WO2023250399A1 - Trex1 inhibitors and uses thereof - Google Patents

Trex1 inhibitors and uses thereof Download PDF

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WO2023250399A1
WO2023250399A1 PCT/US2023/068841 US2023068841W WO2023250399A1 WO 2023250399 A1 WO2023250399 A1 WO 2023250399A1 US 2023068841 W US2023068841 W US 2023068841W WO 2023250399 A1 WO2023250399 A1 WO 2023250399A1
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alkyl
compound
heterocycloalkyl
cycloalkyl
heteroaryl
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PCT/US2023/068841
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French (fr)
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Ryan C. Clark
Henry William Beecroft Johnson
JR. Thomas Walter DUBENSKY
Biswajit Kalita
Athisayamani Jeyaraj DURAISWAMY
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Tempest Therapeutics, Inc.
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Publication of WO2023250399A1 publication Critical patent/WO2023250399A1/en

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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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D417/14—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 three or more 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).
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the cancer is characterized by 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 C 1 -C 10 alkyl.
  • the alkyl is a C 1 - 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 C 1 -C 3 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, -NH 2 , or -NO 2 .
  • 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.
  • a numerical range such as “C 2 -C 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with 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. [0027] “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, -NH 2 , or -NO 2 .
  • 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, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, 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., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl), from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl), from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl), or three to four carbon atoms (e.g.,
  • 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, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • 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. [0036] “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, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .
  • “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, 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 C 1 -C 6 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 include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , - CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • 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, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl 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., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C 2 -C8 fully saturated heterocycloalkyl or C 2 -C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to five carbon atoms (e.g., C
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • 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, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl is C-linked.
  • 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. In some embodiments, 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]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indoly
  • 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, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • 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 [0043] 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.
  • Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I), Ring B is an indole, benzoxazole, benzimidazole, or benzothiazole. In some embodiments of a compound of Formula (I), Ring B is benzimidazole. In some embodiments of a compound of Formula (I), Ring B is an indole. [0046] In some embodiments of a compound of Formula (I), Ring B is bicyclic heterocycloalkyl.
  • Ring B is isoindolinyl, tetrahydroisoquinolinyl, or tetrahydrobenzoazepinyl. In some embodiments of a compound of Formula (I), Ring B is tetrahydroisoquinolinyl. [0047] In some embodiments of a compound of Formula (I), m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I), m is 0, 1, or 2. In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I) or, m is 0. In some embodiments of a compound of Formula (I), m is 1.
  • R 5 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 5a .
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a .
  • R 5 is C 1 -C 6 alkyl, cycloalkyl, or aryl; wherein the alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R 5a .
  • R 5 is C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl is independently optionally substituted with one or more R 5a .
  • R 5 is cycloalkyl optionally substituted with one or more R 5a .
  • R 5 is cyclobutyl or bicyclo[1.1.1]pentane.
  • R 5 is cyclobutyl.
  • R 5 is C 1 -C 6 alkyl.
  • 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; 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 , 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 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 5a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (Ia), each R 5a is independently halogen or C 1 -C 6 alkyl.
  • each R 4 is independently heteroaryl independently optionally substituted with one or more R 4a .
  • each R 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 4a 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 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia), each R 4a is independently halogen or C 1 -C 6 alkyl.
  • each R 6 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 6a .
  • each R 6 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 6a .
  • each R 6 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 6a .
  • each R 6 is independently aryl optionally substituted with one or more R 6a .
  • p is 0, 1, or 2. In some embodiments of a compound of Formula (Ib), p is 0 or 1. In some embodiments of a compound of Formula (Ib), p is 0. In some embodiments of a compound of Formula (Ib), p is 1. In some embodiments of a compound of Formula (Ib), p is 2.
  • q is 0, 1, or 2.
  • q is 0 or 1.
  • q is 0.
  • q is 1.
  • q is 2.
  • Ring A is cycloalkyl or heterocycloalkyl.
  • Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 6-membered heteroaryl.
  • Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is pyridinyl. [0060] In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 5-membered heteroaryl.
  • Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl.
  • Ring A is imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl.
  • Ring A is pyrazolyl, isoxazolyl, or isothiazolyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is isoxazolyl.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, and heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • n is 0, 1, or 2.
  • n is 1 or 2.
  • n is 0 or 1.
  • n is 0. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 1. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 2. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 3. [0063] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is hydrogen or C 1 - C 6 alkyl. [0064] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is hydrogen.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 - C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, 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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, 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, C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. 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, 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 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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or 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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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 C 1 -C 6 alkyl. 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 optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHC 1 -C 3 alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 - C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, or C 1 -C 3 haloalkoxy; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , 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, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • 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 compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
  • Labeled compounds [0075] 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, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this 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 [0079] 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, 1,
  • 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 + (C 1 -C 4 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 [0085] 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 hMSH 2 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). [00103] 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 [00108] 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.
  • 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 a electron beam. [00127] 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. [00128] 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 5-hydroxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N-(1,2 oxazol-4-yl)-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
  • Step 1 To a stirred solution of 1-fluoro-2-nitrobenzene (1.43 mL, 14.2 mmol) in a seal tube, methyl amine (7 mL, 158 mmol) was added under a nitrogen atmosphere at ambient temperature and the mixture was stirred at 80 °C for 16 h.
  • Step 2 To a stirred solution of N-methyl-2-nitroaniline (2 g, 13.1 mmol) in methanol (25 mL) was added palladium 10%w/w (280 mg, 0.02 eq., 0.263 mmol) and the mixture was stirred at ambient temperature with a hydrogen balloon for 3 h.
  • Step 3 To a stirred solution of N1-methylbenzene-1,2-diamine (350 mg, 2.86 mmol) in DMF (3 mL), was added ethyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (688 mg, 2.86 mmol) followed by a water (30 ⁇ L) and oxone (151 mg, 0.491 mmol) mixture. The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction it was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product.
  • Step 4 To a stirred solution of methyl 5-ethoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2- yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (340 mg, 0.993 mmol) in tetrahydrofuran (5 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide (95.1 mg, 4 eq., 3.97 mmol) at ambient temperature and the mixture was stirred for 2 h then concentrated under reduced pressure.
  • Step 5 To a stirred solution of 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-6- oxo-1,6-dihydropyrimidine-4-carboxylic acid (240 mg, 0.764 mmol) in DMF (2.5 mL) was added DIPEA (533 ⁇ L, 4 eq., 3.05 mmol), 1,2-oxazol-4-amine (107 ⁇ L, 2 eq., 1.53 mmol) followed by HATU (581 mg, 2 eq., 1.53 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 8 h.
  • Step 6 To a stirred solution of 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90mg, 0.237mmol) in DMF (2 mL, 0.237 mmol) was added lithium bromide (82.2 mg, 4 eq., 0.946 mmol) at ambient temperature. The reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction mixture monitored by TLC and LCMS.
  • Example 2 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl] -6-oxo-1,6- dihydropyrimidin-2-yl ⁇ -N-methyl-1H-1,3-benzodiazole-6-carboxamide
  • Step 1 To a stirred solution of 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid (0.2 g, 0.444 mmol) in DMF (1 mL) was added DIPEA (232 ⁇ L, 3 eq., 1.33 mmol), tripropyl-1,3,5,2 ⁇ 5,4 ⁇ 5,6 ⁇ 5- trioxatriphosphinane-2,4,6-trione 50%v/v (0.4 mL,
  • Step 1 To a stirred solution of cyclobutanamine (9.84 mL, 1.2 eq., 115 mmol) in 1- methylpyrrolidin-2-one (150 mL) was added DIPEA (50.2 mL, 3 eq., 288 mmol) and 2-fluoro-5- nitroaniline (15 g, 96.1 mmol).
  • Step 2 To a solution of N1-cyclobutyl-4-nitrobenzene-1,2-diamine (0.7 g, 3.38 mmol) in methanesulfinylmethane (10 mL) was added methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (840 mg, 1.1 eq., 3.72 mmol) and disodium (sulfinatooxy)sulfinate (963 mg, 1.5 eq., 5.07 mmol). The reaction mixture was stirred at 85 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with EtOAc (3 x 100 mL).
  • Step 3 To a stirred solution of methyl 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (280 mg, 0.677 mmol) in a mixture of methanol (3.5 mL, 86.4 mmol) and tetrahydrofuran (3.5 mL, 43 mmol) was added lithium hydroxide mono-hydrate (85.3 mg, 3 eq., 2.03 mmol) in water (3 mL) and the mixture was stirred at ambient temperature for 1 h. The reaction was monitored by TLC and LCMS.
  • Step 4 To a stirred solution of 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (240 mg, 0.601 mmol) in DMF (5 mL ) was added 1,2-oxazol-4-amine hydrochloride (86.9 mg, 1.2 eq., 0.7721 mmol), HATU (457 mg, 2 eq., 1.2 mmol), DIPEA (0.333 mL, 3 eq., 1.8 mmol). The reaction mixture was stirred for 3 h at ambient temperature.
  • Step 5 To a stirred solution of 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (150 mg, 0.322 mmol) in methanol (2 mL, 49.4 mmol) and tetrahydrofuran (2 mL, 24.6 mmol) was added palladium on 10% carbon (20 mg, 0.094 mmol) and stirred at ambient temperature under a hydrogen balloon for 1 h . The reaction was monitored by TLC (10% MeOH in DCM).
  • Step 6 To a stirred solution of 2-(5-amino-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (70 mg, 0.161 mmol) in 1,2 dichloroethane (7 mL) was added benzaldehyde (24.6 ⁇ L, 1.5 eq., 0.241 mmol) and acetic acid (33.3 ⁇ L, 3.1 eq., 0.501 mmol).
  • reaction mixture was stirred at ambient temperature under nitrogen for 1 h then sodium bis(acetyloxy)boranuidyl acetate (68.1 mg, 2 eq., 0.322 mmol) was added and reaction mixture was stirred at ambient temperature for 16 h during which time the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction mixture was quenched with NaHCO 3 solution (4 mL), extracted with 10% MeOH in DCM ( 3 x 10 mL ), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford crude compound.
  • Step 7 To a stirred solution of 2-[5-(benzylamino)-1-cyclobutyl-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90 mg, 0.171 mmol) in DCM (1.63 mL, 25.4 mmol) was cooled to -40 °C, tribromoborane (88.2 ⁇ L, 3 eq., 0.514 mmol) was added and stirred at ambient temperature for 4 h, The reaction was monitored by TLC and LCMS.
  • Step 1 To a stirred solution of 1-fluoro-2-nitrobenzene (5 g, 35.4 mmol) in 1- methylpyrrolidin-2-one (5 mL) was added DIPEA (18.5 mL, 106 mmol) and cyclobutanamine (3.64 mL, 42.5 mmol). The reaction mixture was heated to 120 oC for 16 h.
  • Step 2 To a stirred solution of N-cyclobutyl-2-nitroaniline (6.8 g, 35.4 mmol) in methanol (25 mL) was Palladium on 10% carbon (0.1 g, 0.940 mmol) 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 (3.2 g, 19.72 mmol) in dry DMF (48 mL), pyridine (4.76 mL, 59.2 mmol) and dichloro-1 ⁇ 4,2,3-dithiazol-1-ylium chloride (4.52 g, 21.6 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated.
  • Step 4 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) at ambient temperature. The mixture was stirred at ambient temperature for 2 h.
  • Step 5 To a stirred solution of 1-cyclobutyl-N-hydroxy-N-methyl-1H-1,3-benzodiazole-2- carboximidamide (1.2 g, 4.91 mmol) in methanol (15 mL) and water (6 mL), 1,4-dimethyl but-2- ynedioate (0.963 L, 7.86 mmol) was added, and the mixture was stirred at ambient temperature for 5 h.
  • Step 6 To a stirred solution of methyl 3-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-(2- methoxy-2-oxoethyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazole-5-carboxylate (1.4 g, 3.62 mmol) 1,4- xylene (10 mL, 81 mmol) was added and the mixture was stirred at 145 °C for 10 h. After completion, the reaction mixture was concentrated under reduced pressure to provide the crude product.
  • 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 (0.75 g, 2.12 mmol) in tetrahydrofuran (5 mL, 61.4 mmol) and methanol (5 mL, 123 mmol) was added and sodium hydroxide (0.254 g, 3 eq., 6.35 mmol) in water (5 mL, 278 mmol) at ambient temperature. The reaction mixture was heated at 50 °C for 3 h.
  • reaction mixture was concentrated and acidified with 1N HCl to pH ⁇ 5 then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-(1- cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.570 g, 79.1%).
  • ES MS M/Z 341.0 [M+H] + .
  • 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 (0.2 g, 0.588 mmol) in DMF (2 mL, 25.8 mmol), HATU (0.447 g, 1.18 mmol), DIPEA (0.154 mL, 0.881 mmol) and 2-aminophenol (0.083 mg, 0.764 mmol) was added and the mixture was stirred at 100 °C for 48 h.
  • Step 1 To a stirred solution of 3-fluoro-4-nitrobenzoic acid (2.5 g, 13.5 mmol) in DMF (10 mL) was added N-(2,2-dimethoxyethyl)-3-fluoro-4-nitrobenzamide (3.3 g, 11.9 mmol), DIPEA (7.08 mL, 3 eq., 40.5 mmol) and tripropyl-1,3,5,2 ⁇ 5,4 ⁇ 5,6 ⁇ 5-trioxatriphosphinane-2,4,6-trione (12.9 mL, 3 eq., 40.5 mmol) at 0 °C.
  • Step 2 To a stirred solution N-(2,2-dimethoxyethyl)-3-fluoro-4-nitrobenzamide (2.3 g, 8.45 mmol) in methanesulfonic acid (5.49 mL, 10 eq., 84.5 mmol) was added phosphoruspentoxide (5.28 g, 2.2 eq., 18.6 mmol) at 0 °C and the mixture was stirred at 140 °C for 7 h. After completion of the reaction ice cold water was added and the mixture was extracted with ethyl acetate.
  • Step 3 To a stirred solution of 2-(3-fluoro-4-nitrophenyl)-1,3-oxazole (1.49 g, 7.16 mmol) in 1-methylpyrrolidin-2-one (8 mL) was added DIPEA (3.75 mL, 3 eq., 21.5 mmol) and cyclobutanamine (672 ⁇ L, 1.1 eq., 7.87 mmol) at ambient temperature. The reaction mixture was stirred at 120 °C for 4 h. After completion of the reaction it was quenched with ice water and extracted in ethyl acetate.
  • Step 4 To a stirred solution of N-cyclobutyl-2-nitro-5-(1,3-oxazol-2-yl)aniline (970 mg, 3.74 mmol) in methanol (10 mL) was added palladium 10% w/w (199 mg) and the mixture was stirred at ambient temperature under a hydrogen balloon for 4 h. After completion, the reaction mixture was filtered through a celite bed and washed with methanol. The organic layer was filtered and concentrated under reduced pressure to provide the crude product N1-cyclobutyl-5-(1,3-oxazol-2-yl)benzene-1,2- diamine (0.9 g, 92.33%).
  • Step 5 To a stirred solution of N1-cyclobutyl-5-(1,3-oxazol-2-yl)benzene-1,2-diamine (0.5 g, 2.18 mmol) and methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (592 mg, 1.2 eq., 2.62 mmol) in DMSO (2 mL) was added disodium (sulfinatooxy)sulfinate (829 mg, 2 eq., 4.36 mmol) at ambient temperature, The reaction mixture was heated at 80 °C for 16 h.
  • Step 6 To a stirred solution of methyl 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.459 mmol) in mixture of methanol (5 mL), tetrahydrofuran (3 mL) and water (2 mL) was added lithium hydroxide (55 mg, 5 eq., 2.3 mmol) and the mixture was stirred at ambient temperature for 2 h. After completion of the reaction it was concentrated.
  • Step 7 To a stirred solution of 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (95 mg, 0.225 mmol) in DMF (2 mL) was added 1,2-oxazol-4-amine (28.4 mg, 1.5 eq., 0.338 mmol) HATU (171 mg, 2 eq., 0.451 mmol) and DIPEA (0.118 mL, 3 eq., 0.676 mmol). The mixture was stirred at ambient temperature for 16 h.
  • Step 8 To a solution of 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90 mg, 0.185 mmol) in DCM (10 mL) at -60 °C was added tribromoborane (87.6 ⁇ L, 5 eq., 0.923 mmol) drop-wise then the reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was basified with sodium bicarbonate solution and the organic layer was extracted using DCM.
  • Example 6 Synthesis of 1-cyclobutyl-N-(2,2-difluoroethyl)-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxamide; acetic acid [00175]
  • Step 1 To a stirred solution of 3-fluoro-4-nitrobenzoic acid (1 g, 5.4 mmol) in DCM (15 mL) was added N, N-dimethylpyridin-4-amine (0.1 g, 0.819 mmol) and t-butyl alcohol (2.05 mL., 21.6 mmol) followed by N, N'-dicyclohexyl methanediimine (1.34 g, 6.48 mmol) at 0 °C and the mixture as stirred at ambient temperature for 16 h.
  • Step 2 To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (5 g, 20.7 mmol) in 1- methylpyrrolidin-2-one (0.3 mL) was added DIPEA (10.8 mL, 62.2 mmol) and cyclobutanamine (2.12 mL, 24.9 mmol) at r.t and the mixture was stirred at 130 °C for 16 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product.
  • Step 3 To a stirred solution of tert-butyl 3-(cyclobutylamino)-4-nitrobenzoate (5.5 g, 18.8 mmol) in methanol (50 mL) was added palladium on 10% carbon (0.5 g, 4.7 mmol) and the mixture was stirred at ambient temperature under a hydrogen balloon for 6 h. The reaction mixture was filtered through a celite bed and washed with methanol.
  • Step 4 To a stirred solution of tert-butyl 4-amino-3-(cyclobutylamino) benzoate (4.6 g, 17.5 mmol) in THF (40 mL) was added pyridine (4.24 mL, 52.6 mmol) and dichloro-1 ⁇ 4,2,3-dithiazol-1-ylium chloride (4.75 g, 22.8 mmol) at 0 °C and the mixture was stirred at ambient temperature for 3 h.
  • Step 5 To a stirred solution of tert-butyl 2-cyano-1-cyclobutyl-1H-1,3-benzodiazole-5- carboxylate (1.57 g, 5.28 mmol) in methanol (19.6 mL, 484 mmol) and water (7.85 mL, 436 mmol) was added sodium carbonate (0.336 g, 3.17 mmol) and N-methyl hydroxylamine chloride (0.617 g, 7.39 mmol) at ambient temperature The mixture was stirred at 80 °C for 6 h.
  • Step 6 To a stirred solution of tert-butyl 1-cyclobutyl-2-(N-hydroxy-N- methylcarbamimidoyl)-1H-1,3-benzodiazole-6-carboxylate (1.8 g, 5.23 mmol) in methanol (18 mL) and water (18 mL) was added 1,4-dimethyl but-2-ynedioate (0.704 mL, 5.75 mmol) at r.t and stirred for 1 h. The reaction mixture diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried with sodium sulfate and concentrated under pressure to provide crude product.
  • Step 7 A mixture of tert-butyl 1-cyclobutyl-2-[5-(2-methoxy-2-oxoethyl)-5- (methoxycarbonyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazol-3-yl]-1H-1,3-benzodiazole-6-carboxylate (0.6 g, 1.23 mmol) and 1,3-xylene (3 mL) was stirred at 145 °C for 6 h.
  • Step 8 To a stirred solution of tert-butyl 1-cyclobutyl-2-[5-hydroxy-4-(methoxycarbonyl)-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (0.110 g, 0.242 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.030 g, 0.726 mmol) at ambient temperature and the mixture was stirred for 16 h. After completion, the mixture was concentrated under reduced pressure.
  • Step 9 To a stirred solution of 2- ⁇ 6-[(tert-butoxy) carbonyl]-1-cyclobutyl-1H-1,3- benzodiazol-2-yl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 0.227 mmol) and 1,2-oxazol-4-amine (0.022 mg, 0.272 mmol) in DMF(1 mL) was added N, N-diisopropyl ethylamine (0.098 mL, 0.568 mmol) and [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (0.104 g, 0.272 mmol) at ambient temperature and the mixture was stirred for 16 h.
  • Step 10 A mixture of tert-butyl 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylate (0.06 g, 0.118 mmol) and TFA (0.5 mL) was stirred at 0 °C for 3 h.
  • reaction mixture concentrated and washed with n- pentane to provide 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6- dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid; trifluoroacetic acid salt (0.03 g).
  • ES MS M/Z 451.2 [M+H] + .
  • Step 11 To a stirred solution of 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid; trifluoroacetic acid (0.075 g, 0.133 mmol) and 2,2-difluoroethan-1-amine (0.012 mL, 0.173 mmol) in N, N-DMF (1 mL) was added N, N-diisopropyl ethylamine (0.0116 mL, 0.664 mmol) and [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (0.101 g, 0.266 mmol) at ambient temperature The reaction mixture was stirred at ambient temperature for 16
  • Step 1 To a stirred solution of 2-(5-amino-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.050 g, 0.115 mmol) and acetic acid (0.131 mL, 0.230 mmol) in DMF (2 mL) was added HATU (0.087 g, 0.230 mmol), DIPEA (0.064 mL, 0.344 mmol) and stirred at ambient temperature for 16 h.
  • Step 2 To a stirred solution of 2-(1-cyclobutyl-5-acetamido-1H-1,3-benzodiazol-2-yl)-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.060 g, 0.126 mmol) in DCM (2 mL) at -40 °C was added tribromoborane (0.064 mL, 0.377 mmol) and stirred at ambient temperature for 16 h. After completion, the reaction mixture was cooled to 0 °C and quenched with methanol. The reaction mixture was then filtered through celite bed and washed with methanol.
  • Example 8 Synthesis of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5- hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00189]
  • Step 1 A mixture of 4-bromo-2-fluoro-1-nitrobenzene (4 g, 18.2 mmol) in 1-methylpyrrolidin- 2-one (25 mL) was added DIPEA (7.34 mL, 3 eq., 54.5 mmol) and cyclobutanamine (1.29 mL, 1.1 eq., 15 mmol) at ambient temperature, The reaction mixture was heated at 120 °C for 12 h.
  • Step 2 To a stirred solution of 5-bromo-N-cyclobutyl-2-nitroaniline (2 g, 7.38 mmol) in DMF (21.1 mL, 272 mmol) was added 1H-1,2,4-triazole (611 mg, 1.2 eq., 8.85 mmol) and potassium phosphate (3.13 g, 2 eq., 14.8 mmol) and the reaction mixture degassed with N2 for 5 min then copper iodide (281 mg, 0.2 eq., 1.48 mmol) was added and the mixture was stirred at 100 °C for 1 h in microwave.
  • 1H-1,2,4-triazole 611 mg, 1.2 eq., 8.85 mmol
  • potassium phosphate 3.13 g, 2 eq., 14.8 mmol
  • Step 3 To a stirred solution of N-cyclobutyl-2-nitro-5-(1H-1,2,4-triazol-1-yl)aniline (1.6 g, 6.17 mmol) in methanol (30 mL) was added 10% Pd/C (328 mg, 0.5 eq., 3.09 mmol) under a N2 atmosphere. The reaction mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h. After completion, the reaction mixture was passed through celite and the filtrate was concentrated under vacuum to afford N1-cyclobutyl-5-(1H-1,2,4-triazol-1-yl)benzene-1,2-diamine (1.3 g, 92%).
  • Step 4 To a solution of N1-cyclobutyl-5-(1H-1,2,4-triazol-1-yl)benzene-1,2-diamine (340 mg, 1.48 mmol), methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (503 mg, 1.5 eq., 2.22 mmol), DMSO ( 10 ml) and disodium (sulfinatooxy)sulfinate (423 mg, 1.5 eq., 2.22 mmol) was stirred at 60 °C for 12 h.
  • Step 5 To a stirred solution of methyl 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.459 mmol) in methanol (1.76 mL, 43.6 mmol) and tetrahydrofuran (1.76 mL, 21.7 mmol) was added a solution of lithium hydroxide (33 mg, 3 eq., 1.38 mmol) in water (1.76 mL, 98 mmol) and the mixture was stirred at ambient temperature for 2 h.
  • Step 6 To a stirred solution of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (60 mg, 0.142 mmol) in DMF (5 mL) was added DIPEA (0.248 mL, 10 eq., 1.42 mmol) and 1,2-oxazol-4-amine (14.4 mg, 1.2 eq., 0.171 mmol) followed by HATU (108 mg, 2 eq., 0.285 mmol) at ambient temperature and the mixture was stirred for 16 h.
  • Step 7 A stirred solution of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2- yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (60 mg, 123 ⁇ mol) in DCM (5 mL, 78.1 mmol) was cooled to -40 °C, tribromoborane (58.4 ⁇ L, 5 eq., 0.615 mmol) was added and the mixture was stirred at ambient temperature for 3 h. The reaction was monitored by TLC and LCMS.
  • Step 1 To a solution of 3-fluoro-4-nitrobenzoic acid (5 g, 27 mmol) in DCM (75 mL, 1.17 mol) was added DMAP (0.5 g, 4.09 mmol) and t-butyl alcohol (10.3 mL, 4 eq., 108 mmol) followed by DCC (6.69 g, 1.2 eq., 32.4 mmol) at 0 °C and the resulting mixture stirred at ambient temperature for 16 h. The reaction mixture was basified with sat. NaOH solution, then extracted with ethyl acetate.
  • Step 2 To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (9 g, 37.3 mmol) in DMF(50 mL) was added DIPEA (19.5 mL, 3 eq., 112 mmol) and bicyclo[1.1.1]pentan-1-amine (4.03 g, 1.3 eq., 48.5 mmol) was added at ambient temperature and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and the reaction mixture was concentrated under reduced pressure to provide the crude product. The crude product was purified by flash chromatography.
  • Step 3 To a stirred solution of tert-butyl 4-amino-3-( ⁇ bicyclo[1.1.1]pentan-1- yl ⁇ amino)benzoate (1 g, 3.64 mmol) in methanesulfinylmethane (15 mL) was added methyl 2-formyl-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (989 mg, 1.2 eq., 4.37 mmol) and disodium (sulfinatooxy)sulfinate (2.08 g, 3 eq., 10.9 mmol). The reaction was stirred at 80 °C for 12 h.
  • Step 4 To a solution of tert-butyl 1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -2-[5-methoxy-4- (methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (650 mg, 947 ⁇ mol) in a mixture of methanol (4 mL, 98.7 mmol) and tetrahydrofuran (4 mL, 49.1 mmol) was added lithium hydroxide mono-hydrate (199 mg, 5 eq., 4.73 mmol) in water (2 mL) and the mixture was stirred at ambient temperature for 1 h.
  • Step 5 To a solution of 2-(1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -6-[(tert-butoxy)carbonyl]-1H-1,3- benzodiazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.5 g, 0.890 mmol) in DMF were added HATU (677 mg, 2 eq., 1.78 mmol), DIPEA (0.493 mL, 3 eq., 2.67 mmol) and 1,2-oxazol-4-amine hydrochloride (161 mg, 1.5 eq., 1.33 mmol).
  • reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice water, extracted with the ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide crude product which was purified using CombiFlash to afford tert-butyl 1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -2- ⁇ 5-methoxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylate (0.28 g, 473 ⁇ mol) (0.28 g, 53%).
  • Step 6 To a stirred solution of tert-butyl 1- ⁇ bicyclo [1.1.1] pentan-1-yl ⁇ -2- ⁇ 5-methoxy-1- methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6- carboxylate (280 mg, 0.526 mmol) in DCM (5 mL) was cooled to -40 °C, tribromoborane (0.451 mL, 5 eq., 2.63 mmol) was added and stirred at ambient temperature for 16 h.
  • Step 7 To a solution of 1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol- 4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid (80 mg, 0.173 mmol) and ammonium chloride (18.5 mg, 2 eq., 0.346 mmol) in DMF (3 mL) was added HATU (132 mg, 2 eq., 0.346 mmol), DIPEA (95.8 ⁇ L, 3 eq., 0.519 mmol).
  • reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice water and extracted with the ethyl acetate, the combined organic layer washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide crude product.
  • Step 1 To a solution of 2,5-difluoro-4-nitrobenzonitrile (0.2 g, 1.09 mmol) and cyclobutanamine (112 ⁇ L, 1.2 eq., 1.3 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added DIPEA (377 ⁇ L, 2 eq., 2.17 mmol) and the reaction mixture was stirred at 100 °C for 16 h.
  • Step 2 To a stirred solution of 5-(cyclobutylamino)-2-fluoro-4-nitrobenzonitrile (1 g, 4.25 mmol) in DMF (10.0 mL), ammonium chloride (1.14 g, 5 eq., 21.3 mmol) and sodium azide (1.38 g, 5 eq., 21.3 mmol) was added and stirred at 120 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature and washed with 6 N hydrochloride solution.
  • Step 3 To a stirred solution of N-cyclobutyl-4-fluoro-2-nitro-5-(2H-1,2,3,4-tetrazol-5- yl)aniline (750 mg, 2.7 mmol) in methanol (20.0 mL), Pd/C (287 mg, 0.1 eq., 270 ⁇ mol) was added and the mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h.
  • Step 4 To a stirred solution of N1-cyclobutyl-4-fluoro-5-(2H-1,2,3,4-tetrazol-5-yl)benzene- 1,2-diamine (176 mg, 707 ⁇ mol) and methyl 2-formyl-5-methoxy-6-oxo-1,6-dihydropyrimidine-4- carboxylate (150 mg, 707 ⁇ mol) in DMF (3.0 mL) and water (1.0 mL), oxone monopersulfate (217 mg, 707 ⁇ mol) was added and the mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 5 To a stirred solution of methyl 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)- 1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (85 mg, 187 ⁇ mol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added lithium hydroxide (22.4 mg, 5 eq., 935 ⁇ mol) and the mixture was stirred at ambient temperature for 16 h.
  • Step 6 To a stirred solution of 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (85 mg, 193 ⁇ mol) and 1,2-oxazol-4-amine hydrochloride (27.9 mg, 1.2 eq., 232 ⁇ mol) in DMF (1.0 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (110 mg, 1.5 eq., 290 ⁇ mol) and DIPEA (101 ⁇ L, 3 eq., 579 ⁇ mol) at ambient temperature and stirred for 16 h.
  • Step 7 A stirred solution of 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (45 mg, 44.4 ⁇ mol) in DCM (5.0 mL) was cooled to -60 °C and tribromoborane (21.1 ⁇ L, 5 eq., 222 ⁇ mol) was added and the solution was stirred at ambient temperature for 16 h.
  • Step 1 To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) and cyclobutanamine (467 ⁇ L, 1.2 eq., 5.45 mmol) in 1-methylpyrrolidin-2-one (5 mL), N, N- diisopropylethylamine (1.58 mL, 2 eq., 9.09 mmol) was added and the reaction mixture was stirred and heated at 100 °C for 18 h.
  • Step 2 To a stirred solution of 5-bromo-N-cyclobutyl-2-nitroaniline (550 mg, 2.03 mmol) in 1,4-dioxane (8 mL), pyrrolidin-2-one (259 mg, 1.5 eq., 3.04 mmol) and potassium carbonate (841 mg, 3 eq., 6.09 mmol) were added and reaction mixture was purged with argon for 5 min then copper iodide (64.4 mg, 0.1 eq., 203 ⁇ mol) and then 2-aminoacetic acid (30.5 mg, 0.2 eq., 406 ⁇ mol) was added and again the reaction vessel was purged with argon.
  • pyrrolidin-2-one 259 mg, 1.5 eq., 3.04 mmol
  • potassium carbonate 841 mg, 3 eq., 6.09 mmol
  • Step 3 To a stirred solution of 1-[3-(cyclobutylamino)-4-nitrophenyl]pyrrolidin-2-one (240 mg, 799 ⁇ mol) in methanol (10 mL), Pd/C (Pd/C) (42.5 mg, 0.5 eq., 0.4 mmol) was added and reaction mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h.
  • Pd/C Pd/C
  • Step 4 To a stirred solution of 1-[4-amino-3-(cyclobutylamino)phenyl]pyrrolidin-2-one (0.2 g, 815 ⁇ mol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (228 mg, 1.1 eq., 897 ⁇ mol) in DMSO (15 mL), sodium metabisulfite (232 mg, 1.5 eq., 1.22 mmol) was added at ambient temperature.
  • Step 5 To a stirred solution of ethyl 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.13 g, 271 ⁇ mol) in oxolane (30 mL, 209 ⁇ mol) and water (10 mL), lithium hydroxide (32 mg, 5 eq., 1.36 mmol) was added and the mixture was allowed to stir at ambient temperature for 3 h.
  • Step 6 To a stirred solution of 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (150 mg, 332 ⁇ mol), and 1,2- oxazol-4-amine hydrochloride (47.8 mg, 1.2 eq., 399 ⁇ mol) in DMF (13.7 mL, 177 mmol) DIPEA (163 ⁇ L, 3 eq., 997 ⁇ mol) and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (189 mg, 1.5 eq., 498 ⁇ mol) was added and the reaction mixture was allowed to stir at ambient temperature for 15 h.
  • Step 7 To a stirred solution of 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (110 mg, 149 ⁇ mol) in DCM (5 mL, 78.1 mmol), boron tribromide (28.2 ⁇ L, 2 eq., 298 ⁇ mol) was added and the mixture was refluxed for 18 h.
  • Step 1 A stirred solution of 3-fluoro-4-nitroaniline (0.5 g, 3.2 mmol) in acetic anhydride (5.0 mL) was stirred at 70 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 2 To a stirred solution of N-(3-fluoro-4-nitrophenyl)acetamide (3.5 g, 12.4 mmol) and acetonitrile (30.0 mL) in sodium azide (1.61 g, 2 eq., 24.7 mmol) were added to a phosphoroyl trichloride (5.78 mL, 5 eq., 61.8 mmol) .
  • Step 3 To a stirred solution of 1-(3-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,3,4-tetrazole (0.6 g, 2.69 mmol) in (3.0 mL) was added, followed by cyclobutanamine (276 ⁇ L, 1.2 eq., 3.23 mmol) and DIPEA (1.4 mL, 3 eq., 8.07 mmol) and the mixture was stirred at 100 °C for 16 hr. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate.
  • Step 4 To a stirred solution of N-cyclobutyl-5-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-2- nitroaniline (0.5 g, 1.82 mmol) in methanol (5.0 ml) was added Pd/C (194 mg, 0.1 eq., 182 ⁇ mol) and the mixture was stirred at ambient temperature for 16 hr. After completion, the reaction mixture was filtered through celite.
  • Step 5 To a stirred solution of ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (150 mg, 590 ⁇ mol) in DMSO (5.0 mL) was added N1-cyclobutyl-5- (5-methyl-1H-1,2,3,4-tetrazol-1-yl)benzene-1,2-diamine (144 mg, 590 ⁇ mol) and disodium (sulfinatooxy)sulfinate (135 mg, 1.2 eq., 708 ⁇ mol) and the mixture was stirred at 80 °C for 16 h.
  • Step 6 To a stirred solution of ethyl 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)- 1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 209 ⁇ mol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (25 mg, 5 eq., 1.04 mmol) and the mixture was stirred at ambient temperature for 3 h.
  • Step 7 To a stirred solution of 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (90 mg, 0.2 mmol) and 1,2-oxazol-4-amine (20.2 mg, 1.2 eq., 240 ⁇ mol) in DMF (5.0 mL) was added 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (114 mg, 1.5 eq., 0.3 mmol) and DIPEA (104 ⁇ L, 3 eq., 599 ⁇ mol) and the solution was stirred at ambient temperature for 16 h.
  • Step 8 To a stirred solution of 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (50 mg, 89.1 ⁇ mol) in DCM (5 mL) was added tribromoborane (112 mg, 5 eq., 445 ⁇ mol) at -60 °C and the solution was stirred at ambient temperature for 4 h.
  • reaction mixture was quenched with methanol and concentrated to provide crude product which was purified by reverse prep HPLC and the desired fractions were lyophilized to provide 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4- tetrazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (13 mg, 30%).
  • Example 14 1-Cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 To a stirred solution of 4-(cyclobutylamino)-3-nitrobenzonitrile (2.5 g, 11.5 mmol) in DMSO (19.2 mL), hydrogen peroxide (1.7 mL, 72.5 mmol) was added at 0 °C.
  • Step 2 To a stirred solution of 4-(cyclobutylamino)-3-nitrobenzamide (1.5 g, 6.38 mmol) in methanol (21.7 mL), Pd/C (Pd/C) (339 mg, 0.5 eq., 3.19 mmol) was added at ambient temperature under a hydrogen atmosphere for 18 h.
  • Pd/C Pd/C
  • Step 3 To a stirred solution of 3-amino-4-(cyclobutylamino)benzamide (350 mg, 1.71 mmol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (477 mg, 1.1 eq., 1.88 mmol) in DMSO (15 mL), sodium metabisulfite (486 mg, 1.5 eq., 2.56 mmol) was added at ambient temperature.
  • Step 4 To a stirred solution of ethyl 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.3 g, 683 ⁇ mol) in tetrahydrofuran (30 mL) and water (10 mL) lithium hydroxide (81.7 mg, 5 eq., 3.41 mmol) was added and the mixture was stirred at ambient temperature for 3 h.
  • Step 5 To a stirred solution of 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.3 g, 474 ⁇ mol, 69%) [00233] Step 5: To a stirred solution of 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.3 g, 729 ⁇ mol) and 1,2-oxazol-4- amine (73.6 mg, 1.2 eq., 875 ⁇ mol) in DMF (30 mL), DIPEA (358 ⁇ L, 3 eq., 2.19 mmol) and (1- [bis(dimethylamino)
  • Step 6 To a stirred solution of 1-cyclobutyl-2- ⁇ 5-ethoxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-5-carboxamide (190 mg, 318 ⁇ mol, 44%) [00234] Step 6: To a stirred solution of 1-cyclobutyl-2- ⁇ 5-ethoxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-5-carboxamide (190 mg, 398 ⁇ mol) in DCM (10.6 mL, 165 mmol), boron tribromide (75.5 ⁇ L, 2 eq., 796 ⁇ mol) was added and the mixture was
  • Step 1 To a stirred solution of 3-fluoro-4-nitrobenzoic acid (10 g, 54 mmol) in DCM (0.1 L, 1.56 mol) was added DMAP (1.32 g, 0.2 eq., 10.8 mmol) and 2-methylpropan-2-ol (20.5 mL, 4 eq., 216 mmol) followed by N,N'-dicyclohexylmethanediimine (13.4 g, 1.2 eq., 64.8 mmol) at 0 °C and the resulting mixture stirred at ambient temperature for 16 h. The reaction mixture was basified with saturated sodium hydroxide solution then extracted with ethyl acetate.
  • Step 2 To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (7 g, 29 mmol) in 1- methylpyrrolidin-2-one (20 mL), cyclobutanamine (2.48 g, 1.2 eq., 34.8 mmol) and DIPEA (15.4 mL, 3 eq., 87.1 mmol) was added and reaction mixture was heated to 90 °C for 16 h.
  • Step 3 To a stirred solution of tert-butyl 3-(cyclobutylamino)-4-nitrobenzoate (3.0 g, 10.62 mmol) in methanol (10 mL, 6.84 mmol) was added Pd/C (1.63 g, 1.5 eq., 15.39 mmol) and the mixture was stirred at ambient temperature under hydrogen atmosphere for 6 h.
  • Step 4 To a stirred solution of tert-butyl 4-amino-3-(cyclobutylamino)benzoate (2.10 g, 8.00 mmol) in DMSO (15 mL) was added ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (2.04 g, 1.0 eq., 8.0 mmol) and sodium metabisulfite (2.28 g, 1.2 mmol) at ambient temperature, The reaction was stirred at 80°C for 12 h, After completion of the reaction, the mixture was dissolved in water and extracted in ethyl acetate, the organic layer washed with
  • Step 5 To solution of tert-butyl 1-cyclobutyl-2-[5-ethoxy-4-(ethoxycarbonyl)-1-methyl-6- oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (0.55 g, 1.11 ⁇ mol) in a mixture of methanol (5.0 mL, 12.3 mmol), tetrahydrofuran (5.0 mL, 11.14 mmol), lithium hydroxide (0.132 g, 5 eq., 0.30 mmol) was added water (2 mL) and the mixture was stirred at ambient temperature for 1h.
  • methanol 5.0 mL, 12.3 mmol
  • tetrahydrofuran 5.0 mL, 11.14 mmol
  • lithium hydroxide (0.132 g, 5 eq., 0.30 mmol
  • reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ether.
  • the aqueous layer was acidified using citric acid solution, extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure to provide crude 2- ⁇ 6-[(tert-butoxy)carbonyl]-1-cyclobutyl- 1H-1,3-benzodiazol-2-yl ⁇ -5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.550 g).
  • Step 6 To a solution of 2- ⁇ 6-[(tert-butoxy)carbonyl]-1-cyclobutyl-1H-1,3-benzodiazol-2-yl ⁇ - 5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (550 mg, 1.17 mmol) and 1,2-oxazol- 4-amine HCl (118 mg, 1.2 eq., 1.41 mmol) dissolved in DMF (48.3 mL, 624 mmol) was added DIPEA (576 ⁇ L, 3 eq., 3.52 mmol) and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (670 mg, 1.5 eq., 1.76 mmol) and the mixture was stirred at ambient temperature for 15 h.
  • DIPEA 576 ⁇ L, 3 eq., 3.
  • Step 7 To a solution of tert-butyl 1-cyclobutyl-2-(5-ethoxy-4-(isoxazol-4-ylcarbamoyl)-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxylate (0.40 g, 0.74 mmol) in DMF (4 mL) was added lithium bromide (324 mg, 5 eq., 3.74 mmol) and stirred for 16 h at 100 °C. After completion, the reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with water.
  • Step 8 To a stirred solution of tert-butyl 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol- 4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylate (180 mg, 355 ⁇ mol) in DCM (3.6 mL, 56.2 mmol) was added TFA (2 mL) at 0 °C and the mixture was stirred for 24 h then concentrated and washed with n-pentane 2-3 time.
  • Example 17 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6- oxo-1,6-dihydropyrimidin-5-yl pivalate [00250]
  • Step 1 To a stirred solution of in 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.5 g, 701 ⁇ mol) in tetrahydrofuran (10.0 mL) was added triethylamine (489 ⁇ L, 5 eq., 3.51 mmol) followed by 2,2- dimethylpropanoyl chloride (216 ⁇ L, 2.5 eq., 1.75 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • Example 18 2-(1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 To a stirred solution of N-(2-nitrophenyl)bicyclo[1.1.1]pentan-1-amine (1 g, 4.9 mmol) in methanol (15.0 mL), ammonium chloride (1.31 g, 5 eq., 24.5 mmol) and zinc (1.6 g, 5 eq., 24.5 mmol) were added at 0°C and the reaction mixture was stirred for 0.5 h at 0 °C and then for 2 h at ambient temperature.
  • Step 2 To a solution of ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (0.5 g, 0.8 eq., 1.97 mmol) in DMSO (5.0 mL) were added N1- ⁇ bicyclo[1.1.1]pentan-1- yl ⁇ benzene-1,2-diamine (428 mg, 2.46 mmol) and sodium metabisulfite (561 mg, 1.2 eq., 2.95 mmol) and the mixture was stirred for 16 h at 80 °C. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 3 To a solution of ethyl 2-(1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -1H-1,3-benzodiazol-2- yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (250 mg, 612 ⁇ mol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added lithium hydroxide (73.3 mg, 5 eq., 3.06 mmol) and the mixture was stirred at ambient temperature for 3 h.
  • Step 4 To a solution of 2-(1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -1H-1,3-benzodiazol-2-yl)-5-ethoxy- 1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (250 mg, 657 ⁇ mol) and 1,2-oxazol-4-amine hydrochloride (95 mg, 1.2 eq., 789 ⁇ mol) in DMF (2.5 mL) was added DIPEA (344 ⁇ L, 3 eq., 1.97 mmol) and HATU (375 mg, 1.5 eq., 986 ⁇ mol) and the mixture was stirred at ambient temperature for 16 h.
  • DIPEA 344 ⁇ L, 3 eq., 1.97 mmol
  • HATU 375 mg, 1.5 eq., 986 ⁇ mol
  • Step 5 A stirred solution of 2-(1- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (250 mg, 560 ⁇ mol) in DCM (5.0 mL) was cooled to -60 °C and tribromoborane (266 ⁇ L, 5 eq., 2.8 mmol) was added and the solution was stirred at ambient temperature for 16 h.
  • Step 1 To a stirred solution of 3-fluoro-4-nitrobenzonitrile (30 g, 181 mmol) in 1- methylpyrrolidin-2-one (30 mL), cyclobutanamine (18.6 mL, 1.2 eq., 217 mmol) and DIPEA (96.1 mL, 3 eq., 542 mmol) was added and the reaction mixture was heated to 90 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-(cyclobutylamino)-4- nitrobenzonitrile (35 g, 145 mmol, 80%).
  • Step 2 To a stirred solution of 3-(cyclobutylamino)-4-nitrobenzonitrile (20 g, 92.1 mmol) in DMF (30.0 mL), ammonium chloride (24.6 g, 5 eq., 460 mmol) and sodium azide (29.9 g, 5 eq., 460 mmol) was added and the mixture was stirred at 120 °C for 16 h.
  • Step 3 To a stirred solution of N-cyclobutyl-2-nitro-5-(2H-1,2,3,4-tetrazol-5-yl)aniline (0.5 g, 1.92 mmol) in methanol (10.0 mL), Pd/C (102 mg, 0.5 eq., 961 ⁇ mol) was added and the mixture was stirred at ambient temperature under a hydrogen atmosphere for 18 h.
  • Step 4 To a stirred solution N1-cyclobutyl-5-(2H-1,2,3,4-tetrazol-5-yl)benzene-1,2-diamine (950 mg, 4.13 mmol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.05 g, 4.13 mmol) in dimethylsulfoxide (5.0 mL) was added sodium metabisulfite (1.18 g, 1.5 eq., 6.19 mmol) at ambient temperature. The resulting mixture stirred for 16 h at 80 °C.
  • Step 5 To a stirred solution of ethyl 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.2 g, 2.58 mmol) in tetrahydrofuran (12.0 mL, 2.58 mmol) and water (4.0 mL) was added lithium hydroxide (309 mg, 5 eq., 12.9 mmol) and the mixture was stirred at ambient temperature for 3 h.
  • Step 6 To a stirred solution of 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (1.0 g, 2.29 mmol) and isoxazol-4-amine hydrochloride (330 mg, 1.2 eq., 2.75 mmol) in DMF (10.0 mL) was added followed by DIPEA (1.2 mL, 3 eq., 6.87 mmol) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.31 g, 1.5 eq., 3.44 mmol) and the mixture was stirred at ambient temperature for 16 h.
  • DIPEA 1.2 mL, 3 eq
  • Step 7 To a stirred solution of 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (650 mg, 1.29 mmol) in DCM (15.0 mL) and DMF (0.5 mL) was cooled to -60 °C and borontribromide (614 ⁇ L, 5 eq., 6.47 mmol) was added and the solution was stirred at ambient temperature for 16 h.
  • Step 1 To a stirred solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl- 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (25.0 mg, 63.8 ⁇ mol) and 1,2-oxazol-4-amine (6.44 mg, 1.2 eq., 76.5 ⁇ mol) in DMF (1.00 mL) was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (36.4 mg, 1.5 eq., 95.7 ⁇ mol) and DI
  • reaction mixture was concentrated to provide crude product which was purified by reverse prep HPLC and the desired fractions were lyophilized to provide 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (7 mg, 15.6 ⁇ mol).
  • Example 23 2-(1-cyclobutyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol- 4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00267]
  • Step 1 To a solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1 g, 4.78 mmol) in DCM (10 mL) was added cyclobutanamine (1.23 mL, 3 eq., 14.3 mmol) slowly with cooling on an ice bath. After 2 h at ambient temperature the reaction was diluted with water and extracted with DCM.
  • Step 2 To a stirred solution of N-cyclobutyl-2-nitro-5-(trifluoromethyl)aniline (1.1 g, 4.23 mmol) in methanol (30 mL) was added 10% Pd/C (450 mg, 4.23 mmol) and the mixture was stirred at ambient temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a celite bed then washed with methanol.
  • Step 3 To a solution of N1-cyclobutyl-5-(trifluoromethyl)benzene-1,2-diamine (0.3 g, 1.3 mmol), methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (354 mg, 1.2 eq., 1.56 mmol), DMSO (5 mL) and disodium (sulfinatooxy)sulfinate (372 mg, 1.5 eq., 1.95 mmol) was stirred at 85 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with ethyl acetate.
  • Step 4 To a stirred solution of methyl 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (240 mg, 0.551 mmol) in methanol (3.22 mL) and tetrahydrofuran (3.22 mL) was added solution of lithium hydroxide (65.9 mg, 5 eq., 2.75 mmol) in water (3.22 mL) and the mixture was stirred at ambient temperature for 2 h.
  • Step 5 To a stirred solution of 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.2 g, 0.474 mol) in 1,2-oxazol-4- amine hydrochloride (74.2 mg, 1.3 eq., 616 ⁇ mol), HATU (360 mg, 2 eq., 947 ⁇ mol), DMF (2.35 mL) and DIPEA (165 ⁇ L, 2 eq., 0.947 mmol) were added and the mixture was stirred at ambient temperature for 48 h.
  • Step 6 To a stirred solution of 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (140 mg, 0.287 mmol) in DCM (10 mL) was cooled to -40 °C, tribromoborane (0.0136 mL, 5 eq., 1.43 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction was monitored by TLC and LCMS.
  • Example 36 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(pyridazin-4- yl)-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 To a stirred solution of 6-(benzyloxy)-2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- methoxy-1,6-dihydropyrimidine-4-carboxylic acid (90 mg, 208 ⁇ mol) and pyridazin-4-amine (19.8 mg, 208 ⁇ mol) in DMF (4 mL), HATU and DIPEA (90.6 ⁇ L, 2.5 eq., 520 ⁇ mol) were added and stirred at ambient temperature for 12 h.
  • Step 2 To a stirred solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy-1- methyl-6-oxo-N-(pyridazin-4-yl)-1,6-dihydropyrimidine-4-carboxamide (80 mg, 185 ⁇ mol) in DCM (2 mL), boron tribromide (35.2 ⁇ L, 2 eq., 371 ⁇ mol) was added at -60 °C and the mixture was warmed to ambient temperature and stirred for 16 h.
  • Example 42 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00279]
  • Step 1 A solution 4-bromo-2-fluoro-1-nitrobenzene (4 g, 18.2 mmol) in 1-methylpyrrolidin-2- one (15 mL), ethylbis(propan-2-yl) amine (9.5 mL, 3 eq, 54.5 mmol) and cyclobutanamine (1.86 mL, 1.2 eq., 21.8 mmol) was stirred at 130 °C for 6 h.
  • Step 2 To a mixture of 5-bromo-N-cyclobutyl-2-nitroaniline (2 g, 7.38 mmol) in 1,4-dioxane (16 mL, 188 mmol), potassium acetate (1.01 g, 1.4 eq., 10.3 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.68 g, 2.5 eq., 18.4 mmol) was added at ambient temperature and purged with nitrogen for 5 minutes.
  • Step 3 To a mixture of N-cyclobutyl-2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (3.3 g, 10.4 mmol) in 1,4-dioxane (25 mL) and water (5 mL) , cesium carbonate (10.1 g, 3 eq., 31.1 mmol) and 2-chloropyrimidine (1.43 g, 1.2 eq., 12.4 mmol) was added at ambient temperature and purged with nitrogen for 5 min.
  • Step 5 To a stirred solution of methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (0.5 g, 2.21 mmol) in DMSO (5 mL), disodium (sulfinatooxy) sulfinate (630 mg, 1.5 eq., 3.32 mmol) and N1-cyclobutyl-5-(pyrimidin-2-yl)benzene-1,2-diamine (637 mg, 1.2 eq., 2.65 mmol) was added and the mixture was heated at 80 °C for 6 h.
  • Step 6 To a stirred solution of methyl 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol- 2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.448 mmol) in methanol (3.3 mL, 81.5 mmol) and tetrahydrofuran (3.3 mL, 40.6 mmol) was added lithium hydroxide (56.4 mg, 3 eq., 1.34 mmol) in water (1.65 mL, 91.6 mmol) at ambient temperature and the mixture was stirred for 3 h and concentrated under reduced pressure.
  • Step 7 To a stirred solution of 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.2 g, 0.462 mmol) in DMF (2 mL) was added DIPEA (806 ⁇ L, 10 eq., 4.62 mmol) and 1,2-oxazol-4-amine hydrochloride (66.9 mg, 1.2 eq., 0.555 mmol) followed by HATU (352 mg, 2 eq., 0.925 mmol) at ambient temperature and the mixture was stirred for 16 h.
  • DIPEA 806 ⁇ L, 10 eq., 4.62 mmol
  • 1,2-oxazol-4-amine hydrochloride 66.9 mg, 1.2 eq., 0.555 mmol
  • HATU 352 mg, 2 eq.
  • reaction mixture was diluted with DCM and washed with water, dried with sodium sulfate, and concentrated to afford crude product which was purified by CombiFlash using gradient elution 40-50% ethyl acetate /hexane to afford 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (0.1 g, 42%).
  • ES MS M/Z 499.2 [M+H] + .
  • Step 8 To a stirred solution of 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 0.231 mmol) in DCM (4 mL) was added tribromoborane (111 ⁇ L, 5 eq., 1.16 mmol) at -78 °C. The reaction mixture was stirred for 16 h at ambient temperature. The progress of the reaction mixture was monitored by TLC and LCMS and when complete it was concentrated under reduced pressure.
  • 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 N,N-diisopropylethylamine (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-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxylate (0.6 g, 1.48 mmol) in tetrahydrofuran (4.5 mL) and water (1.5 mL) was added lithium hydroxide (177 mg, 5 eq., 7.4 mmol) and stirred at ambient temperature for 16 h.
  • 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 (0.6 g, 1.53 mmol) and 1,2- oxazol-4-amine hydrochloride (222 mg, 1.2 eq., 1.84 mmol) in DMF (6 mL) were added 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (874 mg, 1.5 eq., 2.3 mmol) and DIPEA (801 ⁇ L, 3 eq., 4.6 mmol) and stirred for 16 h at ambient temperature.
  • 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 874
  • Step 4 To a solution of N-(isoxazol-4-yl)-5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxamide (0.3 g, 656 ⁇ mol) in DMF (3.0 mL) was added lithium bromide (285 mg, 5 eq., 3.28 mmol) and the mixture was stirred for 16 h at 100 °C. After completion, the reaction was cooled to ambient temperature, concentrated, diluted with ethyl acetate, and washed with water.
  • Example 31 methyl 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxylate [00291] To a stirred solution of 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid (150 mg, 333 ⁇ mol) in tetrahydrofuran (15 mL, 184 mmol) was added lithium hydroxide (14 mg, 333 ⁇ mol) in a sealed tube.
  • Example 30 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxamide [00292] To a stirred solution of 1-cyclobutyl-2- ⁇ 5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl ⁇ -1H-1,3-benzodiazole-6-carboxylic acid (0.2 g, 444 ⁇ mol) in N,N- dimethylformamide (3 mL) was added DIPEA (232 ⁇ L, 3 eq., 1.33 mmol).
  • Step 2 To a stirred mixture of 2-chloro-6-hydroxy-5-methoxypyrimidine-4-carboxylic acid (300 mg, 1.47 mmol, 1 equiv) and aniline (0.16 g, 1.76 mmol, 1.2 equiv) in CH 2 Cl 2 (20 mL) were added T3P (7.00 g, 21.99 mmol) and DIEA (0.95 g, 7.33 mmol, 5 equiv) dropwise at ambient temperature exposed to air. The resulting mixture was stirred for additional overnight at 40 °C. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification.
  • Step 3 To a stirred mixture of 2-chloro-6-hydroxy-5-methoxy-N-phenylpyrimidine-4- carboxamide (1.0 g, 3.5 mmol, 1 equiv) in DMF (30 mL) were added CH 3 I (1.0 g, 7 mmol, 2 equiv) and Cs 2 CO 3 (3.0 g, 1 mmol, 2.5 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for additional 2 h at ambient temperature. The filtrate was concentrated under reduced pressure.
  • Step 4 A solution of 6-bromo-1-phenyl-1,2,3,4-tetrahydroisoquinoline (5 g, 17.350 mmol, 1 equiv) in DCM (50 mL) was treated with Boc2O (7.57 g, 34.700 mmol, 2 equiv) followed by the addition of Et3N (4.39 g, 43.375 mmol, 2.5 equiv) dropwise at ambient temperature. The resulting mixture was stirred for overnight at ambient temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4.
  • Step 5 To a stirred mixture of tert-butyl 6-bromo-1-phenyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (3.2 g, 8.241 mmol, 1 equiv) and Et3N (4.2 g, 41.205 mmol, 5 equiv) in MeOH (50 mL) were added Pd(dppf)Cl2 (0.90 g, 1.236 mmol, 0.15 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for overnight at 130 °C under carbon monoxide atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (2 x 10 mL).
  • Step 6 Into a 100 mL round-bottom flask were added 2-tert-butyl 6-methyl 1-phenyl-3,4- dihydro-1H-isoquinoline-2,6-dicarboxylate (2.6 g, 7.076 mmol, 1 equiv) and HCl (in 1,4-dioxane, 20 mL) at ambient temperature. The resulting mixture was stirred for additional 1 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with Et2O (20 mL). The precipitated solids were collected by filtration and washed with Et2O (2 x 10 mL).
  • Step 7 A solution of methyl (1R)-2-chloro-1-phenyl-3,4-dihydro-1H-isoquinoline-6- carboxylate (450 mg, 1.491 mmol) in EtOH (5 mL) was treated with 2-chloro-5-methoxy-1-methyl-6-oxo- N-phenylpyrimidine-4-carboxamide (657 mg, 2.237 mmol, 1.5 equiv) at ambient temperature followed by the addition of DIEA (578 mg, 4.473 mmol, 3 equiv) dropwise at ambient temperature. The resulting mixture was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 8 A solution of methyl (1S)-2-[5-methoxy-1-methyl-6-oxo-4- (phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (300 mg, 0.572 mmol, 1.00 equiv) in DMF (5 mL) was treated with dodecyl mercaptan (347 mg, 1.716 mmol, 3.00 equiv) followed by the addition of MeONa (93 mg, 1.716 mmol, 3.00 equiv) in portions at ambient temperature. The resulting mixture was stirred for 12 h at 80 °C.
  • Step 9 A solution of methyl 2-[5-hydroxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2- yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (200 mg, 0.392 mmol, 1 equiv) in THF (5 mL) and H 2 O (5 mL) was treated with LiOH (28 mg, 1.176 mmol, 3 equiv) at ambient temperature then stirred for 12 h. The resulting mixture was concentrated under reduced pressure then diluted with water (10 mL).
  • Example 49 5-hydroxy-2-[3-(hydroxymethyl)-1-methylindol-4-yl]-1-methyl-N-(1,2-oxazol-4-yl)-6- oxopyrimidine-4-carboxamide
  • Step 1 NaH (214 mg, 5.36 mmol, 1.2 equiv, 60%) was added to a solution of 4-bromo-1H- indole-3-carbaldehyde (1 g, 4.463 mmol, 1 equiv) in DMF (10 mL) at 0 °C and the obtained suspension was stirred at rt for 0.5 h.
  • Step 2 A dark brown suspension of 4-bromo-1-methylindole-3-carbaldehyde (400 mg, 1.68 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (512 mg, 2.02 mmol, 1.2 equiv), Pd(dppf)Cl2 (123 mg, 0.168 mmol, 0.1 equiv) and KOAc (214 mg, 2.18 mmol, 1.3 equiv) in 1,4-dioxane (10 mL) was stirred under N2 at 90 °C for 2 h.
  • Step 3 A dark brown suspension of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indole-3-carbaldehyde (720 mg, 2.525 mmol, 1.2 equiv), 2-chloro-5-methoxy-1-methyl-N-(1,2-oxazol- 4-yl)-6-oxopyrimidine-4-carboxamide (599 mg, 2.104 mmol, 1.00 equiv), Pd(dtbpf)Cl2 (137 mg, 0.210 mmol, 0.1 equiv) and K3PO4 (893 mg, 4.208 mmol, 2 equiv) in THF (8 mL) and H 2 O (2 mL) was stirred under N2 at 90 °C for 2 h.
  • Step 4 A yellow solution of 2-(3-formyl-1-methylindol-4-yl)-5-methoxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxopyrimidine-4-carboxamide (75 mg, 0.184 mmol, 1 equiv) and LiBr (80 mg, 0.920 mmol, 5 equiv) in DMF (2 mL) was stirred at 100 °C for 2 h.
  • Step 5 LiBH4 (51 uL, 0.203 mmol, 2.00 equiv, 4M in THF) was added dropwise into a solution of 2-(3-formyl-1-methylindol-4-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxopyrimidine-4- carboxamide (40 mg, 0.102 mmol, 1 equiv) in THF (4 mL) at 0 °C and the obtained yellow solution was stirred at this temperature for 1 h.
  • Human TREX1 Enzymatic Assay with dsDNA Native Oligonucleotide Human TREX1 enzyme (amino acids 1-242) was diluted in assay buffer (20 mM Tris pH 7.7, 5 mM MgCl 2 , 0.01% human serum albumin, 0.01% BrijTM-35, 2 mM dithiothreitol) to 0.3 nM and 5 ⁇ L was added to a 384-well low-binding polypropylene plate (final enzyme concentration in reaction is 0.15 nM) .
  • Test compounds were prepared at 1 mM in DMSO (final DMSO concentration in reaction mixture of 0.3%) and serially diluted 3-fold into 10 stock concentrations.30 nL of each stock concentration was added to the wells with a concentration ranging from 3 ⁇ M to 0.15 nM. The reaction mixtures were incubated for 15 minutes at 24 °C and 5 ⁇ L of a solution of annealed dsDNA oligonucleotide was added to a final concentration of 50 nM.
  • reaction mixtures were incubated at 24 °C for 15 minutes and subsequently quenched by transferring part of the assay reaction to a solution of 100 mM ethylenediaminetetraacetic acid and 0.67% v/v PicogreenTM in a black plate with an opaque bottom.
  • the fluorescence (emission wavelength 480 nm / excitation wavelength 520 nm) was measured using a Molecular Devices SpectraMax plate reader.
  • Wells containing oligonucleotide but no TREX1 enzyme were used as negative controls.
  • Wells containing oligonucleotide, TREX1 enzyme, and DMSO were used as positive controls.
  • Example B Example B.
  • Murine TREX1 Enzymatic Assay with dsDNA Native Oligonucleotide (amino acids 1-242) was diluted in assay buffer (20 mM Tris pH 7.7, 5 mM MgCl 2 , 0.01% human serum albumin, 0.01% BrijTM-35, 2 mM dithiothreitol) to 0.3 nM and 5 ⁇ L was added to a 384-well low-binding polypropylene plate (final enzyme concentration in reaction is 0.15 nM) .
  • Test compounds were prepared at 1 mM in DMSO (final DMSO concentration in reaction mixture of 0.3%) and serially diluted 3-fold into 10 stock concentrations.30 nL of each stock concentration was added to the wells with a concentration ranging from 3 ⁇ M to 0.15 nM. The reaction mixtures were incubated for 15 minutes at 24 °C and 5 ⁇ L of a solution of annealed dsDNA oligonucleotide was added to a final concentration of 50 nM.
  • the reaction mixtures were incubated at 24 °C for 10 minutes and subsequently quenched by transferring part of the assay reaction to a solution of 100 mM ethylenediaminetetraacetic acid and 0.67% v/v PicogreenTM in a black plate with an opaque bottom.
  • the fluorescence (emission wavelength 480 nm / excitation wavelength 520 nm) was measured using a Molecular Devices SpectraMax plate reader.
  • Wells containing oligonucleotide but no TREX1 enzyme were used as negative controls.
  • Wells containing oligonucleotide, TREX1 enzyme, and DMSO were used as positive controls.

Abstract

Described herein are compounds of Formula (I), methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for inhibiting three prime repair exonuclease 1 ("TREX1") Formula (I).

Description

TREX1 INHIBITORS AND USES THEREOF [0001] This application claims the benefit of U. S. Provisional Application Serial No.63/354,612 filed June 22, 2022 and U. S. Provisional Application Serial No. 63/390,203 filed July 18, 2022; which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0002] The presence of tumor infiltrating T cells (“TILs”) is associated with improved clinical outcomes in multiple tumor types and also improves responses to immune checkpoint blockade therapies. Although T-cell responses to some tumors occur spontaneously, the majority of cancers are not naturally recognized by the immune system or have evolved multiple mechanisms of immune evasion. Preclinical and clinical data together have established a central role for type I interferons (“IFNs”) in linking innate and adaptive immune responses to mediate tumor rejection. Non-T cell-inflamed tumors in humans are deficient in type I IFNs. Thus, the development of therapeutic strategies for restoring type I IFN signaling is essential for expanding the number of patients who may be effectively treated with immunotherapy. [0003] Innate immune sensing in the tumor microenvironment (“TME”) is a critical step in promoting spontaneous tumor-initiated T cell priming and subsequent TIL infiltration (Fuertes et al., J. Exp. Med. 2011, 208, 2005-2016). 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-α/β receptor in dendritic cells (“DCs”) cannot reject immunogenic tumors and CD8α+ DCs from these mice are defective in antigen cross-presentation to CD8+ T cells. Furthermore, Baft3-/- mice that lack the CD8α+ 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). These findings in humans and in mice indicate that the tumor-resident antigen presenting cell (“APC”) compartment is deficient/absent in non-T cell-inflamed tumors. Thus, strategies to induce type I IFN signaling and APC activation in the TME to bridge the innate and adaptive immune responses may have therapeutic utility. [0004] How the innate immune system is engaged by targeted ligands shapes the development of an adaptive response and is central to effective immunotherapy (Dubensky et al., Ther. Adv. Vaccines 2013, 1, 131-143; and Dubensky and Reed, Semin. Immunol.2010, 22, 155-161). The design and development of ligands to activate innate immunity is guided by a fundamental understanding that conserved microbial structures known as Pathogen-Associated Molecular Patterns (“PAMPs”) are sensed by germ-line encoded host cell Pattern Recognition Receptors (“PRRs”), triggering a downstream signaling cascade resulting in the induction of cytokines and chemokines, and initiation of a specific adaptive immune response (Iwasaki and Medzhitov, Science 2010, 327, 291-295). Engagement of the innate immune system by PAMPs presented from an infectious agent or by cellular danger signals known as Danger Associated Molecular Patterns (“DAMPs”) shapes the development of the adaptive antigen-specific response. 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). While TLRs present on the cell surface (e.g., TLR-4) and endosomes (e.g., TLR-9) sense extracellular and vacuolar pathogens, 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 surveillance pathway and may be an effective strategy for the design of innate immune activators for cancer immunotherapy. [0005] 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. For example, 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-1β (Strowig et al., Nature 2012, 481, 278-286). The signaling cascade resulting from activation of the inflammasome stimulates priming of Th17-biased CD4+ T cell immunity, associated with protection against diverse pathogens, such as Streptococcus pneumoniae (Olliver et al., Infect. Immun.2011, 79, 4210-4217). [0006] Type I interferons (IFN-α, IFN-β) are the signature cytokines induced by two distinct TLR- independent cytosolic signaling pathways. In the first pathway, various forms of single-stranded and double-stranded (“ds”) RNA are sensed by RNA helicases, including retinoic acid-inducible gene I (“RIG-I”) and melanoma differentiation-associated gene 5 (“MDA-5”), and through the IFN-β promoter stimulator 1 (“IPS-1”) adaptor protein mediate phosphorylation of the IRF-3 transcription factor, leading to induction of IFN-β (Ireton and Gale, Viruses 2011, 3, 906-919). IPS-1-/- deficient mice have increased susceptibility to infection with RNA viruses. Sensors that signal through the IPS-1 pathway are directly targeted for inactivation by various viral proteins, demonstrating a requirement of this cytosolic host defense pathway to control productive virus infection. 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-β, and is currently being evaluated in several diverse clinical settings (Caskey et al., J. Exp. Med. 2011, 208, 2357-2366). [0007] Stimulator of Interferon Genes (“STING”) 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). Alternatively known as 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-β and NF-κB dependent pro-inflammatory cytokines in response to sensing cytoplasmic DNA (Ishikawa and Barber, Nature 2008, 455, 674-678). Significantly, and of particular relevance to the therapeutic modulation of STING, activation of this pathway occurs in response to sensing host cell DNA in the cytoplasm, originating from the nucleus or the mitochondria, both in a paracrine and autocrine fashion (Chen et al., Nat. Immunol.2016, 17, 1142- 1149). [0008] Recent work has demonstrated that activation of the STING pathway in tumor-resident host APCs is required for induction of a spontaneous CD8+ T cell response against tumor-derived antigens in vivo (Woo et al., Immunity 2014, 41, 830-842; and Corrales et al., J. Clin. Invest.2016, 126, 404-411). In addition, activation of this pathway and the subsequent production of IFN-β contributes to the anti-tumor effect of radiation, which can be potentiated with co-administration of a natural STING agonist (Deng et al., Immunity 2014, 41, 843-852). 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-β 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-κB dependent cytokines are also induced (Chen et al., Nat. Immunol.2016, 17, 1142-1149). IFN-β 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. Med.2009, 206, 1899-1911; Sun et al., Science 2013, 339, 786-791; Woodward et al., Science 2010, 328, 1703-1705; and Zhang et al., Mol. Cell 2013, 51, 226-235). IFNs stimulate expression of interferon-stimulated genes (“ISGs”), a key event that links host innate immunity to the initiation of adaptive immunity. These observations suggested that direct activation of the STING pathway in the TME with specific agonists might be an effective therapeutic strategy to promote broad tumor-initiated T cell priming against an individual’s unique tumor antigen repertoire. [0009] STING is expressed ubiquitously in both immune and somatic cells. Initial clinical approaches to target STING have primarily utilized intratumoral (“IT”) administration of synthetic modified CDNs, to avoid possible toxicity including a cytokine storm or cytokine release syndrome due to expression of high levels of pro-inflammatory cytokines such as IL-6 and TNF-α resulting from broad activation of STING with the systemic administration of potent ligands/agonists. As a single agent, IT injection of CDNs demonstrates potent anti-tumor effects in multiple syngeneic mouse tumor models without significant local or systemic toxicity. Direct IT injection of selected CDNs in established B16 melanoma, CT26 colon, and 4T1 breast carcinomas resulted in rapid and profound tumor regression and promoted lasting systemic antigen-specific T cell immunity (Sivick et al., Cell Rep.2018, 25, 3074-3085; Corrales et al., Cell Rep.2015, 11, 1018-1030; Foote et al., Cancer Immunol. Res.2017, 5, 468-479; and Francica et al., Cancer Immunol. Res.2018, 6, 422-433). In particular, these preclinical investigations demonstrated that tumor-specific CD8+ T cells primed locally in the draining lymph node serving the injected tumor could traffic to and cause the regression of distal non-injected tumors, supporting the scientific rationale for evaluation of STING agonists to treat patients with advanced metastatic cancers. [0010] Distinct metastatic tumors are genetically diverse and have unique antigenic repertoires. In order to grow, proliferate, and spread, tumors evolve to avoid immune recognition via a process known as immunoediting. Silencing or deletion of genes encoding proteins required for antigen presentation can prevent presentation of particular antigens of major histocompatibility complex (“MHC”) class I and class II molecules, hindering recognition by antigen-specific cytolytic T cells and preventing tumor cell death (Mittal et al., Curr. Opin. Immunol.2014, 27, 16-25). 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. Thus, 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. This observation in 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. [0011] There is a need for broad priming of tumor antigen-specific CD4+ and CD8+ T cells in the lymph nodes that serve diverse metastatic tumors that are spread throughout the body of an affected individual with advanced cancer. Efficient systemic delivery of ligands to activate designated innate immune receptors selectively in the tumor microenvironment, but not broadly in extra-tumoral tissues where targeted immune receptors are expressed, is a desired therapeutic outcome. Such selective targeting of designated innate immune receptors in the TME is anticipated to induce desired IRF3- and NF-κB-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. On the other hand, broad non-selective activation of innate immune receptors upon systemic delivery is not desired as high systemic levels of IRF3- and NF-κB-dependent pro-inflammatory cytokines and chemokines such as IFN-β, TNF-α, IFN-γ, IL-12p70, and IL-6 limits tolerability, can result in toxicity, and limits the effectiveness of priming tumor-specific immunity resulting from innate immune activation selectively in the TME. 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). However, because STING is expressed broadly in diverse immune cell and somatic cell populations, an efficient means to target activation of the STING pathway selectively in the TME with a systemically delivered (e.g., orally or intravenously) agent is highly desirable as a therapeutic approach to initiate tumor-antigen specific priming against diverse metastases and effective tumor eradication. While STING is ubiquitously expressed in both immune and somatic cell populations, 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-Goutières 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-β, the signature cytokine of activated STING. At high radiation dose levels, 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-β. In contrast, hyperfractionated radiation (lower dose levels of radiation delivered over multiple doses) does not affect TREX1 levels and leads to significantly higher levels of IFN-β and development of effective anti-tumor immunity and tumor regression (Vanpouille-Box et al., Nature Comm.2017, 8, 15618-15632). However, effective anti-tumor immunity and tumor regression can be optimally achieved when delivery of high- dose radiotherapy administered as a single dose and/or hypofractionated in conjunction with SBRT—to maximize tumor killing and dsDNA levels—is combined with 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). Many advanced cancers exhibit deficient DNA repair, due to mutations in genes encoding proteins involved in various DNA repair pathways, leading to genomic plasticity and, consequently, increased tumor virulence. These mutations also result in increased levels of cytosolic DNA and correspondingly increased levels of TREX1, which in turn sufficiently degrades cytosolic DNA and diminishes the extent of activation of the cGAS-STING pathway. Thus, high levels of TREX1 expression facilitate evasion of immune recognition, and therapeutic intervention with agents that both increase the level of TME cytosolic dsDNA and inhibit TREX1 will result in profound activation of the cGAS-STING pathway and development of effective anti-tumor immunity. BRIEF SUMMARY OF THE INVENTION [0012] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
Figure imgf000007_0002
Formula (I) as defined herein. [0013] Disclosed herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
Figure imgf000007_0001
Formula (Ia) as defined herein. [0014] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [0015] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the cancer is characterized by a DNA repair deficiency in one or more DNA repair pathways. In some embodiments, 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. In some embodiments, the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway. In some embodiments, the DNA repair deficiency is a BRCA1 mutation. In some embodiments, the method further comprises administering a DNA repair inhibitor. In some embodiments, the DNA repair inhibitor is a poly ADP ribose polymerase (“PARP”) inhibitor. In some embodiments, the method further comprises administering an alkylating agent. In some embodiments, the alkylating agent is cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, nimustine, fotemustine, streptozocin, or busulfan. In some embodiments, the method further comprises administering a DNA damaging agent. In some embodiments, the DNA damaging agent is camptothecin, etoposide, oxaliplatin, cisplatin, or doxorubicin. In some embodiments, the compound is administered in conjunction with high-dose radiotherapy. In some embodiments, the high-dose radiotherapy is administered as a single dose and/or hypofractionated. In some embodiments, the compound is administered in conjunction with Stereotactic Body Radiation Therapy (SBRT). INCORPORATION BY REFERENCE [0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION Definitions [0017] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0018] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. [0019] “Oxo” refers to =O. [0020] “Amine” refers to -NH2; [0021] “Hydroxyl” refers to -OH; [0022] “Carboxyl” refers to -COOH. [0023] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1- C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. [0024] “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. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3- butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [0025] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2- butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [0026] “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. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH2, or -NO2. 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. [0027] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0028] “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. [0029] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, 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. [0030] “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., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]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, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, sprio[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0031] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0032] “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. [0033] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above. [0034] “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. [0035] “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. [0036] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [0037] “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. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or 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. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with 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, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, 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. [0038] “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. In some embodiments, 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. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl 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. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, 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. [0039] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. 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. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. 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]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, , isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [0040] 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. In this respect, the disclosed methods can provide any amount of any level of treatment, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, 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. Also, for purposes herein, “treatment,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof. [0041] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study. [0042] 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 [0043] Described herein are compounds that are useful in treating diseases associated with TREX1 and STING dysfunction. In some embodiments, 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. [0044] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: wherein:
Figure imgf000016_0001
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1 on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; R3 is hydrogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -CH2OC(=O)ORb, -CH(CH3)OC(=O)ORb, - C(CH3)2OC(=O)ORb, -CH2OC(=O)Ra, -CH(CH3)OC(=O)Ra, -C(CH3)2OC(=O)Ra, - CH2OP(=O)(ORb)2, -P(=O)(ORb)2, -P(=O)(ORb)(NRb), C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; Ring B is a bicyclic ring; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a; each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R4a on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, 4, or 5; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, - C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. [0045] In some embodiments of a compound of Formula (I), Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I), Ring B is an indole, benzoxazole, benzimidazole, or benzothiazole. In some embodiments of a compound of Formula (I), Ring B is benzimidazole. In some embodiments of a compound of Formula (I), Ring B is an indole. [0046] In some embodiments of a compound of Formula (I), Ring B is bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring B is isoindolinyl, tetrahydroisoquinolinyl, or tetrahydrobenzoazepinyl. In some embodiments of a compound of Formula (I), Ring B is tetrahydroisoquinolinyl. [0047] In some embodiments of a compound of Formula (I), m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I), m is 0, 1, or 2. In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I) or, m is 0. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4. [0048] In some embodiments of a compound of Formula (I), the compound is of Formula (Ia): wherein:
Figure imgf000018_0001
R4’ is hydrogen or R4; and R5 is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a; each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. [0049] In some embodiments of a compound of Formula (Ia), R5 is hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a. In some embodiments of a compound of Formula (Ia), R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a. In some embodiments of a compound of Formula (Ia), R5 is C1-C6alkyl, cycloalkyl, or aryl; wherein the alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R5a. In some embodiments of a compound of Formula (Ia), R5 is C1-C6alkyl or cycloalkyl; wherein the alkyl and cycloalkyl is independently optionally substituted with one or more R5a. In some embodiments of a compound of Formula (Ia), R5 is cycloalkyl optionally substituted with one or more R5a. In some embodiments of a compound of Formula (Ia), R5 is cyclobutyl or bicyclo[1.1.1]pentane. In some embodiments of a compound of Formula (Ia), R5 is cyclobutyl. In some embodiments of a compound of Formula (Ia), R5 is C1-C6alkyl. [0050] In some embodiments of a compound of Formula (Ia), each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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. In some embodiments of a compound of Formula (Ia), each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Ia), each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (Ia), each R5a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Ia), each R5a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (Ia), each R5a is independently halogen or C1-C6alkyl. [0051] In some embodiments of a compound of Formula (I) or (Ia), each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R4a. In some embodiments of a compound of Formula (I) or (Ia), each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, 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 R4a. In some embodiments of a compound of Formula (I) or (Ia), each R4 is independently halogen, -NRcRd, -NRbC(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R4a. In some embodiments of a compound of Formula (I) or (Ia), each R4 is independently heteroaryl independently optionally substituted with one or more R4a. [0052] In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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. In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. [0053] In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia), each R4a is independently halogen or C1-C6alkyl. [0054] In some embodiments of a compound of Formula (I), the compound is of Formula (Ib):
Figure imgf000020_0001
wherein: each R6 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6a; each R6a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R6a on the same atom are taken together to form an oxo; p is 0, 1, 2, or 3; each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R7a; each R7a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; q is 0, 1, or 2. [0055] In some embodiments of a compound of Formula (Ib), each R6 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R6a. In some embodiments of a compound of Formula (Ib), each R6 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 R6a. In some embodiments of a compound of Formula (Ib), each R6 is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6a. In some embodiments of a compound of Formula (Ib), each R6 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R6a. In some embodiments of a compound of Formula (Ib), each R6 is independently aryl optionally substituted with one or more R6a. [0056] In some embodiments of a compound of Formula (Ib), p is 0, 1, or 2. In some embodiments of a compound of Formula (Ib), p is 0 or 1. In some embodiments of a compound of Formula (Ib), p is 0. In some embodiments of a compound of Formula (Ib), p is 1. In some embodiments of a compound of Formula (Ib), p is 2. [0057] In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R7a. In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R7a. In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R7a. In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -C(=O)ORb or -C(=O)NRcRd. In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -C(=O)ORb. In some embodiments of a compound of Formula (Ib), each R7 is independently halogen, -C(=O)NRcRd. [0058] In some embodiments of a compound of Formula (Ib), q is 0, 1, or 2. In some embodiments of a compound of Formula (Ib), q is 0 or 1. In some embodiments of a compound of Formula (Ib), q is 0. In some embodiments of a compound of Formula (Ib), q is 1. In some embodiments of a compound of Formula (Ib), q is 2. [0059] In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is pyridinyl. [0060] In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is pyrazolyl, isoxazolyl, or isothiazolyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Ring A is isoxazolyl. [0061] In some embodiments of a compound of Formula (I), (Ia), or (Ib), each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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. In some embodiments of a compound of Formula (I), (Ia), or (Ib), each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, and heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), or (Ib), each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0062] In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 0, 1, or 2. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 1 or 2. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 0 or 1. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 0. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 1. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 2. In some embodiments of a compound of Formula (I), (Ia), or (Ib), n is 3. [0063] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R2 is hydrogen or C1- C6alkyl. [0064] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R2 is hydrogen. [0065] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is hydrogen or C1- C6alkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is hydrogen. [0066] In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -C(=O)Ra. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -C(=O)ORb. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -C(=O)NRcRd. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -CH2OC(=O)Ra, -CH(CH3)OC(=O)Ra, or -C(CH3)2OC(=O)Ra. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is -CH2OC(=O)ORb, -CH(CH3)OC(=O)ORb, or -C(CH3)2OC(=O)ORb. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is - CH(CH3)OC(=O)ORb. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R3 is - CH2OP(=O)(ORb)2, -P(=O)(ORb)2, or -P(=O)(ORb)(NRb). [0067] In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl. [0068] In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl. [0069] In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, Rc and Rd are each hydrogen. In some embodiments of a compound disclosed herein, Rc and Rd are each independently C1-C6alkyl. [0070] In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [0071] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, - S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1- C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. [0072] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, - S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1- C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, - C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1- C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, or C1-C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1- C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; or two R on the same atom form an oxo. [0073] In some embodiments, 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
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [0074] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds [0075] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. [0076] In some embodiments, 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. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein. [0077] In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method. [0078] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [0079] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [0080] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or 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. [0081] 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-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate. [0082] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’- methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts. [0083] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4 alkyl)4 hydroxide, and the like. [0084] 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 [0085] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0086] 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 [0087] 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. . Preparation of the Compounds [0088] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0089] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0090] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions [0091] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [0092] Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [0093] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0094] 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. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [0095] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. [0096] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Methods of Treatment [0097] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for the inhibition of TREX1. [0098] Provided herein are compounds that are inhibitors of TREX1 and are therefore useful for treating one or more disorders associated with the activity of TREX1 or mutants thereof. [0099] Provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, 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. [00100] In some embodiments, the cancer is a solid tumor malignancy. In some embodiments, 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, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, phyllodes tumor, or inflammatory breast cancer), endocrine system cancer (for example, but not limited to, adrenocortical carcinoma, islet cell carcinoma (endocrine pancreas), multiple endocrine neoplasia syndrome, parathyroid cancer, pheochromocytoma, or thyroid cancer), eye cancer (for example, but not limited to, uveal melanoma or retinoblastoma), gastrointestinal cancer (for example, but not limited to, anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumor, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (gist), hepatocellular cancer, pancreatic cancer, or rectal cancer), genitourinary and gynecologic cancer (for example, but not limited to, bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter, transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterus cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms tumor), head and neck cancer (for example, but not limited to, is esophageal cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, or hypopharyngeal cancer), skin cancer (for example, but not limited to, basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (e.g. sebaceous carcinoma), melanoma, Merkel cell carcinoma, or sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans)), or thoracic and respiratory cancer (bronchial adenomas/carcinoid, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, or thymoma and thymic carcinoma). [00101] TREX1 is a component of the cellular DNA repair mechanism. Treatment of patients with cancers having DNA repair deficiencies (such as BRCA1 mutations) with DNA repair inhibitors (such as poly ADP ribose polymerase (“PARP”) inhibitors) is synergistic due to the dramatically reduced probability of developing resistance against two DNA repair insults; this approach is known as synthetic lethality. Hence, TREX1 inhibitors also possess potential utility as effective synthetic lethality partners in patients with cancers characterized by defective DNA repair. [00102] In some embodiments, the DNA repair deficiency is a deficiency in the base excision repair (“BER”) pathway (such as a PolB mutation). In some embodiments, the DNA repair deficiency is a deficiency in the Fanconi anaemia-mediated repair (“FA”) pathway (such as an FANCA mutation). In some embodiments, the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway (such as a BRCA1 mutation). In some embodiments, the DNA repair deficiency is a deficiency in the nucleotide excision repair (“NER”) pathway (such as an XPA mutation). In some embodiments, the DNA repair deficiency is a deficiency in the non-homologous end joining (“NHEJ”) pathway (such as an MRE11 mutation). In some embodiments, 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). [00103] In some embodiments, the cancer is characterized by a deficiency in one or more DNA repair pathways. In some embodiments, 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. In some embodiments, the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway. In some embodiments, the DNA repair deficiency is a BRCA1 mutation. [00104] Provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering a reversible, non-competitive TREX1 inhibitor. In some embodiments, the cancer is a solid tumor malignancy. In some embodiments, 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. [00105] Provided herein is a method of increasing type I interferon production in a subject in need thereof, the method comprising administering a reversible, non-competitive TREX1 inhibitor. In some embodiments, the increase in type I interferon production occurs in the tumor microenvironment. In some embodiments, the TREX1 inhibitor is administered systemically. In some embodiments, the TREX1 inhibitor comprises a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00106] Provided herein is a method of treating an HIV infection in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. [00107] Human immunodeficiency virus (HIV) is a retrovirus and causative agent of acquired immune deficiency syndrome (AIDS). 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. The 3’ exonuclease activity of TREX1 prevents the accumulation of reverse transcribed HIV-1 DNA to avoid the interferon response. In addition, TREX1 processing of the 3’end of HIV-1 DNA in the pre integration complex is critical for successful HIV-1 integration. In some embodiments, treatment strategies to reduce or inhibit TREX1 promote both antiviral immunity and have direct antiviral effects by reducing productive integration. Combination Therapy [00108] 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. [00109] In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00110] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00111] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit. [00112] In certain embodiments, different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [00113] It is understood that 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). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein. [00114] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially. [00115] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00116] 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. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years. [00117] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). [00118] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with a DNA repair inhibitor. In some embodiments, the DNA repair inhibitor is a poly ADP ribose polymerase (“PARP”) inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, or E7016. [00119] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an alkylating agent. In some embodiments, the alkylating agent is cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, nimustine, fotemustine, streptozocin, or busulfan. [00120] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in conjunction with radiation therapy. In some embodiments, the radiation therapy is administered on a standard fractionation, an accelerated fractionation, a hyperfractionation, or a hypofractionation schedule. [00121] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, increases anti-tumor immunity when combined with radiation therapy. [00122] In some embodiments, 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. [00123] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, improves tumor control when combined with radiation therapy. [00124] In some embodiments, 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. [00125] In some embodiments, the radiation therapy is tumor-directed radiation therapy. In some embodiments, the radiation therapy is metastasis-directed radiation therapy. [00126] In some embodiments 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. In some embodiments, 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 a electron beam. [00127] 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. [00128] 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). IGRT is a type of IMRT using imaging scans not only for treatment planning before radiation therapy sessions but also during radiation therapy sessions. [00129] In some embodiments, 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. [00130] In some embodiments, 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. [00131] In some embodiments, the external beam radiation therapy is stereotactic body radiation therapy (SBRT). Stereotactic body radiation therapy is similar to stereotactic radiosurgery, but it is used for small, isolated tumors outside the brain and spinal cord. [00132] In some embodiments 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. In this type of treatment, seeds, ribbons, or capsules that contain a radiation source are placed in the body, in or near the tumor. Like external beam radiation therapy, brachytherapy is a local treatment and treats only a specific part of your body. [00133] In some embodiments, the brachytherapy is low-dose rate (LDR) implants. [00134] In some embodiments, the brachytherapy is high-dose rate (HDR) implants. [00135] In some embodiments, 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. [00136] In some embodiments, 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. [00137] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in conjunction with Stereotactic Body Radiation Therapy (SBRT). EXAMPLES Example 1: 5-hydroxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N-(1,2 oxazol-4-yl)-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
Figure imgf000046_0001
[00138] Step 1: To a stirred solution of 1-fluoro-2-nitrobenzene (1.43 mL, 14.2 mmol) in a seal tube, methyl amine (7 mL, 158 mmol) was added under a nitrogen atmosphere at ambient temperature and the mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to provide crude N-methyl-2-nitroaniline (2.1 g, 92.5%). ES MS M/Z = 153.2 [M+H]+. [00139] Step 2: To a stirred solution of N-methyl-2-nitroaniline (2 g, 13.1 mmol) in methanol (25 mL) was added palladium 10%w/w (280 mg, 0.02 eq., 0.263 mmol) and the mixture was stirred at ambient temperature with a hydrogen balloon for 3 h. After completion, the reaction mixture was filtered through a celite bed and washed with methanol. The organic layer was concentrated under reduced pressure to provide the product N1-methylbenzene-1,2-diamine (1.8 g, crude).1H NMR (400 MHz, CDCl3) δ ppm 6.90-6.86 (m,1H), 6.76-6.68 (m, 3H), 3.33 ( s, 2H ), 2.53 (s, 1H ), 2.89 (s, 3H). [00140] Step 3: To a stirred solution of N1-methylbenzene-1,2-diamine (350 mg, 2.86 mmol) in DMF (3 mL), was added ethyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (688 mg, 2.86 mmol) followed by a water (30 µL) and oxone (151 mg, 0.491 mmol) mixture. The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction it was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product. The crude was purified by flash column chromatography to afford ethyl 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxylate (340 mg, 33.63%). ES MS M/Z = 343.2 [M+H]+. [00141] Step 4: To a stirred solution of methyl 5-ethoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2- yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (340 mg, 0.993 mmol) in tetrahydrofuran (5 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide (95.1 mg, 4 eq., 3.97 mmol) at ambient temperature and the mixture was stirred for 2 h then concentrated under reduced pressure. The crude was dissolved in water and acidified with 1N HCl to pH~1, and the precipitate was filtered and dried under reduced pressure to afford 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (240 mg, 53.82%). ES MS M/Z = 315.2 [M+H]+. [00142] Step 5: To a stirred solution of 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-6- oxo-1,6-dihydropyrimidine-4-carboxylic acid (240 mg, 0.764 mmol) in DMF (2.5 mL) was added DIPEA (533 µL, 4 eq., 3.05 mmol), 1,2-oxazol-4-amine (107 µL, 2 eq., 1.53 mmol) followed by HATU (581 mg, 2 eq., 1.53 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 8 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated to afford crude product. The crude product was purified by flash column chromatography to afford 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90 mg, 27.9%). ES MS M/Z = 381.2 [M+H]+. [00143] Step 6: To a stirred solution of 5-methoxy-1-methyl-2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90mg, 0.237mmol) in DMF (2 mL, 0.237 mmol) was added lithium bromide (82.2 mg, 4 eq., 0.946 mmol) at ambient temperature. The reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction mixture monitored by TLC and LCMS. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure to provide crude product. Crude was purified by following preparative HPLC method to provide pure product 5-hydroxy-1-methyl- 2-(1-methyl-1H-1,3-benzodiazol-2-yl)-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (3 mg, 3.46%). ES MS M/Z = 367.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm; 11.96 (s, 1H), 11.05 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 7.80 - 7.44 (m, 2H), 7.44 (d, J = 4 Hz, 2H), 4.00 (s, 3H), 3.60 (s, 3H). Example 2: 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl] -6-oxo-1,6- dihydropyrimidin-2-yl}-N-methyl-1H-1,3-benzodiazole-6-carboxamide
Figure imgf000048_0001
[00144] Step 1: To a stirred solution of 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid (0.2 g, 0.444 mmol) in DMF (1 mL) was added DIPEA (232 µL, 3 eq., 1.33 mmol), tripropyl-1,3,5,2λ⁵,4λ⁵,6λ⁵- trioxatriphosphinane-2,4,6-trione 50%v/v (0.4 mL, 1.5 eq., 0.666 mmol) and methylamine (20.7 mg, 1.5 eq., 0.666 mmol) at 0 °C. The reaction mixture was stirred for 3 h at ambient temperature. The progress of the reaction mixture was monitored by TLC and LCMS. After the reaction was complete it was concentrated under reduced pressure to provide crude product. Crude was purified by preparative HPLC to provide 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6- dihydropyrimidin-2-yl}-N-methyl-1H-1,3-benzodiazole-6-carboxamide (7 mg, 3.4%). ES MS M/Z = 464.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (s, 1H)., 8.81 (s, 1H), 8.54 (d, J = 4 Hz, 1H), 8.23 (m, 1H), 7.83 (q, J = 8 Hz, 2H), 5.18-5.11 (m, 1H), 3.27 (s, 3H), 2.18 (s, 3H), 2.66 (d, J = 4 Hz, 2H), 2.44 (d, J = 4 Hz, 2H), 2.22-2.18 (m, 2H). Example 3: 2-(5-(benzylamino)-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol-4- yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000048_0002
[00145] Step 1: To a stirred solution of cyclobutanamine (9.84 mL, 1.2 eq., 115 mmol) in 1- methylpyrrolidin-2-one (150 mL) was added DIPEA (50.2 mL, 3 eq., 288 mmol) and 2-fluoro-5- nitroaniline (15 g, 96.1 mmol). The reaction mixture was stirred at 120 °C for 16 h then quenched with ice water and extracted with EtOAc (3 x 100 mL). The combined organic layer washed with brine, dried over Sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash (20% ethyl acetate\hexane). Pure fractions were concentrated under reduced pressure, to afford the desired product (12 g, 59%). ES MS M/Z= 208.1 [M+H]+. [00146] Step 2: To a solution of N1-cyclobutyl-4-nitrobenzene-1,2-diamine (0.7 g, 3.38 mmol) in methanesulfinylmethane (10 mL) was added methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (840 mg, 1.1 eq., 3.72 mmol) and disodium (sulfinatooxy)sulfinate (963 mg, 1.5 eq., 5.07 mmol). The reaction mixture was stirred at 85 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with EtOAc (3 x 100 mL). The organic layer washed with water, combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by CombiFlash (using gradient elution 30-50% EtOAc- Hexane) to afford methyl2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5-methoxy-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxylate (240 mg, 11% yield ). ES MS M/Z= 414.1 [M+H]+. [00147] Step 3: To a stirred solution of methyl 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (280 mg, 0.677 mmol) in a mixture of methanol (3.5 mL, 86.4 mmol) and tetrahydrofuran (3.5 mL, 43 mmol) was added lithium hydroxide mono-hydrate (85.3 mg, 3 eq., 2.03 mmol) in water (3 mL) and the mixture was stirred at ambient temperature for 1 h. The reaction was monitored by TLC and LCMS. After completion of the reaction it was concentrated, diluted with water, and extracted with the ether, the aqueous layer was acidified using citric acid solution and extracted with the EtOAc. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After concentration 2-(1-cyclobutyl-5-nitro-1H-1,3- benzodiazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (220 mg, 75% yield ) was provided. ES MS M/Z= 400.2 [M+H]+. [00148] Step 4: To a stirred solution of 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (240 mg, 0.601 mmol) in DMF (5 mL ) was added 1,2-oxazol-4-amine hydrochloride (86.9 mg, 1.2 eq., 0.7721 mmol), HATU (457 mg, 2 eq., 1.2 mmol), DIPEA (0.333 mL, 3 eq., 1.8 mmol). The reaction mixture was stirred for 3 h at ambient temperature. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water, extracted with EtOAc ( 3 x 50 mL ), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford crude compound which was purified by flash chromatography (eluted at 45% EA in PE) to yield 2-(1-cyclobutyl-5-nitro- 1H-1,3-benzodiazol-2-yl)-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (180 mg, 38% yield ). ES MS M/Z= 466.2 [M+H]+. [00149] Step 5: To a stirred solution of 2-(1-cyclobutyl-5-nitro-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (150 mg, 0.322 mmol) in methanol (2 mL, 49.4 mmol) and tetrahydrofuran (2 mL, 24.6 mmol) was added palladium on 10% carbon (20 mg, 0.094 mmol) and stirred at ambient temperature under a hydrogen balloon for 1 h .The reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to provide the crude product which was purified by CombiFlash chromatography ( eluted at 6% MeOH in DCM ) to afford 2-(5-amino-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (80 mg, 43% yield ). ES MS M/Z= 436.2 [M+H]+. [00150] Step 6: To a stirred solution of 2-(5-amino-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (70 mg, 0.161 mmol) in 1,2 dichloroethane (7 mL) was added benzaldehyde (24.6 µL, 1.5 eq., 0.241 mmol) and acetic acid (33.3 µL, 3.1 eq., 0.501 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1 h then sodium bis(acetyloxy)boranuidyl acetate (68.1 mg, 2 eq., 0.322 mmol) was added and reaction mixture was stirred at ambient temperature for 16 h during which time the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction mixture was quenched with NaHCO3 solution (4 mL), extracted with 10% MeOH in DCM ( 3 x 10 mL ), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford crude compound. This crude compound washed with n-hexane ( 5 mL ) and dried under reduced pressure to yield 2-[5-(benzylamino)- 1-cyclobutyl-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (0.1 g, 79% yield ). ES MS M/Z= 526.2 [M+H]+. [00151] Step 7: To a stirred solution of 2-[5-(benzylamino)-1-cyclobutyl-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90 mg, 0.171 mmol) in DCM (1.63 mL, 25.4 mmol) was cooled to -40 °C, tribromoborane (88.2 µL, 3 eq., 0.514 mmol) was added and stirred at ambient temperature for 4 h, The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with methanol and concentrated. To the residue was added 10% sodium bicarbonate solution (2 mL) and it was extracted with 10% MeOH in DCM (4 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated to provide crude compound. Crude compound was purified by preparative HPLC to afford 2-[5- (benzylamino)-1-cyclobutyl-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo- 1,6-dihydropyrimidine-4-carboxamide (8.7 mg, 10% yield ). ES MS M/Z = 512.3 [M+H]+, UPLC: 97.6%; 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.01 (s , 1 H ) , 9.271 ( s , 1 H ) , 8.807 ( s , 1 H ) , 7.55 ( d , J = 8.8 Hz , 1 H ) , 7.41- 7.39 (m , 2 H ) , 7.34- 7.30 (m , 2 H ) , 7.22 (d, J = 7.6 Hz , 1 H ) , 6.86 (d, J = 8.8 Hz ,1H), 6.69(d, J = 1.6 Hz, 1 H), 6.21 (bs, 1 H), 5.03-4.99 (m, 1 H), 4.32 (s, 2 H), 3.42 (s, 3 H), 2.33 ( m , 4 H ), 1.82- 1.73 (m, 2 H) . Example 4: 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1-methyl-1H-1,2,3- triazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000051_0001
[00152] Step 1: To a stirred solution of 1-fluoro-2-nitrobenzene (5 g, 35.4 mmol) in 1- methylpyrrolidin-2-one (5 mL) was added DIPEA (18.5 mL, 106 mmol) and cyclobutanamine (3.64 mL, 42.5 mmol). The reaction mixture was heated to 120 ºC for 16 h. After completion of the reaction it was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash column chromatography to afford N-cyclobutyl-2- nitroaniline (6.8 g, 98%). ES MS M/Z=193.1 [M+H]+ . [00153] Step 2: To a stirred solution of N-cyclobutyl-2-nitroaniline (6.8 g, 35.4 mmol) in methanol (25 mL) was Palladium on 10% carbon (0.1 g, 0.940 mmol) and the mixture was stirred at ambient temperature under a hydrogen balloon for 3 h. After completion of the reaction the mixture was filtered through a celite bed. The celite pad washed with methanol. The organic layer was filtered and concentrated under reduced pressure to provide N1-cyclobutylbenzene-1,2-diamine (5.6 g, 98%). ES MS M/Z=163.3 [M+H]+ . [00154] Step 3: To a stirred solution of N1-cyclobutylbenzene-1,2-diamine (3.2 g, 19.72 mmol) in dry DMF (48 mL), pyridine (4.76 mL, 59.2 mmol) and dichloro-1λ⁴,2,3-dithiazol-1-ylium chloride (4.52 g, 21.6 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash column chromatography to afford 1-cyclobutyl-1H-1,3- benzodiazole-2-carbonitrile (1.2 g, 31%). ES MS M/Z=198.1 [M+H]+. Step 4: 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) at ambient temperature. The mixture was stirred at ambient temperature for 2 h. The mixture was concentrated to afford 1-cyclobutyl-N-hydroxy-N-methyl- 1H-1,3-benzodiazole-2-carboximidamide (1.2 g, crude) ES MS M/Z=245.2 [M+H]+. [00155] Step 5: To a stirred solution of 1-cyclobutyl-N-hydroxy-N-methyl-1H-1,3-benzodiazole-2- carboximidamide (1.2 g, 4.91 mmol) in methanol (15 mL) and water (6 mL), 1,4-dimethyl but-2- ynedioate (0.963 L, 7.86 mmol) was added, and the mixture was stirred at ambient temperature for 5 h. The reaction mixture was concentrated under reduced pressure to provide the crude product which was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash column chromatography to afford methyl 3-(1-cyclobutyl- 1H-1,3-benzodiazol-2-yl)-5-(2-methoxy-2-oxoethyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazole-5- carboxylate (1.4 g, 59%). ES MS M/Z=387.2 [M+H]+. [00156] Step 6: To a stirred solution of methyl 3-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-(2- methoxy-2-oxoethyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazole-5-carboxylate (1.4 g, 3.62 mmol) 1,4- xylene (10 mL, 81 mmol) was added and the mixture was stirred at 145 °C for 10 h. After completion, the reaction mixture was concentrated under reduced pressure to provide the crude product. The crude washed with pentane 5X and dried under reduced pressure to provide methyl 2-(1-cyclobutyl-1H-1,3- benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (850 mg, 66%). ES MS M/Z=355.0 [M+H]+. [00157] 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 (0.75 g, 2.12 mmol) in tetrahydrofuran (5 mL, 61.4 mmol) and methanol (5 mL, 123 mmol) was added and sodium hydroxide (0.254 g, 3 eq., 6.35 mmol) in water (5 mL, 278 mmol) at ambient temperature. The reaction mixture was heated at 50 °C for 3 h. The reaction mixture was concentrated and acidified with 1N HCl to pH~5 then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-(1- cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.570 g, 79.1%). ES MS M/Z=341.0 [M+H]+. [00158] 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 (0.2 g, 0.588 mmol) in DMF (2 mL, 25.8 mmol), HATU (0.447 g, 1.18 mmol), DIPEA (0.154 mL, 0.881 mmol) and 2-aminophenol (0.083 mg, 0.764 mmol) was added and the mixture was stirred at 100 °C for 48 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by preparative-TLC (70% EtOAc in hexane) followed by preparative HPLC to afford 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-N-(2-hydroxyphenyl)-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxamide (0.008 g, 3%). ES MS M/Z=432.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 9.95 (bs, 1 H), ), 8.19 (d, J = 8 Hz, 1 H), 7.92 (d, J = 8 Hz, 1 H), 7.81 (d, J = 8 Hz, 1 H), 7.44 - 7.35 (m, 2 H), 7.03 - 7.0 (m, 1 H), 6.93 - 6.85 (m, 2 H), 5.23 - 5.31 (m, 1 H), 3.59 (s, 3 H), 2.67 - 2.76 (m, 2 H), 1.96 - 1.79 (m, 2 H). [00159] The following compounds were synthesized in a similar manner: Example 39: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-N-(1-methyl-1H- 1,2,3-triazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00160] MS(ESI)m/z: 421.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.81 (bs, 1 H), 8.16 (s, 1 H), 7.71 (m, 2 H), 7.34 - 7.26 (m, 2 H), 7.10 (bs, 1 H), 5.15 - 5.11 (m, 1 H), 3.96 (s, 3 H), 3.25 (s, 3 H), 2.67 (s, 2 H), 2.07 (s, 2 H), 1.84 - 1.74 (m, 2 H). Example 32: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-N-(1-methyl-1H- pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00161] ES MS M/Z = 420.15 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (brs, 1H), 7.37-7.28 (m, 2H), 7.12 (brs, 1H), 5.15-5.10 (m, 1H), 3.43 (s, 3H), 3.79 (s, 3H), 3.39 (s, 3H), 2.59-2.32 (m, 4H), 1.83-1.75 (m, 2H). Example 33: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(5- oxopyrrolidin-3-yl)-1,6-dihydropyrimidine-4-carboxamide [00162] ES MS M/Z=423 [M+H]+; NMR (400 MHz, DMSO-d6): δ 12.70 (s, 1H), 9.16(s, 1H), 7.85- 7.83 (d, J = 7.6 Hz, 1H), 7.77-7.75 (d, J = 8.8 Hz, 1H), 7.63 (s,1H), 7.36 (m, 2H) ,5.16 (m, 1H), 4.68 (m,1H), 3.32 (s, 3H), 2.40 (s, 1H), 2.36 (s, 2H), 1.82 (s, 2H). Example 34: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-N-(1-methyl-5- oxopyrrolidin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00163] ES MS M/Z = 437.25 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 9.24 (s, 1H), 7.83 ( d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.39-7.30 (m, 2H), 5.17-5.09 (m, 1H), 4.60 (s, 1H), 3.67-3.63 (m, 1H), 5.49 (s, 1H), 3.43 (s, 3H), 3.28-3.26 (m, 1H), 2.68-2.66 (m, 3H), 2.62-.255 (m, 2H), 1.89-1.72 (m, 2H). Example 35: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(pyridazin-4- yl)-1,6-dihydropyrimidine-4-carboxamide [00164] ES MS M/Z=418.25 [M+H)]+; 1H NMR (400 MHz, DMSO-d6) δ 11.92 (bs, 1H), 9.13 (s, 2H), 8.91 (s, 1H), 7.84-7.82 (d, J =8.0 Hz, 1H), 7.77-7.75 (d, J =8.0 Hz 1H), 7.39-7.30 (m, 2H), 6.52 (s, 1H), 5.21-5.12 (m, 1H), 3.45 (s, 3H), 2.66-2.32 (m, 4H) 1.86-1.76 (m, 4H). Example 38: 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-5-carboxamide [00165] ES MS M/Z = 447.25 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.04 (d, J = 2.4 Hz, 6.4 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.39-7.30 (m, 2H), 6.83 (d, J = 9.2 Hz, 1H), 5.21-5.12 (m, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 2.64-2.38 (m, 4H), 1.85-1.78 (m, 2H). Example 40: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(1H-pyrazol- 4-yl)-1,6-dihydropyrimidine-4-carboxamide [00166] ES MS M/Z=438.20 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.85 (bs, 1H), 12.17 (bs, 1H), 7.73-7.70 (t, J = 12.0 Hz, 2H), 7.52-7.50 (d, J =8.0 Hz, 4H), 7.32 (s, 2H), 7.25-7.22 (t, J =12.0 Hz, 4H), 7.13-7.09 (t, J = 16.0 Hz, 2H), 5.84 (s, 1H), 3.75 (s, 3H), 2.50 (s, 3H). Example 5: 2-(1-cyclobutyl-6-(oxazol-2-yl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol-4-yl)- 1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000054_0001
[00167] Step 1: To a stirred solution of 3-fluoro-4-nitrobenzoic acid (2.5 g, 13.5 mmol) in DMF (10 mL) was added N-(2,2-dimethoxyethyl)-3-fluoro-4-nitrobenzamide (3.3 g, 11.9 mmol), DIPEA (7.08 mL, 3 eq., 40.5 mmol) and tripropyl-1,3,5,2λ⁵,4λ⁵,6λ⁵-trioxatriphosphinane-2,4,6-trione (12.9 mL, 3 eq., 40.5 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography to afford N-(2,2- dimethoxyethyl)-3-fluoro-4-nitrobenzamide (3.3 g, 88%). LC-MS(ES) m/z: 271.1 [M-1]. [00168] Step 2: To a stirred solution N-(2,2-dimethoxyethyl)-3-fluoro-4-nitrobenzamide (2.3 g, 8.45 mmol) in methanesulfonic acid (5.49 mL, 10 eq., 84.5 mmol) was added phosphoruspentoxide (5.28 g, 2.2 eq., 18.6 mmol) at 0 °C and the mixture was stirred at 140 °C for 7 h. After completion of the reaction ice cold water was added and the mixture was extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash column chromatography to afford 2-(3-fluoro-4- nitrophenyl)-1,3-oxazole (1.49 g, 59%). LC-MS (ES) m/z: 230.2 [M+H]+. [00169] Step 3: To a stirred solution of 2-(3-fluoro-4-nitrophenyl)-1,3-oxazole (1.49 g, 7.16 mmol) in 1-methylpyrrolidin-2-one (8 mL) was added DIPEA (3.75 mL, 3 eq., 21.5 mmol) and cyclobutanamine (672 µL, 1.1 eq., 7.87 mmol) at ambient temperature. The reaction mixture was stirred at 120 °C for 4 h. After completion of the reaction it was quenched with ice water and extracted in ethyl acetate. Organic layer washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide crude product which was purified by flash column chromatography to afford N-cyclobutyl-2- nitro-5-(1,3-oxazol-2-yl) aniline (1.3 g, 69%). LC-MS(ES) m/z: 260.2 [M+H]+. [00170] Step 4: To a stirred solution of N-cyclobutyl-2-nitro-5-(1,3-oxazol-2-yl)aniline (970 mg, 3.74 mmol) in methanol (10 mL) was added palladium 10% w/w (199 mg) and the mixture was stirred at ambient temperature under a hydrogen balloon for 4 h. After completion, the reaction mixture was filtered through a celite bed and washed with methanol. The organic layer was filtered and concentrated under reduced pressure to provide the crude product N1-cyclobutyl-5-(1,3-oxazol-2-yl)benzene-1,2- diamine (0.9 g, 92.33%). LC-MS(ES) m/z: 230.2 [M+H]+. [00171] Step 5: To a stirred solution of N1-cyclobutyl-5-(1,3-oxazol-2-yl)benzene-1,2-diamine (0.5 g, 2.18 mmol) and methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (592 mg, 1.2 eq., 2.62 mmol) in DMSO (2 mL) was added disodium (sulfinatooxy)sulfinate (829 mg, 2 eq., 4.36 mmol) at ambient temperature, The reaction mixture was heated at 80 °C for 16 h. After completion, the reaction was diluted with water and extracted with EtOAc (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated to afford crude product. The crude was purified by flash column chromatography to afford methyl 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 50%). LC-MS(ES) m/z: 436.1 [M+H]+. [00172] Step 6: To a stirred solution of methyl 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.459 mmol) in mixture of methanol (5 mL), tetrahydrofuran (3 mL) and water (2 mL) was added lithium hydroxide (55 mg, 5 eq., 2.3 mmol) and the mixture was stirred at ambient temperature for 2 h. After completion of the reaction it was concentrated. The crude was diluted with water and the pH was adjusted to ~2 with 1N HCl. The aqueous layer was extracted with EtOAc (50 mL x 3) and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo to afford 2-[1-cyclobutyl-6-(1,3- oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (95 mg, 49%). LC-MS(ES) m/z: 422.0 [M+H]+. [00173] Step 7: To a stirred solution of 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (95 mg, 0.225 mmol) in DMF (2 mL) was added 1,2-oxazol-4-amine (28.4 mg, 1.5 eq., 0.338 mmol) HATU (171 mg, 2 eq., 0.451 mmol) and DIPEA (0.118 mL, 3 eq., 0.676 mmol). The mixture was stirred at ambient temperature for 16 h. After completion, the reaction was diluted with water and extracted with EtOAc (50 mL x 3). The organic layer was dried over sodium sulfate and evaporated under vacuo to afford crude 2-[1-cyclobutyl- 6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (0.1 g, 82%). LC-MS(ES) m/z: 488.0 [M+H]+. [00174] Step 8: To a solution of 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (90 mg, 0.185 mmol) in DCM (10 mL) at -60 °C was added tribromoborane (87.6 µL, 5 eq., 0.923 mmol) drop-wise then the reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was basified with sodium bicarbonate solution and the organic layer was extracted using DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude was purified by CombiFlash (using gradient elution DCM- Methanol) to afford 2-[1-cyclobutyl-6-(1,3-oxazol-2-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl- N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (10 mg, 11%). LC-MS(ES) m/z: 474.2 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ ppm: 13.15 (s, 2H), 9.21 (s, 1H), 8.82 (s, 1H), 8.27 (d, J = 8.0 Hz, 2H),7.94-7.88 (d, J = Hz, 2H), 7.42 (s, 1H), 5.23 (s, 1H), 3.51 (s, 3H), 1.82 (s, 2H), 1.24 (s, 4H). Example 6: Synthesis of 1-cyclobutyl-N-(2,2-difluoroethyl)-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxamide; acetic acid
Figure imgf000056_0001
[00175] Step 1: To a stirred solution of 3-fluoro-4-nitrobenzoic acid (1 g, 5.4 mmol) in DCM (15 mL) was added N, N-dimethylpyridin-4-amine (0.1 g, 0.819 mmol) and t-butyl alcohol (2.05 mL., 21.6 mmol) followed by N, N'-dicyclohexyl methanediimine (1.34 g, 6.48 mmol) at 0 °C and the mixture as stirred at ambient temperature for 16 h. The reaction mixture was basified with saturated sodium hydroxide solution then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product. The crude was purified by flash column chromatography to afford tert-butyl 3-fluoro-4-nitrobenzoate (0.6 g, 45%). ES MS M/Z =241.1 [M+H]+. [00176] Step 2: To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (5 g, 20.7 mmol) in 1- methylpyrrolidin-2-one (0.3 mL) was added DIPEA (10.8 mL, 62.2 mmol) and cyclobutanamine (2.12 mL, 24.9 mmol) at r.t and the mixture was stirred at 130 °C for 16 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude was purified by flash column chromatography to afford tert-butyl 3-(cyclobutylamino)-4-nitrobenzoate (5.5 g, 91%). ES MS M/Z= 293 [M+H]+. Step 3: To a stirred solution of tert-butyl 3-(cyclobutylamino)-4-nitrobenzoate (5.5 g, 18.8 mmol) in methanol (50 mL) was added palladium on 10% carbon (0.5 g, 4.7 mmol) and the mixture was stirred at ambient temperature under a hydrogen balloon for 6 h. The reaction mixture was filtered through a celite bed and washed with methanol. The organic layer was filtered and concentrated under reduced pressure to afford crude tert-butyl 4-amino-3-(cyclobutylamino) benzoate (5 g, 98%). ES MS M/Z=263.2 [M+H]+. [00177] Step 4: To a stirred solution of tert-butyl 4-amino-3-(cyclobutylamino) benzoate (4.6 g, 17.5 mmol) in THF (40 mL) was added pyridine (4.24 mL, 52.6 mmol) and dichloro-1λ⁴,2,3-dithiazol-1-ylium chloride (4.75 g, 22.8 mmol) at 0 °C and the mixture was stirred at ambient temperature for 3 h. After completion, the reaction mixture was combined and concentrated, purified by CombiFlash to afford tert- butyl 2-cyano-1-cyclobutyl-1H-1,3-benzodiazole-6-carboxylate (1.57 g, 27%). ES MS M/Z=298.2 [M+H]+. [00178] Step 5: To a stirred solution of tert-butyl 2-cyano-1-cyclobutyl-1H-1,3-benzodiazole-5- carboxylate (1.57 g, 5.28 mmol) in methanol (19.6 mL, 484 mmol) and water (7.85 mL, 436 mmol) was added sodium carbonate (0.336 g, 3.17 mmol) and N-methyl hydroxylamine chloride (0.617 g, 7.39 mmol) at ambient temperature The mixture was stirred at 80 °C for 6 h. The mixture was then concentrated and quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to afford tert-butyl 1-cyclobutyl-2-(N-hydroxy-N-methylcarbamimidoyl)-1H-1,3- benzodiazole-5-carboxylate (1.8 g, 93%). ES MS M/Z=345.2 [M+H]+. [00179] Step 6: To a stirred solution of tert-butyl 1-cyclobutyl-2-(N-hydroxy-N- methylcarbamimidoyl)-1H-1,3-benzodiazole-6-carboxylate (1.8 g, 5.23 mmol) in methanol (18 mL) and water (18 mL) was added 1,4-dimethyl but-2-ynedioate (0.704 mL, 5.75 mmol) at r.t and stirred for 1 h. The reaction mixture diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried with sodium sulfate and concentrated under pressure to provide crude product. The crude product was purified by flash column chromatography to afford tert-butyl 1-cyclobutyl-2-[5-(2- methoxy-2-oxoethyl)-5-(methoxycarbonyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazol-3-yl]-1H-1,3- benzodiazole-6-carboxylate (1.6 g, 59%). ES MS M/Z=487.3 [M+H]+. [00180] Step 7: A mixture of tert-butyl 1-cyclobutyl-2-[5-(2-methoxy-2-oxoethyl)-5- (methoxycarbonyl)-2-methyl-2,5-dihydro-1,2,4-oxadiazol-3-yl]-1H-1,3-benzodiazole-6-carboxylate (0.6 g, 1.23 mmol) and 1,3-xylene (3 mL) was stirred at 145 °C for 6 h. After completion, the solvent was evaporated under reduced pressure to provide crude product which was purified by preparative TLC to afford tert-butyl 1-cyclobutyl-2-[5-hydroxy-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin- 2-yl]-1H-1,3-benzodiazole-6-carboxylate (0.2 g, 35% ). ES MS M/Z=455.2 [M+H]+. [00181] Step 8: To a stirred solution of tert-butyl 1-cyclobutyl-2-[5-hydroxy-4-(methoxycarbonyl)-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (0.110 g, 0.242 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.030 g, 0.726 mmol) at ambient temperature and the mixture was stirred for 16 h. After completion, the mixture was concentrated under reduced pressure. The crude was dissolved in water and acidified with saturated citric acid solution up to pH~2. The precipitate was filtered and dried under reduced pressure to afford 2-{6-[(tert-butoxy) carbonyl]-1-cyclobutyl-1H-1,3-benzodiazol-2-yl}-5- hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 91%). ES MS M/Z=441.2 [M+H]+. [00182] Step 9: To a stirred solution of 2-{6-[(tert-butoxy) carbonyl]-1-cyclobutyl-1H-1,3- benzodiazol-2-yl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 0.227 mmol) and 1,2-oxazol-4-amine (0.022 mg, 0.272 mmol) in DMF(1 mL) was added N, N-diisopropyl ethylamine (0.098 mL, 0.568 mmol) and [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (0.104 g, 0.272 mmol) at ambient temperature and the mixture was stirred for 16 h. The reaction mixture was diluted with DCM and washed with water. The combined organic layers were dried with sodium sulfate and concentrated to afford crude. The crude compound was purified by preparative TLC to afford tert-butyl 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylate (0.060 g, 42%). ES MS M/Z=507.2 [M+H]+. [00183] Step 10: A mixture of tert-butyl 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylate (0.06 g, 0.118 mmol) and TFA (0.5 mL) was stirred at 0 °C for 3 h. The reaction mixture concentrated and washed with n- pentane to provide 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6- dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid; trifluoroacetic acid salt (0.03 g). ES MS M/Z=451.2 [M+H]+. [00184] Step 11: To a stirred solution of 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid; trifluoroacetic acid (0.075 g, 0.133 mmol) and 2,2-difluoroethan-1-amine (0.012 mL, 0.173 mmol) in N, N-DMF (1 mL) was added N, N-diisopropyl ethylamine (0.0116 mL, 0.664 mmol) and [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (0.101 g, 0.266 mmol) at ambient temperature The reaction mixture was stirred at ambient temperature for 16 h. To the reaction mixture water was added and it was extracted with 10% methanol in DCM. The combined organic layer was dried with sodium sulfate and concentrated to provide crude. The crude compound was purified by preparative HPLC to afford 1-cyclobutyl-N-(2,2-difluoroethyl)-2-{5-hydroxy- 1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6- carboxamide; acetic acid (0.007 g, 15%). ES MS M/Z=514.3 [M+H]+.1HNMR (400MHz, DMSO-d6): δ ppm 13.51 (s, 1 H), 9.17 (s, 1 H), 8.96 (t, J = 5.6 Hz, 1 H), 8.81 (s, 1 H), 8.25 (s, 1 H), 7.85 - 7.83 (d, J = 8.8 Hz, 1 H), 7.79 - 7.76 (d, J = 8.4 Hz, 1 H), 7.09 (bs, 2 H), 6.17 (m, 1 H), 5.16 (m, 1 H), 3.75 (m, 2 H), 3.42 (s, 3 H), 2.6 (m, 3 H), 1.8 (m, 2 H). Example 7: Synthesis of 2-(1-cyclobutyl-5-acetamido-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1- Methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000059_0001
[00185] Step 1: To a stirred solution of 2-(5-amino-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy- 1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.050 g, 0.115 mmol) and acetic acid (0.131 mL, 0.230 mmol) in DMF (2 mL) was added HATU (0.087 g, 0.230 mmol), DIPEA (0.064 mL, 0.344 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was quenched with sodium bicarbonate, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford 2-(1-cyclobutyl-5-acetamido-1H-1,3- benzodiazol-2-yl)-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (0.07 g, 99%) ES MS M/Z=478.2 [M+H]+. [00186] Step 2: To a stirred solution of 2-(1-cyclobutyl-5-acetamido-1H-1,3-benzodiazol-2-yl)-5- methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.060 g, 0.126 mmol) in DCM (2 mL) at -40 °C was added tribromoborane (0.064 mL, 0.377 mmol) and stirred at ambient temperature for 16 h. After completion, the reaction mixture was cooled to 0 °C and quenched with methanol. The reaction mixture was then filtered through celite bed and washed with methanol. The filtrate was concentrated to provide crude product which was purified by preparative HPLC to afford 2- (1-cyclobutyl-5-acetamido-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo- 1,6-dihydropyrimidine-4-carboxamide (0.011 g, 19%).1HNMR (400MHz, DMSO-d6): δ ppm 12.06 (bs, 1 H), 11.10 (bs, 1 H), 10.01 (s, 1 H), 9.28 (s, 1 H), 8.81 (s, 1 H), 8.14 (s, 1H), 7.79 - 7.76 (d, J = 9.2 Hz, 1 H), 7.49 - 7.47 (d, J = 8.8 Hz, 1 H), 5.11 (m, 1 H), 3.44 (s, 3 H), 2.60 (m, 2 H), 2.40 (m, 2 H), 2.07 (s, 3 H), 1.8 (m, 2 H). ES MS M/Z=464.3 [M+H]+. [00187] The following compound was synthesized in a similar manner: Example 12: 2-(1-cyclobutyl-6-acetamido-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00188] ES MS M/Z=464.3 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s,1H), 11.11 (s,1H), 9.96 (s,1H), 9.29 (s,1H), 8.81 (s,1H), 8.059 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 5.16-5.07 (m, 1H), 3.44 (s ,1H), 2.67-2.51 (m, 2H), 2.42-2.32 (m, 2H), 2.17 (s, 3H), 1.90-1.82 (m, 2H). Example 8: Synthesis of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5- hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000060_0001
[00189] Step 1: A mixture of 4-bromo-2-fluoro-1-nitrobenzene (4 g, 18.2 mmol) in 1-methylpyrrolidin- 2-one (25 mL) was added DIPEA (7.34 mL, 3 eq., 54.5 mmol) and cyclobutanamine (1.29 mL, 1.1 eq., 15 mmol) at ambient temperature, The reaction mixture was heated at 120 °C for 12 h. After cooling to ambient temperature the reaction mixture was poured into ice cold water and filtered through Celite to provide crude 5-bromo-N-cyclobutyl-2-nitroaniline (3 g, 61%). ES MS M/Z =273.0 [M+2]. [00190] Step 2: To a stirred solution of 5-bromo-N-cyclobutyl-2-nitroaniline (2 g, 7.38 mmol) in DMF (21.1 mL, 272 mmol) was added 1H-1,2,4-triazole (611 mg, 1.2 eq., 8.85 mmol) and potassium phosphate (3.13 g, 2 eq., 14.8 mmol) and the reaction mixture degassed with N2 for 5 min then copper iodide (281 mg, 0.2 eq., 1.48 mmol) was added and the mixture was stirred at 100 °C for 1 h in microwave. The reaction mixture was diluted with water, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to provide N-cyclobutyl-2-nitro-5-(1H-1,2,4-triazol-1-yl)aniline (1.6 g, 84%). ES MS M/Z =260.2 [M+H]+. [00191] Step 3: To a stirred solution of N-cyclobutyl-2-nitro-5-(1H-1,2,4-triazol-1-yl)aniline (1.6 g, 6.17 mmol) in methanol (30 mL) was added 10% Pd/C (328 mg, 0.5 eq., 3.09 mmol) under a N2 atmosphere. The reaction mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h. After completion, the reaction mixture was passed through celite and the filtrate was concentrated under vacuum to afford N1-cyclobutyl-5-(1H-1,2,4-triazol-1-yl)benzene-1,2-diamine (1.3 g, 92%). ES MS M/Z =230.2 [M+H]+. [00192] Step 4: To a solution of N1-cyclobutyl-5-(1H-1,2,4-triazol-1-yl)benzene-1,2-diamine (340 mg, 1.48 mmol), methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (503 mg, 1.5 eq., 2.22 mmol), DMSO ( 10 ml) and disodium (sulfinatooxy)sulfinate (423 mg, 1.5 eq., 2.22 mmol) was stirred at 60 °C for 12 h. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with Ethyl acetate. The organic layer washed with water, dried over sodium sulfate, and concentrated. The crude compound was purified by silica gel chromatography to afford methyl 2-[1- cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (0.2 g, 31%). ES MS M/Z =436.2 [M+H]+. [00193] Step 5: To a stirred solution of methyl 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.459 mmol) in methanol (1.76 mL, 43.6 mmol) and tetrahydrofuran (1.76 mL, 21.7 mmol) was added a solution of lithium hydroxide (33 mg, 3 eq., 1.38 mmol) in water (1.76 mL, 98 mmol) and the mixture was stirred at ambient temperature for 2 h. After completion of the reaction, the mixture was diluted with water then extracted with diethyl ether (2 X 20 ml). Then reaction mixture was acidified with 1N HCl to pH~2 and extracted with ethyl acetate (2 X 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 2-[1- cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (150 mg, 78%). ES MS M/Z =422.2 [M+H]+. [00194] Step 6: To a stirred solution of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (60 mg, 0.142 mmol) in DMF (5 mL) was added DIPEA (0.248 mL, 10 eq., 1.42 mmol) and 1,2-oxazol-4-amine (14.4 mg, 1.2 eq., 0.171 mmol) followed by HATU (108 mg, 2 eq., 0.285 mmol) at ambient temperature and the mixture was stirred for 16 h. The reaction mixture diluted with DCM and washed with water. The combined organic layers were dried with sodium sulfate and concentrated to afford 2-[1-cyclobutyl-6-(1H-1,2,4- triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (60 mg, 87%). ES MS M/Z =488.2 [M+H]+. [00195] Step 7: A stirred solution of 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2- yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (60 mg, 123 µmol) in DCM (5 mL, 78.1 mmol) was cooled to -40 °C, tribromoborane (58.4 µL, 5 eq., 0.615 mmol) was added and the mixture was stirred at ambient temperature for 3 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with water and sodium bicarbonate slowly then reaction the mixture was diluted with DCM, dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by preparative HPLC to afford 2-[1-cyclobutyl-6-(1H-1,2,4-triazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (9 mg, 15%). ES MS M/Z =474.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.40 (s ,1H), 9.24 (s,1H), 8.82 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.82-7.93 (m, 2H), 5.15-5.20 (m, 1H), 3.16-3.43 (m, 3H), 2.33-2.67 (m, 4H), 1.78-1.85 (m, 2H). Example 9: 1-(bicyclo[1.1.1]pentan-1-yl)-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo- 1,6-dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxamide
Figure imgf000062_0001
[00196] Step 1: To a solution of 3-fluoro-4-nitrobenzoic acid (5 g, 27 mmol) in DCM (75 mL, 1.17 mol) was added DMAP (0.5 g, 4.09 mmol) and t-butyl alcohol (10.3 mL, 4 eq., 108 mmol) followed by DCC (6.69 g, 1.2 eq., 32.4 mmol) at 0 °C and the resulting mixture stirred at ambient temperature for 16 h. The reaction mixture was basified with sat. NaOH solution, then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product which was purified by flash column chromatography to afford tert-butyl 3-fluoro-4-nitrobenzoate (2.4 g, 36%). 1H NMR (400MHz, CDCl3): δ ppm 8.27(m.1 H), 7.98 (m, 1 H), 7.92 (m, 1 H), 1.57 (s, 9 H). [00197] Step 2: To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (9 g, 37.3 mmol) in DMF(50 mL) was added DIPEA (19.5 mL, 3 eq., 112 mmol) and bicyclo[1.1.1]pentan-1-amine (4.03 g, 1.3 eq., 48.5 mmol) was added at ambient temperature and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and the reaction mixture was concentrated under reduced pressure to provide the crude product. The crude product was purified by flash chromatography. The desired fractions were concentrated to afford tert-butyl 3-({bicyclo[1.1.1]pentan-1-yl}amino)-4-nitrobenzoate (8 g, 66%). ES MS M/Z = 305.1 [M+H]+. [00198] Step 3: To a stirred solution of tert-butyl 4-amino-3-({bicyclo[1.1.1]pentan-1- yl}amino)benzoate (1 g, 3.64 mmol) in methanesulfinylmethane (15 mL) was added methyl 2-formyl-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (989 mg, 1.2 eq., 4.37 mmol) and disodium (sulfinatooxy)sulfinate (2.08 g, 3 eq., 10.9 mmol). The reaction was stirred at 80 °C for 12 h. After completion, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography. The desired fractions were concentrated to afford tert-butyl 1-{bicyclo[1.1.1]pentan-1-yl}-2-[5-methoxy-4-(methoxycarbonyl)-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (650 mg, 37%). ES MS M/Z = 481.1 [M+H]+. [00199] Step 4: To a solution of tert-butyl 1-{bicyclo[1.1.1]pentan-1-yl}-2-[5-methoxy-4- (methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (650 mg, 947 µmol) in a mixture of methanol (4 mL, 98.7 mmol) and tetrahydrofuran (4 mL, 49.1 mmol) was added lithium hydroxide mono-hydrate (199 mg, 5 eq., 4.73 mmol) in water (2 mL) and the mixture was stirred at ambient temperature for 1 h. The reaction was monitored by TLC. After completion, the mixture was concentrated, diluted with water, and extracted with the ether. The aqueous layer was acidified using citric acid solution and extracted with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to provide product (0.5 g, crude). ES MS M/Z = 467.2 [M+H]+. [00200] Step 5: To a solution of 2-(1-{bicyclo[1.1.1]pentan-1-yl}-6-[(tert-butoxy)carbonyl]-1H-1,3- benzodiazol-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.5 g, 0.890 mmol) in DMF were added HATU (677 mg, 2 eq., 1.78 mmol), DIPEA (0.493 mL, 3 eq., 2.67 mmol) and 1,2-oxazol-4-amine hydrochloride (161 mg, 1.5 eq., 1.33 mmol). The reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice water, extracted with the ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide crude product which was purified using CombiFlash to afford tert-butyl 1-{bicyclo[1.1.1]pentan-1-yl}-2-{5-methoxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylate (0.28 g, 473 µmol) (0.28 g, 53%). ES MS M/Z = 533.2 [M+H]+. [00201] Step 6: To a stirred solution of tert-butyl 1- {bicyclo [1.1.1] pentan-1-yl}-2-{5-methoxy-1- methyl-4-[(1,2-oxazol-4-yl) carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6- carboxylate (280 mg, 0.526 mmol) in DCM (5 mL) was cooled to -40 °C, tribromoborane (0.451 mL, 5 eq., 2.63 mmol) was added and stirred at ambient temperature for 16 h. After completion, the reaction mixture was cooled to 0 °C and quenched with methanol slowly and the crude was concentrated completely to provide crude product which was purified by preparative HPLC (Column: Sunfire C18 (19 X250) mm ; Mobile phase (A) : 0.1% TFA in water, Mobile phase (B) : Acetonitrile, Flow rate : 19 ml/min) to afford 1-{bicyclo[1.1.1]pentan-1-yl}-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid; trifluoroacetic acid (0.024 g, 8%). LCMS(ESI) m/z: 463.2 [M+H]+; 1HNMR (400 MHz, DMSO-d6): δ ppm 2.34 (s, 6 H), 2.64 (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.97 - 7.99 (m, 1 H), 8.37 (s, 1 H), 8.81 (s, 1H), 9.29 (s, 1 H), 11.15 (s, 1 H), 12.23 (bs, 1 H), 13.10 (bs, 1H). [00202] Step 7: To a solution of 1-{bicyclo[1.1.1]pentan-1-yl}-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol- 4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid (80 mg, 0.173 mmol) and ammonium chloride (18.5 mg, 2 eq., 0.346 mmol) in DMF (3 mL) was added HATU (132 mg, 2 eq., 0.346 mmol), DIPEA (95.8 µL, 3 eq., 0.519 mmol). The reaction mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with ice water and extracted with the ethyl acetate, the combined organic layer washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide crude product. The crude compound was purified by preparative HPLC using analytical conditions: Column: X-Bridge C-18(250 mm X 4.6 mm X 5 mic) Mobile phase (A): 5 mM Ammonium Acetate in water Mobile phase (B): Acetonitrile Flow rate: 1.0 ml/min% of B :0/2,18/98,25/98,27/2,30/2 to afford the 1-{bicycle [1.1.1] pentan-1-yl}-2-{5-hydroxy-1- methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6- carboxamide; acetic acid (20 mg, 22%). ES MS M/Z = 462.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1 H), 8.76 (s, 1H), 8.27 (s, 1 H), 8.16 (s, 1H), 7.89 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1H), 7.10 (bs, 2H), 3.43 (s, 1 H), 3.26 (s, 3 H), 2.33 (s, 6 H), 1.96 (s, 1 H). Example 10: 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5- hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000064_0001
[00203] Step 1: To a solution of 2,5-difluoro-4-nitrobenzonitrile (0.2 g, 1.09 mmol) and cyclobutanamine (112 µL, 1.2 eq., 1.3 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added DIPEA (377 µL, 2 eq., 2.17 mmol) and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction it was filtered and the solid obtained was dried to afford 5-(cyclobutylamino)-2-fluoro-4- nitrobenzonitrile (250 mg, 92%). [00204] Step 2: To a stirred solution of 5-(cyclobutylamino)-2-fluoro-4-nitrobenzonitrile (1 g, 4.25 mmol) in DMF (10.0 mL), ammonium chloride (1.14 g, 5 eq., 21.3 mmol) and sodium azide (1.38 g, 5 eq., 21.3 mmol) was added and stirred at 120 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature and washed with 6 N hydrochloride solution. The solid obtained was filtered and dried under reduced pressure to afford N-cyclobutyl-4-fluoro-2-nitro-5-(2H-1,2,3,4-tetrazol- 5-yl)aniline (750 mg, 63%). [00205] Step 3: To a stirred solution of N-cyclobutyl-4-fluoro-2-nitro-5-(2H-1,2,3,4-tetrazol-5- yl)aniline (750 mg, 2.7 mmol) in methanol (20.0 mL), Pd/C (287 mg, 0.1 eq., 270 µmol) was added and the mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h. After completion, the reaction mixture was passed through celite and the filtrate was concentrated under vacuum to afford N1- cyclobutyl-4-fluoro-5-(2H-1,2,3,4-tetrazol-5-yl)benzene-1,2-diamine (630 mg, 72%). [00206] Step 4: To a stirred solution of N1-cyclobutyl-4-fluoro-5-(2H-1,2,3,4-tetrazol-5-yl)benzene- 1,2-diamine (176 mg, 707 µmol) and methyl 2-formyl-5-methoxy-6-oxo-1,6-dihydropyrimidine-4- carboxylate (150 mg, 707 µmol) in DMF (3.0 mL) and water (1.0 mL), oxone monopersulfate (217 mg, 707 µmol) was added and the mixture was stirred for 16 h at ambient temperature. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash chromatography. The desired fractions were concentrated to afford methyl 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (85 mg, 22%). [00207] Step 5: To a stirred solution of methyl 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)- 1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (85 mg, 187 µmol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added lithium hydroxide (22.4 mg, 5 eq., 935 µmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was acidified with HCl then concentrated to afford 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2- yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (85 mg, 86%). [00208] Step 6: To a stirred solution of 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (85 mg, 193 µmol) and 1,2-oxazol-4-amine hydrochloride (27.9 mg, 1.2 eq., 232 µmol) in DMF (1.0 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (110 mg, 1.5 eq., 290 µmol) and DIPEA (101 µL, 3 eq., 579 µmol) at ambient temperature and stirred for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to provide crude product which was purified by CombiFlash chromatography. The desired fractions were concentrated to afford 2-[1- cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (45 mg, 25%). [00209] Step 7: A stirred solution of 2-[1-cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (45 mg, 44.4 µmol) in DCM (5.0 mL) was cooled to -60 °C and tribromoborane (21.1 µL, 5 eq., 222 µmol) was added and the solution was stirred at ambient temperature for 16 h. After completion, the reaction mixture was cooled to -60 °C and quenched with methanol and concentrated to provide crude product which was purified by prep HPLC. The desired fractions were lyophilized to afford 2-[1- cyclobutyl-5-fluoro-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4 mg, 18%). ES MS M/Z = 493.30 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 11.26 (br s, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 5.27-5.18 (m, 1H), 3.46 (s, 3H), 2.63-2.43 (m, 4H), 1.86-1.76 (m, 2H). [00210] The following compound was synthesized in a similar manner: Example 15: 2-[1-cyclobutyl-5-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00211] ES MS M/Z=475.25 [M+H]+, 1NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 8.10 (s, 2H) 5.20 (t, J = 8.4 Hz, 1H), 3.47(s, 3H), 2.66-2.53 (m, 2H), 2.49-2.32 (m, 2H), 1.88-1.77 (m, 2H). Example 11: 2-(1-Cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N- (isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000066_0001
[00212] Step 1: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) and cyclobutanamine (467 µL, 1.2 eq., 5.45 mmol) in 1-methylpyrrolidin-2-one (5 mL), N, N- diisopropylethylamine (1.58 mL, 2 eq., 9.09 mmol) was added and the reaction mixture was stirred and heated at 100 °C for 18 h. After completion ice cooled water was added and the solid was filtered and dried to afford 5-bromo-N-cyclobutyl-2-nitroaniline (1.1 g, 82%) [00213] Step 2: To a stirred solution of 5-bromo-N-cyclobutyl-2-nitroaniline (550 mg, 2.03 mmol) in 1,4-dioxane (8 mL), pyrrolidin-2-one (259 mg, 1.5 eq., 3.04 mmol) and potassium carbonate (841 mg, 3 eq., 6.09 mmol) were added and reaction mixture was purged with argon for 5 min then copper iodide (64.4 mg, 0.1 eq., 203 µmol) and then 2-aminoacetic acid (30.5 mg, 0.2 eq., 406 µmol) was added and again the reaction vessel was purged with argon. The reaction mixture was heated to 130 °C for 18 h. After completion, the mixture was filtered through celite. The filtrate was concentrated to obtain crude product which was purified by flash chromatography. The desired fractions were concentrated to afford 1-[3-(cyclobutylamino)-4-nitrophenyl]pyrrolidin-2-one (0.24 g, 42%) [00214] Step 3: To a stirred solution of 1-[3-(cyclobutylamino)-4-nitrophenyl]pyrrolidin-2-one (240 mg, 799 µmol) in methanol (10 mL), Pd/C (Pd/C) (42.5 mg, 0.5 eq., 0.4 mmol) was added and reaction mixture was stirred at ambient temperature under hydrogen atmosphere for 3 h. After completion, the reaction mixture was filtered through celite then concentrated and dried to afford 1-[4-amino-3- (cyclobutylamino)phenyl]pyrrolidin-2-one (0.20 g, 82%) [00215] Step 4: To a stirred solution of 1-[4-amino-3-(cyclobutylamino)phenyl]pyrrolidin-2-one (0.2 g, 815 µmol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (228 mg, 1.1 eq., 897 µmol) in DMSO (15 mL), sodium metabisulfite (232 mg, 1.5 eq., 1.22 mmol) was added at ambient temperature. The resulting mixture was heated at 80 °C for 16 h. After completion, the mixture was poured into ice cold water and the obtained solid was filtered, dried, and purified by flash chromatography. The desired fractions were combined and concentrated to afford ethyl 2-[1-cyclobutyl- 6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6 dihydropyrimidine-4- carboxylate (0.13 g, 33%). [00216] Step 5: To a stirred solution of ethyl 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.13 g, 271 µmol) in oxolane (30 mL, 209 µmol) and water (10 mL), lithium hydroxide (32 mg, 5 eq., 1.36 mmol) was added and the mixture was allowed to stir at ambient temperature for 3 h. After completion, the reaction mixture was acidified with 6 N HCl and concentrated to afford 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)- 1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.15 g, 33%). [00217] Step 6: To a stirred solution of 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (150 mg, 332 µmol), and 1,2- oxazol-4-amine hydrochloride (47.8 mg, 1.2 eq., 399 µmol) in DMF (13.7 mL, 177 mmol) DIPEA (163 µL, 3 eq., 997 µmol) and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (189 mg, 1.5 eq., 498 µmol) was added and the reaction mixture was allowed to stir at ambient temperature for 15 h. After completion, the reaction mixture was diluted with water and solid precipitated which was filtered to afford 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol-2- yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (110 mg, 45%). [00218] Step 7: To a stirred solution of 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H-1,3-benzodiazol- 2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (110 mg, 149 µmol) in DCM (5 mL, 78.1 mmol), boron tribromide (28.2 µL, 2 eq., 298 µmol) was added and the mixture was refluxed for 18 h. After completion, the reaction mixture was diluted methanol and concentrated under vacuum to obtain crude product which was purified by reverse phase prep HPLC and the collected fractions were lyophilized to afford methyl 2-[1-cyclobutyl-6-(2-oxopyrrolidin-1-yl)-1H- 1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (19 mg, 25%). ES MS M/Z=490.3 [M+H]+, 1H NMR: (400 MHz, DMSO-d6) δ 12.09 (bs, 1H), 11.06 (s, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.56- 7.54 (dd, J = 1.6 Hz 8.8 HZ, 1H), 5.18-5.10 (m, 1H), 3.98 (t, J = 7.2 Hz, 2H), 3.49 (m, 3H), 2.55-2.49 (m, 6H), 2.15-2.08 (m, 2H), 1.85-1.74 (m, 2H). [00219] The following compound was synthesized in a similar manner: Example 22: 2-[1-cyclobutyl-6-(2-oxo-1,3-oxazolidin-3-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00220] ES MS M/Z = 492.3 [
Figure imgf000068_0001
9.19 (s, 1 H), 8.81 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.07 - 5.03 (m, 1H), 4.46 (t, J = 7.6 Hz, 2H), 4.16 (t, J = 8.4 Hz, 2H), 3.33 (s, 3H), 2.68 - 2.55 (m, 2H), 2.42 - 2.33 (m, 2H), 1.84 - 1.76 (m, 2H). Example 13: 2-(1-cyclobutyl-6-(5-methyl-1H-tetrazol-1-yl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy- N-(isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000068_0002
[00221] Step 1: A stirred solution of 3-fluoro-4-nitroaniline (0.5 g, 3.2 mmol) in acetic anhydride (5.0 mL) was stirred at 70 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtained crude product which was purified by flash chromatography. The desired fractions were concentrated to afford N-(3-fluoro-4-nitrophenyl)acetamide (470 mg, 62%). [00222] Step 2: To a stirred solution of N-(3-fluoro-4-nitrophenyl)acetamide (3.5 g, 12.4 mmol) and acetonitrile (30.0 mL) in sodium azide (1.61 g, 2 eq., 24.7 mmol) were added to a phosphoroyl trichloride (5.78 mL, 5 eq., 61.8 mmol) . The mixture was stirred for 12 h at 60 °C. The progress of the reaction was monitored by TLC and LCMS data. After completion, the reaction mixture was neutralized with sodium bicarbonate solution, extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography. The desired fractions were concentrated to afford 1-(3-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,3,4-tetrazole (1.6 g, 57%). [00223] Step 3: To a stirred solution of 1-(3-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,3,4-tetrazole (0.6 g, 2.69 mmol) in (3.0 mL) was added, followed by cyclobutanamine (276 µL, 1.2 eq., 3.23 mmol) and DIPEA (1.4 mL, 3 eq., 8.07 mmol) and the mixture was stirred at 100 °C for 16 hr. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product (0.70 g, 94%). [00224] Step 4: To a stirred solution of N-cyclobutyl-5-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-2- nitroaniline (0.5 g, 1.82 mmol) in methanol (5.0 ml) was added Pd/C (194 mg, 0.1 eq., 182 µmol) and the mixture was stirred at ambient temperature for 16 hr. After completion, the reaction mixture was filtered through celite. The filtrate was concentrated to provide N1-cyclobutyl-5-(5-methyl-1H-1,2,3,4-tetrazol-1- yl)benzene-1,2-diamine (0.40 g, 87%). [00225] Step 5: To a stirred solution of ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (150 mg, 590 µmol) in DMSO (5.0 mL) was added N1-cyclobutyl-5- (5-methyl-1H-1,2,3,4-tetrazol-1-yl)benzene-1,2-diamine (144 mg, 590 µmol) and disodium (sulfinatooxy)sulfinate (135 mg, 1.2 eq., 708 µmol) and the mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product which was purified by flash chromatography. The desired fractions were concentrated to provide, ethyl 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (110 mg, 182 µmol, 31%). [00226] Step 6: To a stirred solution of ethyl 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)- 1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 209 µmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (25 mg, 5 eq., 1.04 mmol) and the mixture was stirred at ambient temperature for 3 h. After completion, the reaction mixture was acidified with 6 N HCl and concentrated to afford 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol- 1-yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.09 g, 77%). [00227] Step 7: To a stirred solution of 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (90 mg, 0.2 mmol) and 1,2-oxazol-4-amine (20.2 mg, 1.2 eq., 240 µmol) in DMF (5.0 mL) was added 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (114 mg, 1.5 eq., 0.3 mmol) and DIPEA (104 µL, 3 eq., 599 µmol) and the solution was stirred at ambient temperature for 16 h. After completion of the reaction, the mixture was concentrated to provide crude product which was purified by flash chromatography. The desired fractions were concentrated to provide 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.050 g, 45%). [00228] Step 8: To a stirred solution of 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (50 mg, 89.1 µmol) in DCM (5 mL) was added tribromoborane (112 mg, 5 eq., 445 µmol) at -60 °C and the solution was stirred at ambient temperature for 4 h. After completion, the reaction mixture was quenched with methanol and concentrated to provide crude product which was purified by reverse prep HPLC and the desired fractions were lyophilized to provide 2-[1-cyclobutyl-6-(5-methyl-1H-1,2,3,4- tetrazol-1-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (13 mg, 30%). ES MS M/Z = 489.30 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.10 (brs, 1H), 11.03 (s, 1H), 9.28 (s, 1H), 8.79 (s, 1H), 8.19 (dd, J = 1.6, 7.6 Hz, 1H), 7.68-7.63 (m, 2H), 5.27-5.18 (m, 1H), 3.41 (s, 3H), 2.65-2.58 (m, 2H), 2.51 (s, 3H), 2.46-2.41 (m, 2H), 1.92-1.83 (m, 2H). Example 14: 1-Cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-5-carboxamide
Figure imgf000070_0001
[00229] Step 1: To a stirred solution of 4-(cyclobutylamino)-3-nitrobenzonitrile (2.5 g, 11.5 mmol) in DMSO (19.2 mL), hydrogen peroxide (1.7 mL, 72.5 mmol) was added at 0 °C. To the reaction mixture, potassium carbonate (4.77 g, 3 eq., 34.5 mmol) was added and reaction mixture was allowed to stir at ambient temperature for 16 h. After completion, the reaction mixture was poured into ice cold water and the solid was filtered and dried to afford 4-(cyclobutylamino)-3-nitrobenzamide (3.2 g, 13.1 mmol) as a red solid (3.00 g, 98%). [00230] Step 2: To a stirred solution of 4-(cyclobutylamino)-3-nitrobenzamide (1.5 g, 6.38 mmol) in methanol (21.7 mL), Pd/C (Pd/C) (339 mg, 0.5 eq., 3.19 mmol) was added at ambient temperature under a hydrogen atmosphere for 18 h. After completion, the reaction mixture was passed through celite and the filtrate was concentrated under vacuum to afford 3-amino-4-(cyclobutylamino)benzamide (0.90 g, 53%) [00231] Step 3: To a stirred solution of 3-amino-4-(cyclobutylamino)benzamide (350 mg, 1.71 mmol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (477 mg, 1.1 eq., 1.88 mmol) in DMSO (15 mL), sodium metabisulfite (486 mg, 1.5 eq., 2.56 mmol) was added at ambient temperature. The resulting mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was poured into ice cold water and the solid was filtered and dried to obtain crude solid. The crude was purified by flash chromatography. The desired fractions were concentrated to afford ethyl 2-(6- carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (0.30 g, 40%). [00232] Step 4: To a stirred solution of ethyl 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.3 g, 683 µmol) in tetrahydrofuran (30 mL) and water (10 mL) lithium hydroxide (81.7 mg, 5 eq., 3.41 mmol) was added and the mixture was stirred at ambient temperature for 3 h. Upon completion, the reaction mixture was acidified with 6 N HCl and concentrated to afford 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.3 g, 474 µmol, 69%) [00233] Step 5: To a stirred solution of 2-(5-carbamoyl-1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.3 g, 729 µmol) and 1,2-oxazol-4- amine (73.6 mg, 1.2 eq., 875 µmol) in DMF (30 mL), DIPEA (358 µL, 3 eq., 2.19 mmol) and (1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (416 mg, 1.5 eq., 1.09 mmol) were added and the mixture was stirred at ambient temperature for 15 h. After completion, the reaction mixture was diluted with water, filtered, and dried to afford 1-cyclobutyl-2-{5- ethoxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3- benzodiazole-5-carboxamide (190 mg, 318 µmol, 44%) [00234] Step 6: To a stirred solution of 1-cyclobutyl-2-{5-ethoxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-5-carboxamide (190 mg, 398 µmol) in DCM (10.6 mL, 165 mmol), boron tribromide (75.5 µL, 2 eq., 796 µmol) was added and the mixture was refluxed for 18 h. After completion, the reaction mixture was quenched with methanol and concentrated under reduced pressure to obtain crude product which was purified by prep reverse HPLC to afford methyl 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6- dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-5-carboxamide(68 mg, 38%) ES MS M/Z=450.20 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.09 (bs, 1H), 11.11 (bs, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 8.36 (s, 1H), 8.06 (bs, 1H), 7.96-7.94 (dd, J = 1.2 Hz 8.4 HZ, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.36 (bs, 1H), 5.21-5.12 (m, 1H), 3.46 (s, 3H), 2.61-2.39 (m, 4H), 1.89-1.78 (m, 2H). Example 16: 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure imgf000072_0001
[00235] Step 1: To a stirred solution of 3-fluoro-4-nitrobenzoic acid (10 g, 54 mmol) in DCM (0.1 L, 1.56 mol) was added DMAP (1.32 g, 0.2 eq., 10.8 mmol) and 2-methylpropan-2-ol (20.5 mL, 4 eq., 216 mmol) followed by N,N'-dicyclohexylmethanediimine (13.4 g, 1.2 eq., 64.8 mmol) at 0 °C and the resulting mixture stirred at ambient temperature for 16 h. The reaction mixture was basified with saturated sodium hydroxide solution then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product which was purified by flash chromatography. The desired fractions were concentrated to afford tert-butyl 3-fluoro-4-nitrobenzoate (7.0 g, 58%). [00236] Step 2: To a stirred solution of tert-butyl 3-fluoro-4-nitrobenzoate (7 g, 29 mmol) in 1- methylpyrrolidin-2-one (20 mL), cyclobutanamine (2.48 g, 1.2 eq., 34.8 mmol) and DIPEA (15.4 mL, 3 eq., 87.1 mmol) was added and reaction mixture was heated to 90 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl 3-(cyclobutylamino)- 4-nitrobenzoate (6.2 g, 19.5 mmol, 67%) [00237] Step 3: To a stirred solution of tert-butyl 3-(cyclobutylamino)-4-nitrobenzoate (3.0 g, 10.62 mmol) in methanol (10 mL, 6.84 mmol) was added Pd/C (1.63 g, 1.5 eq., 15.39 mmol) and the mixture was stirred at ambient temperature under hydrogen atmosphere for 6 h. The reaction mixture was filtered through celite and washed with methanol. The organic layer was filtered and concentrated under reduced pressure to afford crude tert-butyl 4-amino-3-(cyclobutylamino)benzoate (2.10 g, 78%) [00238] Step 4: To a stirred solution of tert-butyl 4-amino-3-(cyclobutylamino)benzoate (2.10 g, 8.00 mmol) in DMSO (15 mL) was added ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (2.04 g, 1.0 eq., 8.0 mmol) and sodium metabisulfite (2.28 g, 1.2 mmol) at ambient temperature, The reaction was stirred at 80°C for 12 h, After completion of the reaction, the mixture was dissolved in water and extracted in ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired fractions were concentrated to afford tert-butyl 1-cyclobutyl-2-[5-ethoxy-4-(ethoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl]-1H-1,3-benzodiazole-6-carboxylate as a sticky compound. (0.60 g, 15%) [00239] Step 5: To solution of tert-butyl 1-cyclobutyl-2-[5-ethoxy-4-(ethoxycarbonyl)-1-methyl-6- oxo-1,6-dihydropyrimidin-2-yl]-1H-1,3-benzodiazole-6-carboxylate (0.55 g, 1.11 µmol) in a mixture of methanol (5.0 mL, 12.3 mmol), tetrahydrofuran (5.0 mL, 11.14 mmol), lithium hydroxide (0.132 g, 5 eq., 0.30 mmol) was added water (2 mL) and the mixture was stirred at ambient temperature for 1h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ether. The aqueous layer was acidified using citric acid solution, extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure to provide crude 2-{6-[(tert-butoxy)carbonyl]-1-cyclobutyl- 1H-1,3-benzodiazol-2-yl}-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.550 g). [00240] Step 6: To a solution of 2-{6-[(tert-butoxy)carbonyl]-1-cyclobutyl-1H-1,3-benzodiazol-2-yl}- 5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (550 mg, 1.17 mmol) and 1,2-oxazol- 4-amine HCl (118 mg, 1.2 eq., 1.41 mmol) dissolved in DMF (48.3 mL, 624 mmol) was added DIPEA (576 µL, 3 eq., 3.52 mmol) and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (670 mg, 1.5 eq., 1.76 mmol) and the mixture was stirred at ambient temperature for 15 h. After completion, the reaction mixture was diluted with water and the solid obtained was filtered and concentrated to afford tert-butyl 1-cyclobutyl-2-{5-ethoxy-1-methyl-4-[(1,2- oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylate (450 mg, 673 µmol, 57%). [00241] Step 7: To a solution of tert-butyl 1-cyclobutyl-2-(5-ethoxy-4-(isoxazol-4-ylcarbamoyl)-1- methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxylate (0.40 g, 0.74 mmol) in DMF (4 mL) was added lithium bromide (324 mg, 5 eq., 3.74 mmol) and stirred for 16 h at 100 °C. After completion, the reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyrimidin- 2-yl)-1H-benzo[d]imidazole-6-carboxylate (180 mg, 0.35 mmol). [00242] Step 8: To a stirred solution of tert-butyl 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol- 4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylate (180 mg, 355 µmol) in DCM (3.6 mL, 56.2 mmol) was added TFA (2 mL) at 0 °C and the mixture was stirred for 24 h then concentrated and washed with n-pentane 2-3 time. After completion of reaction, the mixture was concentrated and ice cold water was added to obtain a solid which was purified by reverse phase HPLC. The desired fractions were lyophilized to provide 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4- yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid (19.0 mg, 12%). ES MS M/Z=451.20 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.94 (bs, 2H), 9.20 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 7.90-7.78 (dd, J = 8.4 Hz, 9.6 Hz, 2H), 7.10 (m, 3H), 5.23-5.15 (m, 1H), 3.40 (s, 3H), 2.58-2.43 (m, 4H), 1.83-1.78 (m, 2H). [00243] The following compounds were synthesized in a similar manner: Example 24: 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid, acetic acid [00244] ES MS M/Z =451.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm: 13.58 (bs, 1H), 9.17 (s, 1H), 8.81 (s, 1H), 7.92-7.94 (d, J= 8 Hz, 1H), 7.81-7.84 (d, J = 12 Hz, 1H), 5.11-5.16 (m, 1H), 3.32-3.37 (m, 6H), 3.91 (s, 3H), 1.76-1.86 (m, 2H), Example 25: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol-4-yl)-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide [00245] ES MS M/Z = 407.25 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.06 (brs, 1H), 11.06 (s, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.42-7.32 (m, 2H), 5.19-5.10 (m, 1H), 3.45 (s, 3H), 2.60-2.40 (m, 4H), 1.88-1.83 (m, 2H). Example 26: 5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-2-(1-phenyl-1H-1,3-benzodiazol-2-yl)- 1,6-dihydropyrimidine-4-carboxamide [00246] ES MS M/Z = 429.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 10.41 (s, 1H), 9.23 (s, 1H), 8.75 (s, 1H), 7.91 (d, J = 4 Hz, 1H), 7.61 (d, J = 4 Hz, 2H), 7.52 (t, J = 8 Hz, 2H), 7.41-7.45 (m, 4H), 3.56 (s, 3H). Example 27: 2-(1-cyclobutyl-5-fluoro-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol- 4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00247] ES MS M/Z = 425.2 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 11.10 (s, 1H), 9.30 (s, 1H), 8.82 (s, 1H), 7.90-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.31-7.26 (m, 1H), 5.19-5.11 (m, 1H), 3.45 (3, 3H), 2.60-2.55 (m, 2H), 2.45-2.41 (m, 2H), 1.90-1.75 (m, 2H). Example 28: 2-(1-cyclobutyl-6-fluoro-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol- 4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00248] ES MS M/Z=425.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (bs, 1 H), 9.19 (s, 1 H), 8.81 (s, 1 H), 7.76 - 7.72 (m, 1 H), 7.62 (dd, J = 4 Hz, 1 H), 7.10 - 7.18 (m, 3 H), 3.37 (s, 3 H), 2.68 - 2.67 (m, 2 H), 2.46 - 2.40 (m, 2 H), 1.84 -1.71 (m, 2 H). Example 29: 2-(1-cyclobutyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol- 4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00249] LC-MS(ES)m/z: 413.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ ppm : 13.57 (bs, 1H), 9.19 (s, 1H), 8.82 (s, 1H), 8.11 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.64 (d, J = HZ, 1H), 7.17-7.09 (m, 1H), 5.20- 5.16 (m, 1H), 3.42 (m, 4H), 3.39 (s, 3H), 1.82-1.76 (m, 2H). Example 17: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6- oxo-1,6-dihydropyrimidin-5-yl pivalate
Figure imgf000075_0001
[00250] Step 1: To a stirred solution of in 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.5 g, 701 µmol) in tetrahydrofuran (10.0 mL) was added triethylamine (489 µL, 5 eq., 3.51 mmol) followed by 2,2- dimethylpropanoyl chloride (216 µL, 2.5 eq., 1.75 mmol) and the mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product which was purified by flash chromatography. The desired fractions were collected and concentrated to provide 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-1-methyl-4-[(1,2- oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-5-yl2,2-dimethylpropanoate (0.10 g, 29%). ES MS M/Z = 491.25 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 10.93 (brs, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45-7.35 (m, 2H), 5.26-5.18 (m, 1H), 3.56 (s, 1H), 2.58- 0.61 (m, 2H), 2.43-2.42 (m, 2H), 1.90-1.78 (m, 2H), 1.34 (s, 9H). Example 18: 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000075_0002
[00251] Step 1: To a stirred solution of N-(2-nitrophenyl)bicyclo[1.1.1]pentan-1-amine (1 g, 4.9 mmol) in methanol (15.0 mL), ammonium chloride (1.31 g, 5 eq., 24.5 mmol) and zinc (1.6 g, 5 eq., 24.5 mmol) were added at 0°C and the reaction mixture was stirred for 0.5 h at 0 °C and then for 2 h at ambient temperature. After completion, the reaction mixture was passed through celite. The filtrate was extracted with DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford N1- {bicyclo[1.1.1]pentan-1-yl}benzene-1,2-diamine (0.8 g, 67%). [00252] Step 2: To a solution of ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxylate (0.5 g, 0.8 eq., 1.97 mmol) in DMSO (5.0 mL) were added N1-{bicyclo[1.1.1]pentan-1- yl}benzene-1,2-diamine (428 mg, 2.46 mmol) and sodium metabisulfite (561 mg, 1.2 eq., 2.95 mmol) and the mixture was stirred for 16 h at 80 °C. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product which was purified by CombiFlash chromatography. The desired fractions were concentrated to afford ethyl 2-(1-{bicyclo[1.1.1]pentan-1- yl}-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (250 mg, 23%). [00253] [0003] Step 3: To a solution of ethyl 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3-benzodiazol-2- yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (250 mg, 612 µmol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added lithium hydroxide (73.3 mg, 5 eq., 3.06 mmol) and the mixture was stirred at ambient temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to afford crude 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3- benzodiazol-2-yl)-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (250 mg, 95%). [00254] Step 4: To a solution of 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3-benzodiazol-2-yl)-5-ethoxy- 1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (250 mg, 657 µmol) and 1,2-oxazol-4-amine hydrochloride (95 mg, 1.2 eq., 789 µmol) in DMF (2.5 mL) was added DIPEA (344 µL, 3 eq., 1.97 mmol) and HATU (375 mg, 1.5 eq., 986 µmol) and the mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude product which was purified by CombiFlash chromatography. The desired fractions were concentrated to afford 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (250 mg, 60%). [00255] Step 5: A stirred solution of 2-(1-{bicyclo[1.1.1]pentan-1-yl}-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (250 mg, 560 µmol) in DCM (5.0 mL) was cooled to -60 °C and tribromoborane (266 µL, 5 eq., 2.8 mmol) was added and the solution was stirred at ambient temperature for 16 h. After completion of the reaction, the mixture was cooled to -60 °C and quenched with methanol and concentrated to provide crude product which was purified by prep HPLC. The desired fractions were lyophilized to afford 2-(1-{bicyclo[1.1.1]pentan-1- yl}-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (78 mg, 33%). ES MS M/Z = 419.25 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.17 (br s, 1H), 11.21 (br s, 1H), 9.28 (s, 1H), 8.80 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.44-7.35 (m, 2H), 2.60 (s, 1H), 2.32 (s, 6H). Example 20: 2-(1-cyclobutyl-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N- (isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000077_0001
[00256] Step 1: To a stirred solution of 3-fluoro-4-nitrobenzonitrile (30 g, 181 mmol) in 1- methylpyrrolidin-2-one (30 mL), cyclobutanamine (18.6 mL, 1.2 eq., 217 mmol) and DIPEA (96.1 mL, 3 eq., 542 mmol) was added and the reaction mixture was heated to 90 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-(cyclobutylamino)-4- nitrobenzonitrile (35 g, 145 mmol, 80%). [00257] Step 2: To a stirred solution of 3-(cyclobutylamino)-4-nitrobenzonitrile (20 g, 92.1 mmol) in DMF (30.0 mL), ammonium chloride (24.6 g, 5 eq., 460 mmol) and sodium azide (29.9 g, 5 eq., 460 mmol) was added and the mixture was stirred at 120 °C for 16 h. After completion, the reaction mixture was cooled to ambient temperature and washed with 1 N hydrochloride solution, the solid obtained was filtered and dried under reduced pressure to provide N-cyclobutyl-2-nitro-5-(2H-1,2,3,4-tetrazol-5- yl)aniline (21.2 g, 86%). [00258] Step 3: To a stirred solution of N-cyclobutyl-2-nitro-5-(2H-1,2,3,4-tetrazol-5-yl)aniline (0.5 g, 1.92 mmol) in methanol (10.0 mL), Pd/C (102 mg, 0.5 eq., 961 µmol) was added and the mixture was stirred at ambient temperature under a hydrogen atmosphere for 18 h. After completion, the reaction mixture was passed through celite and the filtrate was concentrated under vacuum to afford N1- cyclobutyl-5-(2H-1,2,3,4-tetrazol-5-yl)benzene-1,2-diamine (0.30 g, 48%). [00259] Step 4: To a stirred solution N1-cyclobutyl-5-(2H-1,2,3,4-tetrazol-5-yl)benzene-1,2-diamine (950 mg, 4.13 mmol) and ethyl 5-ethoxy-2-formyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.05 g, 4.13 mmol) in dimethylsulfoxide (5.0 mL) was added sodium metabisulfite (1.18 g, 1.5 eq., 6.19 mmol) at ambient temperature. The resulting mixture stirred for 16 h at 80 °C. After completion, the reaction mixture diluted with water and extracted with ethyl acetate and dried over anhydrous sodium sulfate, filtered, and concentrated to provide crude. The crude was purified by flash chromatography to afford 1-{2-[3,4-bis(benzyloxy)-2-fluoro-5-methoxyphenyl]-1-(3-methyloxetan-3-yl)-1H-1,3- benzodiazol-5-yl}azetidin-2-one (1.00 g, 48%). [00260] Step 5: To a stirred solution of ethyl 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.2 g, 2.58 mmol) in tetrahydrofuran (12.0 mL, 2.58 mmol) and water (4.0 mL) was added lithium hydroxide (309 mg, 5 eq., 12.9 mmol) and the mixture was stirred at ambient temperature for 3 h. After completion, the reaction mixture was acidified with 6 N HCl and concentrated to afford 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5- yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (1 g, 78%). [00261] Step 6: To a stirred solution of 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (1.0 g, 2.29 mmol) and isoxazol-4-amine hydrochloride (330 mg, 1.2 eq., 2.75 mmol) in DMF (10.0 mL) was added followed by DIPEA (1.2 mL, 3 eq., 6.87 mmol) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.31 g, 1.5 eq., 3.44 mmol) and the mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was concentrated under vacuum and quenched with ice cold water. The collected solid was filtered and washed with ether and pentane to afford 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-ethoxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (0.70 g, 61%). [00262] Step 7: To a stirred solution of 2-[1-cyclobutyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-1,3- benzodiazol-2-yl]-5-ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (650 mg, 1.29 mmol) in DCM (15.0 mL) and DMF (0.5 mL) was cooled to -60 °C and borontribromide (614 µL, 5 eq., 6.47 mmol) was added and the solution was stirred at ambient temperature for 16 h. After completion of the reaction, the mixture was cooled to -60 °C and quenched with methanol and concentrated to provide crude product which was purified by prep HPLC to provide 2-[1-cyclobutyl-6- (2H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide (0.071 g, 11%). ES MS M/Z = 475.20 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 11.01 (brs, 1H), 9.30 (s, 1H), 8.81 (s, 1H), 8.48 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 5.27-5.18 (m,1H), 3.47 (s, 3H), 2.71-2.62 (m, 2H), 2.44 (m, 2H), 1.93-1.81 (m, 2H). [00263] The following compounds were synthesized in a similar manner: Example 19: 2-(1-(bicyclo[1.1.1]pentan-1-yl)-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)-5- hydroxy-N-(isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00264] ES-MS M/Z = 487 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.28 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 8.10-8.07 (m, 1H), 8.00 (d, J = 8.8 Hz, 1H), 3.34 (s, 3H), 2.66 (s, 1H), 2.39 (s, 6H). Example 44: 2-(1-cyclobutyl-6-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy- N-(isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00265] ES MS M/Z = 489.25 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.10 (brs, 1H), 11.11 (brs, 1H), 9.29 (s, 1H), 8.81 (s, 1H), 8.42 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.6 (d, J = 8.4 Hz, 4H), 5.26 (m, 1H), 4.46 (m, 3H), 3.84 (m, 3H), 2.50 (m, 3H), 2.47 (m, 2H), 3.65 (s, 2H), 1.89 (m, 2H). Example 21: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-ethoxy-N-(isoxazol-4-yl)-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
Figure imgf000079_0001
[00266] Step 1: To a stirred solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-ethoxy-1-methyl- 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (25.0 mg, 63.8 µmol) and 1,2-oxazol-4-amine (6.44 mg, 1.2 eq., 76.5 µmol) in DMF (1.00 mL) was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (36.4 mg, 1.5 eq., 95.7 µmol) and DIPEA (33.3 µL, 3 eq., 191 µmol) and the solution was stirred at ambient temperature for 3 h. After completion, the reaction mixture was concentrated to provide crude product which was purified by reverse prep HPLC and the desired fractions were lyophilized to provide 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- ethoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (7 mg, 15.6 µmol). ES MS M/Z = 435.35 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.28 (s, 1H), 8.72 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.42-7.33 (m, 2H), 5.21-5.12 (m, 1H), 4.32-4.27 (m, 2H), 3.51 (s, 3H), 2.66-2.58 (m, 2H), 2.50-2.37 (m, 2H), 1.88-1.77 (m, 2H), 1.32-1.29 (t, J = 7.2 Hz, 3H). Example 23: 2-(1-cyclobutyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol- 4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000079_0002
[00267] Step 1: To a solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1 g, 4.78 mmol) in DCM (10 mL) was added cyclobutanamine (1.23 mL, 3 eq., 14.3 mmol) slowly with cooling on an ice bath. After 2 h at ambient temperature the reaction was diluted with water and extracted with DCM. The organic layer was dried with sodium sulfate and concentrated in vacuo to give N-cyclobutyl-2-nitro-5- (trifluoromethyl)aniline (1.1 g, 88%). ES MS M/Z =261.0 [M+H]+]. [00268] Step 2: To a stirred solution of N-cyclobutyl-2-nitro-5-(trifluoromethyl)aniline (1.1 g, 4.23 mmol) in methanol (30 mL) was added 10% Pd/C (450 mg, 4.23 mmol) and the mixture was stirred at ambient temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a celite bed then washed with methanol. The organic layer was filtered and concentrated under reduced pressure to afford crude N1-cyclobutyl-5-(trifluoromethyl)benzene-1,2-diamine (950 mg, 98%). ES MS M/Z =231.1 [M+H]+. [00269] Step 3: To a solution of N1-cyclobutyl-5-(trifluoromethyl)benzene-1,2-diamine (0.3 g, 1.3 mmol), methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (354 mg, 1.2 eq., 1.56 mmol), DMSO (5 mL) and disodium (sulfinatooxy)sulfinate (372 mg, 1.5 eq., 1.95 mmol) was stirred at 85 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer washed with water, dried over sodium sulfate, and concentrated. The crude compound was purified by silica gel chromatography to afford methyl 2-[1- cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (240 mg, 42.21%). ES MS M/Z =437.1 [M+H]+. [00270] Step 4: To a stirred solution of methyl 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (240 mg, 0.551 mmol) in methanol (3.22 mL) and tetrahydrofuran (3.22 mL) was added solution of lithium hydroxide (65.9 mg, 5 eq., 2.75 mmol) in water (3.22 mL) and the mixture was stirred at ambient temperature for 2 h. After completion of the reaction, the mixture was diluted with water, then extracted with diethyl ether (2 X 20 ml). The reaction mixture was then acidified with 1N HCl at pH= 2 and extracted by ethyl acetate (2 X 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated under reduced pressure. To afford crude 2-[1- cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylic acid (0.2 g, 86%). ES MS M/Z =423.2 [M+H]+. [00271] Step 5: To a stirred solution of 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.2 g, 0.474 mol) in 1,2-oxazol-4- amine hydrochloride (74.2 mg, 1.3 eq., 616 µmol), HATU (360 mg, 2 eq., 947 µmol), DMF (2.35 mL) and DIPEA (165 µL, 2 eq., 0.947 mmol) were added and the mixture was stirred at ambient temperature for 48 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by column chromatography to afford 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1- methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (140 mg, 61%). ES MS M/Z =489.1 [M+H]+. [00272] Step 6: To a stirred solution of 2-[1-cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (140 mg, 0.287 mmol) in DCM (10 mL) was cooled to -40 °C, tribromoborane (0.0136 mL, 5 eq., 1.43 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to 0 °C and quenched with water and sodium bicarbonate slowly then the reaction mixture was diluted with DCM, dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by preparative HPLC to afford 2-[1- cyclobutyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6- oxo-1,6-dihydropyrimidine-4-carboxamide (13 mg, 10%). ES MS M/Z =475.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm: 12.10 (bs, 1H), 11.83 (bs, 1H), 9.28 (s, 1 H), 8.81 (s, 1 H), 8.12 (s, 1 H), 7.99- 8.01 (d, J= 8 Hz, 1H), 7.66-7.68 (d, J= 8 Hz, 1H), 5.20-5.24 (m, 2H), 3.51 (s, 3H), 1.79-1.84 (m, 2H). Example 36: 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(pyridazin-4- yl)-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000081_0001
[00273] Step 1: To a stirred solution of 6-(benzyloxy)-2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5- methoxy-1,6-dihydropyrimidine-4-carboxylic acid (90 mg, 208 µmol) and pyridazin-4-amine (19.8 mg, 208 µmol) in DMF (4 mL), HATU and DIPEA (90.6 µL, 2.5 eq., 520 µmol) were added and stirred at ambient temperature for 12 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product which was purified by flash chromatography. The desired fractions were concentrated to afford 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N- (pyridazin-4-yl)-1,6-dihydropyrimidine-4-carboxamide (85 mg, 0.19 mmol). (80 mg 96%). [00274] Step 2: To a stirred solution of 2-(1-cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-methoxy-1- methyl-6-oxo-N-(pyridazin-4-yl)-1,6-dihydropyrimidine-4-carboxamide (80 mg, 185 µmol) in DCM (2 mL), boron tribromide (35.2 µL, 2 eq., 371 µmol) was added at -60 °C and the mixture was warmed to ambient temperature and stirred for 16 h. After completion, the reaction mixture was concentrated and then ice cold water was added to obtain a solid which was purified by reverse phase HPLC to afford 2-(1- cyclobutyl-1H-1,3-benzodiazol-2-yl)-5-hydroxy-1-methyl-6-oxo-N-(pyridazin-4-yl)-1,6- dihydropyrimidine-4-carboxamide (20 mg, 26%) ES MS M/Z=418.25 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.5 (bs, 1H), 9.34 (s, 1H), 8.98-8.96 (d, J =8.0 Hz, 1H), 8.05-8.03(q, J =8.0 Hz, 1H), 7.80- 7.78 (d, J =8.0 Hz, 1H), 7.74-7.72 (d, J =8.0 Hz, 1H), 7.36-7.27 (m, 2H), 7.21- 6.95 (m, 2H), 5.12 (m, 1H), 3.38 (s, 3H),2.66-2.32 (m, 2H),1.84-1.79 (m, 2H). [00275] The following compounds were synthesized in s similar manner: Example 37: 2-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isothiazol-4-yl)-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide [00276] ES MS M/Z = 423.20 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.21 (brs, 1H), 11.30 (brs, 1H), 9.14 (s, 1H), 8.86 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.41-7.30 (m,2H), 5.21-5.13 (m, 1H), 3.46 (s, 3H), 2.61 (s, 2H), 2.42 (s, 2H), 1.85-1.75 (m, 2H). [00277] Example 41: 2-(6-chloro-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-5-hydroxy-N-(isoxazol- 4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide [00278] ES MS M/Z = 441.2 [M+H]+, UPLC: 99.78% ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.57 (s, 1 H), 9.17 (s, 1H), 8.80 (s, 1 H), 7.80 (s, 1 H), 7.73-7.71(d, J = 8.4 Hz,1 H), 7.31-7.29 (d, J = 8.4 Hz ,1 H), 5.11-5.06 (m, 1 H), 2.45-2.33 (m , 4 H ) , 1.80- 1.73(m, 2 H) . Example 42: 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000082_0001
[00279] Step 1: A solution 4-bromo-2-fluoro-1-nitrobenzene (4 g, 18.2 mmol) in 1-methylpyrrolidin-2- one (15 mL), ethylbis(propan-2-yl) amine (9.5 mL, 3 eq, 54.5 mmol) and cyclobutanamine (1.86 mL, 1.2 eq., 21.8 mmol) was stirred at 130 °C for 6 h. After completion, the reaction mixture was diluted with water and cooled to 0 °C and a precipitate formed. The precipitate was filtered and dried to afford 5- bromo-N-cyclobutyl-2-nitroaniline (4 g, 80% yield). ES MS M/Z = 271.2 [M+H]+. [00280] Step 2: To a mixture of 5-bromo-N-cyclobutyl-2-nitroaniline (2 g, 7.38 mmol) in 1,4-dioxane (16 mL, 188 mmol), potassium acetate (1.01 g, 1.4 eq., 10.3 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.68 g, 2.5 eq., 18.4 mmol) was added at ambient temperature and purged with nitrogen for 5 minutes. Then Pd(dppf)Cl2.DCM (602 mg, 0.1 eq., 0.738 mmol) was added and again and the reaction mixture was purged for 5 minutes then heated at 100°C for 16 h. After completion of the reaction the mixture was filtered through a celite bed, washed with ethyl acetate and the filtrate was concentrated to provide crude. The crude compound was purified by CombiFlash to afford N-cyclobutyl-2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (3.3 g, 66% yield). ES MS M/Z = 319.2 [M+H]+. [00281] Step 3 : To a mixture of N-cyclobutyl-2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (3.3 g, 10.4 mmol) in 1,4-dioxane (25 mL) and water (5 mL) , cesium carbonate (10.1 g, 3 eq., 31.1 mmol) and 2-chloropyrimidine (1.43 g, 1.2 eq., 12.4 mmol) was added at ambient temperature and purged with nitrogen for 5 min. Then Pd(dppf)Cl2 DCM (1.69 g, 0.2 eq., 2.07 mmol) was added and again purged for 3 minutes and the reaction mixture was sealed and heated at 100 °C for 2 h in the microwave. After completion, the reaction mixture was filtered through a celite bed, washed with ethyl acetate and the filtrate was concentrated to provide crude product. The crude was purified by CombiFlash to afford N-cyclobutyl-2-nitro-5-(pyrimidin-2-yl) aniline (1.17 g, 52% yield). ES MS M/Z = 271.2 [M+H]+. [00282] Step 4: To a stirred solution of N-cyclobutyl-2-nitro-5-(pyrimidin-2-yl)aniline (1.2 g, 4.44 mmol) in methanol (0.1 L) was added 10% Pd/C (2 g, 18.8 mmol) at ambient temperature. The reaction mixture was stirred under a hydrogen balloon for 2 h. After completion of the reaction it was filtered through celite bed and washed with methanol. The organic layer was filtered and concentrated under reduced pressure to afford crude N1-cyclobutyl-5-(pyrimidin-2-yl) benzene-1,2-diamine (1 g, 71% yield). ES MS M/Z = 241.0 [M+H]+. [00283] Step 5: To a stirred solution of methyl 2-formyl-5-methoxy-1-methyl-6-oxo-1,6- dihydropyrimidine-4-carboxylate (0.5 g, 2.21 mmol) in DMSO (5 mL), disodium (sulfinatooxy) sulfinate (630 mg, 1.5 eq., 3.32 mmol) and N1-cyclobutyl-5-(pyrimidin-2-yl)benzene-1,2-diamine (637 mg, 1.2 eq., 2.65 mmol) was added and the mixture was heated at 80 °C for 6 h. After cooling to ambient temperature the reaction mixture was poured into water and extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated to afford crude product. The crude was purified by CombiFlash to afford methyl 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]-5-methoxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylate (370 mg, 34% ). ES MS M/Z = 447.2 [M+H]+. [00284] Step 6: To a stirred solution of methyl 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol- 2-yl]-5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.2 g, 0.448 mmol) in methanol (3.3 mL, 81.5 mmol) and tetrahydrofuran (3.3 mL, 40.6 mmol) was added lithium hydroxide (56.4 mg, 3 eq., 1.34 mmol) in water (1.65 mL, 91.6 mmol) at ambient temperature and the mixture was stirred for 3 h and concentrated under reduced pressure. The crude was dissolved in water and acidified with saturated citric acid solution to pH~5, the reaction mixture was extracted with DCM, dried with sodium sulfate, and concentrated to afford 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]-5- methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (160 mg, 80%). ES MS M/Z = 433.1 [M+H]+. [00285] Step 7: To a stirred solution of 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.2 g, 0.462 mmol) in DMF (2 mL) was added DIPEA (806 µL, 10 eq., 4.62 mmol) and 1,2-oxazol-4-amine hydrochloride (66.9 mg, 1.2 eq., 0.555 mmol) followed by HATU (352 mg, 2 eq., 0.925 mmol) at ambient temperature and the mixture was stirred for 16 h. The reaction mixture was diluted with DCM and washed with water, dried with sodium sulfate, and concentrated to afford crude product which was purified by CombiFlash using gradient elution 40-50% ethyl acetate /hexane to afford 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3- benzodiazol-2-yl]-5-methoxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide (0.1 g, 42%). ES MS M/Z = 499.2 [M+H]+. [00286] Step 8: To a stirred solution of 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]- 5-methoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.1 g, 0.231 mmol) in DCM (4 mL) was added tribromoborane (111 µL, 5 eq., 1.16 mmol) at -78 °C. The reaction mixture was stirred for 16 h at ambient temperature. The progress of the reaction mixture was monitored by TLC and LCMS and when complete it was concentrated under reduced pressure. The crude was purified by preparative HPLC to provide 2-[1-cyclobutyl-6-(pyrimidin-2-yl)-1H-1,3-benzodiazol-2-yl]-5-hydroxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (18 mg, 16.07%). ES MS M/Z = 485.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (s - 1H), 8.91 (d, J = 4 Hz, 1H), 8.78 (d, J = 8 Hz, 1H), 8.39 (d, J = 4 Hz, 2H), 7.83 (d, J = 8 Hz, 2H), 7.71 (s, 1H), 7.42 (t, J = 4 Hz, 1H), 5.22-5.18 (m - 1H), 3.44 (s, 3H), 2.72-2.60 (m - 2H), 1.82-1.73 (m - 2H), 1.21 (d, J = 8 Hz, 1H). Example 43: 5-hydroxy-N-(isoxazol-4-yl)-1-methyl-6-oxo-2-(1-phenyl-3,4-dihydroisoquinolin- 2(1H)-yl)-1,6-dihydropyrimidine-4-carboxamide
Figure imgf000084_0001
[00287] 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 N,N-diisopropylethylamine (918 µL, 1.1 eq., 5.26 mmol) and the solution was stirred at 110°C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product which was purified by CombiFlash chromatography. The desired fractions were concentrated to afford methyl 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxylate (1.2 g, 60.7%). [00288] 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 (0.6 g, 1.48 mmol) in tetrahydrofuran (4.5 mL) and water (1.5 mL) was added lithium hydroxide (177 mg, 5 eq., 7.4 mmol) and stirred at ambient temperature for 16 h. After completion, the reaction mixture was acidified with HCl and then concentrated under reduced pressure to afford crude 5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxylic acid (550 mg, 88%). [00289] 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 (0.6 g, 1.53 mmol) and 1,2- oxazol-4-amine hydrochloride (222 mg, 1.2 eq., 1.84 mmol) in DMF (6 mL) were added 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (874 mg, 1.5 eq., 2.3 mmol) and DIPEA (801 µL, 3 eq., 4.6 mmol) and stirred for 16 h at ambient temperature. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to provide crude product which was purified by CombiFlash chromatography. The desired fractions were concentrated to afford N-(isoxazol-4-yl)-5- methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4- carboxamide (750 mg, 79%). [00290] Step 4: To a solution of N-(isoxazol-4-yl)-5-methoxy-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxamide (0.3 g, 656 µmol) in DMF (3.0 mL) was added lithium bromide (285 mg, 5 eq., 3.28 mmol) and the mixture was stirred for 16 h at 100 °C. After completion, the reaction was cooled to ambient temperature, concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product which was purified by reverse phase HPLC. The desired fractions were lyophilized to afford 5-hydroxy-N-(isoxazol-4-yl)-1-methyl-6-oxo-2-(1-phenyl-3,4- dihydroisoquinolin-2(1H)-yl)-1,6-dihydropyrimidine-4-carboxamide (43 mg, 14.79%). ES MS M/Z=444.30 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 10.51 (s, 1H), 9.32 (s, 1H), 8.97 (s, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.26-7.09 (m, 6H), 6.82 (d, J = 7.6 Hz, 1H), 6.29 (s, 1H), 3.62-3.56 (m, 1H), 3.52 (s, 3H), 3.39-3.32 (m, 1H), 3.22-3.15 (m, 1H), 2.91 (d, J = 16 Hz, 1H). Example 31: methyl 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxylate
Figure imgf000086_0001
[00291] To a stirred solution of 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid (150 mg, 333 µmol) in tetrahydrofuran (15 mL, 184 mmol) was added lithium hydroxide (14 mg, 333 µmol) in a sealed tube. The mixture was stirred at ambient temperature for 30 min then dimethyl sulfate (31.6 µL, 333 µmol) was added. The mixture was stirred at ambient temperature for 16 h then quenched with water and acidified with 1N HCl up to pH~5, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude compound was purified by preparative HPLC to afford methyl 1-cyclobutyl-2- {5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3- benzodiazole-6-carboxylate ( 5 mg, 3.18%). ES MS M/Z = 465.2 [M+H]+; 1H NMR (400 MHz, DMSO- d6): δ ppm 9.22 (s, 1 H), 8.81 (s, 1 H), 8.32 (s, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 5.24-5.19 (m, 1 H), 3.92 (s, 3 H), 3.43 (bs, 3 H), 2.56-2.55 (m, 2 H), 2.339-2.335 (m, 2 H), 1.81 (d, J = 5.2 Hz, 2 H). Example 30: 1-cyclobutyl-2-(5-hydroxy-4-(isoxazol-4-ylcarbamoyl)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1H-benzo[d]imidazole-6-carboxamide
Figure imgf000086_0002
[00292] To a stirred solution of 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]- 6-oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxylic acid (0.2 g, 444 µmol) in N,N- dimethylformamide (3 mL) was added DIPEA (232 µL, 3 eq., 1.33 mmol). Ammonium chloride (71.3 mg, 3 eq., 1.33 mmol) and HATU (253 mg, 1.5 eq., 666 µmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 10% MeOH in DCM, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by preparative HPLC to afford 1-cyclobutyl-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6- oxo-1,6-dihydropyrimidin-2-yl}-1H-1,3-benzodiazole-6-carboxamide; acetic acid (5 mg, 2%). LCMS(ESI) m/z: 450.2 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (bs, 1 H), 11.19 (bs, 1 H), 9.24 (s, 1 H), 8.76 (s, 1 H), 8.26 (s, 1 H), 8.17 (s, 1 H), 7.86 (d, J = 8 Hz, 1 H), 7.80 (d, J = 8 Hz, 1 H), 7.42 (s, 1 H), 5.14 - 5.09 (m, 1 H), 3.41 (s, 3 H), 2.51 - 2.33 (m, 2 H), 2.12 - 2.02 (m, 2 H), 1.90 (s, 1 H), 1.91- 1.76 (m, 2 H). Examples 45 and 46: (1R)-2-[5-hydroxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2-yl]-1- phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid and (1S)-2-[5-hydroxy-1-methyl-6-oxo-4- (phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid
Figure imgf000087_0001
[00293] Step 1: A solution of methyl 2,6-dichloro-5-methoxypyrimidine-4-carboxylate (130 g, 548.4 mmol, 1 equiv) in THF (800 mL) was treated with LiOH (65.6 g, 2742.2 mmol, 5 equiv) in portions at ambient temperature. The resulting mixture was stirred for 5 h at 50 °C then allowed to cool to ambient temperature. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EA (2 x 300 mL). The water layer was acidified to pH 1 with conc. HCl at 0 °C. The resulting mixture was concentrated under reduced pressure to 200 mL at 80 °C. The precipitated solids were collected by filtration and washed with EA (2 x 100 mL) to afford 2-chloro-6-hydroxy-5- methoxypyrimidine-4-carboxylic acid (100 g, 89.13%) as a colorless solid. ES MS M/Z = 203.0 [M-H]-. [00294] Step 2: To a stirred mixture of 2-chloro-6-hydroxy-5-methoxypyrimidine-4-carboxylic acid (300 mg, 1.47 mmol, 1 equiv) and aniline (0.16 g, 1.76 mmol, 1.2 equiv) in CH2Cl2 (20 mL) were added T3P (7.00 g, 21.99 mmol) and DIEA (0.95 g, 7.33 mmol, 5 equiv) dropwise at ambient temperature exposed to air. The resulting mixture was stirred for additional overnight at 40 °C. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification. [00295] Step 3: To a stirred mixture of 2-chloro-6-hydroxy-5-methoxy-N-phenylpyrimidine-4- carboxamide (1.0 g, 3.5 mmol, 1 equiv) in DMF (30 mL) were added CH3I (1.0 g, 7 mmol, 2 equiv) and Cs2CO3 (3.0 g, 1 mmol, 2.5 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for additional 2 h at ambient temperature. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 2-chloro-5-methoxy-1-methyl-6-oxo-N-phenyl-1,6-dihydropyrimidine-4-carboxamide(0.8 g, 76.18%) as a colorless solid. ES MS M/Z = 294.05 [M+H]+. [00296] Step 4: A solution of 6-bromo-1-phenyl-1,2,3,4-tetrahydroisoquinoline (5 g, 17.350 mmol, 1 equiv) in DCM (50 mL) was treated with Boc2O (7.57 g, 34.700 mmol, 2 equiv) followed by the addition of Et3N (4.39 g, 43.375 mmol, 2.5 equiv) dropwise at ambient temperature. The resulting mixture was stirred for overnight at ambient temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 12:1 to afford tert-butyl 6-bromo-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate as a colorless solid. [00297] Step 5: To a stirred mixture of tert-butyl 6-bromo-1-phenyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (3.2 g, 8.241 mmol, 1 equiv) and Et3N (4.2 g, 41.205 mmol, 5 equiv) in MeOH (50 mL) were added Pd(dppf)Cl2 (0.90 g, 1.236 mmol, 0.15 equiv) in portions at ambient temperature under air atmosphere. The resulting mixture was stirred for overnight at 130 °C under carbon monoxide atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-tert-butyl 6-methyl (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2,6- dicarboxylate (2.7 g, 90%) as a brown oil. ES MS M/Z = 268.15 [M-Boc+H]+. [00298] Step 6: Into a 100 mL round-bottom flask were added 2-tert-butyl 6-methyl 1-phenyl-3,4- dihydro-1H-isoquinoline-2,6-dicarboxylate (2.6 g, 7.076 mmol, 1 equiv) and HCl (in 1,4-dioxane, 20 mL) at ambient temperature. The resulting mixture was stirred for additional 1 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with Et2O (20 mL). The precipitated solids were collected by filtration and washed with Et2O (2 x 10 mL). This resulted in methyl (1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (1.5 g, 79.3%) as a colorless solid. ES MS M/Z = 268.15 [M+H]+. [00299] Step 7: A solution of methyl (1R)-2-chloro-1-phenyl-3,4-dihydro-1H-isoquinoline-6- carboxylate (450 mg, 1.491 mmol) in EtOH (5 mL) was treated with 2-chloro-5-methoxy-1-methyl-6-oxo- N-phenylpyrimidine-4-carboxamide (657 mg, 2.237 mmol, 1.5 equiv) at ambient temperature followed by the addition of DIEA (578 mg, 4.473 mmol, 3 equiv) dropwise at ambient temperature. The resulting mixture was stirred for 16 h at 80 °C. 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 methyl (1S)- 2-[5-methoxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H- isoquinoline-6-carboxylate (700 mg, 85.01%) as a colorless solid. ES MS M/Z =525.20 [M+H]+. [00300] Step 8: A solution of methyl (1S)-2-[5-methoxy-1-methyl-6-oxo-4- (phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (300 mg, 0.572 mmol, 1.00 equiv) in DMF (5 mL) was treated with dodecyl mercaptan (347 mg, 1.716 mmol, 3.00 equiv) followed by the addition of MeONa (93 mg, 1.716 mmol, 3.00 equiv) in portions at ambient temperature. The resulting mixture was stirred for 12 h at 80 °C. The mixture was allowed to cool to ambient temperature. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford methyl (1R)-2-[5-hydroxy-1-methyl-6-oxo-4- (phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (230 mg, 86.19%) as a colorless solid. ES MS M/Z = 511.20 [M+H]+. [00301] Step 9: A solution of methyl 2-[5-hydroxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2- yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylate (200 mg, 0.392 mmol, 1 equiv) in THF (5 mL) and H2O (5 mL) was treated with LiOH (28 mg, 1.176 mmol, 3 equiv) at ambient temperature then stirred for 12 h. The resulting mixture was concentrated under reduced pressure then diluted with water (10 mL). The aqueous layer was extracted with EA (2x10 mL), acidified to pH 1 with HCl (2 M), and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-[5- hydroxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6- carboxylic acid (150 mg, 74.85% ) as a colorless solid. [00302] Step 10: The crude -2-[5-hydroxy-1-methyl-6-oxo-4-(phenylcarbamoyl)pyrimidin-2-yl]-1- phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (150 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK IG3; Mobile Phase A: Hex (0.1% FA):EtOH = 60: 40; Flow rate: 1.0 mL/min; Gradient: isocratic ; Injection Volume: 3 mL) to afford (1R)-2-[5-hydroxy-1-methyl-6- oxo-4-(phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (36.3 mg, 18.66%). ES MS M/Z = 497.20 [M+H]+, UPLC: 93%, 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 11.39 (s, 2H), 9.96 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.72 (t, J = 16.0, 8.4, 1.6 Hz, 3H), 7.54 - 7.34 (m, 4H), 7.24 (t, J = 7.3, 5.3 Hz, 3H), 7.21 - 7.11 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 3.22 (d, J = 9.6 Hz, 1H), 2.98 (d, J = 16.7 Hz, 1H); and (1S)-2-[5-hydroxy-1-methyl-6-oxo-4- (phenylcarbamoyl)pyrimidin-2-yl]-1-phenyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (28.7 mg, 14.75%) ES MS M/Z = 497.20 [M+H]+, UPLC = 96%, 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 11.39 (s, 2H), 9.96 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.72 (t, J = 16.0, 8.4, 1.6 Hz, 3H), 7.54 - 7.34 (m, 4H), 7.24 (td, J = 7.3, 5.3 Hz, 3H), 7.21 - 7.11 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 3.22 (d, J = 9.6 Hz, 1H), 2.98 (d, J = 16.7 Hz, 1H). [00303] The following compounds were synthesized in a similar manner: Example 47: (1R)-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxopyrimidin-2-yl}- N,N-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinoline-7-carboxamide [00304] ES MS M/Z = 515.2 [M+H]+. UPLC:99%; 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 10.51 (s, 1H), 9.34 (s, 1H), 8.99 (s, 1H), 7.39 – 7.29 (m, 3H), 7.27 – 7.19 (m, 3H), 7.19 – 7.10 (m, 1H), 6.87 (d, J = 1.8 Hz, 1H), 6.34 (s, 1H), 3.65 – 3.57 (m, 1H), 3.53 (s, 3H), 3.40 - 3.31 (m, 1H), 3.23 - 3.21 (m, 1H), 2.95 (d, J = 16.6 Hz, 1H), 2.89 (s, 3H), 2.74 (s, 3H). Stereochemistry arbitrarily assigned. Example 48: (1R)-2-{5-hydroxy-1-methyl-4-[(1,2-oxazol-4-yl)carbamoyl]-6-oxopyrimidin-2-yl}-1- phenyl-3,4-dihydro-1H-isoquinoline-7-carboxamide [00305] ES MS M/Z = 487.1 [M+H]+, UPLC: 96%; 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.50 (s, 1H), 9.33 (s, 1H), 8.98 (s, 1H), 7.87 (s, 1H), 7.74 - 7.66 (m, 1H), 7.52 - 7.10 (m, 8H), 6.38 - 6.27 (m, 1H), 3.68 - 3.47 (m, 4H), 3.43 - 3.37 (m, 1H), 3.25 - 2.91 (m, 2H). Stereochemistry arbitrarily assigned. Example 49: 5-hydroxy-2-[3-(hydroxymethyl)-1-methylindol-4-yl]-1-methyl-N-(1,2-oxazol-4-yl)-6- oxopyrimidine-4-carboxamide
Figure imgf000090_0001
[00306] Step 1: NaH (214 mg, 5.36 mmol, 1.2 equiv, 60%) was added to a solution of 4-bromo-1H- indole-3-carbaldehyde (1 g, 4.463 mmol, 1 equiv) in DMF (10 mL) at 0 °C and the obtained suspension was stirred at rt for 0.5 h. Then, CH3I (729 mg, 5.132 mmol, 1.15 equiv) was added slowly. The obtained suspension was stirred at rt for 2 h. To the reaction suspension, EtOAc (50 mL) and water (50 mL) were added. The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel column to provide 4-bromo-1-methylindole-3-carbaldehyde (800 mg, 73.79%) as a yellow solid. ES MS M/Z = 238.1, 240.1 [M+H]+, [M+2H]+. [00307] Step 2: A dark brown suspension of 4-bromo-1-methylindole-3-carbaldehyde (400 mg, 1.68 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (512 mg, 2.02 mmol, 1.2 equiv), Pd(dppf)Cl2 (123 mg, 0.168 mmol, 0.1 equiv) and KOAc (214 mg, 2.18 mmol, 1.3 equiv) in 1,4-dioxane (10 mL) was stirred under N2 at 90 °C for 2 h. To the reaction suspension, EtOAc (50 mL) and water (50 mL) were added. The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried with Na2SO4, filtered and concentrated to provide 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-3-carbaldehyde (500 mg, 42.96%) as a brown solid. ES MS M/Z = 286.2 [M+H]+. [00308] Step 3: A dark brown suspension of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indole-3-carbaldehyde (720 mg, 2.525 mmol, 1.2 equiv), 2-chloro-5-methoxy-1-methyl-N-(1,2-oxazol- 4-yl)-6-oxopyrimidine-4-carboxamide (599 mg, 2.104 mmol, 1.00 equiv), Pd(dtbpf)Cl2 (137 mg, 0.210 mmol, 0.1 equiv) and K3PO4 (893 mg, 4.208 mmol, 2 equiv) in THF (8 mL) and H2O (2 mL) was stirred under N2 at 90 °C for 2 h. After cooling to rt, EtOAc (50 mL) and water (50 mL) were added. The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried with Na2SO4, filtered and concentrated. The residue was submitted to silica gel column and reverse phase column (0.05% TFA) giving 2-(3-formyl-1-methylindol-4-yl)-5-methoxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxopyrimidine-4-carboxamide (80 mg, 8.46%) as a light yellow solid. ES MS M/Z = 408.1 [M+H]+. [00309] Step 4: A yellow solution of 2-(3-formyl-1-methylindol-4-yl)-5-methoxy-1-methyl-N-(1,2- oxazol-4-yl)-6-oxopyrimidine-4-carboxamide (75 mg, 0.184 mmol, 1 equiv) and LiBr (80 mg, 0.920 mmol, 5 equiv) in DMF (2 mL) was stirred at 100 °C for 2 h. After cooling to rt, the solution was purified by reverse phase column (0.05% FA) affording 2-(3-formyl-1-methylindol-4-yl)-5-hydroxy-1-methyl-N- (1,2-oxazol-4-yl)-6-oxopyrimidine-4-carboxamide (45 mg, 61.34%) as a light yellow solid. ES MS M/Z = 394.1 [M+H]+. [00310] Step 5: LiBH4 (51 uL, 0.203 mmol, 2.00 equiv, 4M in THF) was added dropwise into a solution of 2-(3-formyl-1-methylindol-4-yl)-5-hydroxy-1-methyl-N-(1,2-oxazol-4-yl)-6-oxopyrimidine-4- carboxamide (40 mg, 0.102 mmol, 1 equiv) in THF (4 mL) at 0 °C and the obtained yellow solution was stirred at this temperature for 1 h. The reaction was quenched by water (1 mL) and then submitted to Prep- HPLC with following conditions: Column: XBridge Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 10% B to 40% B in 7min; Wave Length: 254nm nm; RT1(min): 6.33; Number Of Runs: 7. After lyophilization, it provided 5-hydroxy-2-[3-(hydroxymethyl)-1-methylindol-4-yl]-1-methyl-N- (1,2-oxazol-4-yl)-6-oxopyrimidine-4-carboxamide (13.2 mg, 32.04%). ES MS M/Z = 394.0 [M-H]-, UPLC: 97%; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.76 (s, 1H), 7.60 - 7.51 (m, 1H), 7.41 - 7.21 (m, 2H), 7.07 (s, 1H), 4.28 - 4.15 (m, 1H), 4.13 - 4.02 (m, 1H), 3.80 (s, 3H), 3.14 (s, 3H). Example A. Human TREX1 Enzymatic Assay with dsDNA Native Oligonucleotide [00311] Human TREX1 enzyme (amino acids 1-242) was diluted in assay buffer (20 mM Tris pH 7.7, 5 mM MgCl2, 0.01% human serum albumin, 0.01% Brij™-35, 2 mM dithiothreitol) to 0.3 nM and 5 µL was added to a 384-well low-binding polypropylene plate (final enzyme concentration in reaction is 0.15 nM) . Test compounds were prepared at 1 mM in DMSO (final DMSO concentration in reaction mixture of 0.3%) and serially diluted 3-fold into 10 stock concentrations.30 nL of each stock concentration was added to the wells with a concentration ranging from 3 µM to 0.15 nM. The reaction mixtures were incubated for 15 minutes at 24 °C and 5 µL of a solution of annealed dsDNA oligonucleotide was added to a final concentration of 50 nM. The reaction mixtures were incubated at 24 °C for 15 minutes and subsequently quenched by transferring part of the assay reaction to a solution of 100 mM ethylenediaminetetraacetic acid and 0.67% v/v Picogreen™ in a black plate with an opaque bottom. The fluorescence (emission wavelength 480 nm / excitation wavelength 520 nm) was measured using a Molecular Devices SpectraMax plate reader. Wells containing oligonucleotide but no TREX1 enzyme were used as negative controls. Wells containing oligonucleotide, TREX1 enzyme, and DMSO were used as positive controls. Example B. Murine TREX1 Enzymatic Assay with dsDNA Native Oligonucleotide [00312] Murine TREX1 enzyme (amino acids 1-242) was diluted in assay buffer (20 mM Tris pH 7.7, 5 mM MgCl2, 0.01% human serum albumin, 0.01% Brij™-35, 2 mM dithiothreitol) to 0.3 nM and 5 µL was added to a 384-well low-binding polypropylene plate (final enzyme concentration in reaction is 0.15 nM) . Test compounds were prepared at 1 mM in DMSO (final DMSO concentration in reaction mixture of 0.3%) and serially diluted 3-fold into 10 stock concentrations.30 nL of each stock concentration was added to the wells with a concentration ranging from 3 µM to 0.15 nM. The reaction mixtures were incubated for 15 minutes at 24 °C and 5 µL of a solution of annealed dsDNA oligonucleotide was added to a final concentration of 50 nM. The reaction mixtures were incubated at 24 °C for 10 minutes and subsequently quenched by transferring part of the assay reaction to a solution of 100 mM ethylenediaminetetraacetic acid and 0.67% v/v Picogreen™ in a black plate with an opaque bottom. The fluorescence (emission wavelength 480 nm / excitation wavelength 520 nm) was measured using a Molecular Devices SpectraMax plate reader. Wells containing oligonucleotide but no TREX1 enzyme were used as negative controls. Wells containing oligonucleotide, TREX1 enzyme, and DMSO were used as positive controls. [00313] The data is shown in Table 2. Table 2
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000094_0002
[00314] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: wherein:
Figure imgf000095_0001
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1 on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; R2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; R3 is hydrogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -CH2OC(=O)ORb, -CH(CH3)OC(=O)ORb, - C(CH3)2OC(=O)ORb, -CH2OC(=O)Ra, -CH(CH3)OC(=O)Ra, -C(CH3)2OC(=O)Ra, - CH2OP(=O)(ORb)2, -P(=O)(ORb)2, -P(=O)(ORb)(NRb), C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; Ring B is a bicyclic ring; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a; each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R4a on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, 4, or 5; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, - C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is a bicyclic heteroaryl.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is an indole, benzoxazole, benzimidazole, or benzothiazole.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is benzimidazole.
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is bicyclic heterocycloalkyl.
6. The compound of claim 1 or 5, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is tetrahydroisoquinolinyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein m is 0, 1, 2, or 3.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein m is 0, 1, or 2.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein m is 1 or 2.
10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is of Formula (Ia): wherein:
Figure imgf000097_0001
R4’ is hydrogen or R4; and R5 is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a; each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a.
12. The compound of claim 10 or 11, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a.
13. The compound of any one of claims 10-12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5 is C1-C6alkyl, cycloalkyl, or aryl; wherein the alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R5a.
14. The compound of any one of claims 10-13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5 is cycloalkyl optionally substituted with one or more R5a.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, - NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R4a.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, - NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R4a.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R4 is independently halogen, -NRcRd, - NRbC(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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 R4a.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, 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.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
20. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is of Formula (Ib): wherein:
Figure imgf000099_0001
each R6 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6a; each R6a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R6a on the same atom are taken together to form an oxo; p is 0, 1, 2, or 3; each R7 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R7a; each R7a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R7a on the same atom are taken together to form an oxo; q is 0, 1, or 2.
21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R6 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R6a.
22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R6 is independently aryl optionally substituted with one or more R6a.
23. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein p is 0 or 1.
24. The compound of any one of claims 20-23, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein p is 1.
25. The compound of any one of claims 20-24, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R7 is independently halogen, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R7a.
26. The compound of any one of claims 20-25, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R7 is independently halogen, -C(=O)ORb or - C(=O)NRcRd.
27. The compound of any one of claims 20-26, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R7 is independently halogen, -C(=O)ORb.
28. The compound of any one of claims 20-27, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R7 is independently halogen, -C(=O)NRcRd.
29. The compound of any one of claims 20-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein q is 0 or 1.
30. The compound of any one of claims 20-29, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein q is 1.
31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is cycloalkyl or heterocycloalkyl.
32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.
33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is heteroaryl.
34. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is 5- or 6-membered heteroaryl.
35. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is 5-membered heteroaryl.
36. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl.
37. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, or triazolyl.
38. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is pyrazolyl, isoxazolyl, or isothiazolyl.
39. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is isoxazolyl.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, and heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein n is 0 or 1.
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R2 is hydrogen or C1-C6alkyl.
44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R2 is hydrogen.
45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R3 is hydrogen or C1-C6alkyl.
46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R3 is hydrogen.
47. A compound selected from the group consisting of a compound found in table 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
48. A pharmaceutical composition comprising the compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
49. A method of treating cancer in a subject in need thereof, the method comprising administering the compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
50. The method of claim 49, wherein the cancer is characterized by a DNA repair deficiency in one or more DNA repair pathways.
51. The method of claim 50, wherein 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.
52. The method of claim 50 or claim 51, wherein the DNA repair deficiency is a deficiency in the homologous recombination (“HR”) pathway.
53. The method of any one of claims 50-52, wherein the DNA repair deficiency is a BRCA1 mutation.
54. The method of any one of claims 50-53, further comprising administering a DNA repair inhibitor.
55. The method of claim 54, wherein the DNA repair inhibitor is a poly ADP ribose polymerase (“PARP”) inhibitor.
56. The method of any one of claims 50-53, further comprising administering an alkylating agent.
57. The method of claim 56, wherein the alkylating agent is cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, nimustine, fotemustine, streptozocin, or busulfan.
58. The method of any one of claims 50-53, further comprising administering a DNA damaging agent.
59. The method of claim 58, wherein the DNA damaging agent is camptothecin, etoposide, oxaliplatin, cisplatin, or doxorubicin.
60. The method of any one of claims 50-53, wherein the compound is administered in conjunction with high-dose radiotherapy.
61. The method of claim 61, wherein the high-dose radiotherapy is administered as a single dose and/or hypofractionated.
62. The method of any one of claims 50-53, wherein the compound is administered in conjunction with Stereotactic Body Radiation Therapy (SBRT).
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