Patent Publication Number: US-2020282048-A1

Title: Use of imidazopyrimidine for modulating human immune response

Description:
RELATED APPLICATION 
     This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/586,137, filed Nov. 14, 2017, the entire contents of which is incorporated herein by reference. 
    
    
     GOVERNMENT SUPPORT 
     This disclosure was made with government support under HHSN272201400052C awarded by the National Institutes of Health (NIH)/National Institute of Allergy &amp; Infectious Diseases (NIAID) Adjuvant Discovery Program. The government has certain rights in this invention. 
    
    
     BACKGROUND 
     Human immunity is crucial to both health and illness, playing key roles in multiple major diseases including infectious diseases, allergy, and cancer. Animal and human studies suggest that certain small molecules act as immune activators. 
     SUMMARY 
     Provided herein are imidazopyrimidine compounds for use in enhancing human immune response. Therapeutic or prophylactic use of the imidazopyrimidine compounds are described. In some embodiments, the imidazopyrimidine compounds are used alone as immune-enhancing or modifying agents. In some embodiments, the imidazopyrimidine compounds are used as adjuvants in vaccine compositions. Adjuvants can enhance, prolong, and modulate immune responses to vaccinal antigens to maximize protective immunity. In some embodiments, using imidazopyrimidine as vaccine adjuvants enable effective immunization in vulnerable populations (e.g., neonates, the elderly, or immunocompromised individuals). In some embodiments, the imidazopyrimidine compound enhance both innate and adaptive immune response. 
     Some aspects of the present disclosure provide composition comprising an antigen and an imidazopyrimidine compound. In some embodiments, the antigen comprises a protein or polypeptide. In some embodiments, the antigen comprises a nucleic acid encoding a protein or a polypeptide. In some embodiments, the nucleic acid is DNA or RNA. 
     In some embodiments, the antigen is from a microbial pathogen. In some embodiments, the microbial pathogen is a mycobacterium, bacterium, fungus, virus, parasite, or prion. In some embodiments, the bacterium is  Bacillus anthracis, Bordetella pertussis, Corynebacterium diphtheriae, Clostridium tetani, Haemophilus influenzae  type b, pneumococcus.  Staphylococci  spp.,  Mycobacterium tuberculosis, Neiserria meningitidis, Salmonella typhi. Vibrio cholerae , or  Yersinia pestis . In some embodiments, the virus is adenovirus, enterovirus such as poliomyelitis, Ebola virus, herpes viruses such as herpes simplex virus, cytomegalovirus and varicella-zoster, measles, mumps, rubella, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Influenza virus, rabies. Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, yellow fever, or Zika Virus. In some embodiments, the parasite is malaria.  Leishmania , or a helminth. In some embodiments, the fungus is  Candida  spp.,  Aspergillus  spp.,  Cryptococcus  spp.,  Mucormycete, Blastomyces dermatitidis, Histoplasma capsulatum , or  Sporothrix schenckii . In some embodiments, the antigen is a cancer-specific antigen. In some embodiments, the antigen is a heteroclitic epitope or a cryptic epitope derived from the cancer-specific antigen. In some embodiments, the cancer-specific antigen is a neoantigen. In some embodiments, the antigen comprises a lipopolysaccharide (LPS). 
     In some embodiments, the imidazopyrimidine compound is of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
     R 1A  is substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl; 
     R 1  is hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ): 
     each instance of R A  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , or —NO 2 : 
     each instance of R B  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN. —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; 
     each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; 
     each instance of R a1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or two instances of R a1  are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; 
     a is 0, 1, 2, or 3; and 
     b is 0, 1, 2, or 3. 
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
     each instance of R 2  is independently hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; 
     each instance of R C  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and 
     c is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, R 1  is halogen or substituted or unsubstituted C 1-6  alkyl. 
     In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, at least one instance of R 2  is substituted or unsubstituted C 1-6  alkyl. In some embodiments, at least one instance of R 2  is Me or Et. In some embodiments, R A  is halogen, substituted or unsubstituted C 1-6  alkyl, or —O(substituted or unsubstituted C 1-6  alkyl). In some embodiments, R A  is —F, Me. or —OMe. In some embodiments, a is 1. In some embodiments, a is 0. In some embodiments, b is 0. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, R C  is halogen or substituted or unsubstituted C 1-6  alkyl. 
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. In some embodiments, the imidazopyrimidine compound is conjugated to the antigen. In some embodiments, the imidazopyrimidine compound is not conjugated to the antigen. 
     In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. 
     In some embodiments, the composition is a vaccine composition. In some embodiments, the imidazopyrimidine compound is an adjuvant. In some embodiments, the antigen is adsorbed onto alum. In some embodiments, the imidazopyrimidine compound is adsorbed onto alum. In some embodiments, the imidazopyrimidine compound is lipidated. 
     In some embodiments, the vaccine composition further comprises a second adjuvant. In some embodiments, the second adjuvant is an agonist of Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptor, C-type Lectin receptors (CLRs), or a stimulator of interferon genes (STING). In some embodiments, second adjuvant is bound to or adsorbed to alum. In some embodiments, the second adjuvant is alum. In some embodiments, the second adjuvant is an emulsion. 
     Some aspects of the present disclosure provide imidazopyrimidine compounds for use as an adjuvant in a vaccine. Some aspects of the present disclosure provide imidazopyrimidine compounds for use in enhancing an immune response in a subject. Some aspects of the present disclosure provide vaccines comprising an antigen and an adjuvant comprising an imidazopyrimidine compound. Some aspects of the present disclosure provide the vaccine is a subunit vaccine, an attenuated vaccine, or a conjugate vaccine. 
     Other aspects of the present disclosure provide methods of enhancing an immune response to an antigen in a subject in need thereof, the method comprising administering to the subject an effective amount of an antigen and an effective amount of an imidazopyrimidine compound. In some embodiments, the antigen comprises a protein or polypeptide. In some embodiments, the antigen comprises a nucleic acid encoding a protein or a polypeptide. In some embodiments, the nucleic acid is DNA or RNA. 
     In some embodiments, the antigen is from a microbial pathogen. In some embodiments, the microbial pathogen is a bacterium, mycobacterium, fungus, virus, parasite, or prion. In some embodiments, the bacterium is  Bacillus anthracis, Bordetella pertussis, Corynebacterium diphtheriae. Clostridium tetani. Haemophilus influenzae  type b, pneumococcus,  Staphylococci  spp.,  Mycobacterium tuberculosis, Neiserria meningitidis, Salmonella typhi, Vibrio cholerae , or  Yersinia pestis . In some embodiments, the virus is adenovirus, enterovirus such as poliomyelitis, Ebola virus, herpes viruses such as herpes simplex virus, cytomegalovirus and varicella-zoster, measles, mumps, rubella, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papilloma virus, Influenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, yellow fever, or Zika Virus. In some embodiments, the parasite is ( Plasmodium  spp.),  Leishmania , another protozoan or a helminth. In some embodiments, the fungus is  Candida  spp.,  Aspergillus  spp.,  Cryptococcus  spp.,  Mucormycete. Blastomyces dermatitidis. Histoplasma capsulatum , or  Sporothrix schenckii . In some embodiments, the antigen is a cancer-specific antigen. In some embodiments, the antigen is a heteroclitic epitope or a cryptic epitope derived from the cancer-specific antigen. In some embodiments, the cancer-specific antigen is a neoantigen. In some embodiments, the antigen comprises a lipopolysaccharide (LPS). 
     In some embodiments, the imidazopyrimidine compound is of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
     R 1A  is substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl: 
     R 1  is hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; each instance of R A  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; 
     each instance of R B  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR 3 , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; 
     each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; 
     each instance of R a1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or two instances of R a1  are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; 
     a is 0, 1, 2, or 3; and 
     b is 0, 1, 2, or 3. 
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
     each instance of R 2  is independently hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; 
     each instance of R C  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and 
     c is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, R 1  is halogen or substituted or unsubstituted C 1-6  alkyl. In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, at least one instance of R 2  is substituted or unsubstituted C 1-6  alkyl. In some embodiments, at least one instance of R 2  is Me or Et. In some embodiments, R A  is halogen, substituted or unsubstituted C 1-6  alkyl, or —O(substituted or unsubstituted C 1-6  alkyl). In some embodiments, R A  is —F, Me, or —OMe. In some embodiments, a is 1. In some embodiments, a is 0. In some embodiments, b is 0. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, R C  is halogen or substituted or unsubstituted C 1-6  alkyl. 
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, the compound is of the formula: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. In some embodiments, the imidazopyrimidine compound is conjugated to the antigen. In some embodiments, the imidazopyrimidine compound is not conjugated to the antigen. 
     In some embodiments, the antigen is adsorbed onto alum. In some embodiments, the imidazopyrimidine compound is adsorbed onto alum. In some embodiments, the imidazopyrimidine compound is lipidated. 
     In some embodiments, the antigen and/or the imidazopyrimidine compound is in an aqueous formulation. In some embodiments, the antigen and/or the imidazopyrimidine is formulated adsorbed onto alum. In some embodiments, the antigen and/or the imidazopyrimidine is formulated in a liposome. In some embodiments, the antigen and/or the imidazopyrimidine compound is formulated in a nanoparticle. 
     In some embodiments, the method further comprises administering to the subject a second adjuvant. In some embodiments, the second adjuvant is an agonist of Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptor, C-type Lectin receptors (CLRs), and or a stimulator of interferon genes (STING). In some embodiments, second adjuvant is bound to or adsorbed to alum. In some embodiments, the second adjuvant is alum. In some embodiments, the second adjuvant is an emulsion. 
     In some embodiments, the antigen and the imidazopyrimidine compound are administered simultaneously. In some embodiments, the antigen and the imidazopyrimidine compound are administered separately. In some embodiments, the antigen and the imidazopyrimidine compound is administered once to the subject. In some embodiments, the antigen and the imidazopyrimidine compound is administered repeatedly to the subject. 
     In some embodiments, the adjuvant activates B cell immunity. In some embodiments, the imidazopyrimidine compound enhances the production of antigen-specific antibodies, compared to when the antigen is administered alone. In some embodiments, the imidazopyrimidine compound enhances the activation of antigen-specific cytotoxic T cells, compared to when the antigen is administered alone. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T helper 1 (Th1) immunity. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T helper 2 (Th2) immunity. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T helper 17 (Th17) immunity. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T follicular helper (Tfh) cell immunity. 
     In some embodiments, the adjuvant directly activates B cell immunity. In some embodiments, the imidazopyrimidine compound prolongs a protective effect in the subject against the antigen, compared to when the antigen is administered alone. 
     In some embodiments, the imidazopyrimidine compound increases rate of an immune response, compared to when the antigen is administered alone. 
     In some embodiments, the antigen produces a same level of immune response against the antigen at a lower dose in the presence of the imidazopyrimidine compound, compared to when the antigen is administered alone. 
     In some embodiments, the subject has or is at risk of developing an infectious disease. In some embodiments, the infectious disease is caused a bacterium, a mycobacterium, a fungus, a virus, a parasite or a prion. In some embodiments, the infectious disease is sepsis. 
     In some embodiments, the subject has or is at risk of developing is cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is melanoma. 
     In some embodiments, the subject has or is at risk of developing an allergic disease. 
     In some embodiments, the administering is done systemically or locally. In some embodiments, the administering is done intramuscularly, intradermally, orally, intravenously, topically, intranasally, intravaginally, or sublingually. In some embodiments, the administration is prophylactic. 
     In some embodiments, the subject is a human neonate, an infant, an adult, or an elderly individual. In some embodiments, the subject is a human neonate. In some embodiments, the human infant is less than 28 days of age (a human newborn) at the time of administration. In some embodiments, the human infant (human newborn) is less than 24 hours of age at the time of administration. In some embodiments, the administration occurs at birth. In some embodiments, a second administration occurs when the subject is less than or equal to 28 days of age. In some embodiments, a second administration occurs when the subject is less than 6 months of age. In some embodiments, the administration occurs when the human infant is 2 months, 4 months, and 6 months of age. 
     In some embodiments, the subject is born prematurely or has low birth weight. 
     In some embodiments, the subject is a human adult. In some embodiments, the subject is an elderly individual. In some embodiments, the administration occurs when the subject is more than 65 years of age. In some embodiments, the subject is immune-compromised (e.g., due to primary or acquired immunodeficiency). 
     Other aspects of the present disclosure provide methods of vaccinating a subject in need thereof, the method comprising administering to the subject an effective amount of the compositions or vaccines described herein. Methods of treating a disease are also provided, the methods comprising administering to a subject in need thereof an effective amount of the composition or vaccines described herein. 
     Further provided herein are methods of enhancing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of an imidazopyrimidine compound. In some embodiments, the immune response is an innate immune response. In some embodiments, the imidazopyrimidine compound activates peripheral blood mononuclear cells (PBMCs). In some embodiments, the imidazopyrimidine compound activates an pattern recognition receptor (PRR). In some embodiments, the PRR is selected from the group consisting of Toll-like receptor, NOD-like receptor, RIG-1-like receptor, C-type Lectin receptors, and STING. In some embodiments, the Toll-like receptor is Toll-like receptor-1, -2, -3, -4, -5, -6, -9, or -10. In some embodiments, the Toll-like receptor is Toll-like receptor-7 or -8. In some embodiments, the imidazopyrimidine compound induces the production of a proinflammatory cytokine in the subject. In some embodiments, the proinflammatory cytokine is TNF, IL-12, IL-6, or IL1-β. 
     Yet other aspects of the present disclosure provide methods of treating a disease, the methods comprising administering to a subject in need thereof an effective amount of an imidazopyrimidine compound. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. In the drawings: 
         FIGS. 1A-1D  deppict scatter plots demonstrating the stimulation of adult peripheral blood mononuclear cells (PBMCs) with hit compounds from a TNF AlphaLISA screen. The PBMCs were stimulated for 18 hours. ( FIGS. 1A-1C ) Individual scatter plots from 3 unique adult PBMC samples/donors, run in duplicate (x and y axes). ( FIG. 1D ) a Venn diagram compares hits between 3 distinct adult donors, with 24 hits identified that passed the analysis threshold for at least 2 donors and ˜10 hits common to all with a rZ&gt;3 for each donor. 
         FIGS. 2A-2B  demonstrate that compounds 037 and 038 induce TNF and IL-1β from adult and elderly PBMCs. ( FIG. 2A ) Human adult (top) and elderly (bottom) PBMCs stimulated for 18 hours with the TLR7/8 agonist R848 and 24 confirmed hit compounds from TNF AlphaLISA screen. TNF (left panels) and IL-1β (right panels) were assessed in cell-free supernatants by ELISA. Data are shown as median and interquartile range of N=5. ( FIG. 2B ) Compound 037 and 038, both small molecules within the same class, were identified as the most potent inducers of innate immune cytokines. 
         FIGS. 3A-3B  depict the potency and efficacy of the 037 compound as compared to R848. ( FIG. 3A ) TNF production measured by ELISA after stimulation of human adult peripheral blood mononuclear cells (PBMCs) with R848 or compound 037 at seven different concentrations (0.05 μM-33 μM) for 18 hours (N=8-12). ( FIG. 3B ) TNF production measured by ELISA after stimulation of PBMCs with compound 037 and R848 at a concentration of 10 μM. Compound R848 is a small imidazoquinoline molecule that activates human leukocytes via PRRs (TLR7/8 and inflammasome). 
         FIG. 4  are radar plots demonstrating that compound 037 induced a broad concentration-dependent cytokine response with distinct potency, efficacy and cytokine pattern as compared with R848. Shown is a 9-plex multiplex cytokine assay after stimulation of adult peripheral blood mononuclear cells (PBMCs) with compound 037 or R848 at four different concentrations (0.1 μM-33 μM). Radar plots of immune polarizing cytokine production from human adult PBMCs stimulated for 18 hours in 10% autologous plasma, represented as fold-change over RPMI unstimulated control (N=4). 
         FIGS. 5A-5B  demonstrates that 037 does not activate THP1-Lucia cells via NF-κB-driven expression of luciferase. ( FIG. 5A ) Human adult PBMCs were stimulated for 18 hours with the positive control compound R848 or compound 037 and its analogs at 33 μM. Production human TNF was measured in cell-free supernatants by ELISA (N=5). ( FIG. 5B ) in comparison to the positive control compound R848, 037 demonstrates little activity towards THP1 cells, as measured by NF-κB-driven expression of luciferase (N=4). Results are shown as the median, the 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers). **p&lt;0.01 determined by repeated measure one-way ANOVA with Dunnett&#39;s multiple comparison test on log-transformed data and comparing each compound with DMSO (control condition). 
         FIGS. 6A-6B  shows the activity of compound 037 and commercially available compound 037 analogs (imidazopyrimidines) on human adult PBMCs. Human adult PBMCs were stimulated for 18 hours with compound 037 and its analogs at 33 μM. Production of human TNF was assessed in cell-free supernatants by ELISA. Results are shown as the median, the 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers) and expressed as percentage TNF production (TNF %) as compared to R848 ( FIG. 6A ) or TNF concentration in ng/ml ( FIG. 6B ) (N=3-5). **p&lt;0.01 determined by repeated measure one-way ANOVA with Dunnett&#39;s multiple comparison test on log-transformed data and comparing each compound with DMSO (control condition). 
         FIGS. 7A-7B  shows the activity of compound 037 and de novo synthesized compound 037 analogs (imidazopyrimidines) on human adult PBMCs. Human adult PBMCs were stimulated for 18 hours with compound 037 and its analogs at 33 μM. Production of human TNF was assessed in cell-free supernatants by ELISA. Results are shown as the median, the 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers) and expressed as percentage TNF production (TNF %) as compared to R848 ( FIG. 7A ) or TNF concentration in ng/ml ( FIG. 7B ) (N=5). Analogs are ranked left to right by TNF % (compound 037 on the far left). Compound 037 analogs have been classified in the following categories according to TNF %: high activity—class A: TNF %&gt;15%; medium activity—class B: 1%&lt;TNF %≤15%; low activity—class C: TNF %≤1%. **p&lt;0.01 determined by repeated measure one-way ANOVA with Dunnett&#39;s multiple comparison test on log-transformed data and comparing each compound with DMSO (control condition). 
         FIG. 8  demonstrates that the compound 037 analog 02-144-3 activates both human PBMCs and mouse splenocytes. Splenocytes isolated from 6-8 weeks old C57BL/6 mice and human adult PBMCs were stimulated for 18 hours with compound 037 and its analogs at 33 μM. Production of murine IL-6 and human TNF was assessed in cell-free supernatants by ELISA. Results are presented as scatter plot in which each dot represents median production of human TNF (N=3-5) or murine IL-6 (N=6) for each compound. 
         FIG. 9  shows correlation between in vitro and in vivo activities of compound 037 analogs. 6-8 weeks old C57BL/6 mice were immunized on Day 0 (prime) and Day 28 (boost) with rHA alone or formulated with compound 02-184-02 (inactive analog), compound 037, compound 02-144-3 (analog that is active on both human and murine cells) or alum. Serum samples were collected at Day 28 (pre-boost) and Day 42 (14 post-boost) and anti-rHA IgG titers were assessed by ELISA. Results are shown as the median, the 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers) of 10 mice per group. *p&lt;0.05 and **p&lt;0.01 determined by Kruskal-Wallis with Dunn&#39;s multiple comparison test. 
         FIG. 10  demonstrates that imidazopyrimidines induce TNF production in a human newborn whole blood assay. Human newborn cord blood was anticoagulated with pyrogen-free heparin and stimulated with compound 037 analog family or R848 at 11 μM for 18 hours. After centrifugation, supernatants were collected and cryopreserved prior to measurement of TNF production by ELISA. N=5. **p&lt;0.01 determined by repeated measure one-way ANOVA with Dunn&#39;s multiple comparison test on log-transformed data and comparing each compound with DMSO (control condition). 
     
    
    
     DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 
     Some aspects of the present disclosure are based, at least in part, on the finding that imidazopyrimidine compounds induce robust activation of human leukocytes in vitro and act as adjuvants in vivo. Accordingly, provided herein are imidazopyrimidine compounds for use in modifying human immune responses, including innate and adaptive immune responses. In some embodiments, the imidazopyrimidine compounds are used as adjuvants in vaccines. Adjuvants can enhance, prolong, and modulate immune responses to vaccinal antigens to maximize protective immunity. In some aspects, using imidazopyrimidine as vaccine adjuvants enable effective immunization in vulnerable populations (e.g., neonates, elderly, or immunocompromised individuals). In some embodiments, the imidazopyrimidine compounds are used in the treatment (both prophylactically or therapeutically) of infectious diseases, cancer, or allergy. In some embodiments, novel imidazopyrimidine compounds are synthesized and used. 
     Imidazopyrimidine Compounds 
     Some aspects of the present disclosure provide compositions comprising an antigen and an imidazopyrimidine compound. A “imidazopyrimidine compound,” as used herein, encompasses any compounds comprising an imidazopyrimidine core structure, including analogs, derivatives, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. In some embodiments, the general imidazopyrimidine core structure is of the formula 
     
       
         
         
             
             
         
       
     
     wherein the compound is optionally substituted at any position. 
     In some embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In one aspect, the present disclosure provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: 
     R 1A  is substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, or substituted or unsubstituted 6-membered heteroaryl; 
     R 1  is hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 : 
     each instance of R A  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; 
     each instance of R B  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 : 
     each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom: 
     each instance of R a1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or two instances of R a1  are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; 
     a is 0, 1, 2, or 3; and 
     b is 0, 1, 2, or 3. 
     Formula (I) includes substituent R 1  on the phenyl ring. In some embodiments, R 1  is hydrogen. In some embodiments, R A1  is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1  is substituted or unsubstituted C 1-6 , alkyl (e.g., substituted or unsubstituted Me or substituted or unsubstituted Et). In some embodiments, R 1  is Me. In some embodiments. R 1  is Et. In some embodiments, R 1  is —OR a  (e.g., —OH, —O(substituted or unsubstituted C 1-6  alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn). In some embodiments, R 1  is —N(R a1 ) 2  (e.g., —NH 2 , —NH(substituted or unsubstituted C 1-6  alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted C 1-6  alkyl)-(substituted or unsubstituted C 1-6  alkyl) (e.g., —NMe 2 )). 
     Formula (I) includes substituent R 1A . In some embodiments, R 1A  is substituted or unsubstituted phenyl. In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein each instance of R C  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and c is 0, 1, 2, 3, 4, or 5. In some embodiments, at least one instance of R C  is halogen. In some embodiments, at least one instance of R C  is F. In some embodiments, at least one instance of R C  is Br. In some embodiments, at least one instance of R C  is Cl. In some embodiments, at least one instance of R C  is I. In some embodiments, at least one instance of R C  is substituted or unsubstituted alkyl (e.g., C 1-6  alkyl). In some embodiments, at least one instance of R C  is substituted or unsubstituted Me. In some embodiments, at least one instance of R C  is Me. In some embodiments, at least one instance of R C  is substituted methyl (e.g., —CF 3  or Bn). In some embodiments, at least one instance of R C  is —CF 3 . In some embodiments, at least one instance of R A  is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6  alkenyl). In some embodiments, at least one instance of R C  is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2-6  alkynyl). In some embodiments, at least one instance of R A  is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, at least one instance of R C  is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R C  is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In some embodiments, at least one instance of R C  is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R C  is —OR a  (e.g., —OH or —O(substituted or unsubstituted C 1-6  alkyl) (e.g., —OMe)). In some embodiments, at least one instance of R C  is —OMe. In some embodiments, at least one instance of R C  is —N(R a1 ) 2  (e.g., —NH 2 , —NH(substituted or unsubstituted C 1-6  alkyl) (e.g., —NHMe), or —NMe 2 ). In some embodiments, at least one instance of R C  is —SR a  (e.g., —SH, —S(substituted or unsubstituted C 1-6  alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In some embodiments, at least one instance of R C  is —CN. In some embodiments, at least one instance of R A  is —C(═O)R a  (e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R C  is —C(═O)OR a  (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R A  is —C(═O)N(R′) 2  (e.g., —C(═O)NH 2 , —C(═O)NH(substituted or unsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In some embodiments, at least one instance of R C  is —NO 2 . 
     In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 1A  is substituted or unsubstituted benzyl. In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein each instance of R 2  is independently hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; each instance of R C  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and c is 0, 1, 2, 3, 4, or 5. In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; each instance of R C  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and
 
c is 0, 1, 2, 3, 4, or 5. In some embodiments, R 1A  is of the formula:
 
     
       
         
         
             
             
         
       
     
     In some embodiments, at least one instance of R 2  is hydrogen. In some embodiments, at least one instance of R 2  is halogen (e.g., F, Cl, Br, or I). In some embodiments, at least one instance of R 2  is substituted or unsubstituted C, alkyl (e.g., substituted or unsubstituted Me or substituted or unsubstituted Et). In some embodiments, at least one instance of R 2  is Me. In some embodiments, at least one instance of R 2  is substituted or unsubstituted Me. In some embodiments, R 2  is —CH 2 OH. In some embodiments, at least one instance of R 2  is Et. In some embodiments, at least one instance of R 2  is —OR a  (e.g., —OH, —O(substituted or unsubstituted C 1-6  alkyl) (e.g., —OMe, —OEt, —OPr, —OBu, or —OBn). In some embodiments, at least one instance of R 2  is —N(R a1 ) 2  (e.g., —NH 2 , —NH(substituted or unsubstituted C 1-6  alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted C 1-6  alkyl)-(substituted or unsubstituted C 1-6  alkyl) (e.g., —NMe 2 )). In some embodiments, R 1A  is of the formula: 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 1A  is substituted or unsubstituted 6-membered heteroaryl. 
     In some embodiments, R 1A  is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine. 
     Formula (I) may include one or more instances of R A  on the imidazopyrimidine ring. When Formula (I) includes two or more instances of R A , any two instances of R A  may be the same or different from each other. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, at least one instance of R A  is halogen. In some embodiments, at least one instance of R A  is F. In some embodiments, at least one instance of R A  is Br, Cl, or I. In some embodiments, at least one instance of R A  is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6  alkyl). In some embodiments, at least one instance of R A  is Me. In some embodiments, at least one instance of R A  is substituted methyl (e.g., —CF 3  or Bn). In some embodiments, at least one instance of R A  is Et. In some embodiments, at least one instance of R A1  is substituted ethyl. In some embodiments, at least one instance of R A  is n-Pr. In some embodiments, at least one instance of R A  is i-Pr. In some embodiments, at least one instance of R A  is substituted propyl (e.g., perfluoropropyl). In some embodiments, at least one instance of R A  is Me, Et. or n-Pr. In some embodiments, at least one instance of R A  is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6  alkenyl). In some embodiments, at least one instance of R A  is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2-6  alkynyl). In some embodiments, at least one instance of R A  is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, at least one instance of R A  is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R A  is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In some embodiments, at least one instance of R A  is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R A  is —OR a  (e.g., —OH or —O(substituted or unsubstituted C 1-6  alkyl) (e.g., —OMe)). In some embodiments, at least one instance of R A  is —OMe. In some embodiments, at least one instance of R A  is —N(R a1 ) 2  (e.g., —NH 2 , —NH(substituted or unsubstituted C 1-6  alkyl) (e.g., —NHMe), or —NMe 2 ). In some embodiments, at least one instance of R A  is —SR a  (e.g., —SH, —S(substituted or unsubstituted C 1-6  alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In some embodiments, at least one instance of R A  is —CN. In some embodiments, at least one instance of R A  is —C(═O)R a  (e.g., —C(═O)substituted or unsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R A  is —C(═O)OR a  (e.g., —C(═O)OH. —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R A  is —C(═O)N(R a1 ) 2  (e.g., —C(═O)NH 2 , —C(═O)NH(substituted or unsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In some embodiments, at least one instance of R A  is —NO 2 . 
     Formula (I) may include one or more instances of R B  on the phenyl ring. When Formula (I) includes two or more instances of R B , any two instances of R B  may be the same or different from each other. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, at least one instance of R B  is halogen. In some embodiments, at least one instance of R B  is F. In some embodiments, at least one instance of R B  is Br, Cl, or I. In some embodiments, at least one instance of R B  is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6  alkyl). In some embodiments, at least one instance of R B  is Me. In some embodiments, at least one instance of R B  is substituted methyl (e.g., —CF 3  or Bn). In some embodiments, at least one instance of R B  is Et. In some embodiments, at least one instance of R B  is substituted ethyl. In some embodiments, at least one instance of R B  is n-Pr. In some embodiments, at least one instance of R B  is i-Pr. In some embodiments, at least one instance of R B  is substituted propyl (e.g., perfluoropropyl). In some embodiments, at least one instance of R B  is Me. Et, or n-Pr. In some embodiments, at least one instance of R B  is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-, alkenyl). In some embodiments, at least one instance of R B  is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2-6  alkynyl). In some embodiments, at least one instance of R B  is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, at least one instance of R B  is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R B  is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In some embodiments, at least one instance of R B  is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R B  is —OR a  (e.g., —OH or —O(substituted or unsubstituted C 1-6  alkyl) (e.g., —OMe)). In some embodiments, at least one instance of R B  is —OMe. In some embodiments, at least one instance of R B  is —N(R a1 ) 2  (e.g., —NH 2 , —NH(substituted or unsubstituted C 1-6  alkyl) (e.g., —NHMe), or —NMe 2 ). In some embodiments, at least one instance of R B  is —SR a  (e.g., —SH, —S(substituted or unsubstituted C 1-6  alkyl) (e.g., —SMe, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In some embodiments, at least one instance of R B  is —CN. In some embodiments, at least one instance of R B  is —C(═O)R a  (e.g., —C(═O)(substituted or unsubstituted alkyl) or —C(═O)(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R B  is —C(═O)OR a  (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In some embodiments, at least one instance of R B  is —C(═O)N(R a1 ) 2  (e.g., —C(═O)NH 2 , —C(═O)NH(substituted or unsubstituted alkyl), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In some embodiments, at least one instance of R B  is —NO 2 . 
     Formula (I) may include one or more instances of R. In some embodiments, at least one instance of R a  is hydrogen. In some embodiments, at least one instance of R a  is substituted or unsubstituted acyl (e.g., —C(═O)Me). In some embodiments, at least one instance of R a  is substituted or unsubstituted alkyl (e.g., C 1-4  alkyl). In some embodiments, at least one instance of R a  is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6  alkenyl). In some embodiments, at least one instance of R a  is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2 , alkynyl). In some embodiments, at least one instance of R a  is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, at least one instance of R 8  is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R 3  is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In some embodiments, at least one instance of R a  is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R a  is a nitrogen protecting group when attached to a nitrogen atom (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, at least one instance of R a  is an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In some embodiments, at least one instance of R a  is a sulfur protecting group when attached to a sulfur atom. 
     Formula (I) may include one or more instances of R a1 . In some embodiments, at least one instance of R a1  is hydrogen. In some embodiments, at least one instance of R a1  is substituted or unsubstituted acyl (e.g., —C(═O)Me). In some embodiments, at least one instance of R a1  is substituted or unsubstituted alkyl (e.g., C 1-6  alkyl). In some embodiments, at least one instance of R a J is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6  alkenyl). In some embodiments, at least one instance of R a1  is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 1-6  alkynyl). In some embodiments, at least one instance of R a1  is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3-to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, at least one instance of R a1  is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R a1  is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In some embodiments, at least one instance of R a1  is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur, or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, at least one instance of R a1  is a nitrogen protecting group when attached to a nitrogen atom (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, two instances of R a1  are joined to form a substituted or unsubstituted, heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, two instances of Rat are joined to form a substituted or unsubstituted, heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: 
     each instance of R 2  is independently hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, —OR a , or —N(R a1 ) 2 ; 
     each instance of R C  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R′) 2 , or —NO 2 ; and 
     c is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: 
     each instance of R C  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a1 ) 2 , —SR a , —CN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a1 ) 2 , or —NO 2 ; and 
     c is 0, 1, 2, 3, 4, or 5. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     In some embodiments, the compound of Formula (I) is of the formula: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version,  Handbook of Chemistry and Physics,  75 th  Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell,  Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March,  March&#39;s Advanced Organic Chemistry,  5 th  Edition, John Wiley &amp; Sons. Inc., New York, 2001; Larock,  Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers,  Some Modern Methods of Organic Synthesis,  3 rd  Edition. Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein. 
     Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al.,  Enantiomers. Racemates and Resolutions  (Wiley Interscience, New York, 1981); Wilen et al.,  Tetrahedron  33:2725 (1977); Eliel,  Stereochemistry of Carbon Compounds  (McGraw-Hill, N Y, 1962); and Wilen,  Tables of Resolving Agents and Optical Resolutions  p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. 
     When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C 1-6 ” is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 . 
     The term “aliphatic” includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term “alkyl” includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like. Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass both substituted and unsubstituted groups. In some embodiments, “lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. 
     In some embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, —CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, —CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, —CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like. 
     The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10  alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9  alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8  alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7  alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6  alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5  alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4  alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3  alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2  alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1  alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6  alkyl”). Examples of C 1-6  alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In some embodiments, the alkyl group is an unsubstituted C 1-10  alkyl (such as unsubstituted C 1-6  alkyl, e.g., —CH 3  (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C 1-10  alkyl (such as substituted C 1-6  alkyl, e.g., —CF 3 , Bn). 
     “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C 2-20  alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10  alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9  alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8  alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7  alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6  alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5  alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4  alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3  alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2  alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 2-4  alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like. Examples of C 2-6  alkenyl groups include the aforementioned C 2-4  alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is unsubstituted C 2-10  alkenyl. In some embodiments, the alkenyl group is substituted C 2-10  alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH 3  or 
     
       
         
         
             
             
         
       
     
     may be an (E)- or (Z)-double bond. 
     “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C 2-20  alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10  alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9  alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8  alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7  alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6  alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5  alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4  alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3  alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2  alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C 2-4  alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like. Examples of C 2-6  alkenyl groups include the aforementioned C 2-4  alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is unsubstituted C 2-10  alkynyl. In some embodiments, the alkynyl group is substituted C 2-20  alkynyl. 
     “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3-10  carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8  carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6  carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6  carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10  carbocyclyl”). Exemplary C 3-6  carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Exemplary, C 3-8  carbocyclyl groups include, without limitation, the aforementioned C 3-6  carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like. Exemplary C 3-10  carbocyclyl groups include, without limitation, the aforementioned C 3-8  carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, In some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is unsubstituted C 3-10  carbocyclyl. In some embodiments, the carbocyclyl group is substituted C 3-10  carbocyclyl. 
     In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3-10  cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8  cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6  cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6  cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10  cycloalkyl”). Examples of C 5-6  cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6  cycloalkyl groups include the aforementioned C 5-6  cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3-8  cycloalkyl groups include the aforementioned C 3-6  cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C 3-10  cycloalkyl. In some embodiments, the cycloalkyl group is substituted C 3-10  cycloalkyl. 
     “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In some embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. 
     In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. 
     Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C 6  aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. 
     “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14  aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C 6  aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C 10  aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 1-4  aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted C 6-14  aryl. In some embodiments, the aryl group is substituted C 6-14  aryl. 
     “Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In some embodiments, the aralkyl is optionally substituted benzyl. In some embodiments, the aralkyl is benzyl. In some embodiments, the aralkyl is optionally substituted phenethyl. In some embodiments, the aralkyl is phenethyl. 
     “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (arylheteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). 
     In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. 
     Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. 
     “Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. 
     “Unsaturated” or “partially unsaturated” refers to a group that includes at least one double or triple bond. A “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds. 
     Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix-ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene. 
     An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise provided expressly. The term “optionally substituted” refers to substituted or unsubstituted. 
     A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent. 
     Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3   + X − , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa . —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —Si(R aa ) 3 , —OSi(R aa ) 3 , —C(═S)N(R bb ) 2 , —C(═O)SR aa , —C(═S)SR aa , —SC(═S)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O)(N(R bb ) 2 ) 2 , —OP(═O)(N(R bb ) 2 ) 2 , —NR bb P(—O)(R aa ) 2 , —NR bb P(O)(OR cc ) 2 , —NR bb P(═O)(N(R bb ) 2 ) 2 , —P(R cc ) 2 , —P(OR cc ) 2 , —P(R cc ) 3   + X − , —P(OR cc ) 3   + X − , —P(R cc ) 4 , —P(OR cc ) 4 , —OP(R cc ) 2 , —OP(R cc ) 3   − X − , —OP(OR cc ) 2 , —OP(OR cc ) 3   + X − , —OP(R cc ) 4 , —OP(OR cc ) 4 , —B(R aa ) 2 , —B(OR cc ) 2 , —BR aa (OR cc ), C 1-10  alkyl. C 1-10  perhaloalkyl. C 2-10  alkenyl, C 2-10  alkynyl, heteroC 1-10  alkyl, heteroC 2-10  alkenyl, heteroC 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups; wherein X −  is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R bb ) 2 , ═NNR bb C(═O)R aa , ═NNR bb C(═O)OR aa , ═NNR bb S(═O) 2 R aa , ═NR bb , or ═NOR cc ; each instance of R aa  is, independently, selected from C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl. C 2-10  alkynyl, heteroC 1-10  alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl. C 6-14  aryl, and 5-14 membered heteroaryl, or two R aa  groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups; each instance of R bb  is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —P(═O)N(R cc ) 2 ) 2 , C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl. C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two R bb  groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups; wherein X −  is a counterion; each instance of R cc  is, independently, selected from hydrogen, C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroC 1-10  alkyl, heteroC 2-10  alkenyl, heteroC 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two R cc  groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups; each instance of R dd  is, independently, selected from halogen. —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3   + X − . —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═O)N(R ff ) 2 , —C(═NR ff )OR ee , —OC(═NR ff )R ee . —OC(═NR ff )OR ee , —C(═NR ff )N(R ff ) 2 , —OC(═NR ff )N(R ff ) 2 . —NR ff C(═NR ff )N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —Si(R ee ) 3 , —OSi(R ee ) 3 , —C(═S)N(R ff ) 2 , —C(═O)SR ee , —C(═S)SR ee , —SC(═S)SR ee , —P(═O)(OR ee ) 2 , —P(═O)(R ee ) 2 , —OP(═O)(R ee ) 2 , —OP(═O)(OR ee ) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl. C 3-10  carbocyclyl, 3-10 membered heterocyclyl, C 6-10  aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg  groups, or two geminal R dd  substituents can be joined to form ═O or ═S; wherein X is a counterion; each instance of R ee  is, independently, selected from C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, heteroC 1-6  alkyl, heteroC 2-6 alkenyl, heteroC 2-6  alkynyl, C 3-10  carbocyclyl, C 6-10  aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg  groups; 
     each instance of R ff  is, independently, selected from hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10  carbocyclyl, 3-10 membered heterocyclyl, C 6-10  aryl and 5-10 membered heteroaryl, or two R ff  groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg  groups; and each instance of R gg  is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6  alkyl, —ON(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 3   + X − , —NH(C 1-6  alkyl) 2   + X − , —NH 2 (C 1-6  alkyl) + X − , —NH 3   + X − , —N(OC 1-6  alkyl)(C 1-6  alkyl), —N(OH)(C 1-6  alkyl), —NH(OH), —SH, —SC 1-6  alkyl, —SS(C 1-6  alkyl), —C(═O)(C 1-6  alkyl), —CO 2 H, —CO 2 (C 1-6  alkyl), —OC(═O)(C 1-6  alkyl), —OCO 2 (C 1-6  alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6  alkyl) 2 , —OC(═O)NH(C 1-6  alkyl), —NHC(═O)(C 1-6  alkyl), —N(C 1-6  alkyl)C(═O)(C 1-6  alkyl), —NHCO 2 (C 1-6  alkyl), —NHC(═O)N(C 1-6  alkyl) 2 , —NHC(═O)NH(C 1-6  alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6  alkyl), —OC(═NH)C 1-6  alkyl), —OC(═NH)OC 1-6  alkyl, —C(═NH)N(C 1-6  alkyl) 2 , —C(═NH)NH(C 1-6  alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6  alkyl) 2 , —OC(NH)NH(C 1-6  alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6  alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6  alkyl), —SO 2 N(C 1-6  alkyl) 2 , —SO 2 NH(C 1-6  alkyl), —SO 2 NH 2 , —SO 2 C 1-6  alkyl, —SO 2 OC 1-6  alkyl, —OSO 2 C 1-6  alkyl, —SOC 1-6  alkyl, —Si(C 1-6  alkyl) 3 , —OSi(C 1-6  alkyl) 3 , —C(═S)N(C 1-6  alkyl) 2 , C(═S)NH(C 1-6  alkyl), C(═S)NH 2 , —C(═O)S(C 1-6  alkyl), —C(═S)SC 1-6  alkyl, —SC(═S)SC 1-6  alkyl, —P(═O)(OC 1-6  alkyl) 2 , —P(═O)(C 1-6  alkyl) 2 , —OP(═O)(C 1-6  alkyl) 2 , —OP(═O)(OC 1-6  alkyl) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl. C 2-6  alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl. C 3-10  carbocyclyl C 6-10  aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg  substituents can be joined to form ═O or ═S; wherein X −  is a counterion. 
     A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F − , Cl − , Br − , I − ), NO 3   − , ClO 4   − , OH − , H 2 PO 4   − , HCO 3   − , HSO 4   − , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4   − , PF 4   − , PF 6   − , AsF 6   − , SbF 6   − , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] − , B(C 6 F 5 ) 4   − , BPh 4   − , Al(OC(CF 3 ) 3 ) 4   − , and carborane anions (e.g., CB 11 H 12   −  or (HCB 11 Me 5 Br 6 ) − ). Exemplary counterions which may be multivalent include CO 3   2− , HPO 4   2− , PO 4   3− , B 4 O 7   2− , SO 4   2− , S 2 O 3   2− , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. 
     “Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I). 
     “Acyl” refers to a moiety selected from the group consisting of —C(═O)R aa , —CHO, —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —C(═S)N(R bb ) 2 , —C(═O)SR aa , or —C(═S)SR aa , wherein R aa  and R bb  are as defined herein. 
     Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN. —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR bb )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(OR cc ) 2 , —P(═O)(R aa ) 2 , —P(═O)(N(R cc ) 2 ) 2 , C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two R cc  groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups, and wherein R aa , R bb , R cc  and R dd  are as defined above. 
     In some embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, —OH, —OR aa , —N(R cc ) 2 , —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(—S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc . C 1-10  alkyl (e.g., aralkyl, heteroaralkyl), C 2-10  alkenyl, C 2-10  alkynyl, heteroC 1-10  alkyl, heteroC 2-10  alkenyl, heteroC 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl. C 6-14  aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd  groups, and wherein R aa , R bb , R cc  and R dd  are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd  edition, John Wiley &amp; Sons, 1999, incorporated herein by reference. 
     For example, nitrogen protecting groups such as amide groups (e.g., —C(═O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide. 
     Nitrogen protecting groups such as carbamate groups (e.g., —C(═O)OR aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate. S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, I-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. 
     Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O) 2 R aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide. N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine. N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine. N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). 
     In some embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, —R aa , —N(R bb ) 2 , —C(═O)SR aa , —C(═O)R aa , —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —S(═O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3   + X − , —P(OR cc ) 2 , —P(OR cc ) 3   + X − , —P(═O)(R aa ) 2 , —P(═O)OR cc ) 2 , and —P(═O)(N(R bb ) 2 ) 2 , wherein X − , R aa , R bb , and R cc  are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd  edition, John Wiley &amp; Sons, 1999, incorporated herein by reference. 
     Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4.4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). 
     In some embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —R aa , —N(R bb ) 2 , —C(═O)SR aa , —C(═O)R aa , —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —S(═O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3   + X − , —P(OR cc ) 2 , —P(OR cc ) 3   + X − , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , and —P(═O)N(R bb ) 2 ) 2 , wherein R aa , R bb , and R cc  are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3d edition, John Wiley &amp; Sons, 1999, incorporated herein by reference. 
     As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SR aa , —OC(═O)R aa , —OCO 2 R aa , —OC(═O)N(R bb ) 2 , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —OC(═NR bb )N(R bb ) 2 , —OS(═O)R aa , —OSO 2 R aa , —OP(R cc ) 2 , —OP(R cc ) 3 , —OP(═O) 2 R aa , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —OP(═O) 2 N(R bb ) 2 , and —OP(═O)(NR bb ) 2 , w herein R aa , R bb , and R cc  are as defined herein). 
     A “hydrocarbon chain” refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally one or more substituents (“non-chain substituents.” which are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms consists of consecutively connected carbon atoms (“chain atoms”) and does not include hydrogen atoms or heteroatoms. However, a non-chain substituent of a hydrocarbon chain may include any atoms, including hydrogen atoms, carbon atoms, and heteroatoms. For example, hydrocarbon chain —C A H(C B H 2 C C H 3 )— includes one chain atom C A , one hydrogen atom on C A , and non-chain substituent —(C B H 2 C C H 3 ). The term “C x  hydrocarbon chain,” wherein x is a positive integer, refers to a hydrocarbon chain that includes x number of chain atom(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain. For example, —CH(C 2 H 5 )— is a C 1  hydrocarbon chain, and 
     
       
         
         
             
             
         
       
     
     is a C 3  hydrocarbon chain. When a range of values is used, the meaning of the range is as described herein. For example, a C 3-10  hydrocarbon chain refers to a hydrocarbon chain where the number of chain atoms of the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbon chain may be saturated (e.g., —(CH 2 ) 4 —). A hydrocarbon chain may also be unsaturated and include one or more C═C and/or C≡C bonds anywhere in the hydrocarbon chain. For instance, —CH—CH—(CH 2 ) 2 —, —CH 2 —C═C—CH 2 —, and —C≡C—CH═CH— are all examples of a unsubstituted and unsaturated hydrocarbon chain. In some embodiments, the hydrocarbon chain is unsubstituted (e.g., —C≡C— or —(CH 2 ) 4 —). In some embodiments, the hydrocarbon chain is substituted (e.g., —CH(C 2 H 5 )— and —CF 2 —). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For instance 
     
       
         
         
             
             
         
       
     
     and are all examples of a hydrocarbon chain. In contrast, In some embodiments, 
     
       
         
         
             
             
         
       
     
     are not within the scope of the hydrocarbon chains described herein. When a chain atom of a C x  hydrocarbon chain is replaced with a heteroatom, the resulting group is referred to as a C x  hydrocarbon chain wherein a chain atom is replaced with a heteroatom, as opposed to a C x-1  hydrocarbon chain. For example, 
     
       
         
         
             
             
         
       
     
     is a C 3  hydrocarbon chain wherein one chain atom is replaced with an oxygen atom. 
     The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in  J. Pharmaceutical Sciences,  1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4  alkyl) 4   −  salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. 
     The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid. DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. 
     The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R.x H 2 O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R.2 H 2 O) and hexahydrates (R.6 H 2 O)). 
     The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. 
     It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. 
     Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. 
     The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. 
     The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard. H.,  Design of Prodrugs. pp.  7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl. C 7 -C 12  substituted aryl, and C 7 -C 12  arylalkyl esters of the compounds described herein may be preferred. 
     Antigens 
     The composition described herein comprises an antigen and an imidazopyrimidine compound. An “antigen” refers to an entity that is bound by an antibody or receptor, or an entity that induces the production of the antibody. In some embodiments, an antigen increases the production of antibodies that specifically bind the antigen. In some embodiments, an antigen comprises a protein or polypeptide. Such protein or peptide are referred to herein as “immunogenic polypeptide.” In some embodiments, the term “antigen” encompasses nucleic acids (e.g., DNA or RNA molecules) that encode immunogenic polypeptides. In some embodiments, the antigen is from a microbial pathogen. For example, the antigen may comprise parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, fungi, and other microorganisms. In some embodiments, the antigen is a cancer-specific antigen. 
     In some embodiments, a protein or polypeptide antigen is a wild type protein or polypeptide. In some embodiments, a protein or polypeptide antigen is a polypeptide variant to a wild type protein or polypeptide. The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. In some embodiments, polypeptide variants possess at least 50% identity to a native or reference sequence. In some embodiments, variants share at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identity with a native or reference sequence. 
     In some embodiments, a polypeptide variant comprises substitutions, insertions, deletions. In some embodiments, a polypeptide variant encompasses covalent variants and derivatives. The term “derivative” is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule. 
     In some embodiments, sequence tags or amino acids, such as one or more lysines, can be added to peptide sequences (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide detection, purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support. 
     In some embodiments, the polypeptide variants comprises at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. Substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule. In some embodiments, the antigen is a polypeptide that includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more substitutions compared to a reference protein. 
     In some embodiments, the substitution is a conservative amino acids substitution. The term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue. 
     In some embodiments, protein fragments, functional protein domains, and homologous proteins are used as antigens in accordance with the present disclosure. For example, an antigen may comprise any protein fragment (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) of a reference protein 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length. In another example, any protein that includes a stretch of 20, 30, 40, 50, or 100 amino acids which are 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% identical to a reference protein (e.g., a protein from a microbial pathogen) herein can be utilized in accordance with the disclosure. 
     In some embodiments, the antigen comprises more than one immunogenic proteins or polypeptides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). In some embodiments, the more than one immunogenic proteins or polypeptides are derived from one protein (e.g., different fragments or one protein). In some embodiments, the more than one immunogenic proteins or polypeptides are derived from multiple proteins (e.g., from 2, 3, 4, 5, 6, 7, 8, 9, 10, or more proteins). 
     In some embodiments, the antigen comprises a nucleic acid encoding an immunogenic protein or polypeptide. In some embodiments, the antigen comprises an immunogenic protein or polypeptide and a nucleic acid encoding the immunogenic protein or polypeptide. The term “nucleic acid” or “polynucleotide,” in its broadest sense, includes any compound and/or substance that comprises a polymer of nucleotides. Nucleic acids encoding immunogenic proteins or polypeptides typically comprise an open reading frame (ORF), and one or more regulatory sequences. Nucleic acids (also referred to as polynucleotides) may be or may include, for example, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino-α-LNA having a 2′-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or chimeras or combinations thereof. 
     In some embodiments, the nucleic acid encoding the immunogenic polypeptide is a DNA (e.g., an expression vector for an immunogenic protein or polypeptide). In some embodiments, the nucleic acid encoding the immunogenic polypeptide is a RNA (e.g., a messenger RNA). A “messenger RNA” (mRNA) refers to any polynucleotide that encodes a (at least one) polypeptide (a naturally-occurring, non-naturally-occurring, or modified polymer of amino acids) and can be translated to produce the encoded polypeptide in vitro, in vivo, in situ, or ex vivo. The basic components of an mRNA molecule typically include at least one coding region, a 5′ untranslated region (UTR), a 3′ UTR, a 5′ cap and a poly-A tail. 
     In some embodiments, the coding region of the nucleic acid (e.g., DNA or RNA) encoding an immunogenic polypeptide is codon optimized. Codon optimization methods are known in the art and may be used as provided herein. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures: minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove/add post translation modification sites in encoded protein (e.g. glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art—non-limiting examples include services from GeneArt (Life Technologies). DNA2.0 (Menlo Park Calif.) and/or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms. 
     In some embodiments, a codon optimized sequence shares less than 95% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 90% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 85% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 80% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). In some embodiments, a codon optimized sequence shares less than 75% sequence identity to a naturally-occurring or wild-type sequence (e.g., a naturally-occurring or wild-type mRNA sequence encoding an immunogenic protein or polypeptide). 
     In some embodiments, the nucleic acid encoding an immunogenic protein or polypeptide comprises one or more chemical modifications. The terms “chemical modification” and “chemically modified” refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribonucleosides or deoxyribnucleosides in at least one of their position, pattern, percent or population. 
     In some embodiments, the nucleic acids (e.g., DNA or RNA) comprise various (more than one) different modifications. In some embodiments, a particular region of a nucleic acid (e.g., DNA or RNA) contains one, two or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified nucleic acid (e.g., DNA or RNA), introduced to a cell or organism, exhibits reduced degradation in the cell or organism, respectively, relative to an unmodified nucleic acid. In some embodiments, a modified nucleic acid (e.g., DNA or RNA), introduced into a cell or organism, may exhibit reduced immunogenicity in the cell or organism, respectively (e.g., a reduced innate response). 
     Modified nucleic acid (e.g., DNA or RNA) may comprise modifications that are naturally-occurring, non-naturally-occurring or the polynucleotide may comprise a combination of naturally-occurring and non-naturally-occurring modifications. Polynucleotides may include any useful modification, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage or to the phosphodiester backbone). Modified nucleic acid (e.g., DNA or RNA), in some embodiments, comprise non-natural modified nucleotides that are introduced during synthesis or post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleotide linkages, purine or pyrimidine bases, or sugars. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a nucleic acid may be chemically modified. 
     In some embodiments, a chemically modified nucleic acid comprises one or more modified nucleosides. A “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). A nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Polynucleotides may comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages may be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides. 
     In some embodiments, a modified nucleobase is a modified uridine. Exemplary nucleobases and nucleosides having a modified cytosine include N4-acetyl-cytidine (ac4C), 5-methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl-pseudoisocytidine, 2-thio-cytidine (s2C), and 2-thio-5-methyl-cytidine. 
     In some embodiments, a modified nucleobase is a modified uridine. Exemplary nucleobases and In some embodiments, a modified nucleobase is a modified cytosine, nucleosides having a modified uridine include 5-cyano uridine, and 4′-thio uridine. 
     In some embodiments, a modified nucleobase is a modified adenine. Exemplary nucleobases and nucleosides having a modified adenine include 7-deaza-adenine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), and N6-methyl-adenosine (m6A). 
     In some embodiments, a modified nucleobase is a modified guanine. Exemplary nucleobases and nucleosides having a modified guanine include inosine (I), 1-methyl-inosine (m1I), wyosine (imG), methylwyosine (mimG), 7-deaza-guanosine, 7-cyano-7-deaza-guanosine (preQ0), 7-aminomethyl-7-deaza-guanosine (preQ1), 7-methyl-guanosine (m7G), 1-methyl-guanosine (m1G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine. 
     In some embodiments, the antigen of the present disclosure is from a microbial pathogen, e.g., from a bacterium, mycobacterium, fungus, a virus, parasite, or prion. For example, the antigen may comprise a protein or polypeptide, or a nucleic acid encoding the protein or polypeptide from the microbial pathogen. In some embodiments, the antigen may comprise a microbial pathogen (e.g., a bacterial cell, a viral particle, or a fungus cell). In some embodiments, the microbial pathogen cell is live or killed. In some embodiments, the microbial pathogen is attenuated its pathogenicity. An attenuated microbial pathogen may elicit immune response but does not cause the disease that a wild-type microbial pathogen would cause. 
     Exemplary, non-limiting bacterial taxa, species, and strains, suitable for use in some embodiments of this disclosure include:  Escherichia  spp.,  Enterobacter  spp. (e.g.,  Enterobacter cloacae ),  Salmonella  spp. (e.g.,  Salmonella enteritidis, Salmonella typhi ),  Shigella  spp.,  Pseudomonas  spp. (e.g.,  Pseudomonas aeruginosa. Pseudomonas pachastrellae. Pseudomonas stutzeri ),  Moraxella  spp. (e.g.,  Moraxella catarrhalis ).  Neisseria  spp. (e.g., 20  Neisseria gonorrhoeae, Neisseria meningitidis ).  Helicobacter  spp., (e.g.,  Helicobacter pylori )  Stenotrophomonas  spp.,  Vibrio  spp. (e.g.,  Vibrio cholerae ),  Legionella  spp. ( Legionella pneumophila ),  Hemophilus  spp. (e.g.,  Hemophilus influenzae ),  Klebsiella  spp. (e.g.,  Klebsiella pneumoniae ),  Proteus  spp. (e.g.,  Proteus mirabilis ),  Serratia  spp. ( Serratia marcescens ),  Streptococcus  spp.,  Staphylococcus  spp.,  Corynebacterium  spp.,  Listeria  spp., and  Clostridium  spp.,  Bacillus  spp. (e.g.,  Bacillus anthracis )  Bordetella  spp. (e.g.,  Bordetella pertussis );  Borrelia  spp. (e.g.,  Borrelia burgdorferi );  Brucella  spp. (e.g.,  Brucella abortus, Brucella canis. Brucella melitensis, Brucella suis );  Campylobacter  spp. (e.g.,  Campylobacter. lejuni );  Chlamydia  spp. and  Chlamydophila  spp. (e.g.,  Chlamydia pneumoniae, Chlamydia trachomatis, Chlamtdophila psittaci );  Clostridium  spp. (e.g.,  Clostridium botulinum, Clostridium difficile, Clostridium perfringens. Clostridium tetani );  Corynebacterium  spp. (e.g.,  Corynebacterium diphtheriae );  Enterococcus  spp. (e.g.,  Enterococcus faecalis, Enterococcus faecium );  Escherichia  spp. (e.g.,  Escherichia coli. Enterotoxic E, coli, enteropathogenic E, coli; E, coli  O157:H7);  Francisella  spp. (e.g.,  Francisella tularensis );  Haemophilus  spp. (e.g.,  Haemophilus influenzae );  Helicobacter  spp. (e.g.,  Helicobacter pylori );  Legionella  spp. (e.g.,  Legionella pneumophila );  Leptospira  spp. (e.g.,  Leptospira interrogans );  Listeria  spp. (e.g.,  Listeria monocytogenes );  Mycobacterium  spp. (e.g.,  Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans );  Mycoplasma  spp. (e.g.,  Mycoplasma pneumoniae );  Neisseria  spp. (e.g.,  Neisseria gonorrhoeae, Neisseria meningitidis );  Pseudomonas  spp. (e.g.,  Pseudomonas aeruginosa );  Rickettsia  spp. (e.g.,  Rickettsia rickettsii );  Salmonella  spp. (e.g.,  Salmonella typhi. Salmonella typhimurium );  Shigella  spp. (e.g.,  Shigella sonnei );  Staphylococcus  spp. (e.g.,  Staphylococcus  aureus,  Staphylococcus  epidermidis,  Staphylococcus saprophyticus );  Streptococcus  spp. (e.g.,  Streptococcus agalactiae. Streptococcus pneumoniae. Streptococcus pyogenes );  Treponema  spp. (e.g.,  Treponema pallidum );  Pseudodiomarina  spp. (e.g.,  P. maritima );  Marinobacter  spp. (e.g.,  Marinobacter hydrocarbonoclasticus. Marinobacter vinifirmus )  Alcanivorax  spp. (e.g.,  alcanivorax dieselolei );  Acetinobacter  spp. (e.g.  A. venetianus );  Halomonas  spp. (e.g.,  H. shengliensis );  Labrenzia  spp.;  Microbulifer  spp. (e.g.,  M. schleiferi );  Shewanella  spp. (e.g.,  S. algae );  Vibrio  spp. (e.g.,  Vibrio  cholerae,  Vibrio  alginolyticus,  Vibrio hepatarius ); and  Yersinia  spp. (e.g.,  Yersinia pestis ). 
     In some embodiments, the bacterium is  Bacillus anthracis  (causing anthrax),  Bordetella pertussis  (causing whooping cough),  Corynebacterium diphtheriae  (causing diphtheria),  Clostridium tetani  (causing tetanus),  Haemophilus influenzae  type b, pneumococcus (causing pneumococcal infections),  Staphylococci  spp. (including Group A or B streptococci).  Mycobacterium tuberculosis, Neiserria meningitidis  (causing meningococcal disease),  Salmonella typhi  (causing typhoid),  Vibrio cholerae  (causing Cholera), or  Yersinia pestis  (causing plague). 
     In some embodiments, the antigen is derived from a Gram-negative bacterium. In some embodiments, the antigen is a lipopolysaccharide endotoxin (LPS) from a Gram-negative bacterium. Non-limiting examples of gram-negative bacterial species include:  Neisseria  species including  Neisseria gonorrhoeae  and  Neisseria meningitidis, Branhamella  species including  Branhamella catarrhalis, Escherichia  species including  Escherichia coli. Enterobacter  species,  Proteus  species including  Proteus mirabilis. Pseudomonas  species including  Pseudomonas aeruginosa. Pseudomonas mallei , and  Pseudomonas pseudomallei. Klebsiella  species including  Klebsiella pneumoniae. Salmonella  species,  Shigella  species,  Serratia  species,  Acinetobacter  species;  Haemophilus  species including  Haemophilus influenzae  and  Haemophilus ducreyi; Brucella  species,  Yersinia  species including  Yersinia pestis  and  Yersinia enterocolitica. Francisella  species including  Francisella tularensis. Pasteurella  species including  Pasteurella multocida. Vibrio cholerae. Flavobacterium  species,  meningosepticum. Campylobacter  species including  Campylobacter jejuni. Bacteroides  species (oral, pharyngeal) including  Bacteroides fragilis, Fusobacterium  species including  Fusobacterium nucleatum. Calymmatobacterium granulomatis. Streptobacillus  species including  Streptobacillus moniliformis. Legionella  species including  Legionella pneumophila.    
     In some embodiments, the antigen is derived from a Gram-positive bacterium. Exemplary Gram-positive bacteria include, but are not limited to,  Staphylococcus  spp.,  Streptococcus  spp.,  Micrococcus  spp.,  Peptococcus  spp.,  Peptostreptococcus  spp.,  Enterococcus  spp.,  Bacillus  spp.,  Clostridium  spp.,  Lactobacillus  spp.,  Listeria  spp.,  Erysipelothrix  spp.,  Propionibacterium  spp.,  Eubacterium  spp.,  Corynebacterium  spp.,  Capnocytophaga  spp.,  Bifidobacterium  spp., and  Gardnerella  spp., In some embodiments, the Gram-positive bacteria is a bacteria of the phylum Firmicutes. In some embodiments, the Gram-positive bacteria is  Streptococcus.    
     Other types of bacteria include acid-fast bacilli, spirochetes, and actinomycetes. Examples of acid-fast bacilli include  Mycobacterium  species including  Mycobacterium tuberculosis  and  Mycobacterium leprae . Examples of spirochetes include  Treponema  species including  Treponema pallidum, Treponema pertenue, Borrelia  species including  Borrelia burgdorferi  (Lyme disease), and  Borrelia recurrentis , and  Leptospira  species. Examples of actinomycetes include:  Actinomyces  species including  Actinomyces israelii , and  Nocardia  species including  Nocardia asteroides.    
     Examples of viruses include but are not limited to: Retroviruses, human immunodeficiency viruses including HIV-1, HDTV-III, LAVE, HTLV-III/LAV, HIV-III, HIV-LP. Cytomegaloviruses (CMV), Picomaviruses, polio viruses, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, Calciviruses, Togaviruses, equine encephalitis viruses, rubella viruses, Flaviruses, dengue viruses, encephalitis viruses, yellow fever viruses, Coronaviruses, Rhabdoviruses, vesicular stomatitis viruses, rabies viruses. Filoviruses, ebola virus, Paramyxoviruses, parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus (RSV), Orthomyxoviruses, influenza viruses. Bungaviruses, Hantaan viruses, phleboviruses and Nairo viruses, Arena viruses, hemorrhagic fever viruses, reoviruses, orbiviruses, rotaviruses, Bimaviruses, Hepadnaviruses, Hepatitis B virus, parvoviruses, Papovaviridae, papilloma viruses, polyoma viruses, Adenoviruses, Herpesviruses including herpes simplex virus 1 and 2, varicella zoster virus, Poxviruses, variola viruses, vaccinia viruses, Irido viruses, African swine fever virus, delta hepatitis virus, non-A, non-B hepatitis virus, Hepatitis C, Norwalk viruses, astroviruses, and unclassified viruses. In some embodiments, the virus is adenovirus, enterovirus such as poliomyelitis (polio), Ebola virus, herpes viruses such as herpes simplex virus, cytomegalovirus and varicella-zoster (chickenpox and shingles), measles, mumps, rubella, hepatitis-A, —B, or -C, human papilloma virus, Influenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, yellow fever, or Zika Virus. 
     In some embodiments, the antigen comprises a viral protein and/or a nucleic acid encoding a viral protein (e.g., a viral structural or non-structural protein). In some embodiments, the antigen comprises a nucleic acid encoding the viral genome. In some embodiments, the viral genome is modified to produce a modified virus that is attenuated. 
     Examples of fungus include, but are not limited to:  Cryptococcus  species including  Crytococcus neoformans, Histoplasma  species including  Histoplasma capsulatum, Coccidioides  species including  Coccidiodes immitis, Paracoccidioides  species including  Paracoccidioides brasiliensis, Blastomyces  species including  Blastomyces dermatitidis, Chlamydia  species including  Chlamydia trachomatis, Candida  species including  Candida albicans, Sporothrix  species including  Sporothrix schenckii, Aspergillus  species, and fungi of mucormycosis. In some embodiments, the fungus is  Candida  spp.,  Aspergillus  spp.,  Cryptococcus  spp.,  Mucormycete, Blastomyces dermatitidis  (causing blastomycosis), or endemic mycosis causing fungus such as  Histoplasma capsulatum  (causing histoplasmosis), or  Sporothrix schenckii  (causing sporotrichosis). 
     Other infectious organisms include, without limitation: parasites. Parasites include  Plasmodium  species, such as  Plasmodium  species including  Plasmodium falciparum. Plasmodium malariae. Plasmodium ovale , and  Plasmodium vivax  and  Toxoplasma gondii . Blood-borne and/or tissues parasites include  Plasmodium  species,  Babesia  species including  Babesia microti  and  Babesia divergens. Leishmania  species including  Leishmania tropica. Leishmania  species.  Leishmania braziliensis. Leishmania donovani. Trypanosoma  species including  Trypanosoma gambiense. Trypanosoma rhodesiense  (African sleeping sickness), and  Trypanosoma cruzi  (Chagas&#39; disease). In some embodiments, the parasite is  Plasmodium  spp.,  Leishmania , or a helminth. 
     Other medically relevant microorganisms have been described extensively in the literature, e.g., see C. G. A Thomas,  Medical Microbiology , Bailliere Tindall, Great Britain 1983, incorporated herein by reference. 
     In some embodiments, the antigen of the present disclosure comprises a cancer-specific antigen and/or a nucleic acid encoding such. A “cancer-specific antigen” refers to a protein that is specifically expressed or upregulated in a cancer cell, as compared to non-cancerous cells of the same origin. A cancer-specific antigen, or epitopes derived therefrom, can be recognized by the immune system to induce a immune response against the cancer. Classes of proteins that may be cancer-specific antigen include, without limitation: enzymes, receptors, and transcription factors. 
     A large number of proteins that specifically express in cancer cells or are upregulated in cancer cells have been identified (Hassane et al., Holland-Frei Cancer Medicine, 6th edition, incorporated herein by reference). The known tumor specific antigens are classified into different classes: cancer-testis antigens (e.g., MAGE family members or NY-ESO-1), differentiation antigens (e.g., tyrosinase and Melan-A/MART-1 for melanoma, and PSA for prostate cancer), overexpressed cancer-specific antigens (e.g., Her-2/neu, Survivin, Telomerase and WT1), cancer-specific antigens arising from mutations of normal genes (e.g., mutated β-catenin or CDK4), cancer-specific antigens arising from abnormal post-translational modifications (e.g., altered glycosylation patterns) that lead to novel epitopes in tumors (e.g., MUC1), and oncoviral proteins (e.g., human papilloma type 16 virus proteins. E6 and E7). In some embodiments, the tumor-specific antigen is expressed in a broad range of different types of cancers. In some embodiments, the tumor-specific antigen is expressed only in one or a few types of cancers. 
     In some embodiments, the antigen comprises a fragment or an epitope derived from a cancer-specific antigen and/or a nucleic acid encoding such. For example, the fragment or an epitope derived from a cancer-specific antigen may be 5-40 amino acids long. In some embodiments, the fragment or an epitope derived from a cancer-specific antigen is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids long. 
     In some embodiments, the fragment or epitope derived from a cancer-specific antigen is a heteroclitic epitope. A “heteroclitic epitope” refers to an altered version of an endogenous peptide sequence (i.e., an analog) from a cancer-specific antigen engineered to elicit potent immune reactions. Heteroclitic epitopes have increased stimulatory capacity or potency for a specific T cell, as measured by increased responses to a given dose, or by a requirement of lesser amounts to achieve the same response and therefore provide benefit as vaccine components since these epitopes induce T cell responses stronger than those induced by the native epitope. 
     In some embodiments, the heteroclitic epitope comprises modifications, e.g., amino acid substitutions, as compared to the native sequence in the cancer-specific antigen. In some embodiments, the heteroclitic epitope comprises more than one amino acid substitutions (e.g., 2, 3, 4, 5, or more) compared to the native sequence of the cancer-specific antigen it is derived from. In some embodiments, a heteroclitic epitope is at least 60%, at least 70%, at least 80%, at least 90%, at least 98%, or at least 99% identical to the native sequence that it is derived from. In some embodiments, a heteroclitic epitope is 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the native sequence that it is derived from. 
     In some embodiments, a heteroclitic epitope is more immunogenic than a peptide of its native sequence. For example, a heteroclitic epitope may be at least 30% more immunogenic (i.e., induces a stronger immune response) than its corresponding native peptide. In some embodiments, a heteroclitic epitope may be at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or more immunogenic than its corresponding native peptide. 
     In some embodiments, the fragment or epitope derived from a cancer-specific antigen is a cryptic epitope. A “cryptic epitope” refers to an epitope derived from a cancer-specific antigen that does not necessarily undergo antigen processing/presentation and are ‘hidden’ from immune recognition. Cryptic epitopes usually appear in very low concentration on APC and do not delete auto-reactive T cells. Cryptic epitopes are not presented for recognition by T cells unless they are produced in unusually large concentrations or unless they are freed from the configuration of their native antigen. Cryptic epitopes derived from cancer-specific antigens may be used to break the tolerance of T cells to the tumor and induce potent immune response against the tumor. Such principles have been described in Pardoll, et al., PNAS, Vol. 96, pp. 5340-5342 (1999), the entire contents of which are incorporated herein by reference. 
     In some embodiments, the cryptic epitope is generated from translation of a non-coding region of the cancer-specific antigen gene or translation of a different reading frame of a coding region of the cancer-specific antigen. A cryptic epitope may be more immunogenic (i.e., induces a stronger immune response) than any native peptide derived from the cancer-specific antigen. For example, a cryptic epitope may be at least 30% more immunogenic than any native peptide derived from the cancer-specific antigen. In some embodiments, a cryptic epitope is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or more immunogenic than any native peptide derived from the cancer-specific antigen. One skilled in the art is familiar with how to assess the immune response induced by an antigen, e.g., measuring antibody titers. 
     In some embodiments, the cancer-specific antigen is a neoantigen. A “neoantigen” refers to an antigen generated via random somatic mutations occurring in cancer cells and are thus specific to the lineage of cancer cells it is derived from. Neoantigens are regarded in the art to be responsible for the immunogenicity of tumors ((Srivastava et al., 1993, Duan et al., 2009; van der Bruggen et al., 2013, incorporated herein by reference), and mathematic modeling has predicted the existence of tens to hundreds of neoepitopes (epitopes derived from neoantigens) in individual human tumors (Srivastava 2009, incorporated herein by reference). The recent revolution in high-throughput DNA sequencing and accompanying bioinformatics approaches has finally made it possible to actually identify the individually specific neoepitopes in individual cancers. 
     In some embodiments, the antigen described herein is an antigen designed to provide broad heterologous protection against a range of pathogens. Heterologous immunity refers to the phenomenon whereby a history of an immune response against a stimulus or pathogen can provide a level of immunity to a second unrelated stimulus or pathogen (e.g., as described in Chen et al., Virology 2015 482: 89-97, incorporated herein by reference). For example, an antigen that induces cross-reactive memory CD8+ T cells against multiple unrelated viruses such as influenza A and Epstein-Barr Virus (EBV), as described in Watkin et al., J Allerg Clin Immunol 2017 October; 140(4) 1206-1210, incorporated herein by reference. In some embodiments, the imidazopyrimidine compounds described herein induce and/or enhance the heterologous protection. 
     Polypeptide or polynucleotide molecules of the present disclosure may share a certain degree of sequence similarity or identity with reference molecules (e.g., reference polypeptides or reference polynucleotides), for example, wild-type molecules. The term “identity” as known in the art, refers to a relationship between the sequences of two or more polypeptides or polynucleotides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between them as determined by the number of matches between strings of two or more amino acid residues or nucleic acid residues. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (e.g., “algorithms”). Identity of related peptides can be readily calculated by known methods. “% identity” as it applies to polypeptide or polynucleotide sequences is defined as the percentage of residues (amino acid residues or nucleic acid residues) in the candidate amino acid or nucleic acid sequence that are identical with the residues in the amino acid sequence or nucleic acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity. Methods and computer programs for the alignment are well known in the art. It is understood that identity depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation. Generally, variants of a particular polynucleotide or polypeptide have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 10% sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art. Such tools for alignment include those of the BLAST suite (Stephen F. Altschul, et al (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25:3389-3402). Another popular local alignment technique is based on the Smith-Waterman algorithm (Smith, T. F. &amp; Waterman, M. S. (1981) “Identification of common molecular subsequences.” J. Mol. Biol. 147:195-197.) A general global alignment technique based on dynamic programming is the Needleman-Wunsch algorithm (Needleman, S. B. &amp; Wunsch, C. D. (1970) “A general method applicable to the search for similarities in the amino acid sequences of two proteins.” J. Mol. Biol. 48:443-453.). More recently a Fast Optimal Global Sequence Alignment Algorithm (FOGSAA) has been developed that purportedly produces global alignment of nucleotide and protein sequences faster than other optimal global alignment methods, including the Needleman-Wunsch algorithm. Other tools are described herein, specifically in the definition of “identity” below. 
     As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Polymeric molecules (e.g. nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or polypeptide molecules) that share a threshold level of similarity or identity determined by alignment of matching residues are termed homologous. Homology is a qualitative term that describes a relationship between molecules and can be based upon the quantitative similarity or identity. Similarity or identity is a quantitative term that defines the degree of sequence match between two compared sequences. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). Two polynucleotide sequences are considered homologous if the polypeptides they encode are at least 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. Two protein sequences are considered homologous if the proteins are at least 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least 20 amino acids. 
     Homology implies that the compared sequences diverged in evolution from a common origin. The term “homolog” refers to a first amino acid sequence or nucleic acid sequence (e.g., gene (DNA or RNA) or protein sequence) that is related to a second amino acid sequence or nucleic acid sequence by descent from a common ancestral sequence. The term “homolog” may apply to the relationship between genes and/or proteins separated by the event of speciation or to the relationship between genes and/or proteins separated by the event of genetic duplication. “Orthologs” are genes (or proteins) in different species that evolved from a common ancestral gene (or protein) by speciation. Typically, orthologs retain the same function in the course of evolution. “Paralogs” are genes (or proteins) related by duplication within a genome. Orthologs retain the same function in the course of evolution, whereas paralogs evolve new functions, even if these are related to the original one. 
     The term “identity” refers to the overall relatedness between polymeric molecules, for example, between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In some embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 5%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleic acid sequences can be determined using methods such as those described in Computational Molecular Biology. Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993: Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press. New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleic acid sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleic acid sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)). 
     Compositions and Vaccines 
     The composition of the present disclosure comprises an antigen and an imidazopyrimidine compound. In some embodiments, the imidazopyrimidine compound is conjugated to the antigen. In some embodiments, the imidazopyrimidine compound is not conjugated to the antigen. In some embodiments, the imidazopyrimidine compound is lipidated. 
     Methods of conjugating a compound to another molecule (e.g., a protein or a nucleic acid) is known to those skilled in the art. For example, in some embodiments, conjugation may be achieved via reactive chemical groups by incorporating one of a pair of reactive chemical groups that react with each other to each of the two molecules to be conjugated. A “reactive chemical group” or “functional chemical group” refers to specific groups (moieties) of atoms or bonds within molecules that are responsible for the characteristic chemical reactions of those molecules. These terms are used interchangeably herein. One example of such reactive group is a “click chemistry handle.” Click chemistry is a chemical approach introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition (2001) 40: 2004-2021; Evans, Australian Journal of Chemistry (2007) 60: 384-395). Exemplary coupling reactions (some of which may be classified as “Click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide-alkyne Huisgon cycloaddition; thiol-yne addition; imine formation; and Michael additions (e.g., maleimide addition). Non-limiting examples of a click chemistry handle include an azide handle, an alkyne handle, or an aziridine handle. Azide is the anion with the formula N3-. It is the conjugate base of hydrazoic acid (HN3). N3-is a linear anion that is isoelectronic with CO2, NCO—, N2O, NO2+ and NCF. Azide can be described by several resonance structures, an important one being —N═N+=N—. An alkyne is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. The simplest acyclic alkynes with only one triple bond and no other functional groups form a homologous series with the general chemical formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature. Like other hydrocarbons, alkynes are generally hydrophobic but tend to be more reactive. Aziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one amine group (—NH—) and two methylene bridges (—CH2-). The parent compound is aziridine (or ethylene imine), with molecular formula C2H5N. 
     Other non-limiting, exemplary reactive groups include: acetals, ketals, hemiacetals, and hemiketals, carboxylic acids, strong non-oxidizing acids, strong oxidizing acids, weak acids, acrylates and acrylic acids, acyl halides, sulfonyl halides, chloroformates, alcohols and polyols, aldehydes, alkynes with or without acetylenic hydrogen amides and imides, amines, aromatic, amines, phosphines, pyridines, anhydrides, aryl halides, azo, diazo, azido, hydrazine, and azide compounds, strong bases, weak bases, carbamates, carbonate salts, chlorosilanes, conjugated dienes, cyanides, inorganic, diazonium salts, epoxides, esters, sulfate esters, phosphate esters, thiophosphate esters borate esters, ethers, soluble fluoride salts, fluorinated organic compounds, halogenated organic compounds, halogenating agents, aliphatic saturated hydrocarbons, aliphatic unsaturated hydrocarbons, hydrocarbons, aromatic, insufficient information for classification, isocyanates and isothiocyanates, ketones, metal hydrides, metal alkyls, metal aryls, and silanes, alkali metals, nitrate and nitrite compounds, inorganic, nitrides, phosphides, carbides, and silicides, nitriles, nitro, nitroso, nitrate, nitrite compounds, organic, non-redox-active inorganic compounds, organometallics, oximes, peroxides, organic, phenolic salts, phenols and cresols, polymerizable compounds, quaternary ammonium and phosphonium salts, strong reducing agents, weak reducing agents, acidic salts, basic salts, siloxanes, inorganic sulfides, organic sulfides, sulfite and thiosulfate salts, sulfonates, phosphonates, organic thiophosphonates, thiocarbamate esters and salts, and dithiocarbamate esters and salts. In some embodiments, the reactive group is a carboxylic acid group. 
     The composition comprising an antigen and an imidazopyrimidine compound described herein are immunogenic. Being “immunogenic” means that the composition elicits immune response when administered to a subject (e.g., a mammalian subject such as a human). As used herein, an “immune response” refers to a response by a cell of the immune system, such as an antigen-presenting cell, dendritic cell, monocyte, macrophage, NKT cell, NK cell, basophil, eosinophil, or neutrophil, B cell, T cell (CD4 or CD8), regulatory T cell, antigen-presenting cell, dendritic cell, monocyte, macrophage, NKT cell, NK cell, basophil, eosinophil, or neutrophil, to a stimulus (e.g., to an antigen or an adjuvant). 
     In some embodiments, the immune response elicited by the composition described herein is specific for a particular antigen (an “antigen-specific response” or “adaptive immune response”), and refers to a response by a CD4 T cell, CD8 T cell, or B cell via their antigen-specific receptor. In some embodiments, an immune response is a T cell response, such as a CD4+ response or a CD8+ response. Such responses by these cells can include, for example, cytotoxicity, proliferation, cytokine or chemokine production, trafficking, or phagocytosis, and can be dependent on the nature of the immune cell undergoing the response. 
     In some embodiments, an antigen-specific immune response includes both a humoral and/or a cell-mediated immune response to the antigen. A “humoral immune response” is an antibody-mediated immune response and involves the induction and generation of antibodies that recognize and bind with some affinity for the antigen in the immunogenic composition of the invention, while a “cell-mediated immune response” is one mediated by T-cells and/or other white blood cells. A “cell-mediated immune response” is elicited by the presentation of antigenic epitopes in association with Class I or Class II molecules of the major histocompatibility complex (MHC), CD1 or other non-classical MHC-like molecules. This activates antigen-specific CD4+T helper cells or CD8+ cytotoxic lymphocyte cells (“CTLs”). CTLs have specificity for peptide antigens that are presented in association with proteins encoded by classical or non-classical MHCs and expressed on the surfaces of cells. CTLs help induce and promote the intracellular destruction of intracellular microbes, or the lysis of cells infected with such microbes. Another aspect of cellular immunity involves an antigen-specific response by helper T-cells. Helper T-cells act to help stimulate the function, and focus the activity of, nonspecific effector cells against cells displaying peptide or other antigens in association with classical or non-classical MHC molecules on their surface. A “cell-mediated immune response” also refers to the production of cytokines, chemokines and other such molecules produced by activated T-cells and/or other white blood cells, including those derived from CD4+ and CD8+ T-cells. The ability of a particular antigen or composition to stimulate a cell-mediated immunological response may be determined by a number of assays, such as by lymphoproliferation (lymphocyte activation) assays, CTL cytotoxic cell assays, by assaying for T-lymphocytes specific for the antigen in a sensitized subject, or by measurement of cytokine production by T cells in response to re-stimulation with antigen. Such assays are well known in the art. See, e.g., Erickson et al. (1993) J. Immunol. 151:4189-4199; and Doe et al. (1994) Eur. J. Immunol. 24:2369-2376. 
     In some embodiments, the immune response elicited by the composition described herein is an innate immune response. An “innate immune response” refers to the response by the innate immune system. The innate immune system uses a set of germline-encoded receptors (“pattern recognition receptor” or “PRR”) for the recognition of conserved molecular patterns present in microorganisms. These molecular patterns occur in certain constituents of microorganisms including: lipopolysaccharides, peptidoglycans, lipoteichoic acids, phosphatidyl cholines, bacteria-specific proteins, including lipoproteins, bacterial DNAs, viral single and double-stranded RNAs, unmethylated CpG-DNAs, mannans and a variety of other bacterial and fungal cell wall components. Such molecular patterns can also occur in other molecules such as plant alkaloids. These targets of innate immune recognition are called Pathogen Associated Molecular Patterns (PAMPs) since they are produced by microorganisms and not by the infected host organism. In some embodiments, the innate immune response elicited by the composition described herein confers heterologous (“non-specific”) immunity to a broad range of pathogenic microbes by enhancing innate immune responses to subsequent stimuli, a phenomenon known as “trained immunity”, a form of innate memory, e.g., as described in Netea et al. (Trained Immunity: An Ancient Way of Remembering. Cell Host Microbe. 2017 Mar. 8; 21(3):297-300, incorporated herein by reference). 
     The receptors of the innate immune system that recognize PAMPs are called Pattern Recognition Receptors (PRRs). (Janeway et al. (1989) Cold Spring Harb. Symp. Quant. Biol. 54: 1-13: Medzhitov et al. (1997) Curr. Opin. Immunol. 94: 4-9, incorporated herein by reference). PRRs vary in structure and belong to several different protein families. Some of these receptors recognize PAMPs directly (e.g., CD14, DEC205, collectins), while others (e.g., complement receptors) recognize the products generated by PAMP recognition. Members of these receptor families can, generally, be divided into three types: 1) humoral receptors circulating in the plasma; 2) endocytic receptors expressed on immune-cell surfaces, and 3) signaling receptors that can be expressed either on the cell surface or intracellularly. (Medzhitov et al. (1997) Curr. Opin. Immunol. 94: 4-9; Fearon et al. (1996) Science 272: 50-3, incorporated herein by reference). Non-limiting examples of PRRs include: toll-like receptors (e.g., TLR2), NOD1/2, RIG-1/MDA-5, C-type lectins, and STING. 
     Cellular PRRs are expressed on effector cells of the innate immune system, including cells that function as professional antigen-presenting cells (APC) in adaptive immunity. Such effector cells include, but are not limited to, macrophages, dendritic cells, B lymphocytes and surface epithelia. This expression profile allows PRRs to directly induce innate effector mechanisms, and also to alert the host organism to the presence of infectious agents by inducing the expression of a set of endogenous signals, such as inflammatory cytokines and chemokines, including, without limitation: chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors. This latter function allows efficient mobilization of effector forces to combat the invaders. 
     In some embodiments, the composition comprising an antigen and an imidazopyrimidine is a vaccine composition. A “vaccine composition” is a composition that activates or enhances a subject&#39;s immune response to an antigen after the vaccine is administered to the subject. In some embodiments, a vaccine stimulates the subject&#39;s immune system to recognize the antigen as foreign, and enhances the subject&#39;s immune response if the subject is later exposed to the pathogen, whether attenuated, inactivated, killed, or not. Vaccines may be prophylactic, for example, preventing or ameliorating a detrimental effect of a future exposure to a pathogen, or therapeutic, for example, activating the subject&#39;s immune response to a pathogen after the subject has been exposed to the pathogen. In some embodiments, a vaccine composition is used to protect or treat an organism against a disease (e.g., an infectious disease or cancer). In some embodiments, the vaccine is a subunit vaccine (e.g., a recombinant subunit vaccine), an attenuated vaccine (e.g., containing an attenuated pathogen such as a bacterial cell or a viral genome), a live vaccine (e.g., containing a live attenuated pathogen such as a bacterium or virus), or a conjugated vaccine (e.g., a vaccine containing an antigen that is not very immunogenic covalently attached to an antigen that is more immunogenic). One non-limiting example of a conjugated vaccine comprises a LPS attached to a strong protein antigen. 
     The terms “vaccine composition” and “vaccine” are used interchangeably herein. Vaccines that contain cancer-specific antigens are termed herein as “cancer vaccine.” Cancer vaccines induce cancer-specific immune response against a cancer or a cancer-specific antigen. Such immunoresponse is effective in inhibiting cancer growth and/or preventing reoccurrence of tumor. Cancer vaccines may be used for cancer immunotherapy, which is a type of cancer treatment designed to boost the body&#39;s natural defenses to fight the cancer. It uses substances either made by the body or in a laboratory to improve or restore immune system function. 
     In some embodiments, the imidazopyrimidine compounds described herein is used as an adjuvant in a vaccine composition (e.g., to enhance an immune response in a subject). It is demonstrated herein that imidazopyrimidine compounds alone induced cytokine (e.g., proinflammatory cytokines such as TNF, IL-12. IL-6, or IL1-β) and/or chemokine (e.g., CXCL-8) production by human peripheral blood mononuclear cells (PBMC) in vitro and enhanced antigen-specific immune response against influenza hemagglutinin antigen in vivo. 
     An “adjuvant” refers to a pharmacological or immunological agent that modifies the effect of other agents, for example, of an antigen in a vaccine. Adjuvants are typically included in vaccines to enhance the recipient subject&#39;s immune response to an antigen. The use of adjuvants allows the induction of a greater immune response in a subject with the same dose of antigen, or the induction of a similar level of immune response with a lower dose of injected antigen. Adjuvants are thought to function in several ways, including by increasing the surface area of antigen, prolonging the retention of the antigen in the body thus allowing time for the lymphoid system to have access to the antigen, slowing the release of antigen, targeting antigen to macrophages, activating macrophages, activating leukocytes such as antigen-presenting cells (e.g., monocytes, macrophages, and/or dendritic cells), or otherwise eliciting broad activation of the cells of the immune system see, e.g., H. S. Warren et al, Annu. Rev. immunol., 4:369 (1986), incorporated herein by reference. The ability of an adjuvant to induce and increase a specific type of immune response and the identification of that ability is thus a key factor in the selection of particular adjuvants for vaccine use against a particular pathogen. Adjuvants that are known to those of skill in the art, include, without limitation: aluminum salts (referred to herein as “alum”), liposomes, lipopolysaccharide (LPS) or derivatives such as monophosphoryl lipid A (MPLA) and glycopyranosyl lipid A (GLA), molecular cages for antigen, components of bacterial cell walls, endocytosed nucleic acids such as double-stranded RNA (dsRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA. Typical adjuvants include water and oil emulsions, e.g., Freund&#39;s adjuvant and MF59, and chemical compounds such as aluminum hydroxide or alum. At present, currently licensed vaccines in the United States contain only a limited numer of adjuvants, such as alum that enhances production of TH 2 cells and MPLA which activates innte immunity via Toll-like receptor 4 (TLR4). Many of the most effective adjuvants include bacteria or their products, e.g., microorganisms such as the attenuated strain of  Mycobacterium bovis , Bacille Calmette-Guerin (BCG); microorganism components, e.g., alum-precipitated diphtheria toxoid, bacterial lipopolysaccharides (“endotoxins”) and their derivatives such as MPLA and GLA. 
     In some embodiments, the vaccine composition described herein further comprises a second adjuvant, in addition to the imidazopyrimidine compound (as the first adjuvant). Any known adjuvants may be used as the second adjuvant in the composition described herein. In some embodiments, the second adjuvant is an agonist of Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptor, C-type Lectin receptors (CLRs), and a stimulator of interferon genes (STING). An “agonist” is a chemical that binds to a receptor and activates the receptor to produce a biological response. Agonists of the PPRs enhance immune responses (e.g., innate or adaptive immune response). Agonists of PPRs are known to those skilled in the art. For example, various TLR and NLR agonists are described in Kaczanowska et al, J Leukoc Biol. 2013 June; 93(6): 847-863; Higgins et al., Curr Infect Dis Rep. 2010 January; 12(1):4-12; and Maisonneuve et al., Proc Natl Acad Sci USA. 2014 Aug. 26; 111(34): 12294-12299, incorporated herein by reference. RIG-I-like receptor agonists are described in Ranjith-Kumar et al., J Biol Chem. 2009 Jan. 9: 284(2): 1155-1165; and Goulet et al., PLOS Pathogens 9(8): 10, incorporated herein by reference. CLR agonists are described in Lamb et al., Biochemistry. 2002 Dec. 3; 41(48): 14340-7; and Yan et al., Front Immunol. 2015; 6: 408, incorporated herein by reference. STING agonists are described in Fu et al., Sci Transl Med. 2015 Apr. 15; 7(283): 283ra52; and Foote et al., Cancer Immunology Research. DOI: 10.1158/2326-6066.CIR-16-0284, incorporated herein by reference. The PPR agonists described herein are also commercially available, e.g., from InvivoGen (California, USA). In some embodiments, the second adjuvant is alum. 
     In some embodiments, the vaccine composition described herein are formulated for administration to a subject. In some embodiments, the vaccine composition is formulated or administered in combination with one or more pharmaceutically-acceptable excipients. In some embodiments, vaccine compositions comprise at least one additional active substances, such as, for example, a therapeutically-active substance, a prophylactically-active substance, or a combination of both. Vaccine compositions may be sterile, pyrogen-free or both sterile and pyrogen-free. General considerations in the formulation and/or manufacture of pharmaceutical agents, such as vaccine compositions, may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams &amp; Wilkins, 2005 (incorporated herein by reference in its entirety). 
     Formulations of the vaccine compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the antigen and/or the adjuvant (e.g., imidazopyrimidine compounds) into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit. 
     Relative amounts of the antigen, the adjuvant, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient. 
     In some embodiments, the vaccine composition described herein are formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation); (4) alter the biodistribution (e.g., target to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein (antigen) in vivo. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with DNA or RNA vaccines (e.g., for transplantation into a subject), hyaluronidase, nanoparticle mimics and combinations thereof. 
     In some embodiments, the vaccine composition is formulated in an aqueous solution. In some embodiments, the vaccine composition is formulated in a nanoparticle. In some embodiments, the vaccine composition is formulated in a lipid nanoparticle. In some embodiments, the vaccine composition is formulated in a lipid-polycation complex, referred to as a lipid nanoparticle. The formation of the lipid nanoparticle may be accomplished by methods known in the art and/or as described in U.S. Pub. No. 20120178702, incorporated herein by reference. As a non-limiting example, the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and the cationic peptides described in International Pub. No. WO2012013326 or US Patent Pub. No. US20130142818; each of which is incorporated herein by reference. In some embodiments, the vaccine composition is formulated in a lipid nanoparticle that includes a non-cationic lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE). 
     A lipid nanoparticle formulation may be influenced by, but not limited to, the selection of the ionizable lipid component, the degree of ionizable lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size. In one example by Semple et al. (Nature Biotech. 2010 28:172-176; incorporated herein by reference), the lipid nanoparticle formulation is composed of 57.1% cationic lipid, 7.1% dipalmitoylphosphatidylcholine, 34.3% cholesterol, and 1.4% PEG-c-DMA. As another example, changing the composition of the cationic lipid can more effectively deliver siRNA to various antigen presenting cells (Basha et al. Mol Ther. 2011 19:2186-2200; incorporated herein by reference). 
     In some embodiments, lipid nanoparticle formulations may comprise 35 to 45% ionizable cationic lipid, 40% to 50% ionizable cationic lipid, 50% to 60% ionizable cationic lipid and/or 55% to 65% ionizable cationic lipid. In some embodiments, the ratio of lipid to RNA (e.g., mRNA) in lipid nanoparticles may be 5:1 to 20:1, 10:1 to 25:1, 15:1 to 30:1 and/or at least 30:1. 
     In some embodiments, the ratio of PEG in the lipid nanoparticle formulations may be increased or decreased and/or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and/or biodistribution of the lipid nanoparticle formulations. As a non-limiting example, lipid nanoparticle formulations may contain 0.5% to 3.0%, 1.0% to 3.5%, 1.5% to 4.0%, 2.0% to 4.5%, 2.5% to 5.0% and/or 3.0% to 6.0% of the lipid molar ratio of PEG-c-DOMG (R-3-[((ω-methoxy-poly(ethyleneglycol)2000)carbamoyl)]-1,2-dimyristloxypropyl-3-amine) (also referred to herein as PEG-DOMG) as compared to the cationic lipid, DSPC and cholesterol. In some embodiments, the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1,2-Distearoyl-sn-glycerol, methoxypolyethylene glycol), PEG-DMG (1,2-Dimyristoyl-sn-glycerol) and/or PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol). The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA. 
     In some embodiments, a vaccine formulation described herein is a nanoparticle that comprises at least one lipid (termed a “lipid nanoparticle” or “LNP”). The lipid may be selected from, but is not limited to, DLin-DMA. DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA. DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In some embodiments, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA. DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid may be the lipids described in and/or made by the methods described in US Patent Publication No. US20130150625, incorporated herein by reference. As a non-limiting example, the cationic lipid may be 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,2Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en-1-yloxy]-2-{[(9Z)-octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 2 in US20130150625); 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-[(octyloxy)methyl]propan-1-ol (Compound 3 in US20130150625); and 2-(dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof. 
     Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, for example, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), or di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid. 
     In some embodiments, a lipid nanoparticle formulation consists essentially of (i) at least one lipid selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319); (ii) a neutral lipid selected from DSPC. DPPC, POPC, DOPE and SM; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, e.g., PEG-DMG or PEG-cDMA, in a molar ratio of 20-60% ionizable cationic lipid: 5-25% neutral lipid: 25-55% sterol: 0.5-15% PEG-lipid. 
     Non-limiting examples of lipid nanoparticle compositions and methods of making them are described, for example, in Semple et al. (2010) Nat. Biotechnol. 28:172-176; Jayarama et al. (2012), Angew. Chem. Int. Ed., 51: 8529-8533; and Maier et al. (2013) Molecular Therapy 21, 1570-1578 (the contents of each of which are incorporated herein by reference in their entirety). 
     The lipid nanoparticles described herein may be made in a sterile environment by the system and/or methods described in US Patent Publication No. US20130164400, incorporated herein by reference. 
     In some embodiments, the lipid nanoparticle formulation may be formulated in a nanoparticle such as a nucleic acid-lipid particle described in U.S. Pat. No. 8,492,359, the contents of which are incorporated herein by reference. As a non-limiting example, the lipid nanoparticle may comprise one or more active agents or therapeutic agents: one or more cationic lipids comprising from about 50 mol % to about 85 mol % of the total lipid present in the particle; one or more non-cationic lipids comprising from about 13 mol % to about 49.5 mol % of the total lipid present in the particle; and one or more conjugated lipids that inhibit aggregation of particles comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the particle. The nucleic acid in the nanoparticle may be the polynucleotides described herein and/or are known in the art. 
     In some embodiments, the lipid nanoparticle formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, the antigen and the imidazopyrimidine compound described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; the contents of each of which are herein incorporated by reference in their entirety. 
     In some embodiments, lipid nanoparticle formulations described herein may comprise a polycationic composition. As a non-limiting example, the polycationic composition may be selected from formula 1-60 of US Patent Publication No. US20050222064; the content of which is incorporated herein by reference. In another embodiment, the LNP formulations comprising a polycationic composition may be used for the delivery of the modified RNA described herein in vivo and/or in vitro. 
     In some embodiments, the lipid nanoparticle formulations described herein may additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in US Patent Publication No. US20050222064; the content of which is incorporated herein by reference. 
     In some embodiments, the vaccine compositions may be formulated in liposomes such as, but not limited to, DiLa2 liposomes (Marina Biotech, Bothell, Wash.), SMARTICLES® (Marina Biotech, Bothell, Wash.), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology &amp; Therapy 2006 5(12)1708-1713); incorporated herein by reference) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel). 
     In some embodiments, the vaccine compositions may be formulated in a lyophilized gel-phase liposomal composition as described in US Publication No. US2012060293, incorporated herein by reference. 
     In some embodiments, the vaccine compositions described herein may be formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and/or about 90 to about 100 nm. 
     In some embodiments, the lipid nanoparticles may have a diameter from about 10 to 500) nm. In some embodiments, the lipid nanoparticle may have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. 
     In some embodiments, the vaccine composition is formulated in a liposome. Liposomes are artificially-prepared vesicles which may primarily be composed of a lipid bilayer and may be used as a delivery vehicle for the administration of nutrients and pharmaceutical formulations. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter. Liposome design may include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis. Liposomes may contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations. 
     The formation of liposomes may depend on the physicochemical characteristics such as, but not limited to, the pharmaceutical formulation entrapped and the liposomal ingredients, the nature of the medium in which the lipid vesicles are dispersed, the effective concentration of the entrapped substance and its potential toxicity, any additional processes involved during the application and/or delivery of the vesicles, the optimization size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products. 
     As a non-limiting example, liposomes such as synthetic membrane vesicles may be prepared by the methods, apparatus and devices described in US Patent Publication No. US20130177638, US20130177637, US20130177636, US20130177635, US20130177634, US20130177633, US20130183375, US20130183373 and US20130183372, the contents of each of which are incorporated herein by reference. 
     In some embodiments, the vaccine compositions described herein may include, without limitation, liposomes such as those formed from 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, Wash.), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), and MC3 (US20100324120; incorporated herein by reference) and liposomes which may deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, Pa.). 
     In some embodiments, pharmaceutical compositions described herein may include, without limitation, liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy, 1999 6:271-281; Zhang et al. Gene Therapy. 1999 6:1438-1447; Jeffs et al. Pharm Res. 2005 22:362-372; Morrissey et al., Nat Biotechnol. 2005 2:1002-1007; Zimmermann et al., Nature. 2006 441:111-114; Heyes et al. J Contr Rel. 2005 107:276-287; Semple et al. Nature Biotech. 2010 28:172-176; Judge et al. J Clin Invest. 2009 119:661-673; deFougerolles Hum Gene Ther. 2008 19:125-132; U.S. Patent Publication No US20130122104; all of which are incorporated herein in their entireties). The original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al, and is referred to as the spontaneous vesicle formation method. The liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide. As an example a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), as described by Jeffs et al. As another example, certain liposome formulations may contain, but are not limited to, 48% cholesterol, 200/o DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2-distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA), as described by Heyes et al. 
     In some embodiments, liposomes may be formulated for targeted delivery. As a non-limiting example, the liposome may be formulated for targeted delivery to the liver. The liposome used for targeted delivery may include, but is not limited to, the liposomes described in and methods of making liposomes described in US Patent Publication No. US20130195967, the contents of which are incorporated herein by reference. 
     In some embodiments, the antigen and/or the imidazopyrimidine compound may be formulated in a cationic oil-in-water emulsion where the emulsion particle comprises an oil core and a cationic lipid which can interact with the polynucleotide anchoring the molecule to the emulsion particle (see International Pub. No. WO2012006380; incorporated herein by reference). 
     In some embodiments, the antigen and/or the imidazopyrimidine compound may be formulated in a water-in-oil emulsion comprising a continuous hydrophobic phase in which the hydrophilic phase is dispersed. As a non-limiting example, the emulsion may be made by the methods described in International Publication No. WO201087791, the contents of which are incorporated herein by reference. 
     The antigen, the imidazopyrimidine compound, and/or optionally the second adjuvant may be formulated using any of the methods described herein or known in the art separately or together. For example, the antigen and the imidazopyrimidine compound may be formulated in one lipid nanoparticle or two separately lipid nanoparticles. In some embodiments, the antigen, the imidazopyrimidine compound are formulated in the same aqueous solution or two separate aqueous solutions. In some embodiments, the antigen, the imidazopyrimidine compound, and/or optionally the second adjuvant is adsorbed onto alum (e.g., as described in Jones et al., Journal of Biological Chemistry 280, 13406-13414, 2005, incorporated herein by reference). 
     In some embodiments, the vaccine composition described herein comprises two or more adjuvants (also referred to as an “adjuvant system”). The adjuvant system comprises the imidazopyrimidine compound and one or more other adjuvants described herein. 
     Methods 
     Other aspects of the present disclosure provide methods of enhancing an immune response in a subject. In some embodiments, the methods comprise administering to the subject an effective amount of an imidazopyrimidine compound described herein (e.g., for enhancing an innate immune response, including induction of heterologous or “trained” immunity or innate memory). In some embodiments, the methods comprising administering to the subject an effective amount of an imidazopyrimidine compound and an effective amount of an antigen (e.g., for enhancing an antigen-specific immune response). In some embodiments, the imidazopyrimidine compounds are administered separately from the antigen. In some embodiments, the imidazopyrimidine compound is administered prior to administering the antigen. In some embodiments, the imidazopyrimidine compound is administered after administering the antigen. In some embodiments, the imidazopyrimidine compound and the antigen are administered simultaneously. In some embodiment, imidazopyrimidine compound and the antigen as an admixture. 
     The antigen and/or the imidazopyrimidine compound (e.g., the antigen alone, the imidazopyrimidine compound alone, or the antigen and the imidazopyrimidine compound together) described herein elicits an immune response in the subject. In some embodiments, the antigen and/or the imidazopyrimidine compound activates cytokine and/or chemokine (e.g., CXCL-8) production. In some embodiments, the immune response is an innate immune response. In some embodiments, the immune response is an adaptive immune response specific to the antigen in the composition or vaccine. In some embodiments, the antigen and/or the imidazopyrimidine compound activates B cell immunity. In some embodiments, the antigen and/or the imidazopyrimidine compound elicits antibody production. In some embodiments, the composition or the vaccine activates cytotoxic T cells specific to the antigen. 
     In some embodiments, the imidazopyrimidine compounds, whether administered alone or in an admixture with an antigen, enhance the innate immune response, compared to without the imidazopyrimidine compounds or when the antigen is administered alone. In some embodiments, the imidazopyrimidine compound activates peripheral blood mononuclear cells (PBMCs). In some embodiments, the number of PBMCs that are activated is increased by at least 20% in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. For example, the number of PBMCs that are activated may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. In some embodiments, the number of PBMCs that are activated is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. 
     In some embodiments, the imidazopyrimidine compound activates an pattern recognition receptor (PRR). In some embodiments, the PRR is selected from the group consisting of toll-like receptors (e.g., TLR2), NOD1/2, RIG-1/MDA-5, C-type lectins, and STING. In some embodiments, the Toll-like receptor is Toll-like receptor-1, -2, -3, -4, -5, -6, -9, -10. In some embodiments, the Toll-like receptor is Toll-like receptor-7 or -8. In some embodiments, the number of PRRs that are activated is increased by at least 20% in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. For example, the number of PRRs that are activated may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. In some embodiments, the number of PRRs that are activated is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. 
     In some embodiments, the imidazopyrimidine compound induces the production of a proinflammatory cytokine (e.g., TNF, IL-12, IL-6, or IL1-β) and/or chemokines (e.g., CXCL-8) in the subject. In some embodiments, the level of proinflammatory cytokines and/or chemokines (e.g., CXCL-8) is increased by at least 20% in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. For example, the level of proinflammatory cytokines and/or chemokines (e.g., CXCL-8) may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. In some embodiments, the level of proinflammatory cytokines and/or chemokines (e.g., CXCL-8) is increased by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. 
     In some embodiments, the imidazopyrimidine compound enhances innate immune memory (also referred to as trained immunity). “Innate immune memory” confers heterologous immunity that provides broad protection against a range of pathogens. In some embodiments, the innate immune memory is increased by at least 20% in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. For example, the innate immune memory may be increased by at least 20%, at least 30%, at least 40%, at least 50/%, at least 60%, at least 70%, at least 80%, at least 90%, at least 1000/%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. In some embodiments, the innate immune memory is increased by 20%, 30/6, 40%, 50%0, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound or when the antigen is administered alone. 
     In some embodiments, the imidazopyrimidine compound, when administered as an admixture with an antigen (e.g., the vaccine composition described herein), enhances the anti-specific immune response against the antigen or against the invading agent where the antigen is derived from (e.g., a microbial pathogen or cancer), compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the imidazopyrimidine compound enhances the production of antigen-specific antibody titer (e.g., by at least 20%) in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). For example, the imidazopyrimidine compound may enhance the production of antigen-specific antibody titer by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the imidazopyrimidine compound enhances the production of antigen-specific antibody titer by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). One skilled in the art is familiar with how to evaluate the level of an antibody titer, e.g., by ELISA. 
     In some embodiments, the imidazopyrimidine compound enhances the activation of cytotoxic T-cells (e.g., by at least 20%) in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). For example, the imidazopyrimidine compound may enhance activation of cytotoxic T-cells by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%6, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the imidazopyrimidine compound enhances the activation of cytotoxic T-cells by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). 
     In some embodiments, the imidazopyrimidine compound polarizes the innate and adaptive immune response by shaping the pattern of cytokine and/or chemokine responses toward T helper 1 (Th1) immunity, important for host defense against intracellular pathogens. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T helper 2 (Th2) immunity important for humeral immunity including antibody production. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T helper 17 (Th17) immunity important for mucosal immunity. In some embodiments, the imidazopyrimidine compound polarizes the innate immune response toward T follicular helper (Tfh) cell immunity. 
     It has been demonstrated that the innate immune system plays a crucial role in the control of initiation of the adaptive immune response and in the induction of appropriate cell effector responses. (Fearon et al. (1996) Science 272: 50-3; Medzhitov et al. (1997) Cell 91: 295-8, incorporated herein by reference). As such, in some embodiments, the imidazopyrimidine compound enhances the innate immune response in a subject (e.g., when administered alone or in an admixture with an antigen), which in turn enhances the adaptive immune response against the antigen in the subject. This is particular useful in subjects that have a undeveloped (e.g., in an neonatal infant), weak (e.g., in an elderly), or compromised immune systems (e.g., in a patient with primary immunodeficiency or acquired immunodeficiency secondary to HIV patient infection or a cancer patient undergoing with or without chemotherapy and/or radiation therapy). 
     In some embodiments, the imidazopyrimidine compound prolongs the effect of a vaccine (e.g., by at least 20%) in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). For example, the imidazopyrimidine compound may prolong the effect of a vaccine by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the imidazopyrimidine compound prolongs the effect of a vaccine by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). 
     In some embodiments, the imidazopyrimidine compound increases rate of (accelerates) an immune response, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). For example, the imidazopyrimidine compound may increase the rate of an immune response by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 700/6, at least 80%, at least 90%, at least 100%, at least 2-fold, at least 5-fold, at least 10-fold, at least 100-fold, at least 1000-fold or more, in the subject, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the imidazopyrimidine compound increases the rate of an immune response by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold or more, in the presence of an imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). “Increase the rate of immune response” mean it takes less time for the immune system of a subject to react to an invading agent (e.g., a microbial pathogen). 
     In some embodiments, the antigen produces a same level of immune response against the antigen at a lower dose in the presence of the imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the amount of antigen needed to produce the same level of immune response is reduced by at least 20% in the presence of the imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). For example, the amount of antigen needed to produce the same level of immune response may be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or more, in the presence of the imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). In some embodiments, the amount of antigen needed to produce the same level of immune response is reduced by at 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, in the presence of the imidazopyrimidine compound, compared to without the imidazopyrimidine compound (i.e., when the antigen is administered alone). 
     The prophylactic or therapeutic use of the imidazopyrimidine compounds, or the composition or vaccine composition described herein is also within the scope of the present disclosure. In some embodiments, the composition or vaccine composition described herein are used in methods of vaccinating a subject by prophylactically administering to the subject an effective amount of the composition or vaccine composition described herein. “Vaccinating a subject” refer to a process of administering an immunogen, typically an antigen formulated into a vaccine, to the subject in an amount effective to increase or activate an immune response against the antigen and, thus, against a pathogen displaying the antigen. In some embodiments, the terms do not require the creation of complete immunity against the pathogen. In some embodiments, the terms encompass a clinically favorable enhancement of an immune response toward the antigen or pathogen. Methods for immunization, including formulation of a vaccine composition and selection of doses, routes of administration and the schedule of administration (e.g. primary dose and one or more booster doses), are well known in the art. In some embodiments, vaccinating a subject reduces the risk of developing a disease (e.g., an infectious disease or cancer) in a subject. 
     In some embodiments, the imidazopyrimidine compounds alone, or composition or vaccine composition comprising an antigen and an imidazopyrimidine compounds described herein are used in methods of treating a disease (e.g., an infectious disease, allergy, or cancer) by administering to the subject an effective amount of the composition or vaccine composition described herein. 
     In some embodiments, the disease is an infectious disease. An “infectious disease” refers to an illness caused by a pathogenic biological agent that results from transmission from an infected person, animal, or reservoir to a susceptible host, either directly or indirectly, through an intermediate plant or animal host, vector, or inanimate environment. See Last J M. ed. A dictionary of epidemiology. 4th ed., New York: Oxford University Press, 1988. Infectious disease is also known as transmissible disease or communicable disease. In some embodiments, infectious diseases may be asymptomatic for much or even all of their course in a given host. Infectious pathogens include some viruses, bacteria, fungi, protozoa, multicellular parasites, and aberrant proteins known as prions. In some embodiments, the infectious disease is caused by any of the microbial pathogens (e.g., a bacterium, a mycobacterium, a fungus, a virus, a parasite or a prion) described herein or known to one skilled in the art. In some embodiments, the infectious disease is caused by  Plasmodium  spp. (malaria),  Bacillus anthracis  (anthrax),  Bordetella pertussis  (whooping cough),  Corynebacterium diphtheriae  (diphtheria),  Clostridium tetani  (tetanus),  Haemophilus influenzae  type b, pneumococcus (pneumococcal infections),  Staphylococci  spp., Group A or B streptococci,  Mycobacterium tuberculosis, Neiserria meningitidis  (meningococcal disease),  Salmonella typhi  (typhoid),  Vibrio cholerae  (Cholera), or  Yersinia pestis  (plague). In some embodiments, the infectious disease is caused by adenovirus, enterovirus such as poliomyelitis (polio), Ebola virus, herpes viruses such as herpes simplex virus, cytomegalovirus and varicella-zoster (chickenpox and shingles), measles, mumps, rubella, hepatitis-A, —B, or -C, human papilloma virus, Influenza virus, rabies, Japanese encephalitis, rotavirus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), smallpox, yellow fever, or Zika Virus. In some embodiments, the infectious disease is caused by malaria,  Leishmania , or a helminth. In some embodiments, the infectious disease is caused by  Candida  spp.,  Aspergillus  spp.,  Cryptococcus  spp.,  Mucormycete, Blastomyces dermatitidis, Histoplasma capsulatum , or  Sporothrix schenckii . In some embodiments, the infectious disease is caused by prion. 
     In some embodiments, the composition or vaccine composition may be administered in combination with another therapeutic agent for the infectious diseases. Such other therapeutic agents may be, without limitation: antibiotics, anti-viral agents, anti-fungal agents, or anti-parasitic agents. One skilled in the art is familiar with how to select or administer the additional therapeutic agent based on the disease to be treated. 
     In some embodiments, the disease is allergy (e.g., allergic rhinitis) or asthma. It has been demonstrated that Th1/Th2 imbalance results in the clinical manifestation of allergy or asthma (e.g., as described in Ngoc et al., Curr Opin Allergy Clin Immunol. 2005 April; 5(2): 161-6, incorporated herein by reference). The imidazopyrimidine compounds described herein may be able to restore Th1/Th2 balance and possess therapeutic potential to allergy or asthma. 
     In some embodiments, the disease is cancer. Vaccine compositions comprising cancer-specific antigens and the imidazopyrimidine compounds may be used in cancer immunotherapy by eliciting cancer-specific immune response against the cancer. The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g.,  Stedman&#39;s Medical Dictionary.  25th ed.: Hensyl ed.; Williams &amp; Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematological malignancies. Additional exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a. Wilms&#39; tumor, renal cell carcinoma); acoustic neuroma adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi&#39;s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett&#39;s adenocarcinoma); Ewing&#39;s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget&#39;s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget&#39;s disease of the vulva). In some embodiments, the cancer treated using the composition and methods of the present disclosure is melanoma. 
     In some embodiments, additional anti-cancer agents may be administered in combination with the composition or vaccine composition described herein. In some embodiments, the anti-cancer agent is selected from the group consisting of: small molecules, oligonucleotides, polypeptides, and combinations thereof. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: Actinomycin, All-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin. Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed. Teniposide. Tioguanine, Topotecan, Valrubicin, Vinblastine. Vincristine. Vindesine, and Vinorelbine. In some embodiments, the chemotherapeutic agent is Doxorubicin. 
     In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor. An “immune checkpoint” is a protein in the immune system that either enhances an immune response signal (co-stimulatory molecules) or reduces an immune response signal. Many cancers protect themselves from the immune system by exploiting the inhibitory immune checkpoint proteins to inhibit the T cell signal. Exemplary inhibitory checkpoint proteins include, without limitation, Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4), Programmed Death 1 receptor (PD-1), T-cell Immunoglobulin domain and Mucin domain 3 (TIM3), Lymphocyte Activation Gene-3 (LAG3), V-set domain-containing T-cell activation inhibitor 1 (VTVN1 or B7-H4), Cluster of Differentiation 276 (CD276 or B7-H3), B and T Lymphocyte Attenuator (BTLA), Galectin-9 (GAL9), Checkpoint kinase 1 (Chk1), Adenosine A2A receptor (A2aR), Indoleamine 2,3-dioxygenase (IDO), Killer-cell Immunoglobulin-like Receptor (KIR), Lymphocyte Activation Gene-3 (LAG3), and V-domain Ig suppressor of T cell activation (VISTA). 
     Some of these immune checkpoint proteins need their cognate binding partners, or ligands, for their immune inhibitory activity. For example, A2AR is the receptor of adenosine A2A and binding of A2A to A2AR activates a negative immune feedback loop. As another example, PD-1 associates with its two ligands, PD-L1 and PD-L2, to down regulate the immune system by preventing the activation of T-cells. PD-1 promotes the programmed cell death of antigen specific T-cells in lymph nodes and simultaneously reduces programmed cell death of suppressor T cells, thus achieving its immune inhibitory function. As yet another example, CTLA4 is present on the surface of T cells, and when bound to its binding partner CD80 or CD86 on the surface of antigen-present cells (APCs), it transmits an inhibitory signal to T cells, thereby reducing the immune response. 
     An “immune checkpoint inhibitor” is a molecule that prevents or weakens the activity of an immune checkpoint protein, For example, an immune checkpoint inhibitor may inhibit the binding of the immune checkpoint protein to its cognate binding partner. e.g., PD-1, CTLA-4, or A2aR. In some embodiments, the immune checkpoint inhibitor is a small molecule. In some embodiments, the immune checkpoint inhibitors is a nucleic acid aptamer (e.g., a siRNA targeting any one of the immune checkpoint proteins). In some embodiments, the immune checkpoint inhibitor is a recombinant protein. In some embodiments, the immune checkpoint inhibitor is an antibody. In some embodiments, the antibody comprises an anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-TIM3, anti-LAG3, anti-B7-H3, anti-B7-H4, anti-BTLA, anti-GAL9, anti-Chk, anti-A2aR, anti-IDO, anti-KIR, anti-LAG3, anti-VISTA antibody, or a combination of any two or more of the foregoing antibodies. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody. In some embodiments, the immune checkpoint inhibitor comprises anti-PD1, anti-PD-L1, anti-CTLA-4, or a combination of any two or more of the foregoing antibodies. For example, the anti-PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®) and the anti-CTLA-4 antibody is ipilimumab (Yervoy®). Thus, in some embodiments, the immune checkpoint inhibitor comprises pembrolizumab, nivolumab, ipilimumab, or any combination of two or more of the foregoing antibodies. The examples described herein are not meant to be limiting and that any immune checkpoint inhibitors known in the art and any combinations thereof may be used in accordance with the present disclosure. 
     Additional exemplary agents that may be used in combination with the compositions described herein include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In some embodiments, the additional agent is an anti-proliferative agent (e.g., anti-cancer agent). In some embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase  Erwinia Chrysanthemi ), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride). MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine). PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine). TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In some embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine). BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin). CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH. FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate). HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride). METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride). NEOSAR (cyclophosphamide). OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V. TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate). ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In some embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine). LEUSTATIN (cladribine), or a combination thereof. In some embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride). ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab). BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide). CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELLX, DOXIL (doxorubicin hydrochloride liposome), DO)(ORUBICIN HYDROCHLORIDE. DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC. FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB. FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib). INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b). PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib). STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel). TAXOTERE (docetaxel), TEMODAR (temozolomide). THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide). TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine). XELOX. XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept). ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PC 1-32765 , AC220, dovitinib lactate (TKI258, CHIR-258). BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265. DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF 1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine, or a combination thereof. In some embodiments, the additional pharmaceutical agent is a binder or inhibitor of an HMT (e.g., EZH1, EZH2, DOT1). In some embodiments, the additional agent is a protein kinase inhibitor (e.g., tyrosine protein kinase inhibitor). In some embodiments, the additional agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and  vinca  alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. 
     In some embodiments, the composition or vaccine composition described herein are formulated for administration to a subject. In some embodiments, the composition or vaccine composition further comprises a pharmaceutically acceptable carrier. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the tissue of the patient (e.g., physiologically compatible, sterile, physiologic pH, etc.). The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the composition or vaccine composition described herein also are capable of being co-mingled with the molecules of the present disclosure, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer&#39;s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation. 
     The composition or vaccine composition described herein may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. The term “unit dose” when used in reference to a composition or vaccine composition described herein of the present disclosure refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle. 
     The formulation of the composition or vaccine composition described herein may dependent upon the route of administration. Injectable preparations suitable for parenteral administration or intratumoral, peritumoral, intralesional or perilesional administration include, for example, sterile injectable aqueous or oleaginous suspensions and may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 propanediol or 1,3 butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. 
     For topical administration, the composition or vaccine composition described herein can be formulated into ointments, salves, gels, or creams, as is generally known in the art. Topical administration can utilize transdermal delivery systems well known in the art. An example is a dermal patch. 
     Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the anti-inflammatory agent. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir or an emulsion. 
     Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the anti-inflammatory agent, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono- di- and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the anti-inflammatory agent is contained in a form within a matrix such as those described in U.S. Pat. Nos. 4,452,775, 4,667,014, 4,748,034 and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos. 3,832,253, and 3,854,480. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation. 
     Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. Long-term release, are used herein, means that the implant is constructed and arranged to delivery therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. 
     In some embodiments, the composition or vaccine composition described herein used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Alternatively, preservatives can be used to prevent the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. The cyclic Psap peptide and/or the composition or vaccine composition described herein ordinarily will be stored in lyophilized form or as an aqueous solution if it is highly stable to thermal and oxidative denaturation. The pH of the preparations typically will be about from 6 to 8, although higher or lower pH values can also be appropriate in certain instances. The chimeric constructs of the present disclosure can be used as vaccines by conjugating to soluble immunogenic carrier molecules. Suitable carrier molecules include protein, including keyhole limpet hemocyanin, which is a preferred carrier protein. The chimeric construct can be conjugated to the carrier molecule using standard methods. (Hancock et al., “Synthesis of Peptides for Use as Immunogens,” in Methods in Molecular Biology: Immunochemical Protocols, Manson (ed.), pages 23-32 (Humana Press 1992)). 
     In some embodiments, the present disclosure contemplates a vaccine composition comprising a pharmaceutically acceptable injectable vehicle. The vaccines of the present disclosure may be administered in conventional vehicles with or without other standard carriers, in the form of injectable solutions or suspensions. The added carriers might be selected from agents that elevate total immune response in the course of the immunization procedure. 
     Liposomes have been suggested as suitable carriers. The insoluble salts of aluminum, that is aluminum phosphate or aluminum hydroxide, have been utilized as carriers in routine clinical applications in humans. Polynucleotides and polyelectrolytes and water soluble carriers such as muramyl dipeptides have been used. 
     Preparation of injectable vaccines of the present disclosure, includes mixing the antigen and/or the imidazopyrimidine compounds with muramyl dipeptides or other carriers. The resultant mixture may be emulsified in a mannide monooleate/squalene or squalane vehicle. Four parts by volume of squalene and/or squalane are used per part by volume of mannide monooleate. Methods of formulating vaccine compositions are well-known to those of ordinary skill in the art. (Rola, Immunizing Agents and Diagnostic Skin Antigens. In: Remington&#39;s Pharmaceutical Sciences, 18th Edition, Gennaro (ed.), (Mack Publishing Company 1990) pages 1389-1404). 
     Additional pharmaceutical carriers may be employed to control the duration of action of a vaccine in a therapeutic application. Control release preparations can be prepared through the use of polymers to complex or adsorb chimeric construct. For example, biocompatible polymers include matrices of poly(ethylene-co-vinyl acetate) and matrices of a polyanhydride copolymer of a stearic acid dimer and sebacic acid. (Sherwood et al. (1992) Bio/Technology 10: 1446). The rate of release of the chimeric construct from such a matrix depends upon the molecular weight of the construct, the amount of the construct within the matrix, and the size of dispersed particles. (Saltzman et al. (1989) Biophys. J. 55: 163: Sherwood et al, supra; Ansel et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th Edition (Lea &amp; Febiger 1990); and Gennaro (ed.). Remington&#39;s Pharmaceutical Sciences, 18th Edition (Mack Publishing Company 1990)). The chimeric construct can also be conjugated to polyethylene glycol (PEG) to improve stability and extend bioavailability times (e.g., Katre et al.; U.S. Pat. No. 4,766,106). 
     The terms “treatment,” “treat.” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Prophylactic treatment refers to the treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In some embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. 
     An “effective amount” of a composition described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a composition described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is a prophylactic treatment. In some embodiments, an effective amount is the amount of a compound described herein in a single dose. In some embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. When an effective amount of a composition is referred herein, it means the amount is prophylactically and/or therapeutically effective, depending on the subject and/or the disease to be treated. Determining the effective amount or dosage is within the abilities of one skilled in the art. 
     The terms “administer,” “administering.” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. The composition of the vaccine composition described herein may be administered systemically (e.g., via intravenous injection) or locally (e.g., via local injection). In some embodiments, the composition of the vaccine composition described herein is administered orally, intravenously, topically, intranasally, or sublingually. Parenteral administering is also contemplated. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered prophylactically. 
     In some embodiments, the composition or vaccine composition is administered once or multiple times (e.g., 2, 3, 4, 5, or more times). For multiple administrations, the administrations may be done over a period of time (e.g., 6 months, a year, 2 years, 5 years, 10 years, or longer). In some embodiments, the composition or vaccine composition is administered twice (e.g., Day 0 and Day 7, Day 0 and Day 14, Day 0 and Day 21, Day 0 and Day 28, Day 0 and Day 60, Day 0 and Day 90, Day 0 and Day 120. Day 0 and Day 150, Day 0 and Day 180, Day 0 and 3 months later, Day 0 and 6 months later, Day 0 and 9 months later, Day 0 and 12 months later, Day 0 and 18 months later, Day 0 and 2 years later, Day 0 and 5 years later, or Day 0 and 10 years later). 
     A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In some embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. A “subject in need thereof” refers to a human subject in need of treatment of a disease or in need of reducing the risk of developing a disease. In some embodiments, the subject has any of the diseases described herein (e.g., infectious disease, cancer, or allergy). In some embodiments, the subject is at risk of developing any of the diseases described herein (e.g., infectious disease, cancer, or allergy). In some embodiments, administering the antigen and the imidazopyrimidine compound described herein to a subject having a disease treats the disease (therapeutic use). In some embodiments, administering the antigen and the imidazopyrimidine compound described herein to a subject at risk of developing a disease reduces the likelihood (e.g., by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more) of the subject developing the disease (prophylactic use). 
     In some aspects, the present disclosure contemplates the vaccination of human infants or neonates. In some embodiments, the subject is a human infant. In some embodiments, the human infant is a neonate that is less than 28 days of age. In some embodiments, the human infant is 0-28 days, 0-27 days, 0-26 days, 0-25 days, 0-24 days, 0-23 days, 0-22 days, 0-21 days, 0-20 days, 0-19 days, 0-18 days, 0-17 days, 0-16 days, 0-15 days, 0-14 days, 0-13 days, 0-12 days, 0-11 days, 0-10 days, 0-9 days, 0-8 days, 0-7 days, 0-6 days, 0-5 days, 0-4 days, 0-3 days, 0-2 days, 0-1 days, 0-12 hours, 0-6 hours, 0-2 hours, 0-1 hour, 1-28 days, 1-27 days, 1-26 days, 1-25 days, 1-24 days, 1-23 days, 1-22 days, 1-21 days, 1-20 days, 1-19 days, 1-18 days, 1-17 days, 1-16 days, 1-15 days, 1-14 days, 1-13 days, 1-12 days, 1-11 days, 1-10 days, 1-9 days, 1-8 days, 1-7 days, 1-6 days, 1-5 days, 1-4 days, 1-3 days, 1-2 days, 2-28 days, 2-27 days, 2-26 days, 2-25 days, 2-24 days, 2-23 days, 2-22 days, 2-21 days, 2-20 days, 2-19 days, 2-18 days, 2-17 days, 2-16 days, 2-15 days, 2-14 days, 2-13 days, 2-12 days, 2-11 days, 2-10 days, 2-9 days, 2-8 days, 2-7 days, 2-6 days, 2-5 days, 2-4 days, 2-3 days, 3-28 days, 3-27 days, 3-26 days, 3-25 days, 3-24 days, 3-23 days, 3-22 days, 3-21 days, 3-20 days, 3-19 days, 3-18 days, 3-17 days, 3-16 days, 3-15 days, 3-14 days, 3-13 days, 3-12 days, 3-11 days, 3-10 days, 3-9 days, 3-8 days, 3-7 days, 3-6 days, 3-5 days, 3-4 days, 4-28 days, 4-27 days, 4-26 days, 4-25 days, 4-24 days, 4-23 days, 4-22 days, 4-21 days, 4-20 days, 4-19 days, 4-18 days, 4-17 days, 4-16 days, 4-15 days, 4-14 days, 4-13 days, 4-12 days, 4-11 days, 4-10 days, 4-9 days, 4-8 days, 4-7 days, 4-6 days, 4-5 days, 5-28 days, 5-27 days, 5-26 days, 5-25 days, 5-24 days, 5-23 days, 5-22 days, 5-21 days, 5-20 days, 5-19 days, 5-18 days, 5-17 days, 5-16 days, 5-15 days, 5-14 days, 5-13 days, 5-12 days, 5-11 days, 5-10 days, 5-9 days, 5-8 days, 5-7 days, 5-6 days, 6-28 days, 6-27 days, 6-26 days, 6-25 days, 6-24 days, 6-23 days, 6-22 days, 6-21 days, 6-20 days, 6-19 days, 6-18 days, 6-17 days, 6-16 days, 6-15 days, 6-14 days, 6-13 days, 6-12 days, 6-11 days, 6-10 days, 6-9 days, 6-8 days, 6-7 days, 7-28 days, 7-27 days, 7-26 days, 7-25 days, 7-24 days, 7-23 days, 7-22 days, 7-21 days, 7-20 days, 7-19 days, 7-18 days, 7-17 days, 7-16 days, 7-15 days, 7-14 days, 7-13 days, 7-12 days, 7-11 days, 7-10 days, 7-9 days, 7-8 days, 9-28 days, 9-27 days, 9-26 days, 9-25 days, 9-24 days, 9-23 days, 9-22 days, 9-21 days, 9-20 days, 9-19 days, 9-18 days, 9-17 days, 9-16 days, 9-15 days, 9-14 days, 9-13 days, 9-12 days, 9-11 days, 9-10 days, 10-28 days, 10-27 days, 10-26 days, 10-25 days, 10-24 days, 10-23 days, 10-22 days, 10-21 days, 10-20 days, 10-19 days, 10-18 days, 10-17 days, 10-16 days, 10-15 days, 10-14 days, 10-13 days, 10-12 days, 10-11 days, 11-28 days, 11-27 days, 11-26 days, 11-25 days, 11-24 days, 11-23 days, 11-22 days, 11-21 days, 11-20 days, 11-19 days, 11-18 days, 11-17 days, 11-16 days, 11-15 days, 11-14 days, 11-13 days, 11-12 days, 12-28 days, 12-27 days, 12-26 days, 12-25 days, 12-24 days, 12-23 days, 12-22 days, 12-21 days, 12-20 days, 12-19 days, 12-18 days, 12-17 days, 12-16 days, 12-15 days, 12-14 days, 12-13 days, 13-28 days, 13-27 days, 13-26 days, 13-25 days, 13-24 days, 13-23 days, 13-22 days, 13-21 days, 13-20 days, 13-19 days, 13-18 days, 13-17 days, 13-16 days, 13-15 days, 13-14 days, 14-28 days, 14-27 days, 14-26 days, 14-25 days, 14-24 days, 14-23 days, 14-22 days, 14-21 days, 14-20 days, 14-19 days, 14-18 days, 14-17 days, 14-16 days, 14-15 days, 15-28 days, 15-27 days, 15-26 days, 15-25 days, 15-24 days, 15-23 days, 15-22 days, 15-21 days, 15-20 days, 15-19 days, 15-18 days, 15-17 days, 15-16 days, 16-28 days, 16-27 days, 16-26 days, 16-25 days, 16-24 days, 16-23 days, 16-22 days, 16-21 days, 16-20 days, 16-19 days, 16-18 days, 16-17 days, 17-28 days, 17-27 days, 17-26 days, 17-25 days, 17-24 days, 17-23 days, 17-22 days, 17-21 days, 17-20 days, 17-19 days, 17-18 days, 18-28 days, 18-27 days, 18-26 days, 18-25 days, 18-24 days, 18-23 days, 18-22 days, 18-21 days, 18-20 days, 18-19 days, 19-28 days, 19-27 days, 19-26 days, 19-25 days, 19-24 days, 19-23 days, 19-22 days, 19-21 days, 19-20 days, 20-28 days, 20-27 days, 20-26 days, 20-25 days, 20-24 days, 20-23 days, 20-22 days, 20-21 days, 21-28 days, 21-27 days, 21-26 days, 21-25 days, 21-24 days, 21-23 days, 21-22 days, 22-28 days, 22-27 days, 22-26 days, 22-25 days, 22-24 days, 22-23 days, 23-28 days, 23-27 days, 23-26 days, 23-25 days, 23-24 days, 24-28 days, 24-27 days, 24-26 days, 24-25 days, 25-28 days, 25-27 days, 25-26 days, 26-28 days, 26-27 days, or 27-28 days of age at the time of administration of the vaccine composition described herein. In some embodiments, the human neonate is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of age at the time of administration of the vaccine composition described herein. 
     In some embodiments, the human infant is less than 28 days of age at the time of administration (vaccination). In some embodiments, the human infant is less than 4 days of age at the time of administration (vaccination). In some embodiments, the human infant is less than 2 days of age at the time of administration (vaccination). In some embodiments, the human infant is less than 24 days of age at the time of administration (vaccination). In some embodiments, the administration (vaccination) occurs at birth. In some embodiments, a human neonate (less than 28 days of age) receives 1 or 2 doses of the vaccine described herein. In some embodiments, the human neonate receives one dose before 28-days of age (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 days of age) and a second dose before or at 28-days of age. In some embodiments, the human subject receives one dose at 2 months, 4 months, or 6 months of age, and a second dose after the first dose at 2 months, 4 months, or 6 months of age. In some embodiments, a human subject receives a second dose before or equal to 6-months of age (e.g., 1, 2, 3, 4, 5, 6 months of age). In some embodiments, the administration occurs when the human infant is 2 months, 4 months, and 6 months of age. In some embodiments, a human subject receives a second dose after 6-months of age (e.g., 1 year, 2 years, 3 years of age). 
     In some embodiments, the human subject is more than 28-days old (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, 3 years, 4 years, 5 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years old). In some embodiments, the human subject is an adult (e.g., more than 18 years old). In some embodiments, the human subject is an elderly (e.g., more than 60 years old). In some embodiments, the human subject is more than 65-years of age. In some embodiments, the human subject receives one or two doses of the vaccine described herein after 65-years of age. 
     In some embodiments, the human subject is born prematurely or has low birth weight. “Born prematurely” means the human subject is born before 40-weeks of term. In some embodiments, the human subject is born before 37-weeks of term. In some embodiments, the human subject is born before 32 weeks of term. In some embodiments, the human subject is born before 24 weeks of term. In some embodiments, the human subject is born before 40 weeks, 39 weeks, 38 weeks, 37 weeks, 36 weeks, 35 weeks, 34 weeks, 33 weeks, 32 weeks, 31 weeks, 30 weeks, 29 weeks, 28 weeks, 27 weeks, 26 weeks, 25 weeks, or 24 weeks of term. In some embodiments, the human subject is born with low birth weight (e.g., at least 20% lower than a normal birth weight). 
     In some embodiments, the human subject has an undeveloped (e.g., an infant or a neonate), weak (an elderly), or compromised immune system. Immunocompromised subjects include, without limitation, subjects with primary immunodeficiency or acquired immunodeficiency such as those suffering from sepsis. HIV infection, and cancers, including those undergoing chemotherapy and/or radiotherapy. 
     In some embodiments, the subject is a companion animal (a pet). The use of the imidazopyrimidine compounds described herein in veterinary vaccine is also within the scope of the present disclosure. “A companion animal,” as used herein, refers to pets and other domestic animals. Non-limiting examples of companion animals include dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. In some embodiments, the subject is a research animal. Non-limiting examples of research animals include: rodents (e.g., ferrets, pigs, rats, mice, guinea pigs, and hamsters), rabbits, or non-human primates. 
     Some of the embodiments, advantages, features, and uses of the technology disclosed herein will be more fully understood from the Examples below. The Examples are intended to illustrate some of the benefits of the present disclosure and to describe particular embodiments, but are not intended to exemplify the full scope of the disclosure and, accordingly, do not limit the scope of the disclosure. 
     EXAMPLES 
     Example 1. Immunomodulatory Activity of Imidazopyrimidine Compounds 
     Human immunity is crucial to both health and illness, playing key roles in infectious diseases, allergic, autoimmune, and canceroncologic and chronic diseases. In this context there is growing interest in development of approaches to modulate the human immune system to prevent and/or treat illness. Infectious diseases are the leading cause of morbidity and mortality in early life. Immunization is a key strategy for preventing infectious diseases. However, immunization of newborns and infants may result in sub-optimal responses, often requires multiple booster doses and can be limited by waning immunity. Adjuvantation is a key approach to enhance vaccine-induced immunity. Adjuvants can enhance, prolong, and modulate immune responses to vaccinal antigens to maximize protective immunity, and may potentially enable effective immunization in vulnerable populations (e.g., in the very young and the elderly or for diseases lacking effective vaccines). Vaccine adjuvants also hold great potential as cancer immunotherapeutics. Small molecules that may be used as adjuvants have been reported. Utility in redirecting immune responses away from allergy (e.g., restoring a Th1/Th2 balance) has also been demonstrated for some molecules (e.g., as described in J Immunol Mar. 15, 1998, 160 (6) 2555-2559: and Adv Drug Deliv Rev. 2009 Mar. 28; 61(3):256-62, incorporated herein by reference). 
     Described herein is a novel molecular approach to shape human immune responses using formulations of imidazopyrimidine small molecules to induce robust activation of human leukocytes in vitro and as adjuvants in vivo. The parental compound identified to have the immune enhancing and adjuvant activity was designated “Compound 037” as it was the 37th compound ordered into the Levy Lab (Boston Children&#39;s Hospital) for hit verification. 
     To identify immunomodulators/adjuvants that robustly activate human immune cells, ˜200,000 small molecules were tested against THP1 NF-κB reporter cells in a screen. As there is evidence that cell culture lines such as THP-1 cells may not model responses of natural primary human leukocytes, smaller-scale novel high throughput screening methodology was also employed, in which ˜9,000 commercially available compounds (focusing on small molecule library plates that had relatively high # of hits form the THP-1 screen) were screened using primary human blood mononuclear cells (PBMC) from three different adult human donors (TNFαLISA Assay) ( FIGS. 1A-1C ). 
     TNF AlphaLISA screen was comprised of three parts: 1) human peripheral blood collection and PBMC isolation—human adult peripheral blood was collected with written consent. PBMCs were isolated from the blood using Ficoll density gradient. PBMCs were stored at 50 million cells per vial in 1 ml RPMI containing 20% autologous plasma and 10% DMSO at −80° C. until use; 2) TNFαLISA Assay—On Day 1, PBMCs were thawed in 37° C. water bath for 3 min and washed twice with PBS. Trypan blue viable cell count was performed and cells were resuspended to viable 6.67×10 5  cells/ml in DMEM with 10% autologous plasma. Cells were dispensed in 30 μl per well in Corning 2712 black 384-well cell culture plates (final concentration was 20,000 cells/well). Controls were added to cells manually and the test compounds were added by robotic pin transfer. Plates were then incubated at 37° C./5% CO 2  humidity-controlled incubator for −24 hours. On Day 2 of the assay, plates were centrifuged and 2 μl supernatants were collected into Perkin Elmer Alpha plates. Perkin Elmer Human TNFα kits (cat # AL208F) were used to detect the presence of TNFα in supernatants. Plates were run on the EnVision instrument (Perkin Elmer) to detect light emission at 615 nm; 3) Hit Calling Method—test compounds that resulted in a robust Z score greater than 2 in both duplicates and of at least 2 of the 3 human samples of PBMCs were considered hits. 
     Based on antibody-coated fluorometric excitation/emission beads, the Alpha technology (PerkinElmer) enables the detection and screening of target molecules, in this case TNFα, in a no-wash, highly sensitive, quantitative assay compatible with high throughput screening. 
     The chemical libraries screened included known bioactive and commercial libraries from various sources including commercial libraries such as ChemDiv, ChemBridge, and Asinex (see attached pdf of all libraries). All libraries were owned and provided by the Institute of Chemistry and Cell Biology (ICCB)-Longwood (Harvard Medical School). Compound 037 was identified in the PBMC TNFαLISA screen. 
     Hits were determined based on the ability of small molecules to induce TNF production in at least two of the three human adult donors screened ( FIG. 1D ). From this screen, the imidazopyrimidine compounds emerged as the chemical family with greatest potency in inducing robust TNF production in vitro ( FIGS. 2A-2B ). These results were confirmed in human PBMC assays measuring cytokine production by ELISA as well as multiplexing assay for other Th-polarizing cytokines (IL-12, IL-6, IL-1β etc.) ( FIGS. 3A, 3B, and 4 ). 
     Of note, imidazopyrimidines did not activate the human THP-1 cell line in any assay formatted tested, as demonstrated by the lack of activity towards the THP-1 NF-κB reporter cell lines ( FIGS. 5A-5B ). This great discrepancy in activity of the imidazopyrimidines between primary cells and THP1 cells is noteworthy, as for practical convenience many conventional high throughput screens employ cell lines such as THP-1 cells, highlighting the novelty and importance of the PBMC screening methodology in the identification of imidazopyrimidines as immune stimulating compounds. The ability of imidazopyrimidines to activate human newborn and elderly leukocytes as well as murine leukocytes was also confirmed in vitro ( FIGS. 2A, 8 , and  10 , expanding potential utility of this compound family (e.g., to sub-populations at high risk for infection). 
     Additionally, in vivo studies in a murine model of influenza immunization indicate that the addition of imidazopyrimidines markedly enhances vaccine responses of adult mice (FIG.  9 ). Mice vaccinated with recombinant Influenza Hemagglutinin (rHA)+imidazopyrimidines demonstrated higher antibody titers compared to mice vaccinated with rHA alone and equivalent or enhanced titers as compared to mice vaccinated with rHA+Alum, the most commonly used vaccine adjuvant. 
     Additional commercially available analogs of compound 037 were profiled in the PBMC assay ( FIGS. 6A, 6B , and Table 1) with R848 as a positive control, to generate some initial structure activity relationships (SAR) within the imidazopyrimidine series. Certain structural features appeared important for activity, and a further set of imidazopyrimidines was prepared and tested, with some examples showing equivalent or superior activity to both compound 037 and R848 in this assay (e.g.  FIGS. 7A, 7B  and Table 1). 
     In summary, imidazopyrimidine compounds have activity as immunomodulators/adjuvants, activating human leukocytes in vitro and demonstrating adjuvanticity in mice in vivo. 
     The imidazopyrimidine compounds described herein may be used as stand alone agents to modify human immune responses, e.g., to be applied topically to treat infections by enhancing an immune response: given orally to enhance mucosal immunity or intranasally to treat respiratory infection or to reduce allergy (e.g., allergic rhinitis); injected locally or systemically to enhance immune responses against tumors and cancers. The compounds may also be given prophylactically to induce heightened immunity for broad protection against infection or radiation injury in high risk populations. The adjunctive therapy may also be coupled with other treatments for the conditions described herein. Further, the compounds may be used as vaccine adjuvant to be formulated with vaccinal antigen to enhance, accelerate, and/or broaden immune responses and/or to reduce the number of doses required (“dose sparing”), which is very important given the costs of vaccinal antigens and challenges of multiple clinic visits when vaccine boosting is required to achieve protective immune responses. 
     The imidazopyrimidine compounds, compositions, and methods described herein are advantageous for the following, but are not limited to, reasons:
         (1) Small molecule category amenable to affordable scale up for mass production/use;   (2) Molecular scaffold of the compounds appears to be relatively favorable from a medicinal chemistry perspective for production and creation of congeners/analogues;   (3) The compounds are active towards human cells including those at the extremes of age—e.g., newborns and the elderly; and   (4) The compounds induce a distinct pattern of cytokines relative to other established small molecule adjuvants (e.g., different from R848), suggesting distinct activity.       

     Table 1. Activity of Exemplary Imidazopyrimidine Compounds on Stimulating TNF Production in PBMCs as Compared to Compound R848 
     Table 1 provides the activity of exemplary compounds on stimulating TNF production in PBMCs as compared to the benchmark compound R848. Specifically, TNF production was measured by ELISA after stimulation of adult PBMCs with compound 037 analog family or the compound R848 at 33 μM for 18 hours. Analogs are ranked top to bottom by median percentage TNF production (TNF %) as compared to R848 (N=3-5). The compounds have been classified in the following categories according to TNF %: high activity—class A: TNF %&gt;15%; medium activity—class B: 1%&lt;TNF %≤15%; low activity—class C: TNF %≤1%. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Activity of Exemplary Imidazopyrimidine Compounds on Stimulating TFN 
               
               
                 Production in PBMCs as compared to Compound R848 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Com- 
                   
                   
                   
                 # 
                   
                   
                   
               
               
                 pound 
                 TNF 
                 TNF % 
                 Activity 
                 repli- 
                   
                 Molecular 
                   
               
               
                 ID 
                 (Median) 
                 (Median) 
                 class 
                 cates 
                 Series 
                 weight 
                 Compound Structure 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 FRF-02- 144-2 
                 2.5245 
                 104.32 
                 A 
                 5 
                 6-Me Imidazo- pyrimidine 
                 376.84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 144-3 
                 5.397 
                 99.81 
                 A 
                 5 
                 6-Me Imidazo- pyrimidine 
                 410.40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 193 
                 2.997 
                 91.73 
                 A 
                 5 
                 Imidazo- pyrimidine 
                 372.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37.16 
                 3.5625 
                 90.17 
                 A 
                 3 
                 Imidazo- pyrimidine 
                 407.27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37.37 
                 3.73 
                 71.12 
                 A 
                 3 
                 Imidazo- pyrimidine 
                 396.37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Com- pound 37 
                 2.403 
                 69.79 
                 A 
                 5 
                 Imidazo- pyrimidine 
                 370.46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 171 
                 2.1615 
                 65.93 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                 428.39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 144-1 
                 3.144 
                 55.24 
                 A 
                 5 
                 6-Me Imidazo- pyrimidine 
                 384.48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 166 
                 2.0745 
                 53.91 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                 432.35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 167 
                 1.101 
                 51.62 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                 432.35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF- 02-118 
                 1.8795 
                 43.53 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                 414.36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-03- 082 
                 1.008 
                 41.65 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 174-1 
                 0.924 
                 35.71 
                 A 
                 5 
                 6-Me Imidazo- pyrimidine 
                 404.90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 187 
                 1.191 
                 31.32 
                 A 
                 5 
                 6-F Imidazo- pyrimidine 
                 390.42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37.33 
                 0.288 
                 22.94 
                 A 
                 4 
                 Imidazo- pyrimidine 
                 362.82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37.17 
                 0.865 
                 20.64 
                 A 
                 3 
                 Imidazo- pyrimidine 
                 342.40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 174-2 
                 0.1455 
                 13.99 
                 B 
                 5 
                 6-Me Imidazo- pyrimidine 
                 430.82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 116 
                 0.594 
                 8.48 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 425.26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-03- 081 
                 0.3195 
                 7.51 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 162-2 
                 0.309 
                 6.34 
                 B 
                 5 
                 6-Me Imidazo- pyrimidine 
                 356.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-03- 084-1 
                 0.24 
                 6.00 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 119 
                 0.219 
                 4.35 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 388.45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 176 
                 0.087 
                 3.81 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 390.42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 117 
                 0.138 
                 3.06 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 360.39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 115 
                 0.0625 
                 2.42 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 380.81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 135 
                 0.0705 
                 1.60 
                 B 
                 5 
                 6-MeO Imidazo- pyrimidine 
                 426.40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 175 
                 0.063 
                 1.43 
                 B 
                 5 
                 6-F Imidazo- pyrimidine 
                 432.35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 137 
                 0.04 
                 1.27 
                 B 
                 5 
                 6-MeO Imidazo- pyrimidine 
                 400.48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 183 
                 0.008 
                 0.77 
                 C 
                 5 
                 Imidazo- pyrimidine 
                 372.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 162-1 
                 0.008 
                 0.42 
                 C 
                 5 
                 6-Me Imidazo- pyrimidine 
                 356.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 182 
                 0.008 
                 0.39 
                 C 
                 5 
                 Imidazo- pyrimidine 
                 372.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 103 
                 0.008 
                 0.18 
                 C 
                 5 
                 Imidazo- pyrimidine 
                 342.40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 169 
                 0.008 
                 0.18 
                 C 
                 5 
                 6-F Imidazo- pyrimidine 
                 448.81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 132 
                 0.008 
                 0.18 
                 C 
                 5 
                 6-MeO Imidazo- pyrimidine 
                 437.30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 131 
                 0.008 
                 0.18 
                 C 
                 5 
                 6-MeO Imidazo- pyrimidine 
                 392.84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 134 
                 0.008 
                 0.18 
                 C 
                 5 
                 6-MeO Imidazo- pyrimidine 
                 372.43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 FRF-02- 194 
                 0.008 
                 0. 18 
                 C 
                 5 
                 6-F Imidazo- pyrimidine 
                 390.42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Materials and Methods 
     Overview. 
     To identify immunomodulators/adjuvants that robustly activate human immune cells, screening of ˜200,000 small molecules tested against THP1 NF-κB reporter cells was conducted. As there is evidence that cell culture lines such as THP1 cells may not model responses of natural primary human leukocytes, also employed was a smaller-scale novel high throughput screening methodology in which ˜9,000 commercially available compounds were screened, focusing on small molecule library plates that had relatively high # of hits form the THP1 screen, using primary human blood mononuclear cells from three different adult human donors and a TNFαLISA Assay (commercially purchased from PerkinElmer). See Schildberger et al.,  Mediators of Inflammation, Volume  2013, Article ID 697972 (2013). 
     THP-1 Cell Line and Culture Conditions. 
     The THP1-Lucia™ cell line was obtained from Invivogen (San Diego, Calif.). THP1-Lucia cells, which are human monocytic cells derived from the blood of a boy with leukemia, contain an NF-kB-inducible Luc reporter construct. This allows NF-kB activation to be measured by quantifying the luminescence from the secreted luciferase enzyme. THP1-Lucia cells were cultured in RPMI 1640 supplemented with 10% non-heat inactivated fetal bovine serum (FBS), 10 mM HEPES, 1.0 mM sodium pyruvate, 50 ug/ml Pen-Strep, and 100 ug/mL Normocin™. Once cultured, the cells were stored in a 37° C. incubator with 5% CO 2  and a humidified atmosphere. Cells were passaged every 2-3 days and not allowed to exceed a concentration of 2.0×10 6  cells/ml media. 
     Chemical Libraries. 
     The chemical libraries screened included known bioactive and commercial libraries from various sources (e.g., commercial libraries such as ChemDiv, ChemBridge, and Asinex; see attached pdf of all libraries). All libraries were owned and provided by the Institute of Chemistry and Cell Biology (ICCB)—Longwood (Harvard Medical School). 
     NF-kB-Induced Luminescence Assay. 
     THP1-Lucia cells between passage 15 and 18 and suspended in culture medium were dispensed into 384-well black clear-bottom plates (Corning 3712) at 30,000 cells/30 μl/well using a Combi liquid dispenser. To allow comparison to a benchmark small molecule with known immune stimulating activity, cells at the same concentration were stimulated with 50 μM R848, a TLR7/8 agonist, in 0.3% DMSO and added to every other well of column 24, which was left empty of cells, by multichannel pipette at the same volume. Five μl of 700 nM Phorbol myristate acetate (PMA) in THP1 culture media and 2.3% DMSO, a known peripheral blood cell mitogen, was added to every other well of column 23 by multichannel pipette (final concentration in well: 100 nM in 0.3% DMSO). Five μl of THP1 culture media with 2.3% DMSO was added to the remaining wells of column 23 by multichannel pipette (final concentration 0.3% DMSO). One hundred nl aliquots of library compounds diluted in 100% DMSO were transferred from their original 384-well plates to the assay plates using a Seiko pin transfer machine. Each library plate was pinned in duplicate, yielding two assay plates with identical conditions for comparison. Plates were then incubated for 24 hours at 37C with 5% CO 2  in humid conditions. Following incubation, 10 μL of supernatant was removed from each well and transferred to a white plate (Corning 3570) using a Vprep liquid transfer machine. 10 μL of recombinant Lucia protein (Invivogen) diluted 1:2000 in THP1 culture media was added to empty well 24P. Using a Combi liquid dispenser, 50 μL/well of Quanti-Luc substrate (Invivogen) diluted 1:3 in sterile water was added to the assay plate. Immediately after adding the substrate, the luminescence was read using a PerkinElmer Envision plate reader. 
     TNFαLISA Assay. 
     Human adult peripheral blood was collected according to approved protocols. PBMCs were isolated from blood using a Ficoll density gradient. PBMCs were stored at 5×10 7  cells per vial in 1 mL RPMI containing 20% autologous plasma and 10% DMSO at −80° C. until use. On Day 1, PBMCs were thawed in 37° C. water bath for 3 min and washed twice with PBS. Viability was assessed by trypan blue staining and cells were then resuspended to 6.67×10 5  viable cells/mL in DMEM with 10% autologous plasma 30 μl of cells were dispensed per well in Corning 2712 black 384-well cell culture plates (final concentration was 20,000 cells/well). Controls were added to cells manually and the test compounds were added by robotic pin transfer. Plates were then incubated at 37° C./5% CO 2  humidity-controlled incubator for 18 hours. On Day 2 of the assay, plates were centrifuged and 2 μl supernatants were collected into Perkin Elmer Alpha plates. Perkin Elmer Human TNFα kits (cat # AL208F) were used to detect the presence of TNFα in supernatants. Plates were run on the EnVision (Perkin Elmer) instrument to detect light emission at 615 nm. 
     Hit Calling Method 
     Test compounds that resulted in a robust Z score &gt;2 in both duplicates and at ≥2 of the 3 human samples of PBMCs were considered hits. The following hit calling standard operating procedures (SOPs) were used for the THP-1 and TNFαLISA Assay: 
     All Data is log 10-transformed (log 10)—CrossTalk Corrected luminescence data from columns E, and F is log-transformed (log 10) in columns K, and L. Only experimental wells are evaluated, referencing column C with an “if” logic statement. An example of the calculation in column Q, log-transforming data from column E, is shown below: 
       =IF( C 2=“ X ”,LOG 10( E 2),“ ”)
 
     A robust Z score is calculated for each experimental well with adjusted median absolute deviation (MAD) values. First, the plate median and MAD values are generated from the log-transformed data. The absolute deviation for each well value is calculated in columns M and N, an example of which is shown below: 
       =IF( C 2=“ X ”,ABS( K 2−$ I $3),“ ”)
 
     wherein K2 is a log transformed data point, and 13 is the median value for that plate for that readout. 
     The MAD is then calculated as the median of each of columns U-X multiplied by 1.4286, an example of which is shown below: 
       =MEDIAN( M 2: M 385)*1.4286 
     The robust Z score is then calculated as (well_value−median_plate)/(MAD_plate*1.4286), an example calculation is shown below: 
       =IF($ C 2=“ X ”,(( K 2−$ I $3)/$ I $5),“ ”)
 
     wherein K2 is a log-transformed well value, 13 is the plate experimental median for that readout, and I5 is the plate experimental MAD for that readout. 
     Any wells with robust Z score values of 2 or greater in both replicates are considered a hit. This is evaluated in column Q as shown in the example below: 
       =IF(AND(( O 2&gt;$1$7),( P 2&gt;$ J $7),($ C 2=“ X ”)),TRUE,FALSE)
 
     wherein O2 and P2 are robust Z scores for replicates of the luminescence readout, while I7 and J7 represent the luminescence robust Z score threshold (2). “TRUE” will be returned in column Q if the compound meets these hit criteria. 
     For any well that is determined to be a hit, the Plate:Well compound ID will be displayed in column R as shown in the example below: 
       =IF( Q 2,CONCATENATE( A 2,“:”, B 2),“ ”)
 
     in which Q2 is the TRUE/FALSE value determining the hit status of the compound while A2 is the plate ID and B2 is the well ID. 
     ELISAs and Multiplex-Analyte Assays. 
     Supernatants derived from human PBMCs and DC stimulations were assayed by ELISA for TNF (ThermoFisher Scientific; Waltham, Mass., USA). Cytokine and chemokine expression profiles (e.g., IFNγ, IL-10, IL-12 (p70), IL-1β, IL-6, IL-8, MIP-1α/CCL3, TNF and GM-CSF) in cell culture supernatants were measured using a customized 9-plex Milliplex® Human Th17 Magnetic Bead Panel according to the manufacturer&#39;s instructions (Millipore, Chicago, Ill., USA). Assays were read and analyzed on the Luminex® 100/200™ System and xPOTENT® software (Luminex, Austin, Tex.). A minimum threshold was set at the minimum detectable concentration for each individual assay, defined as three standard deviations above the mean background. 
     In Vitro PBMC Stimulation. 
     PBMCs were isolated from blood using a Ficoll density gradient. PBMCs either used fresh or stored at 5×10 7  cells per vial in 1 mL RPMI containing 20% autologous plasma and 10% DMSO at −80° C. until use. Stimulation plates were prepared by transferring 0.66 μl of DMSO-dissolved compounds (10 mM) to each well of a round bottom 96-well plate. PBMCs isolated from human adult or elderly donors were resuspended at a concentration of 10 5  cells/200 μl of RPMI supplemented with 10% of platelet-poor plasma. 200 μl of the cell suspension were transferred to each well resulting in a final compound concentration of 33 μM. After 18 hours of incubation (37° C., 5% CO 2 ), plates were centrifuged (500×g, room temperature, 5 minutes) and supernatants were harvested for further analysis. 
     Human Newborn Whole Blood Assay. 
     Human newborn cord blood was collected from term newborns (N=5) immediately after Cesarean section using pyrogen-free heparin as anti-coagulant. Cord blood was diluted 1:1 (v/v) in RPMI 1640 medium. One microliter of each of the indicated compounds (or DMSO as control condition) was added to each well containing 200 microliters of diluted blood in a 96-well round-bottomed plate at the final concentration of 11 μM. The plate was then incubated in the presence of 5% CO2 at 37° C. in a humidified incubator for 18 hours. Then, plates were centrifuged (500×g, room temperature, 5 minutes) and supernatants were harvested for further analysis. 
     Animals 
     C57BU6 and BALB/c mice were obtained from Taconic Biosciences or Charles River Laboratories and housed in specific pathogen-free conditions in the animal research facilities at Boston Children&#39;s Hospital. 
     Splenocyte Isolation and In Vitro Stimulation. 
     Spleens were harvested from 6-8 weeks old C57BL/6 mice. For splenocyte isolation, spleens were mashed through a 70 μM strainer, washed with PBS, and erythrocytes were lysed with 2 min of incubation in ammonium chloride-based lysis buffer (BD Biosciences). Cells were then counted and plated 2×10 6  per well (round bottom 96-well plate) in 200 μl of complete culture medium (RPMI 1640 plus 10% heat-inactivated fetal bovine serum [FBS, GE Healthcare HyClone], 50 μM 2-mercaptoethanol, 2 mM 1-glutamine, 100 U/ml penicillin/streptomycin [Gibco ThermoFisher Scientific]) with 0.66 μl of DMSO-dissolved compounds (10 mM) in order to achieve a final compound concentration of 33 μM. After 18 hours of incubation (37° C., 5% CO 2 ), plates were centrifuged (500×g, room temperature, 5 minutes) and supernatants were harvested for further analysis. 
     Antigens, Immunization and Antibody Quantification. 
     For immunization experiments, adult mice were immunized intramuscularly (i.m.) in the right posterior thigh with 50 μl of vaccine containing 0.33 μg of each of the following recombinant influenza virus hemagglutinins (rHA): A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008, contained in the 2016-2017 formulation of the FluBlok vaccine (Protein Sciences Corp.). Mice were immunized with a prime-boost schedule (two injections four weeks apart). Vaccine in all experimental groups was formulated with 10% (v/v) DMSO (except for the groups immunized with the small molecules since they were dissolved in DMSO) and 5% (v/v) Tween-80. As indicated for specific experimental groups, vaccine was also formulated with Aluminium hydroxide (100 μg) and/or compound 037 (100 nmol, final DMSO concentration 10%). Serum was collected 28 days post-prime (pre-boost blood sample) and 14 days post-boost for antibody detection, rHA-specific IgG were quantified by ELISA. High binding flat bottom 96-well plates (Corning Life Sciences) were coated with 1 μg/ml rHA in carbonate buffer pH 9.6, incubated overnight at 4° C. and blocked with PBS+BSA 1% (Sigma-Aldrich) for 1 h at room temperature (RT). Then, sera from vaccinated mice were added with an initial dilution of 1:100 and 1:4 serial dilutions in PBS+BSA 1% and incubated for 2 h at RT. Plates were then washed and incubated for 1 h at RT with HRP-conjugated anti-mouse IgG (Southern Biotech). At the end of the incubation plates were washed again and developed with tetramethylbenzidine (BD Biosciences) for 5 minutes, then stopped with 1 N H 2 SO 4 . The optical density was read at 450 nm Versamax microplate reader with SoftMax Pro Version 5 (both from Molecular Devices) and endpoint titers were calculated using as cutoff three times the optical density of the background. 
     Statistical Analysis. 
     Statistical significance and graphic output were generated using Prism v. 5.0b (GraphPad Software) and Microsoft Excel (Microsoft Corporation, Redmond, Wash.). Results were considered significant at p values &lt;0.05, and indicated as follows: *p&lt;0.05, **p&lt;0.01. 
     REFERENCES 
     
         
         1. Dowling, D. J., et al., The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PLoS One, 2013, 8(3): p. e58164. 
         2. Palmer, C. D., et al., The effect of stable macromolecular complexes of ionic polyphosphazene on HIV Gag antigen and on activation of human dendritic cells and presentation to T-cells. Biomaterials, 2014, 35(31): p. 8876-86. 
         3. Philbin, V. J., et al., Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways. J Allergy Clin Immunol, 2012, 130(1): p. 195-204 e9. 
         4. Ganapathi. L., et al., The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes. PLoS One, 2015, 10(8): p. e0134640. 
         5. Dowling. D. J., et al., Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses. J Allergy Clin Immunol, 2017. 
         6. Dowling, D. J., et al., TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth,  JCI Insight.  2017; 2(6). 
       
    
     Example 2. Preparation of Compounds of Formula I 
     The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. For example, compounds of Formula (I) can be prepared according to Scheme 1. Where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. 
     Preparation of Examples 
     
       
         
         
             
             
         
       
     
     2-Bromo-1-(4-methyl-3-nitrophenyl)ethanone (1) 
     
       
         
         
             
             
         
       
     
     4′-Methylacetophenone (1 g, 7.5 mmol) was dissolved in conc. H 2 SO 4  (10 mL) and the solution was cooled to 0° C. KNO 3  (1 g, 9.9 mmol) was added in portions, and the mixture was stirred at 0° C. for 2 hours, then poured onto crushed ice (100 g), and extracted with EtOAc (2×50 mL). The organic phase was washed with brine and concentrated to give 1.3 g of a yellow solid. The nitro intermediate (200 mg, 1.1 mmol) was dissolved in acetonitrile (2 mL). NBS (237 mg, 1.3 mmol) and p-TsOH (200 mg, 1.1) were added. The reaction mixture was heated at 60° C. for 4 hours, then diluted with EtOAc (20 mL) and washed with sat. Na 2 S20 3  solution and brine. The organic layer was concentrated to give the title compound (260 mg, yield 91%) as a yellow solid.  1 H NMR (400 MHz, CDCl 3 ): δ 8.56 (s, 1H), 8.12 (d, 1H), 7.52 (d, 1H), 4.46 (s, 2H), 2.70 (s, 3H). 
     6-Methyl-2-(4-methyl-3-nitrophenyl)imidazo[1,2-a]pyrimidine (2) 
     
       
         
         
             
             
         
       
     
     2-Bromo-1-(4-methyl-3-nitrophenyl)ethanone (300 mg, 1.16) and 2-amino-5-methylpyrimidine (200 mg, 1.83 mmol) were dissolved in EtOH (10 mL) and the solution refluxed overnight. The solution was diluted with DCM and washed with NaHCO 3  solution. The organic layer was concentrated and the residue purified by column chromatography to give the title compound (102 mg, yield 30%) as a yellow solid. MS m/z 269.9 [M+H]+. 
     2-Methyl-5-(6-methylimidazo[1,2-a]pyrimidin-2-yl)aniline (3) 
     
       
         
         
             
             
         
       
     
     6-Methyl-2-(4-methyl-3-nitrophenyl)imidazo[1,2-a]pyrimidine (600 mg, 2.24 mmol) was dissolved in THF and methanol (3:1, 4 mL). Zinc powder (2.3 g, 35.4 mmol) and NH 4 Cl (2 g, 37.0 mmol) were added to the solution and the mixture was stirred for 1 hour. The solid was filtered, and the filtrate was concentrated, dissolved in EtOAc, and then washed with water. The organic phase was concentrated to give compound the title compound (400 mg, 75% yield) as a yellow solid. MS m/z 238.7 [M+H] + . 
     2-Bromo-1-(4-chloro-3-nitrophenyl)ethan-1-one (4) 
     
       
         
         
             
             
         
       
     
     2-Bromo-1-(4-chloro-3-nitrophenyl)ethan-1-one was prepared using a similar procedure to that described for 1, from 4′-chloroacetophenone.  1 H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.26 (d, 1H), 8.00 (d, 1H), 5.02 (s, 2H). 
     Anilines 5-8 were prepared by similar methods to 3, from the corresponding aminopyrimidine and either 1 or 4. 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   1 H NMR (d 6 - 
                 m/z 
                 Starting 
               
               
                 Aniline 
                 Name 
                 DMSO) 
                 [M + 1] +   
                 materials 
               
               
                   
               
             
            
               
                 5 
                                   
   5-(Imidazo[1,2-a]pyrimidin-2- 
                 (500 MHz) 8.92 (m, 1H), 8.48 (m, 1H), 8.16 (s, 1H), 7.32 (d, 1H), 7.09 (d, 1H), (m, 2H), 4.95 (s, 2H), 2.09 (s, 3H) 
                 224.91 
                                   
   and 1 
               
               
                   
                 yl)-2-methylaniline 
                   
                   
                   
               
               
                   
               
               
                 6 
                                   
   5-(6-Fluoroimidazo[1,2- 
                 (500 MHz) 9.18 (m, 1H), 8.65 (d, 1H), 8.18 (s, 1H), 7.31 (d, 1H), 7.09 (m, 1H) 7.00 (d, 1H), 4.95 (s, 2H), 2.09 (s, 3H) 
                 242.98 
                                   
   and 1 
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                   
                   
                   
               
               
                   
                 methylaniline 
                   
                   
                   
               
               
                   
               
               
                 7 
                                   
   5-(6-Fluoroimidazo[1,2- 
                 (500 MHz) 8.66 (d, 1H), 8.36 (d, 1H), 8.05 (s, 1H), 7.27 (d, 1H), 7.05 (m, 1H), 6.98 (d, 1H), 4.92 (s, 2H), 3.85 (s, 3H), 2.08 (s, 3H) 
                 254.68 
                                   
   and 1 
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                   
                   
                   
               
               
                   
                 methylaniline 
                   
                   
                   
               
               
                   
               
               
                 8 
                                   
   Chloro-5-(6- 
                   
                 259.1 
                                   
   and 4 
               
               
                   
                 methylimidazo[1,2- 
                   
                   
                   
               
               
                   
                 a]pyrimidin-2-yl)aniline 
               
               
                   
               
            
           
         
       
     
     Analog I. FRF-02-144-1 
     N-(2-Methyl-5-(6-methylimidazo[1,2-a]pyrimidin-2-yl)phenyl)-2-phenylbutanamide 
     
       
         
         
             
             
         
       
     
     2-Methyl-5-(6-methylimidazo[1,2-a]pyrimidin-2-yl)aniline (75 mg, 0.32 mmol) was dissolved in DMF (5 mL). Triethylamine (0.09 mL, 0.64 mmol) and 2-phenylbutanoyl chloride (150 mg, 0.82 mmol) were added and the mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc (20 mL) and washed with sat. NaHCO 3  solution (20 mL). The organic phase was concentrated and purified by flash chromatography to give the title compound (26 mg, 21% yield).  1 H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.72 (s, 1H), 8.41 (d, 1H), 8.23 (s, 1H), 7.90 (s, 1H), 7.68 (d, 1H), 7.44 (m, 2H), 7.37 (m, 2H), 7.27 (m, 2H), 3.69 (m, 1H), 2.30 (s, 3H), 2.11 (s, 3H), 2.10 (m, 1H), 1.74 (m, 1H), 0.94 (t, 3H). MS m/z 385.3 [M+H] + . 
     Analog II. FRF-02-119 
     N-(5-(6-Fluoroimidazo[1,2-a]pyrimidin-2-yl)-2-methylphenyl)-2-phenylbutanamide 
     
       
         
         
             
             
         
       
     
     2-Phenylbutanoic acid (16 mg, 0.099 mmol), diisopropylethylamine (29 uL, 0.165 mmol) and HATU (38 mg, 0.0099 mmol) were dissolved in DMF (6 mL). After 20 minutes, 5-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-2-methylaniline (20 mg, 0.082 mmol) was added. After stirring for 18 hours, further portions of 2-phenylbutanoic acid (8 mg), diisopropylethylamine (15 uL) and HATU (18.5 mg) were added, and the mixture stirred for a further 4 hours. The mixture was diluted with DCM, washed with brine, concentrated and the residue purified by column chromatography on silica gel (0 to 5% MeOH in DCM) to give the title compound (19 mg, 56% yield).  1 H NMR (500 MHz, DMSO-d6): δ 9.57 (s, 1H), 9.18 (m, 1H), 8.69 (d, 1H), 8.33 (s, 1H), 7.93 (d, 1H), 7.70 (m, 1H), 7.45 (m, 2H), 7.36 (m, 2H), 7.27 (m, 2H), 3.70 (m, 1H), 2.12 (s, 3H), 2.09 (m, 1H), 1.74 (m, 1H), 0.94 (t, 3H). MS m/z 389.16 [M+H] − . 
     Analogs 3-31 were prepared by similar methods to Analogs 1 and 2, from the corresponding aniline and either the acid chloride or carboxylic acid. 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   1 H NMR 
                   
                   
               
               
                 Ana- 
                   
                 (d 6 - 
                 m/z 
                   
               
               
                 logs 
                 Name 
                 DMSO) 
                 [M + 1] +   
                 Starting materials 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 3 FRF- 02- 162-1 
                                   
   N-(2-Methyl-5-(6- methylimidazo[1,2-a]pyrimidin-2- yl)phenyl)-2-phenylacetamide 
                 (400 MHz) 9.60 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.69 (d, 1H), 7.38 (m, 4H), 7.28 (m, 2H), 3.71 (s, 
                 357.4 
                                   
   and 2-phenylacetyl chloride 
               
               
                   
                   
                 2H), 2.30 
                   
                   
               
               
                   
                   
                 (s, 3H), 
                   
                   
               
               
                   
                   
                 2.20 (s, 
                   
                   
               
               
                   
                   
                 3H) 
                   
                   
               
               
                   
               
               
                 4 FRF- 02- 162-2 
                                   
   2-Methyl-N-(2-methyl-5-(6- methylimidazo[1,2-a]pyrimidin-2- yl)phenyl)benzamide 
                 (400 MHz) 9.86 (s, 1H), 8.76 (s, 1H), 8.42 (d, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.77 (d, 1H), 7.56 (d, 1H), 7.41 (m, 1H) 7.34 (m, 3H), 2.48 (s, 3H), 
                 357.4 
                                   
   and 2-methylbenzoyl chloride 
               
               
                   
                   
                 2.32 (s, 
                   
                   
               
               
                   
                   
                 3H), 3 
                   
                   
               
               
                   
                   
                 protons 
                   
                   
               
               
                   
                   
                 masked 
                   
                   
               
               
                   
                   
                 by DMSO 
                   
                   
               
               
                   
               
               
                 5 FRF- 02- 144-2 
                                   
   2-Chloro-N-(2-methyl-5-(6- methylimidazo[1,2-a]pyrimidin-2- yl)phenyl)benzamide 
                 (400 MHz) 10.08 (s, 1H), 8.76 (s, 1H), 8.43 (s, 1H), 8.28 (s, 1H), 1H), 7.77 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.49 (m, 2H), 7.35 (d, 1H), 2.33 (s, 
                 377.3 
                                   
   and 2-chlorobenzoyl chloride 
               
               
                   
                   
                 3H), 2.32 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 6 FRF 02- 144-3 
                                   
   N-(2-Methyl-5-(6- methylimidazo[1,2-a]pyrimidin-2- yl)phenyl)-2- (trifluoromethyl)benzamide 
                 (400 MHz) 10.13 (s, 1H), 8.77 (s, 1H), 8.46 (d, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.88 (d, 1H), 7.77 (m, 4H), 7.35 (d, 1H), 2.31 (s, 6H) 
                 411.2 
                                   
   and 2- (trifluoromethyl)benzoyl chloride 
               
               
                   
               
               
                 7 FRF- 02- 118 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2- (trifluoromethyl)benzamide 
                 (500 MHz) 10.13 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.37 (s, 1H), 8.09 (d, 1H), 7.87 (d, 1H), 7.82 (m, 3H), 7.77 (m, 1H), 7.38 (d, 1H), 2.32 (s, 3H) 
                 414.86 
                                   
   and 2- (trifluoromethyl)benzoyl chloride 
               
               
                   
               
               
                 8 FRF- 02- 117 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2- methylbenzamide 
                 (500 MHz) 9.87 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.38 (s, 1H), 8.08 (d, 1H), 7.79 (d, 1H), 7.57 (d, 1H), 7.40 (m, 1H), 7.37 (d, 1H), 7.33 (m, 2H), 2.48 (s, 
                 361.22 
                                   
   and 2-methylbenzoyl chloride 
               
               
                   
                   
                 3H), 2.33 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 9 FRF- 02- 116 
                                   
   2-Bromo-N-(5-(6- fluoroimidazo[1,2-a]pyrimidin-2- yl)-2-methylphenyl)benzamide 
                 (500 MHz) 10.07 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.38 (s, 1H), 8.12 (d, 1H), 7.79 (m, 1H), 7.75 (d, 1H), 7.65 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 
                 425.3 
                                   
   and 2-bromobenzoyl chloride 
               
               
                   
                   
                 7.37 (d, 
                   
                   
               
               
                   
                   
                 1H), 2.36 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 10 FRF- 02- 115 
                                   
   2-Chloro-N-(5-(6- fluoroimidazo[1,2-a]pyrimidin-2- yl)-2-methylphenyl)benzamide 
                 (500 MHz) 10.09 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.38 (s, 1H), 1H), 7.79 (m, 1H), 7.68 (m, 1H), 7.59 (d, 1H), 7.52 (m, 2H), 7.38 (d, 1H), 2.35 (s, 3H) 
                 381.25 
                                   
   and 2-chlorobenzoyl chloride 
               
               
                   
               
               
                 11 FRF- 02- 137 
                                   
   N-(5-(6-Methoxyimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2- phenylbutanamide 
                 (500 MHz) 9.56 (s, 1H), 8.64 (d, 1H), 8.39 (d, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.65 (m, 1H), 7.45 (m, 2H), 7.36 (m, 2H), 7.26 (m, 2H), 3.85 (s, 3H), 3.69 (m, 1H), 
                 401.4 
                                   
   and 2-phenylbutanoic acid 
               
               
                   
                   
                 2.11 (s, 
                   
                   
               
               
                   
                   
                 3H), 2.09 
                   
                   
               
               
                   
                   
                 (m, 1H), 
                   
                   
               
               
                   
                   
                 1.74 (m, 
                   
                   
               
               
                   
                   
                 1H), 0.94 
                   
                   
               
               
                   
                   
                 (t, 3H) 
                   
                   
               
               
                   
               
               
                 12 FRF- 02- 135 
                                   
   N-(5-(6-Methoxyimidazo[1,2- a]pyrimidin-2-yl-2- methylphenyl)-2- (trifluoromethyl)benzamide 
                 (500 MHz) 10.11 (s, 1H), 8.68 (d, 1H) 8.42 (d, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.87 (d, 1H), 7.81 (m, 2H), 7.74 (m, 2H), 7.35 (d, 1H), 3.86 (s, 3H), 2.31 (s, 3H) 
                 426.9 
                                   
   and 2- (trifluoromethyl)benzoyl chloride 
               
               
                   
               
               
                 13 FRF- 02- 134 
                                   
   N-(5-(6-Methoxyimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2- methylbenzamide 
                 (500 MHz) 9.85 (s, 1H), 8.68 (d, 1H), 8.41 (d, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.75 (m, 1H), 7.57 (d, 1H), 7.40 (m, 1H), 7.33 (m, 3H), 3.86 (s, 3H), 2.48 (s, 
                 372.98 
                                   
   and 2-methylbenzoyl chloride 
               
               
                   
                   
                 3H), 2.34 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 14 FRF- 02- 132  
                                   
   2-Bromo-N-(5-(6- methoxyimidazo[1,2-a]pyrimidin- 2-yl)-2-methylphenyl)benzamide 
                 (500 MHz) 10.05 (s, 1H), 8.68 (d, 1H), 8.42 (d, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.34 (d, 1H), 
                 439.09 
                                   
   and 2-bromobenzoyl chloride 
               
               
                   
                   
                 3.86 (s, 
                   
                   
               
               
                   
                   
                 3H), 2.34 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 15 FRF- 02- 131 
                                   
   2-Chloro-N-(5-(6- methoxyimidazo[1,2-a]pyrimidin- 2-yl)-2-methylphenyl)benzamide 
                 (500 MHz) 10.06 (s, 1H), 8.68 (d, 1H), 8.42 (d, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.59 (d, 1H), 7.51 (m, 2H), 7.35 (d, 1H), 
                 393.22 
                                   
   and 2-chlorobenzoyl chloride 
               
               
                   
                   
                 3.86 (s, 
                   
                   
               
               
                   
                   
                 3H), 2.33 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 16 FRF- 02- 166 
                                   
   5-Fluoro-N-(5-(6- fluoroimidazo[1,2-a]pyrimidin-2- yl)-2-methylphenyl)-2- (trifluoromethyl)benzamide 
                 (500 MHz) 10.19 (s, 1H), 9.24 (m, 1H), 8.72 (d, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.97 (m, 1H), 7.80 (m, 2H), 7.59 (m, 1H), 7.38 (d, 1H), 2.32 (s, 3H) 
                 433.3 
                                   
   and 5-fluoro-2- (trifluoromethyl)benzoic acid 
               
               
                   
               
               
                 17 FRF- 02- 167 
                                   
   4-Fluoro-N-(5-(6- 
                 (500 MHz) 10.15 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.37 (s, 1H) 8.10 (s, 1H), 7.92 7.81 (m, 2H), 7.72 (m, 1H), 7.38 (d, 1H), 2.31 (s, 3H) 
                 433.28 
                                   
   and 4-fluoro-2- (trifluoromethyl)benzoic acid 
               
               
                   
                 fluoroimidazo[1,2-a]pyrimidin-2- 
                   
                   
                   
               
               
                   
                 yl)-2-methylphenyl)-2- 
                   
                   
                   
               
               
                   
                 (trifluoromethyl)benzamide 
                   
                   
                   
               
               
                   
               
               
                 18 FRF- 02- 169 
                                   
   4-Chloro-N-(5-(6- fluoroimidazo[1,2-a]pyrimidin-2- yl)-2-methylphenyl)-2- (trifluoromethyl)benzamide 
                 (500 MHz) 10.17 (s, 1H), 9.23 (m, 1H), 8.72 (d, 1H), 8.36 8.10 (s, 1H), 7.98 (d, 1H), 7.94 (m, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.37 (d, 1H), 2.31 (s, 3H) 
                 449.7 
                                   
   and 4-chloro-2- (trifluoromethyl)benzoic acid 
               
               
                   
               
               
                 19 FRF- 02- 171 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-4-methyl-2- (trifluoromethyl)benzamide 
                 (500 MHz) 10.05 (s, 1H), 9.23 (m, 1H), 8.71 (d, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.79 (m, 1H), 7.69 (m, 2H), 7.62 (d, 1H), 7.36 (d, 1H), 2.46 (s, 3H), 2.31 (s, 3H) 
                 428.93 
                                   
   and 4-methyl-2- (trifluoromethyl)benzoic acid 
               
               
                   
               
               
                 20 FRF- 02- 174-1 
                                   
   N-(2-Chloro-5-(6- methylimidazo[1,2-a]pyrimidin-2- yl)phenyl)-2-phenylbutanamide 
                 (400 MHz) 9.78 (s, 1H), 8.74 (s, 1H), 8.44 (d, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.27 (m, 1H), 3.80 (m, 
                 405.3 
                                   
   and 2-phenylbutanoyl chloride 
               
               
                   
                   
                 1H), 2.31 
                   
                   
               
               
                   
                   
                 (s, 3H), 
                   
                   
               
               
                   
                   
                 2.09 (m, 
                   
                   
               
               
                   
                   
                 1H), 1.74 
                   
                   
               
               
                   
                   
                 (m, 1H), 
                   
                   
               
               
                   
                   
                 0.93 (t, 
                   
                   
               
               
                   
                   
                 3H) 
                   
                   
               
               
                   
               
               
                 21 FRF- 02- 174-2 
                                   
   N-(2-Chloro-5-(6- methylimidazo[1,2-a]pyrimidin-2- 
                 (400 MHz) 10.43 (s, 1H), 8.79 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.81 (m, 5H), 7.63 (d, 1H), 2.32 (s, 3H) 
                 431.3 
                                   
   and 2- (trifluoromethyl)benzoyl chloride 
               
               
                   
                 yl)phenyl)-2- 
                   
                   
                   
               
               
                   
                 trifluoromethyl)benzamide 
                   
                   
                   
               
               
                   
               
               
                 22 FRF- 02- 175 
                                   
   2-Fluoro-N-(5-(6- 
                 (500 MHz) 10.37 (s, 1H), 9.21 (m, 1H), 8.72 (d, 1H), 8.38 8.06 (s, 1H), 7.76 (m, 4H), 7.38 (d, 1H), 2.30 (s, 3H) 
                 432.93 
                                   
   and 2-fluoro-6- (trifluoromethyl)benzoic acid 
               
               
                   
                 fluoroimidazo[1,2-a]pyrimidin-2- 
                   
                   
                   
               
               
                   
                 yl)-2-methylphenyl)-6- 
                   
                   
                   
               
               
                   
                 (trifluoromethyl)benzamide 
                   
                   
                   
               
               
                   
               
               
                 23 FRF- 02- 176 
                                   
   N-(5-(6-Fluoroimidazo[1,2- 
                 (500 MHz) 9.70 (s, 1H), 9.22 (m, 1H), 8.71 (d, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.77 (m, 1H), 7.57 (d, 1H), 7.35 (d, 1H), 6.87 (m, 2H), 3.81 
                 391.05 
                                   
   and 4-methoxy-2- methylbenzoic acid 
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                 (s, 3H), 
                   
                   
               
               
                   
                 methylphenyl)-4-methoxy-2- 
                 2.47 (s, 
                   
                   
               
               
                   
                 methylbenzamide 
                 3H), 2.31 
                   
                   
               
               
                   
                   
                 (s, 3H) 
                   
                   
               
               
                   
               
               
                 24 FRF- 02- 182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 373.3 
                                   
   and 4-methoxy-2- methylbenzoic acid 
               
               
                   
               
               
                   
                 N-(5-(Imidazo[1,2-a]pyrimidin-2- 
                   
                   
                   
               
               
                   
                 yl)-2-methylphenyl)-4-methoxy-2- 
                   
                   
                   
               
               
                   
                 methylbenzamide 
                   
                   
                   
               
               
                   
               
               
                 25 FRF- 02- 183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 373.1 
                                   
   and 5-methoxy-2- methylbenzoic acid 
               
               
                   
               
               
                   
                 N-(5-(Imidazo[1,2-a]pyrimidin-2- 
                   
                   
                   
               
               
                   
                 yl)-2-methylphenyl)-5-methoxy-2- 
                   
                   
                   
               
               
                   
                 methytbenzamide 
                   
                   
                   
               
               
                   
               
               
                 26 FRF- 02- 187 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-5-methoxy-2- methylbenzamide 
                 (500 MHz) 9.84 (s, 1H), 9.23 (m, 1H), 8.71 (d, 1H), 8.38 8.08 (s, 1H), 7.79 (m, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 7.13 (s, 1H), 6.98 (m, 1H), 3.81 (s, 3H), 2.39 
                 391.05 
                                   
   and 5-methoxy-2- methylbenzoic acid 
               
               
                   
                   
                 (s, 3H), 
                   
                   
               
               
                   
                   
                 2.32 (s, 
                   
                   
               
               
                   
                   
                 3H) 
                   
                   
               
               
                   
               
               
                 27 FRF- 02- 193 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 373.4 
                                   
   and 3-hydroxy-2- phenylpropanoic acid 
               
               
                   
               
               
                   
                 3-Hydroxy-N-(5-(imidazo[1,2- 
                   
                   
                   
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                   
                   
                   
               
               
                   
                 methylphenyl)-2- 
                   
                   
                   
               
               
                   
                 phenylpropanamide 
                   
                   
                   
               
               
                   
               
               
                 28 FRF- 02- 194 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 391.26 
                                   
   and 3-hydroxy-2- phenylpropanoic acid 
               
               
                   
               
               
                   
                 N-(5-(6-Fluoroimidazo[1,2- 
                   
                   
                   
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                   
                   
                   
               
               
                   
                 methylphenyl)-3-hydroxy-2- 
                   
                   
                   
               
               
                   
                 phenylpropanamide 
                   
                   
                   
               
               
                   
               
               
                 29 FRF- 03- 081 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2- phenylpropanamide 
                 (500 MHz) 9.51 (s, 1H), 9.19 (m, 1H), 8.71 (d, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.70 (m, 1H), 7.46 (m, 2H), 7.37 (m, 2H), 7.28 (m, 2H), 3.97 (q, 1H), 2.12 (s, 3H), 1.47 (d, 3H) 
                 375.1 
                                   
   and 2-phenylpropanoic acid 
               
               
                   
               
               
                 30 FRF- 03- 082 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 403.4 
                                   
   and 3-methyl-2- phenylbutanoic acid 
               
               
                   
               
               
                   
                 N-(5-(6-Fluoroimidazo[1,2- 
                   
                   
                   
               
               
                   
                 a]pyrimidin-2-yl)-2- 
                   
                   
                   
               
               
                   
                 methylphenyl)-3-methyl-2- 
                   
                   
                   
               
               
                   
                 phenylbutanamide 
                   
                   
                   
               
               
                   
               
               
                 31 FRF- 03- 084-1 
                                   
   N-(5-(6-Fluoroimidazo[1,2- a]pyrimidin-2-yl)-2- methylphenyl)-2-methyl-2- phenylpropanamide 
                 (500 MHz) 9.19 (m, 1H), 8.76 (s, 1H), 8.70 (d, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.72 (d, 1H), 7.47 (m, 2H), 7.41 (m, 2H), 7.28 (m, 2H), 2.04 (s, 3H), 1.62 (s, 3H) 
                 389.2 
                                   
   and 2-methyl-2- phenylpropanoic acid 
               
               
                   
               
            
           
         
       
     
     All publications, patents, patent applications, publication, and database entries (e.g., sequence database entries) mentioned herein, e.g., in the Background, Summary, Detailed Description, Examples, and/or References sections, are hereby incorporated by reference in their entirety as if each individual publication, patent, patent application, publication, and database entry was specifically and individually incorporated herein by reference. In case of conflict, the present application, including any definitions herein, will control. 
     EQUIVALENTS AND SCOPE 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the embodiments described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims. 
     Articles such as “a.” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between two or more members of a group are considered satisfied if one, more than one, or all of the group members are present, unless indicated to the contrary or otherwise evident from the context. The disclosure of a group that includes “or” between two or more group members provides embodiments in which exactly one member of the group is present, embodiments in which more than one members of the group are present, and embodiments in which all of the group members are present. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed. 
     It is to be understood that the disclosure encompasses all variations, combinations, and permutations in which one or more limitation, element, clause, or descriptive term, from one or more of the claims or from one or more relevant portion of the description, is introduced into another claim. For example, a claim that is dependent on another claim can be modified to include one or more of the limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of making or using the composition according to any of the methods of making or using disclosed herein or according to methods known in the art, if any, are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. 
     Where elements are presented as lists, e.g., in Markush group format, it is to be understood that every possible subgroup of the elements is also disclosed, and that any element or subgroup of elements can be removed from the group. It is also noted that the term “comprising” is intended to be open and permits the inclusion of additional elements or steps. It should be understood that, in general, where an embodiment, product, or method is referred to as comprising particular elements, features, or steps, embodiments, products, or methods that consist, or consist essentially of, such elements, features, or steps, are provided as well. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed. 
     Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in some embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For purposes of brevity, the values in each range have not been individually spelled out herein, but it will be understood that each of these values is provided herein and may be specifically claimed or disclaimed. It is also to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range. 
     Where websites are provided, URL addresses are provided as non-browser-executable codes, with periods of the respective web address in parentheses. The actual web addresses do not contain the parentheses. 
     In addition, it is to be understood that any particular embodiment of the present disclosure may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the disclosure, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.