, 0.376 mmol, 1 equiv) in DMF (2 mL) was added tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (567 mg, 3.01 mmol, 8 equiv) and LiF (20 mg, 0.752 mmol, 2 equiv) and Pd(t-Bu3P)2 (19 mg, 0.038 mmol, 0.1 e
  • Step 2 To a stirred mixture of methyl 2-[4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)phenyl]acetate (160 mg, 0.305 mmol, 1 equiv) in DMF (2 mL) was added 1-dodecanethiol (185 mg, 0.915 mmol, 3 equiv) and NaOMe (49 mg, 0.915 mmol, 3 equiv). The reaction was stirred at 110 C under nitrogen atmosphere for 2 h.
  • Step 3 To a stirred mixture of methyl 2-[4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl](methyl)amino ⁇ (phenyl)methyl)phenyl]acetate (40 mg, 0.078 mmol, 1 equiv) in DCE (1 mL) were added trimethylstannanol (113 mg, 0.624 mmol, 8 equiv). The reaction was stirred at 80 C for 12 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in DMF (1 mL).
  • the crude product was purified by Prep-HPLC (Column: XSelect CSH C 18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min mL/min; Gradient: 47% B to 77% B in7min; Wavelength: 254nm nm; RT(min): 6.89).
  • the fractions were combined and lyophilized to afford [4-( ⁇ [4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin- 2-yl](methyl)amino ⁇ (phenyl)methyl)phenyl]acetic acid (1.2 mg, 3%).
  • Example 123 and 124 (S)-6-(benzo[d]oxazol-2-yl)-2-((bicyclo[1.1.1]pentan-1- yl(phenyl)methyl)(methyl)amino)-5-hydroxy-3-methylpyrimidin-4(3H)-one and (R)-6- (benzo[d]oxazol-2-yl)-2-((bicyclo[1.1.1]pentan-1-yl(phenyl)methyl)(methyl)amino)-5-hydroxy-3- methylpyrimidin-4(3H)-one [00582] To a stirred mixture of benzophenone (5 g, 27.439 mmol, 1 equiv) in DCM (50 mL) was added benzylamine (2.94 g, 27.439 mmol, 1 equiv) dropwise at ambient temperature under air atmosphere.
  • Example 125 6-(1,3-benzoxazol-2-yl)-5-hydroxy-3-methyl-2- ⁇ methyl[phenyl(pyridin-2- yl)methyl]amino ⁇ pyrimidin-4-one [00589]
  • Step 1 To a stirred solution of ethyl 2-chloro-5-methoxy-1-methyl-6-oxopyrimidine-4- carboxylate (1.99 g, 8.088 mmol, 1.49 equiv) and 1-phenyl-1-(pyridin-2-yl)methanamine (1 g, 5.428 mmol, 1 equiv) in DMSO (30 mL) was added DIEA (2836.28 ⁇ L, 16.284 mmol, 3 equiv) in portions at ambient temperature under air atmosphere.
  • the resulting mixture was stirred overnight at 110 °C under air atmosphere. The reaction was monitored by TLC. Desired product could be detected by TLC. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 To a stirred solution of methyl 5-methoxy-1-methyl-6-oxo-2- ⁇ [phenyl(pyridin-2- yl)methyl]amino ⁇ pyrimidine-4-carboxylate (1.8 g, 4.732 mmol, 1 equiv) and cesium carbonate (4.02 g, 7.098 mmol, 1.5 equiv) in DMF (20 mL) was added iodomethane (0.29 mL, 4.732 mmol, 1 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for 2 h at ambient temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL).
  • Step 3 A solution of ethyl 5-methoxy-1-methyl-2- ⁇ methyl[phenyl(pyridin-2- yl)methyl]amino ⁇ -6-oxopyrimidine-4-carboxylate (2 g, 4.90 mmol, 1 equiv) in THF (25 mL) was treated with LiOH (0.58 g, 24.48 mmol, 5 equiv) in H 2 O (10 mL) for 2 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at ambient temperature under air atmosphere. The reaction was monitored by LCMS. The mixture was neutralized to pH 3 with HCl (1M.).
  • Step 4 To a stirred solution of 5-ethoxy-1-methyl-2- ⁇ methyl[phenyl(pyridin-2- yl)methyl]amino ⁇ -6-oxopyrimidine-4-carboxylic acid (1.40 g, 3.694 mmol, 1 equiv) and 2-iodoaniline (0.89 g, 4.048 mmol, 1.1 equiv) in DMF (20 mL) were added Tcfh (2.07 g, 7.360 mmol, 2 equiv) and NMI (0.91 g, 11.040 mmol, 3 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred overnight at ambient temperature under air atmosphere.
  • Step 5 A solution of N-(2-iodophenyl)-5-methoxy-1-methyl-2- ⁇ methyl[phenyl(pyridin-2- yl)methyl]amino ⁇ -6-oxopyrimidine-4-carboxamide (100 mg, 0.172 mmol, 1 equiv) in Toluene (2 mL) was treated with DMEDA (15 mg, 0.172 mmol, 1 equiv) for 1 min at ambient temperature under nitrogen atmosphere followed by the addition of CuI (4 mg, 0.017 mmol, 0.1 equiv) in portions at ambient temperature. The resulting mixture was stirred overnight at 110 °C under nitrogen atmosphere.
  • Step 6 To the mixture of 6-(1,3-benzoxazol-2-yl)-5-methoxy-3-methyl-2- ⁇ methyl[phenyl(pyridin-2-yl)methyl]amino ⁇ pyrimidin-4-one (30 mg, 0.066 mmol, 1 equiv) in DCM (2 mL) was added BBr 3 (0.13 mL, 0.132 mmol, 2 equiv) in DCM at -78 °C. The mixture was stirred at ambient temperature for 2 h. The mixture was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC (Column: Xselect CSH F-Phenyl OBD, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 32% B to 48% B in 7 min, 48% B; Wave Length: 254 nm; RT(min): 6.23) to afford 6-(1,3-benzoxazol-2-yl)-5-hydroxy-3- methyl-2- ⁇ methyl[phenyl(pyridin-2-yl)methyl]amino ⁇ pyrimidin-4-one (2.8 mg, 9.35%).
  • Step 1 To a stirred solution of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3- benzoxazol-2-yl)-5-methoxy-3-methylpyrimidin-4-one (100 mg, 0.226 mmol, 1 equiv) in DCM (5 mL) was added BBr3 (85 mg, 0.339 mmol, 1.5 equiv) dropwise at -60 °C under nitrogen atmosphere.
  • Step 2 A solution of tert-butyl N- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl]-3-cyclobutyl-1,3-benzodiazol-5-yl ⁇ carbamate (100 mg, 0.189 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.4 mL). The mixture was stirred for 1 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated NaHCO3 (aq.).
  • Step 3 To a stirred mixture of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3- benzoxazol-2-yl)-5-hydroxy-3-methylpyrimidin-4-one (50 mg, 0.117 mmol, 1 equiv) and methyl chloroformate (11 mg, 0.117 mmol, 1 equiv) in DCM (2 mL) were added TEA (20 ⁇ L, 0.140 mmol, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred for 30 min at ambient temperature. The resulting mixture was concentrated under reduced pressure.
  • Example 127 6-(1,3-benzoxazol-2-yl)-2-[1-cyclobutyl-6-(5-oxo-4H-1,2,3,4-tetrazol-1-yl)-1,3- benzodiazol-2-yl]-5-hydroxy-3-methylpyrimidin-4-one [00598]
  • Step 1 To the mixture of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3-benzoxazol-2- yl)-5-methoxy-3-methylpyrimidin-4-one (90 mg, 0.203 mmol, 1 equiv) and triphosgene (60 mg, 0.203 mmol, 1 equiv) in DCM (2 mL) was added TEA (24 mg, 0.244 mmol, 1.2 equiv) at 0 °C.
  • Step 2 To the mixture of 6-(1,3-benzoxazol-2-yl)-2-[1-cyclobutyl-6-(5-oxo-4H-1,2,3,4- tetrazol-1-yl)-1,3-benzodiazol-2-yl]-5-methoxy-3-methylpyrimidin-4-one (60 mg, 0.117 mmol, 1 equiv) in DCM (2 mL) was added BBr3 in DCM (0.59 mL, 0.585 mmol, 5 equiv) at -78°C. The mixture was stirred at ambient temperature for 1 h then quenched by MeOH (3 mL) at 0°C. The mixture was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 39% B to 69% B in 7 min, 69% B; Wave Length: 254 nm; RT(min): 6.88; Injection Volume: 0.5 mL) to afford 6-(1,3- benzoxazol-2-yl)-2-[1-cyclobutyl-6-(5-oxo-4H-1,2,3,4-tetrazol-1-yl)-1,3-benzodiazol-2-yl]-5-hydroxy-3- methylpyrimidin-4-one (12.8 mg, 21%).
  • Example 128 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-3-cyclobutyl- 1,3-benzodiazole-5-carboxylic acid [00600] To the mixture of methyl 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-1,3-benzodiazole-5-carboxylate (40 mg, 0.085 mmol, 1 equiv) in THF (2.00 mL) was added NaOH (17 mg, 0.425 mmol, 5 equiv) in H2O (0.1 mL).
  • Example 129 N- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-3- cyclobutyl-1,3-benzodiazol-5-yl ⁇ acetamide
  • Step 1 A solution of 3-fluoro-4-nitroaniline (10 g, 64.055 mmol, 1 equiv) and di-tert-butyl dicarbonate (13.98 g, 64.06 mmol, 1.00 equiv) and DMAP (0.78 g, 6.41 mmol, 0.1 equiv) in DCM (150 mL) was stirred for 3 days at ambient temperature under nitrogen atmosphere. The resulting mixture was extracted with DCM (3 x 400 ml). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 A solution of tert-butyl N-(3-fluoro-4-nitrophenyl)carbamate (2 g, 7.805 mmol, 1.5 equiv) and cyclobutylamine (370 mg, 5.203 mmol, 1 equiv) and DIEA (1345.10 mg, 10.407 mmol, 2 equiv) in NMP (20 mL) was stirred for 15 h at 105 °C. To the mixture was added H2O (50 mL), The mixture was extracted with EA (3 x 300ml). The combined organic layers were washed with NaCl (1 x 200ml), dried over anhydrous sodium sulfate.
  • Step 3 A solution of tert-butyl N-[3-(cyclobutylamino)-4-nitrophenyl]carbamate (1.8 g, 5.857 mmol, 1 equiv) in MeOH (20 mL) was added Pd/C (0.19 g, 1.757 mmol, 0.3 equiv) . The mixture was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure.
  • Step 4 To the mixture of 4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidine-2- carbaldehyde (300 mg, 1.052 mmol, 1 equiv) in DMF (10 mL) and H2O (5 mL) was added tert-butyl N- [4-amino-3-(cyclobutylamino)phenyl]carbamate (292 mg, 1.052 mmol, 1 equiv) and oxone (177 mg, 1.052 mmol, 1 equiv). The mixture was stirred at ambient temperature for 2h. The resulting mixture was diluted with water (20 mL).
  • Step 5 A mixture of tert-butyl N- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-3-cyclobutyl-1,3-benzodiazol-5-yl ⁇ carbamate (100 mg, 0.184 mmol, 1 equiv) in TFA (0.5 mL) and DCM (2 mL). The mixture was stirred for 1 h at ambient temperature. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with DCM (3 x 30 mL).
  • Step 6 A solution of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3-benzoxazol-2-yl)- 5-methoxy-3-methylpyrimidin-4-one (50 mg, 0.113 mmol, 1 equiv) in DCM (2 mL) was added AcCl (18 mg, 0.226 mmol, 2 equiv) and TEA (23 mg, 0.226 mmol, 2 equiv) in portions at ambient temperature. The resulting mixture was stirred for 1 h at ambient temperature.
  • Step 7 A mixture of N- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-1,3-benzodiazol-5-yl ⁇ acetamide (40 mg, 0.083 mmol, 1 equiv) and LiBr (36 mg, 0.415 mmol, 5 equiv) in DMF (1 mL). The mixture was stirred for 16 h at 100 °C. Desired products could be detected by LCMS. The resulting mixture was diluted with water (5 mL). The residue was purified by trituration with water (5 mL).
  • Example 133 6-(1,3-benzoxazol-2-yl)-2-(1-cyclobutylindol-2-yl)-5-hydroxy-3-methylpyrimidin-4- one
  • Step 1 Into a 2 L 3-necked round-bottom flask were added EtOH (600 mL), sodium ethanolate (31.68 g, 465.581 mmol, 1.1 equiv) and ethyl oxalate (68.04 g, 465.6 mmol, 1.1 equiv) at ambient temperature. This was followed by addition of ethyl 2-methoxyacetate (50 g, 423.255 mmol, 1 equiv) dropwise with stirring at ambient temperature under nitrogen atmosphere.
  • EtOH 600 mL
  • sodium ethanolate 31.68 g, 465.581 mmol, 1.1 equiv
  • ethyl oxalate 68.04 g, 465.6 mmol, 1.1 equiv
  • Step 2 Into a 2 L round-bottom flask were added 1,4-diethyl 2-methoxy-3-oxobutanedioate (80 g, 366.628 mmol, 1 equiv), methylurea (27.16 g, 366.628 mmol, 1 equiv), AcOH (900 mL) and HCl(gas)in 1,4-dioxane (300 mL) at ambient temperature. The resulting mixture was stirred for 3 h at 105°C under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was washed with hexane (1 x 500 mL).
  • Step 3 Into a 2 L round-bottom flask were added ethyl 2-methoxy-2-[(4E)-1-methyl-2,5- dioxoimidazolidin-4-ylidene]acetate (85 g, 372.474 mmol, 1 equiv) and KOH (1000 mL) at ambient temperature.
  • Step 4 Into a 250 mL 3-necked round-bottom flask were added 2-hydroxy-5-methoxy-1- methyl-6-oxopyrimidine-4-carboxylic acid (20 g, 99.925 mmol, 1 equiv) and EtOH (400 mL) at °C. This was followed by the addition of AcCl (106.97 mL, 1498.875 mmol, 15 equiv) dropwise with stirring at 0 °C. The resulting mixture was stirred overnight at 90 °C under argon atmosphere. The mixture was allowed to cool down to 0 °C.
  • Step 5 Into a 500 mL 3-necked round-bottom flask were added ethyl 2-hydroxy-5-methoxy-1- methyl-6-oxopyrimidine-4-carboxylate (16 g, 70.113 mmol, 1 equiv) and POCl3 (320 mL) at ambient temperature.
  • Step 6 A solution of indole (5 g, 42.680 mmol, 1 equiv) and KOH (4.79 g, 85.360 mmol, 2 equiv) in DMF (55 mL) was added with KOH (4.79 g, 85.360 mmol, 2 equiv). The mixture was stirred for 5 h at 80 °C under air atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate.
  • Step 7 To the mixture of 1-cyclobutylindole (3.8 g, 22.191 mmol, 1 equiv) in THF (100 mL) was added sec-BuLi (34.14 mL, 44.38 mmol, 2 equiv) at -78 °C slowly under nitrogen atmosphere. The mixture was stirred at the -40 °C for 1h.
  • Step 8 To the mixture of ethyl 2-chloro-5-methoxy-1-methyl-6-oxopyrimidine-4-carboxylate (1.5 g, 6.081 mmol, 1 equiv) and 1-cyclobutyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole (4.52 g, 15.203 mmol, 2.5 equiv) in dioxane (60.00 mL) was added Pd2(dba)3 (0.33 g, 0.365 mmol, 0.06 equiv) , tri-tert-butylphosphine tetrafluoroborate (211 mg, 0.730 mmol, 0.12 equiv) and KF (39 mg, 0.670 mmol, 3.3 equiv).
  • Step 9 To the mixture of ethyl 2-(1-cyclobutylindol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidine-4-carboxylate (280 mg, 0.734 mmol, 1 equiv) in THF (5 mL) was added LiOH (105 mg, 4.404 mmol, 6 equiv) in H 2 O (0.2 mL). The mixture was stirred at ambient temperature for 4h. The mixture was concentrated to remove THF. The residue was acidified to pH 4 with HCl (2 M). The mixture was extracted by EtOAc (5 mL x 3).
  • Step 10 The mixture of 2-(1-cyclobutylindol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidine-4- carboxylic acid (100 mg, 0.283 mmol, 1 equiv) and HATU (215 mg, 0.566 mmol, 2 equiv) in THF (5 mL) was stirred at ambient temperature for 2 min. The mixture was added with DIEA (55 mg, 0.424 mmol, 1.5 equiv) and stirred at ambient temperature for 2 min, and 2-aminophenol (46 mg, 0.42 mmol, 1.5 equiv) was added. The mixture was stirred at 65°C for 16 h. The mixture was concentrated under reduced pressure.
  • Step 11 To the mixture of 2-(1-cyclobutylindol-2-yl)-N-(2-hydroxyphenyl)-5-methoxy-1- methyl-6-oxopyrimidine-4-carboxamide (40 mg, 0.090 mmol, 1 equiv) in NMP (3 mL) was added P 2 O 5 (51 mg, 0.360 mmol, 4 equiv) and TsOH (62 mg, 0.360 mmol, 4 equiv) at 200°C. Desired products could be detected by LCMS.
  • Example 135 6-(6-chloro-1,3-benzoxazol-2-yl)-2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-hydroxy-3- methylpyrimidin-4-one [00625]
  • ES MS M/Z 448.0 [M+H] + , UPLC: 96%;
  • Example 137 6-(4-chlorobenzo[d]oxazol-2-yl)-2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5- hydroxy-3-methylpyrimidin-4(3H)-one [00627]
  • Example 139 2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-hydroxy-3-methyl-6-(4,5,6,7-tetrahydro-1,3- benzoxazol-2-yl)pyrimidin-4-one [00629]
  • Step 1 A solution of 2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6- oxopyrimidine-4-carboxylic acid (500 mg, 1.469 mmol, 1 equiv) in THF (10 mL) was treated with HATU (1.1 g, 2.938 mmol, 2 equiv) for 2 min at ambient temperature under air atmosphere followed by the addition of 2-aminocyclohexan-1-one (199 mg, 1.763 mmol, 1.2 equiv) and DIEA (283 mg, 2.204 mmol, 1.5 equiv) in portions at ambient temperature.
  • HATU 1.1 g, 2.938 mmol,
  • Step 2 To a stirred mixture of 2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6- oxo-N-(2-oxocyclohexyl)pyrimidine-4-carboxamide (300 mg, 0.689 mmol, 1 equiv) in DMF (6 mL) was added K2CO3 (190 mg, 1.378 mmol, 2 equiv) and CH3I (147 mg, 1.033 mmol, 1.5 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred overnight at ambient temperature. The reaction was monitored by LCMS.
  • Step 3 To a stirred solution of 2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-methoxy-1-methyl-6- oxo-N-(2-oxocyclohexyl)pyrimidine-4-carboxamide (80 mg, 0.178 mmol, 1 equiv) in CH3CN (2 mL, 38.048 mmol, 213.79 equiv) was added POCl3 (273 mg, 1.78 mmol, 10 equiv) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at ambient temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
  • Step 4 To a solution of 2-(1-cyclobutyl-1,3-benzodiazol-2-yl)-5-methoxy-3-methyl-6- (4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)pyrimidin-4-one (30 mg, 0.070 mmol, 1 equiv) in DMF (2 mL, 25.84 mmol, 371.71 equiv) was added LiBr (60.38 mg, 0.700 mmol, 10 equiv). The mixture was stirred at 100 °C for 16 h.
  • the crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: 31% B to 61% B in 7 min, 61% B to 61% B in 9 min, 61% B; Wave Length: 254 nm; RT(min): 8.88; Injection Volume: 0.7 mL) to afford 2-(1- cyclobutyl-1,3-benzodiazol-2-yl)-5-hydroxy-3-methyl-6-(4,5,6,7-tetrahydro-1,3-benzoxazol-2- yl)pyrimidin-4-one (4.1 mg, 14%) as a dark blue solid.
  • Example 140 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-3-cyclobutyl-N- methyl-1,3-benzodiazole-5-carboxamide
  • Step 1 To the mixture of methyl 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6- oxopyrimidin-2-yl]-3-cyclobutyl-1,3-benzodiazole-5-carboxylate (280 mg, 0.577 mmol, 1 equiv) in CH3CN (5 mL) was added sodium trimethylsilonoate (0.87 mL, 0.87 mmol, 1.5 equiv) in H2O (0.02 mL, 1.110 mmol, 107.8 equiv).
  • Step 2 To the mixture of 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-1,3-benzodiazole-5-carboxylic acid (100 mg, 0.212 mmol, 1 equiv) in DMF (5 mL) was added HATU (161 mg, 0.424 mmol, 2 equiv), methylamine (7 mg, 0.212 mmol, 1 equiv), DIEA (7 mg, 0.053 mmol, 2.5 equiv). The mixture was stirred at ambient temperature for 2h.
  • Step 3 To the mixture of 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-N-methyl-1,3-benzodiazole-5-carboxamide (50 mg, 0.103 mmol, 1 equiv) in DMF (2 mL) was added LiBr (54 mg, 0.618 mmol, 6 equiv). The mixture was stirred at 100 °C for 4h.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 34% B to 64% B in 7 min, 64% B; Wave Length: 254 nm; RT(min): 6.97; Injection Volume: 0.8 mL) to afford 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-N-methyl-1,3-benzodiazole-5-carboxamide (3.6 mg, 7%).
  • Example 141 1- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-3-cyclobutyl- 1,3-benzodiazol-5-yl ⁇ -3-methylurea
  • Step 1 To a stirred mixture of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3- benzoxazol-2-yl)-5-methoxy-3-methylpyrimidin-4-one (70 mg, 0.158 mmol, 1 equiv) and N- methylcarbamoyl chloride (30 mg, 0.316 mmol, 2 equiv) in DCM were added TEA (44 ⁇ L, 0.316 mmol, 2 equiv) dropwise at ambient temperature.
  • Step 2 A mixture of 1- ⁇ 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2- yl]-3-cyclobutyl-1,3-benzodiazol-5-yl ⁇ -3-methylurea (35 mg, 0.070 mmol, 1 equiv) in DMF (1 mL) was added LiBr (30 mg, 0.350 mmol, 5 equiv). The mixture was stirred for 16 h at 100 °C.
  • Example 142 1-(2-(4-(benzo[d]oxazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)- 1-cyclobutyl-1H-benzo[d]imidazol-6-yl)urea [00638] Step 1: A mixture of 2-(6-amino-1-cyclobutyl-1,3-benzodiazol-2-yl)-6-(1,3-benzoxazol-2-yl)- 5-methoxy-3-methylpyrimidin-4-one (50 mg, 0.113 mmol, 1 equiv) and sodium cyanate (9 mg, 0.136 mmol, 1.2 equiv) in acetic acid (0.5 mL) and H2O (1 mL, 0.005 mmol, 0.5 equiv) was stirred for 2 h at 50 °C.
  • Step 2 A mixture of 2-[4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2-yl]-3- cyclobutyl-1,3-benzodiazol-5-ylurea (35 mg, 0.072 mmol, 1 equiv) in DMF was added LiBr (31 mg, 0.360 mmol, 5 equiv). The mixture was stirred for 16 h at 100 °C.
  • the crude product was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% HCOOH), 10% to 60% gradient in 20 min; detector, UV 254 nm) to afford 2-[4-(1,3-benzoxazol-2-yl)-5- hydroxy-1-methyl-6-oxopyrimidin-2-yl]-3-cyclobutyl-1,3-benzodiazol-5-ylurea (8.6 mg, 25.13%).
  • Example 143 6-(1,3-benzoxazol-2-yl)-2-(1-cyclobutyl-4,5,6,7-tetrahydro-1,3-benzodiazol-2-yl)-5- hydroxy-3-methylpyrimidin-4-one
  • Step 1 The mixture of 4-(1,3-benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidine-2- carbaldehyde (100 mg, 0.351 mmol, 1 equiv) and cyclobutylamine (49 mg, 0.702 mmol, 2 equiv) in EtOH (5 mL) was stirred at 80°C for 30 min. The reaction worked according to TLC.
  • Step 2 To the mixture of 6-(1,3-benzoxazol-2-yl)-2-(1-cyclobutyl-4,5,6,7-tetrahydro-1,3- benzodiazol-2-yl)-5-methoxy-3-methylpyrimidin-4-one (100 mg, 0.232 mmol, 1 equiv) in DMF (3 mL) was added LiBr (120 mg, 1.392 mmol, 6 equiv). The mixture was stirred at 100°C for 4 h.
  • the mixture was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile in water (0.05% FA), 10% to 50% gradient in 20 min; detector, UV 254 nm)
  • the product was purified by trituration with acetonitrile (1 mL) to afford 6-(1,3-benzoxazol-2-yl)-2-(1-cyclobutyl-4,5,6,7-tetrahydro- 1,3-benzodiazol-2-yl)-5-hydroxy-3-methylpyrimidin-4-one (9.5 mg, 9%).
  • Example 150 2-[4-(1,3-benzoxazol-2-yl)-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]-N,N-dimethyl- 1-(1-methylimidazol-2-yl)-3,4-dihydro-1H-isoquinoline-7-carboxamide [00642]
  • Step 1 To a stirred solution of 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (5 g, 22.117 mmol, 1 equiv) in THF (50 mL) was added TEA (6.71 g, 66.35 mmol, 3 equiv) at ambient temperature.
  • Boc2O (7.24 g, 33.18 mmol, 1.5 equiv) dropwise at 0 °C followed by DMAP (0.27 g, 2.21 mmol, 0.1 equiv) at ambient temperature.
  • EtOAc 100 mL
  • water 100 mL
  • the aqueous phase was extracted with EtOAc (50 mL x 2).
  • the combined organic phases were washed with brine (100 mL), dried with sodium sulfate, filtered, and concentrated.
  • Step 2 n-BuLi (3.68 mL, 7.357 mmol, 1.2 equiv) was added dropwise into a colorless solution of 2-bromo-1-methylimidazole (0.99 g, 6.131 mmol, 1 equiv) in THF (85 mL) at -78 °C giving a yellow solution, which was stirred at this temperature for 1 h.
  • Step 3 NaBH 4 (0.37 g, 9.8 mmol, 2 equiv) was added into a solution of tert-butyl N- ⁇ 2-[4- bromo-2-(1-methylimidazole-2-carbonyl)phenyl]ethyl ⁇ carbamate (2 g, 4.9 mmol, 1 equiv) in MeOH (40 mL) at 0 °C giving a yellow suspension, which was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water (50 mL). The mixture was extracted with CH(CH 3 ) 2 OH/CHCl 3 (v/v, 1/3, 50 mL X 3).
  • Step 4 A light brown solution of tert-butyl N-(2- ⁇ 4-bromo-2-[hydroxy(1-methylimidazol-2- yl)methyl]phenyl ⁇ ethyl)carbamate (500 mg, 1.219 mmol, 1 equiv) in DCM (50 mL) and TFAA (0.25 mL) was stirred at ambient temperature for 1 h. The reaction was quenched with NaHCO3 (aq, 30 mL). The mixture was extracted with DCM (50 mL X 3). The combined organic phases were washed with brine (50 mL x 2), dried with sodium sulfate, filtered, and concentrated.
  • Step 5 A brown solution of tert-butyl 7-bromo-1-(1-methylimidazol-2-yl)-3,4-dihydro-1H- isoquinoline-2-carboxylate (400 mg, 1.020 mmol, 1 equiv) in DCM (2 mL) and TFA (2 mL) was stirred at ambient temperature for 1 h. The solvents were evaporated under 0 °C. The residue was diluted with CH(CH3)2OH/CHCl3 (v/v, 1/3, 10 mL), then adjusted to pH ⁇ 8 with NH3.H2O. The mixture was extracted with CH(CH3)2OH/CHCl3 (v/v, 1/3, 10 mL x 3).
  • Step 6 A brown solution of 7-bromo-1-(1-methylimidazol-2-yl)-1,2,3,4- tetrahydroisoquinoline (290 mg, 0.993 mmol, 1 equiv), CsF (196 mg, 1.291 mmol, 1.3 equiv) in DMSO (3 mL) was stirred at 100 °C for 2 h. After cooling to ambient temperature, the reaction was diluted with EtOAc (20 mL) and water (10 mL). After separation of phases, the aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried with sodium sulfate, filtered, and concentrated.
  • Step 7 A dark brown solution of 6-(1,3-benzoxazol-2-yl)-2-[7-bromo-1-(1-methylimidazol-2- yl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-methoxy-3-methylpyrimidin-4-one (300 mg, 0.548 mmol, 1 equiv) , Pd(OAc)2 (6 mg, 0.027 mmol, 0.05 equiv) , DMAP (134 mg, 1.096 mmol, 2 equiv) , dicobalt(2+) ion octakis(methanidylidyneoxidanium) (47 mg, 0.137 mmol, 0.25 equiv) and [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (32 mg, 0.055 mmol, 0.1
  • Step 8 BBr3 (181 mg, 0.723 mmol, 3 equiv) was added dropwise into a solution of 2-[4-(1,3- benzoxazol-2-yl)-5-methoxy-1-methyl-6-oxopyrimidin-2-yl]-N,N-dimethyl-1-(1-methylimidazol-2-yl)- 3,4-dihydro-1H-isoquinoline-7-carboxamide (130 mg, 0.241 mmol, 1 equiv) in DCM (2.6 mL) at 0 °C and the obtained solution was stirred at ambient temperature for 2 d.

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Abstract

L'invention concerne des composés, des procédés de fabrication de tels composés, des compositions pharmaceutiques et des médicaments comprenant de tels composés, et des procédés d'utilisation de tels composés pour inhiber l'exonucléase TREX1 (Three Prime Repair Exonuclease 1).
PCT/US2023/068909 2022-06-22 2023-06-22 Inhibiteurs de trex1 et leurs utilisations WO2023250439A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080280891A1 (en) * 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US20110257152A1 (en) * 2010-04-19 2011-10-20 Abbott Laboratories Pyrrolopyridine inhibitors of kinases
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
WO2015030847A1 (fr) * 2013-08-30 2015-03-05 Ptc Therapeutics, Inc. Inhibiteurs de bmi-1 à base de pyrimidines substituées
WO2020028706A1 (fr) * 2018-08-01 2020-02-06 Araxes Pharma Llc Composés hétérocycliques spiro et procédés d'utilisation correspondants pour le traitement du cancer
WO2020118133A1 (fr) * 2018-12-06 2020-06-11 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021016317A1 (fr) * 2019-07-23 2021-01-28 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021222761A1 (fr) * 2020-05-01 2021-11-04 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021263079A1 (fr) * 2020-06-26 2021-12-30 Tempest Therapeutics, Inc. Inhibiteurs de trex1 et leurs utilisations

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080280891A1 (en) * 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US20110257152A1 (en) * 2010-04-19 2011-10-20 Abbott Laboratories Pyrrolopyridine inhibitors of kinases
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
WO2015030847A1 (fr) * 2013-08-30 2015-03-05 Ptc Therapeutics, Inc. Inhibiteurs de bmi-1 à base de pyrimidines substituées
WO2020028706A1 (fr) * 2018-08-01 2020-02-06 Araxes Pharma Llc Composés hétérocycliques spiro et procédés d'utilisation correspondants pour le traitement du cancer
WO2020118133A1 (fr) * 2018-12-06 2020-06-11 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021016317A1 (fr) * 2019-07-23 2021-01-28 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021222761A1 (fr) * 2020-05-01 2021-11-04 Constellation Pharmaceuticals, Inc. Modulateurs de trex1
WO2021263079A1 (fr) * 2020-06-26 2021-12-30 Tempest Therapeutics, Inc. Inhibiteurs de trex1 et leurs utilisations

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