WO2019177971A1 - Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp-1) inhibitors and uses thereof - Google Patents

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

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Publication number
WO2019177971A1
WO2019177971A1 PCT/US2019/021614 US2019021614W WO2019177971A1 WO 2019177971 A1 WO2019177971 A1 WO 2019177971A1 US 2019021614 W US2019021614 W US 2019021614W WO 2019177971 A1 WO2019177971 A1 WO 2019177971A1
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alkyl
solvate
stereoisomer
compound
pharmaceutically acceptable
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PCT/US2019/021614
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French (fr)
Inventor
William Michael Gallatin
Joshua Odingo
Gregory N. Dietsch
Vincent FLORIO
Chandregowda VENKATESHAPPA
Athisayamani Jeyaraj DURAISWAMY
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Mavupharma, Inc.
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Publication of WO2019177971A1 publication Critical patent/WO2019177971A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Cancer immunotherapy comprises the use of the patient’s immune system to combat tumor cells.
  • cancer immunotherapy utilizes the presence of tumor antigens (e.g., tumor- specific antigens) to facilitate the recognition of the tumor cells by the immune system.
  • cancer immunotherapy utilizes immune system components such as lymphocytes and cytokines to coordinate a general immune response.
  • Pathogenic microorganisms include bacteria, viruses, fungi, protozoa, and helminths.
  • antimicrobials such as broad spectrum fluoroquinolones and oxazolidinones fight infection by inhibiting microbial reproduction within a host.
  • antimicrobials enhance or strengthen a host’s immune response to the pathogenic infection.
  • L 1 is -(CR 18 R 19 )-;
  • Ring B1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 12 or R 13 is not hydrogen
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • L 2 is a bond or -(CR 28 R 29 )-;
  • Ring A2 is imidazolyl, pyrrolyl, oxazolyl, or thiazolyl;
  • Ring B2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 28 and R 29 are taken together to form an oxo; each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • n2 is 1-4;
  • p2 is 1-4.
  • composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • a method of treating cancer in a subject in need thereof comprising administering a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein.
  • the cancer is a solid tumor.
  • the solid tumor is breast cancer, lung cancer, or glioblastoma.
  • the cancer is a hematologic malignancy.
  • the hematologic malignancy is a leukemia, a lymphoma, or a myeloma.
  • the hematologic malignancy is a B-cell malignancy. In some embodiments of a method of treating cancer, the hematologic malignancy is multiple myeloma. In some embodiments of a method of treating cancer, the cancer is a relapsed or refractory cancer. In some embodiments of a method of treating cancer, the cancer is a metastatic cancer.
  • Also disclosed herein is a method of treating an infection in a subject in need thereof comprising administering a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein.
  • the infection is a viral infection.
  • the viral infection is due to a DNA virus.
  • the viral infection is a due to a herpesvirus.
  • the herpesvirus is selected from herpes simplex viruses 1 (HSV-l), herpes simplex viruses 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6A (HHV-6A), human herpesvirus 6B (HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma- associated herpesvirus (KSHV).
  • the herpesvirus is herpes simplex viruses 1 (HSV-l).
  • the viral infection is a due to a retrovirus.
  • the retrovirus is human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the viral infection is a due to a hepatitis virus.
  • the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV).
  • the viral infection is due to vaccinia virus (VACV), adenovirus, or human papillomaviruses (HPV).
  • the viral infection is due to a RNA virus. In some embodiments of a method of treating an infection, the viral infection is due to dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
  • the immunophenotype of a tumor microenvironment modulates the responsiveness of the tumor to a cancer therapy.
  • tumor-infiltrating lymphocytes are correlated with favorable prognosis in different types of tumors and are correlated with positive clinical outcome in response to several lines of immunotherapy.
  • innate immune sensing in the tumor microenvironment promotes T-cell priming and subsequent infiltration of tumor-infiltrating lymphocytes.
  • transcriptional profiling analyses of melanoma patients have shown that tumors containing infiltrating activated T cells are characterized by a type I IFN transcriptional signature.
  • mice lacking the IFN- a/b receptor in dendritic cells are unable to reject immunogenic tumors and the CD8a+ dendritic cells from these mice are defective in antigen cross-presentation to CD8+ T cells.
  • systemic delivery of type I IFNs has shown efficacy in cancer settings. Indeed, systemic injection of IFN-b in a mouse xenograft model of human colorectal cancer liver metastases has shown tumor regression and improved survival.
  • the innate immune system is the first line of defense to a microbial infection.
  • the host innate immunity is activated through recognition of conserved microbial signatures termed pathogen- associated molecular patterns (PAMPs) and host damage-associated molecular patterns (DAMPs).
  • PAMPs pathogen- associated molecular patterns
  • DAMPs host damage-associated molecular patterns
  • signal cascades are activated to produce type I interferons and/or multiple cytokines and chemokines, culminating in the synthesis of antiviral proteins.
  • the presence of antiviral proteins and cytokines e.g., interferons or chemokines
  • cytokines e.g., interferons or chemokines
  • Pattern recognition receptors are germ-line encoded receptors that recognize PAMPs and DAMPs and faciliate the rapid and efficient innate immune response.
  • Cytosolic DNA sensor is a type of PRRthat detects the intracellular presence of pathogenic DNA.
  • DNA-dependent activator of IFN -regulatory factors (DAI) a cytosolic DNA sensor, utilizes the cGAS-STING pathway for production of type I interferons.
  • the methods comprise activating and enhancing the cGAS-STING response.
  • the methods comprise priming a cancer with an immunogenic cell death inducer prior to stimulating the cGAS-STING pathway.
  • the methods comprise blocking the degradation of a STING activating substrate prior to priming a cancer with an immunogenic cell death inducer.
  • the methods comprise use of an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., an inhibitor of a phosphodiesterase) with an immunogenic cell death inducer for the treatment of a cancer.
  • disclosed herein include methods of designing inhibitors of 2’3’-cGAMP degradation polypeptides and assays for evaluating the enzyme activity of the GMP degradation polypeptides.
  • Cytosolic DNA can signal the presence of cellular damage and/or the presence of cancerous cells and/or an infection within a cell or at a nearby cell.
  • cytosolic DNAs e.g., double stranded DNAs
  • DNA sensors such as RNA pol III, DAI, IFI16, DDX41, LSml4A, cyclic- GMP-AMP synthase, LRRFIP1, Sox2, DHX9/36, Ku70 and AIM2.
  • Cyclic-GMP-AMP synthase (cGAS or cGAMP synthase) is a 522 amino acid protein that belongs to the nucleotidyltransferase family of cytosolic DNA sensors.
  • cGAS Upon cytosolic DNA stimulation, cGAS synthesizes cGAMP, which comprises a first bond between the 2’-OH of GMP and the 5’-phosphate of AMP and a second bond between the 3’-OH of AMP and the 5’-phosphate of GMP.
  • cGAMP also known as cyclic GMP- AMP, 2’3’-cGAMP, cGAMP (2’-5’) or cyclic Gp(2’-5’)Ap(3’-5’) serves as a ligand to STING, thereby activating the STING-mediated IFN (e.g., PT ⁇ b) production.
  • STING also known as stimulator of interferon genes, TMEM173, MITA, ERIS, or MPYS
  • STING is a 378 amino acid protein that comprises aN-terminal region containing four trans -membrane domains and a C-terminal domain that comprises a dimerization domain.
  • STING undergoes a conformational rearrangement enclosing the 2’ 3’-cGAMP molecule.
  • Binding of 2’3’-cGAMP activates a cascade of events whereby STING recruits and activates IKB kinase (IKK) and TANK-binding kinase (TBK1), which following their
  • type I IFNs further drives the development of cytolytic T cell response and enhances expression of MHC, thereby increasing antigen processing and presentation within a tumor microenvironment. In such cases, enhanced type I IFN production further renders the tumor cells to be more vulnerable by enhancing their recognition by the immune system.
  • STING is capable of directly sensing bacterial cyclic dinucleotides (CDNs) such as c[di-GMP]
  • CDNs bacterial cyclic dinucleotides
  • 2’3’-cGAMP acts as a second messenger binding to STING in response to cells exposed to cytosolic DNA.
  • cytosolic DNA is generated through“self-DNA” or endogenous DNA from the host through the DNA structure-specific endonuclease methyl methane -sulphonate (MMS) and ultraviolet-sensitive 81 (MUS81).
  • MMS DNA structure-specific endonuclease methyl methane -sulphonate
  • MUS81 ultraviolet-sensitive 81
  • the DNA structure-specific endonuclease MUS81 is a member of the XPF family of endonucleases that forms a heterodimeric complex with essential meiotic endonuclease 1 (EME1).
  • EME1 essential meiotic endonuclease 1
  • the MUS81-EME1 complex cleaves DNA structures at stalled replication forks.
  • MUS81 cleavage of self-DNA leads to accumulation of cytosolic DNA and activation of the STING pathway.
  • cytosolic DNA is generated through immunogenic cell death (ICD)- mediated events, activation of the STING-pathway, production of type I INFs, and further priming of the tumor cell microenvironment.
  • ICD immunogenic cell death
  • immunogenic cell death is a cell death modality which further stimulates an immune response against tumor expressed antigens.
  • tumor expressed antigens are tumor neoantigens or antigens that are formed by mutated proteins and unique to the tumor.
  • tumor expressed antigens comprise overexpressed proteins such as MUC1, CA-125, MART-l or carcinoembyonic antigen (CEA).
  • ICD is characterized by a series of biochemical events that comprises: 1) the cell surface translocation of calreticulin (CALR or CRT), an endoplasmic reticulum (ER) resident chaperone protein and a potent DC "eat me” signal; 2) the extracellular release of high mobility group box 1 (HMGB1), a DNA binding protein and toll-like receptor 4 (TLR-4) mediated DC activator; and 3) the liberation of adenosine-5 '-triphosphate (ATP), a cell-cell signaling factor in the extracellular matrix (ECM) that serves to activate P2X7 purinergic receptors on DCs, triggering DC inflammasome activation, secretion of IL-Ib, and subsequent priming of interferon-g (IFNy) producing CD8 + T cells.
  • CACR cell surface translocation of calreticulin
  • ER endoplasmic reticulum
  • TLR-4 toll-like receptor 4
  • ATP adenosine-5 '-
  • the cumulative effects of the 3 arms of ICD and in particular CRT exposure act to promote DC phagocytosis of tumor cells, thereby facilitating DC processing of tumor-expressed antigens and subsequent DC-associated cross-priming of CD8 + cytotoxic T lymphocytes.
  • Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene. Calreticulin is a multifunctional protein that binds Ca 2+ ions (a second messenger in signal transduction), rendering it inactive. In some instances, calreticulin is located in the lumen of the endoplasmic reticulum, where it interacts with misfolded proteins, inhibits their export from the endoplasmic reticulum into the Golgi apparatus and subsequently tags these misfolded proteins for degradation. In some cases, calreticulin further serves as a signaling ligand to recruit DCs to initiate phagocytosis.
  • ICD is further sub-categorized into different types of ICD based on the ICD inducer.
  • an ICD inducer initiates the process of immunogenic cell death.
  • an ICD inducer comprises radiation.
  • Exemplary types of radiation include UV radiation and g radiation.
  • an ICD inducer comprises UV radiation.
  • an ICD inducer comprises g radiation.
  • an ICD inducer comprises a small molecule.
  • the small molecule comprises a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, an anthracycline such as doxorubicin or mitoxantrone; a cyclophosphamide such as mafosfamide; bortezomib, daunorubicin, docetaxel, oxaliplatin or paclitaxel.
  • an ICD inducer comprises doxorubicin, mitoxantrone, mafosfamide, bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or any combinations thereof.
  • an ICD inducer comprises digitoxin or digoxin.
  • an ICD inducer comprises digitoxin.
  • an ICD inducer comprises digoxin.
  • an ICD inducer comprises septacidin.
  • an ICD inducer comprises a combination of cisplatin and thapsigargin.
  • an ICD inducer comprises a combination of cisplatin and tunicamycin.
  • the ICD inducer is a PARP inhibitor.
  • the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, or E7016.
  • an ICD inducer comprises a biologic.
  • a biologic comprises a protein or functional fragments thereof, a polypeptide, an oligosaccharide, a lipid, a nucleic acid (e.g., DNA or RNA) or a protein-payload conjugate.
  • a protein or functional fragments thereof comprises an enzyme, a glycoprotein, or a protein capable of inducing ICD.
  • a protein or functional fragments thereof comprises a humanized antibody or binding fragment thereof, a chimeric antibody or binding fragment thereof, a veneer antibody or binding fragment thereof, a monoclonal antibody or binding fragment thereof, a bispecific antibody or binding fragment thereof, an Fab, an Fab’, an F(ab’) 2 , an F(ab’) 3 , an scFv, an sc(Fv) 2 , a dsFv, a diabody, a minibody, or a nanobody or binding fragments thereof.
  • a protein-payload conjugate comprises a protein or functional fragments thereof conjugated to a payload (e.g., a small molecule payload).
  • an exemplary protein-payload conjugate is trastuzumab emtansine.
  • CRT exposure leads to phagocytosis by dendritic cells, leading to generating a population of cytosolic DNA.
  • cytosolic DNA sensor such as cyclic GMP- AMP synthase detects the presence of the cytosolic DNA and subsequently triggers inflammatory responses (e.g., generation of type I IFNs) via the STING-mediated pathway.
  • the presence of intracellular nucleic acid from a pathogen activates cGAS, leading to production of 2’3’-cGAMP, and subsequent activation of the STING pathway.
  • the pathogen is a virus, e.g., a DNA virus or an RNA virus.
  • the pathogen is a retrovirus.
  • Exemplary viruses capable of subsequent activation of STING include, but are not limited to, herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68),
  • the pathogen is a bacterium.
  • Exemplary bacteria include, but are not limited to, Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
  • the pathogen is a DNA virus.
  • the DNA virus is a single-stranded DNA virus.
  • the DNA virus is a double -stranded DNA virus.
  • the virus utilizes a DNA-dependent DNA polymerase for replication.
  • the pathogen is an RNA virus.
  • the RNA virus is a single-stranded RNA virus (e.g., single-stranded-positive sense or single -stranded-negative sense).
  • the RNA virus is a double -stranded RNA virus.
  • Exemplary RNA viruses include vesicular stomatitis virus (VSV), sendai virus, hepatitis C virus, dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
  • VSV vesicular stomatitis virus
  • sendai virus hepatitis C virus
  • dengue fever virus yellow fever virus
  • ebola virus Marburg virus
  • Venezuelan encephalitis virus or zika virus.
  • the pathogen is a retrovirus.
  • Retroviruses are single -stranded RNA viruses with a DNA intermediate. In most viruses, DNA is transcribed into RNA, and then RNA is translated into protein. However, retroviruses function differently, as their RNA is reverse -transcribed into DNA.
  • the retroviral RNA genome Upon infection of a cell by a retrovirus, the retroviral RNA genome is transcribed into its corresponding double-stranded DNA by a reverse transcriptase enzyme which is coded for by the viral genome, which is the reverse of the usual pattern, thus retro (backwards). This DNA then enters the nucleus and integrates into the host DNA using an integrase enzyme which is also coded for by the viral genome.
  • the integrated viral DNA ("proviral" DNA) becomes a component of the host genome, replicating with it and producing the proteins required in assembling new copies of the virus. It is difficult to detect the virus until it has infected the host.
  • the information contained in a retroviral gene is thus used to generate the corresponding protein via the sequence: RNA DNA RNA polypeptide.
  • the genome of a retrovirus (in either the RNA or DNA form) is divided conceptually into two parts.
  • the first, or "trans-acting,” category consists of the regions coding for viral proteins. These include the group specific antigen (“gag”) gene for synthesis of the core coat proteins, the "pol” gene for the synthesis of various enzymes (such as reverse transcriptase), and the envelope (“env”) gene for the synthesis of envelope glycoproteins.
  • the full-length RNA transcript is packaged by the viral proteins into a viral particle which then buds off in a piece of cell membrane, in which are embedded env-derived peptides. This membrane-coated viral particle is a fully competent viral particle and go on to infect other cells.
  • the second part of the retroviral genome is referred to as the "cis-acting" portion and consists of the regions which must be on the genome to allow its packaging and replication.
  • LTRs Long Terminal Repeats
  • the promoters, enhancers, and other regions of the LTRs are also capable of conferring tissue specificity such that the virus will only be “expressed” (i.e., transcribed and translated) in specific cell types even though it infects others.
  • HSV-1 Herpes simplex virus 1
  • HSV-l is a highly contagious infection, which is common and endemic throughout the world. Most HSV-l infections are acquired during childhood. The vast majority of HSV-l infections are oral herpes (infections in or around the mouth, sometimes called orolabial, oral-labial or oral- facial herpes), but a proportion of HSV-l infections are genital herpes (infections in the genital or anal area). HSV-l is mainly transmitted by oral-to-oral contact to cause oral herpes infection, via contact with the HSV-l virus in sores, saliva, and surfaces in or around the mouth. However, HSV-l is also transmitted to the genital area through oral -genital contact to cause genital herpes.
  • MHV-68 is a rodent pathogen and a member of the gammaherpesvirus subfamily. MHV-68 has the ability to establish latent infections within lymphocytes and make close associations with cell tumors. MHV-68 establishes latency unless the host immune system is compromised, and this latency is regulated by multiple cellular controls, such as virus-specific open reading frames that result in gene products promoting the maintenance of latency or activation of lytic cycles.
  • MHV-68 infection sites consist of primarily lung epithelial cells, adrenal glands, and heart tissue, with latent infection in B lymphocytes. Kaposi’s sarcoma-associated herpesvirus (KSHV)
  • KSHV or human herpesvirus 8 is a human rhadinovirus (gamma-2 herpesvirus) belonging to the family of herpesviruses.
  • KSHV is a large double -stranded DNA virus with a protein covering that packages its nucleic acids, called the capsid, which is then surrounded by an amorphous protein layer called the tegument, and finally enclosed in a lipid envelope derived in part from the cell membrane. This virus is transmitted both sexually and through body fluids, for example, saliva and blood).
  • KSHV causes a blood vessel cancer called Kaposi's sarcoma (KS), a lymphoma (a cancer of the lymphocyte) called body cavity -based lymphoma and some forms of severe lymph node enlargement, called Castleman's disease.
  • VACV Vaccinia virus
  • Vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family.
  • the poxviruses are the largest known DNA viruses and are distinguished from other viruses by their ability to replicate entirely in the cytoplasm of infected cells. Poxviruses do not require nuclear factors for replication and, thus, replicate with little hindrance in enucleated cells.
  • VACV has a linear, double-stranded DNA genome of approximately 190 kb in length, which encodes for around 250 genes. The genome is surrounded by a lipoprotein core membrane.
  • Vaccinia virus is well-known for its role as a vaccine that eradicated the smallpox disease.
  • Vaccinia virus The natural host of Vaccinia virus is unknown, but the virus replicates in cows and humans. During its replication cycle, Vaccinia virus produces four infectious forms which differ in their outer membranes: intracellular mature virion (IMV), the intracellular enveloped virion (IEV), the cell-associated enveloped virion (CEV) and the extracellular enveloped virion (EEV).
  • IMV intracellular mature virion
  • IEV intracellular enveloped virion
  • CEV cell-associated enveloped virion
  • EEV extracellular enveloped virion
  • Adenoviruses are double -stranded DNA viruses and are now known to be a common cause of asymptomatic respiratory tract infection.
  • An extremely hardy virus, adenovirus is ubiquitous in human and animal populations, survives long periods outside a host, and is endemic throughout the year.
  • Possessing 52 serotypes adenovirus is recognized as the etiologic agent of various diverse syndromes. It is transmitted via direct inoculation to the conjunctiva, a fecal -oral route, aerosolized droplets, or exposure to infected tissue or blood.
  • the virus is capable of infecting multiple organ systems; however, most infections are asymptomatic.
  • HPV Human papillomaviruses
  • HPV Human papillomaviruses
  • DNA virus from the papillomavirus family are common viruses that cause warts.
  • HPV Human papillomaviruses
  • High-risk HPV leads to cancers of the cervix, vulva, vagina, and anus in women and cancers of the anus and penis in men.
  • HBV Hepatitis B virus
  • HBV a member of the Hepadnaviridae family
  • HBV replicates through an RNA intermediate and integrates into the host genome.
  • Hepatitis B is one of a few known non -retroviral viruses which use reverse transcription as a part of its replication process.
  • the features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells.
  • HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
  • Acute HBV infection is either asymptomatic or presents with symptomatic acute hepatitis. About 5%— 10% of population infected is unable to clear the virus and becomes chronically infected. Many chronically infected persons have mild liver disease. Other individuals with chronic HBV infection develop active disease, which progresses to cirrhosis and liver cancer.
  • HDV Hepatitis D virus
  • hepatitis D virus is a small spherical enveloped viroid. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV).
  • HDV high-density virus
  • coinfection coinfection
  • superimposed on chronic hepatitis B or hepatitis B carrier state superinfection
  • Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections.
  • hepatitis D In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.
  • HIV Human immunodeficiency virus
  • the human immunodeficiency virus is a lentivirus (a subgroup of retrovirus) that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS).
  • HIV is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. HIV infects vital cells in the human immune system such as helper T cells (specifically CD4 + T cells), macrophages, and dendritic cells.
  • helper T cells specifically CD4 + T cells
  • macrophages and dendritic cells.
  • HIV infection leads to low levels of CD4 + T cells through a number of mechanisms, including but not limited to, pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4 + T cells by CD8 cytotoxic lymphocytes that recognize infected cells.
  • CD4 + T cell numbers decline below a critical level, cell -mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.
  • Human cytomegalovirus (HCMV) Human cytomegalovirus
  • HCMV Human cytomegalovirus
  • HCMV Human cytomegalovirus
  • Primary HCMV infection is generally asymptomatic in healthy hosts but causes severe and sometimes fatal disease in immunocompromised individuals, organ transplant recipients, and neonates.
  • HCMV is the leading infectious cause of congenital abnormalities in the Western world, affecting 1-2.5% of all live births.
  • After infection HCMV remains latent within the body throughout life and is reactivated at any time. Eventually, it causes mucoepidermoid carcinoma and other malignancies such as prostate cancer. Although they are found throughout the body, HCMV infections are frequently associated with the salivary glands.
  • HCMV HCMV transmission from person to person is entirely unknown but is presumed to occur through bodily fluids. Infection requires close, intimate contact with a person secreting the virus in their saliva, urine, or other bodily fluids. HCMV is transmitted sexually and via breast milk, and also occurs through receiving transplanted organs or blood transfusions.
  • Dengue fever virus is an RNA virus of the family Flaviviridae; genus Flavivirus. It is transmitted by arthropods (mosquitoes or ticks), and is therefore also referred to as an arbovirus (arthropod-borne virus). Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus but it also circulates in nonhuman primates.
  • Ebola virus is one of five known viruses within the genus Ebolavirus. Four of the five known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD).
  • Ebola virus disease Ebola virus disease
  • the EBOV genome is a single - stranded RNA approximately 19,000 nucleotides long. It encodes seven structural proteins:
  • NP nucleoprotein
  • VP35 polymerase cofactor
  • VP40 polymerase cofactor
  • GP transcription activator
  • VP30 transcription activator
  • VP24 RNA-dependent RNA polymerase
  • Marburg virus is a hemorrhagic fever virus of the Filoviridae family of viruses and a member of the species Marburg marburgvirus, genus Marburgvirus.
  • Marburg virus causes Marburg virus disease in humans and nonhuman primates, a form of viral hemorrhagic fever. The virus is considered to be extremely dangerous. Zika virus
  • Zika virus is a member of the virus family Flaviviridae. It is spread by daytime - active Aedes mosquitoes, such as A. aegypti and A. albopictus. Zika virus is related to the dengue, yellow fever, Japanese encephalitis, and West Nile viruses. Since the 195 Os, it has been known to occur within a narrow equatorial belt from Africa to Asia. The infection, known as Zika fever or Zika virus disease, often causes no or only mild symptoms, similar to a very mild form of dengue fever. While there is no specific treatment, paracetamol (acetaminophen) and rest may help with the symptoms. Zika can spread from a pregnant woman to her baby. This can result in microcephaly, severe brain malformations, and other birth defects. Zika infections in adults may result rarely in Guillain-Barre syndrome.
  • a pathogen described herein is a bacterium.
  • Bacteria are microscopic single-celled microorganisms that exist either as independent (free-living) organisms or as parasites (dependent on another organism for life) and thrive in diverse environments. As prokaryotes, the organism consists of a single cell with a simple internal structure. Bacterial DNA floats free, in a twisted thread-like mass called the nucleoid. Bacterial cells also contain separate, circular pieces of DNA called plasmids. Bacteria lack membrane -bound organelles, specialized cellular structures that are designed to execute a range of cellular functions from energy production to the transport of proteins. However, both bacterial cells contain ribosomes. A few different criteria are used to classify bacteria. They are distinguished by the nature of their cell walls, by their shape, or by differences in their genetic makeup.
  • Listeria monocytogenes is the species of pathogenic bacteria that causes the infection listeriosis.
  • L monocytogenes is a motile, non-spore-forming, gram-positive bacillus that has aerobic and facultative anaerobic characteristics making it capable of surviving in the presence or absence of oxygen. It grows best at neutral to slightly alkaline pH and is capable of growth at a wide range of temperatures, from l-45°C. It is beta-hemolytic and has a blue-green sheen on blood-free agar. It exhibits characteristic tumbling motility when viewed with light microscopy.
  • CNS infection manifests as meningitis, meningoencephalitis, or abscess. Endocarditis is another possible presentation. Localized infection manifests as septic arthritis, osteomyelitis, and, rarely, pneumonia.
  • Mycobacterium tuberculosis is an obligate pathogenic bacterial species in the family Mycobacteriaceae and the causative agent of tuberculosis.
  • M. tuberculosis has an unusual, waxy coating on its cell surface (primarily due to the presence of mycolic acid), which makes the cells impervious to Gram staining.
  • the physiology ofM tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. Francisella novicida
  • Francisella novicida is a bacterium of the Francisellaceae family, which consist of Gram negative pathogenic bacteria. These bacteria vary from small cocci to rod-shaped, and are most known for their intracellular parasitic capabilities. Some of the main symptoms associated with this infection include pneumonia, muscle pain, and fever.
  • Legionella pneumophila is a thin, aerobic, pleomorphic, flagellated, nonspore-forming, Gram-negative bacterium of the genus Legionella.
  • L. pneumophila infection causes Legionnaires' disease, a severe form of pneumonia. The symptoms of Legionnaire's disease include confusion, headache, diarrhea, abdominal pain, fever, chills, and myalgia as well as a non-productive cough.
  • Pontiac fever is a non-pneumonic form of L. pneumophila infection. Symptoms are flu-like, including fever, tiredness, myalgia, headache, sore throat, nausea, and sometimes cough. L. pneumophila is transmitted by aerosols and aspiration of contaminated water.
  • Chlamydia trachomatis is a gram-negative bacterium that infects the columnar epithelium of the cervix, urethra, and rectum, as well as nongenital sites such as the lungs and eyes.
  • the bacterium is the cause of the most frequently reported sexually transmitted disease in the United States. Most persons with this infection are asymptomatic. Untreated infection results in serious complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy in women, and epididymitis and orchitis in men. Men and women experience chlamydia-induced reactive arthritis. In neonates and infants, the bacterium causes conjunctivitis and pneumonia. Adults also experience conjunctivitis caused by chlamydia. Trachoma is a recurrent ocular infection caused by chlamydia. Streptococcus pneumoniae
  • Streptococcus pneumoniae or pneumococcus is a Gram-positive, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), facultative anaerobic member of the genus Streptococcus, that is responsible for the majority of community-acquired pneumonia. It is a commensal organism in the human respiratory tract, meaning that it benefits from the human body, without harming it. However, infection by pneumococcus is dangerous, causing not only pneumonia, but also bronchitis, otitis media, septicemia, and meningitis. Pneumococcal pneumonia causes fever and chills, coughs, difficulty breathing, and chest pain.
  • S. pneumoniae primarily spreads through the air in the form of aerosol droplets from coughing and sneezing.
  • Neisseria gonorrhoeae also known as gonococci (plural), or gonococcus (singular), is a species of Gram-negative, fastidious, coffee bean-shaped diplococci bacteria responsible for the sexually transmitted infection gonorrhea.
  • Neisseria gonorrhoeae grow and rapidly multiply in the mucous membranes, especially the mouth, throat, and anus of males and females, and the cervix, fallopian tubes, and uterus of the female reproductive tract.
  • N. gonorrhoeae is transmitted from person to person via oral, vaginal, and anal sexual contact. During childbirth, infants contract the infection in the birth canal resulting in bilateral conjunctivitis.
  • tumor cells circumvent the STING-mediated type I IFN production through overexpression of a phosphodiesterase.
  • phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication.
  • Phosphodiesterases comprise a class of enzymes that catalyze the hydrolysis of a phosphodiester bond.
  • this class comprises cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small-molecule phosphodiesterases .
  • Cyclic nucleotide phosphodiesterases regulate the cyclic nucleotides cAMP and cGMP.
  • cAMP and cGMP function as intracellular second messengers to transduce a variety of extracellular signals including hormones, light, and neurotransmitters.
  • PDEs degrade cyclic nucleotides to their corresponding monophosphates, thereby regulating the intracellular concentrations of cyclic nucleotides and their effects on signal transduction.
  • cGAMP acts as a second messenger binding to STING.
  • the cGAMP acts as an intracellular second messenger.
  • the cGAMP acts as an extracellular second messenger.
  • the extracellular second messenger cGAMP is transferred between cells through, e.g., gap junctions and/or viral particles, and enables activation of the STING pathway in a paracrine fashion.
  • PDEs are classified into classes I, II and III.
  • mammalian PDEs which belong to Class I PDEs, are further divided into 12 families (PDE1-PDE12) based on their amino acid sequences, substrate specificity and affinity, sensitivity to cofactors, and sensitivity to inhibitory agents.
  • the different families of mammalian PDEs further contain splice variants that can be unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association proteins.
  • PDE1 family comprises Ca2+/calmodulin-dependent PDEs.
  • PDE1 is encoded by at least three different genes (PDE1A, PDE1B, and PDE1C), each having at least two different splice variants, e.g. PDE1C1 and PDE1C3.
  • PDE1 isozymes are regulated in vitro by phosphorylation/dephosphorylation. For example, phosphorylation decreases the affinity of PDE for calmodulin, decreases the activity of PDE1, and increases steady state levels of cAMP. In some cases, PDE1 is observed in the lung, heart, and brain.
  • PDE2s are cGMP-stimulated PDEs that have been observed in the cerebellum, neocortex, heart, kidney, lung, pulmonary artery, and skeletal muscle. In some cases, PDE2 mediates the effects of cAMP on catecholamine secretion, participate in the regulation of aldosterone, and play a role in olfactory signal transduction.
  • PDE3 The family of PDE3s has a high affinity for both cGMP and cAMP.
  • PDE3 plays a role in stimulating myocardial contractility, inhibiting platelet aggregation, relaxing vascular and airway smooth muscle, inhibiting proliferation of T-lymphocytes and cultured vascular smooth muscle cells, and regulating catecholamine-induced release of free fatty acids from adipose tissue.
  • isozymes of PDE3 are regulated by cAMP -dependent protein kinase, or by insulin- dependent kinases.
  • PDE4s are specific for cAMP and are activated by cAMP -dependent phosphorylation. In some cases, PDE4s are localized to airway smooth muscle, the vascular endothelium, and all inflammatory cells. PDE4 plays a role in regulation of immune cell function.
  • PDE5s exert selective recognition for cGMP as a substrate and comprise two allosteric cGMP-specific binding sites. In some cases, binding of cGMP to these allosteric binding sites modulate phosphorylation of PDE5 by cGMP -dependent protein kinase. In some cases, elevated levels of PDE5 are found in vascular smooth muscle, platelets, lung, and kidney. PDE5 plays a role in regulating vascular resistance and responsivity to the vasodilating mediator nitric oxide.
  • PDE6s the photoreceptor cyclic nucleotide phosphodiesterases, are involved in the phototransduction cascade. In association with the G-protein transducin, PDE6s hydrolyze cGMP to regulate cGMP -gated cation channels in photoreceptor membranes. In addition to the cGMP -binding active site, PDE6s also have two high-affinity cGMP-binding sites which may further play a regulatory role in PDE6 function.
  • the PDE7 family of PDEs is cAMP specific and comprises one known member having multiple splice variants. Although mRNAs encoding PDE7s are found in skeletal muscle, heart, brain, lung, kidney, and pancreas, expression of PDE7 proteins is restricted to specific tissue types. Further, PDE7s shares a high degree of homology to the PDE4 family.
  • PDE8s are cAMP specific. In some cases, PDE8s are expressed in thyroid gland, testis, eye, liver, skeletal muscle, heart, kidney, ovary, and brain. [0070] PDE9s are cGMP specific. In some cases, PDE9s are expressed in kidney, liver, lung, brain, spleen, and small intestine.
  • PDElOs are dual-substrate PDEs, hydrolyzing both cAMP and cGMP. In some instances, PDElOs are expressed in brain, thyroid, and testis.
  • PDE1 ls similar to PDElOs, are dual -substrate PDEs that hydrolyze both cAMP and cGMP. In some instances, PDE1 ls are expressed in the skeletal muscle, brain, lung, spleen, prostate gland, and testis.
  • PDEl2s hydrolyze cAMP and oligoadenylates (e.g., 2’,5’-oligoadenylate). In some cases, although PDE12 hydrolyzes the 2’5’ linkage, PDE12 does not exhibit activity toward 2’3’-cGAMP.
  • the class of phosphodiesterases also comprises an ecto-nucleotide pyrophosphatase/phosphodiesterase.
  • Ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP) or nucleotide pyrophosphatase/phosphodiesterases (NPP) are a subfamily of ectonucleotidases which hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to nucleoside 5’- monophosphates.
  • ENPP (or NPP) comprises seven members, ENPP-l, ENPP- 2, ENPP-3, ENPP-4, ENPP-5, ENPP-6 and ENPP-7.
  • ENPP-l ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP-l) protein
  • PC-l ecto-nucleotide pyrophosphatase/phosphodiesterase 1
  • ENPP-l is a type II transmembrane glycoprotein comprising two identical disulfide -bonded subunits.
  • ENPP-l is expressed in precursor cells and promotes osteoblast differentiation and regulates bone mineralization.
  • ENPP-l negatively regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates (NTPs) to produce inorganic pyrophosphate (PPi).
  • NTPs extracellular nucleotide triphosphates
  • PPi inorganic pyrophosphate
  • expression of ENPP-l has been observed in pancreas, kidney, bladder, and the liver.
  • ENPP-l has been observed to be overexpressed in cancer cells, e.g., in breast cancer cells and glioblast
  • ENPP-l has a broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars.
  • ENPP-l functions to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and also hydrolyze diadenosine polyphosphates.
  • ENPP-l hydrolyzes the 2’5’ linkage of cyclic nucleotides.
  • ENPP-l degrades 2’3’-cGAMP, an activator of STING.
  • ENPP-l comprises two N-terminal somatomedin B (SMB)-like domains (SMB1 and SMB2), a catalytic domain and a C-terminal nuclease-like domain.
  • SMB N-terminal somatomedin B
  • the two SMB domains are connected to the catalytic domain by a first flexible linker, while the catalytic domain is further connected to the nuclease-like domain by a second flexible linker.
  • the SMB domains facilitate ENPP-l dimerization.
  • the catalytic domain contains the NTP and cGAMP binding sites.
  • the nuclease-like domain contains an EF- hand motif, which binds Ca+2 ion.
  • ENPP-2 and ENPP-3 are type II transmembrane glycoproteins that share a similar architecture with ENPP-l, for example, comprising the two N-terminal SMB-like domains, a catalytic domain, and a nuclease-like domain. In some instances, ENPP-2 hydrolyzes
  • lysophospholipids to produce lysophosphatidic acid (LPA) or sphingosylphosphorylcholine (SPC) to produce sphingosine-l phosphate (S1P).
  • LPA lysophosphatidic acid
  • SPC sphingosylphosphorylcholine
  • S1P sphingosine-l phosphate
  • ENPP-3 is identified to regulate N- acetylglucosaminyltransferase GnT-IX (GnT-Vb).
  • ENPP-4-ENPP-7 are shorter proteins compared to ENPP-l -ENPP-3 and comprise a catalytic domain and lack the SMB-like and nuclease-like domains.
  • ENPP-6 is a choline-specific glycerophosphodiesterase, with lysophospholipase C activity towards
  • ENPP-7 is an alkaline sphingomyelinase (alk-SMase) with no detectable nucleotidase activity.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a reversible inhibitor.
  • a reversible inhibitor interacts with an enzyme via non-covalent interactions, e.g., hydrogen bonds, hydrophobic interactions, and/or ionic bonds.
  • a reversible inhibitor is further classified as a competitive inhibitor, a noncompetitive inhibitor, an allosteric inhibitor or a mixed inhibitor. In competitive inhibition, both the inhibitor and the substrate compete for the same active site. In noncompetitive inhibition, the inhibitor and the substrate bind simultaneously to the enzyme and the inhibitor decreases the enzyme’s activity.
  • the inhibitor binds to the enzyme at a site distant from the active site, which binding reduces the enzyme’s activity.
  • Some inhibitors act via a combination of competitive, noncompetitive, and/or allosteric mechanisms: these are referred to as mixed inhibitors.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a competitive inhibitor.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a noncompetitive inhibitor.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is an allosteric inhibitor.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a mixed inhibitor.
  • an ENPP-l inhibitor described herein is a competitive inhibitor. In other instances, a ENPP-l inhibitor described herein is a noncompetitive inhibitor In other instances, a ENPP-l inhibitor described herein is an allosteric inhibitor. In other instances, a ENPP-l inhibitor described herein is a mixed inhibitor. [0082] In some embodiments, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is an irreversible inhibitor. Irreversible inhibitors interact with an enzyme with covalent interaction. In some cases, the ENPP-l is an irreversible inhibitor.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide binds to one or more domains of a PDE described herein.
  • a PDE inhibitor binds to one or more domains of ENPP-l.
  • ENPP-l comprises a catalytic domain and a nuclease-like domain.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide binds to the catalytic domain of ENPP-l.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide binds to the nuclease like domain of ENPP-l.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP but interacts weakly with the region that is bound by AMP.
  • an inhibitor of a 2’3’-cGAMP degradation polypeptide e.g., a ENPP-l inhibitor
  • Alkyl refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • saturated hydrocarbon monoradical examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2- methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2- methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2 -pentyl, 2, 2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl,
  • a numerical range such as“Ci-C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Ci 0 alkyl, a Ci-C 9 alkyl, a Ci-C 8 alkyl, a Ci-C 7 alkyl, a Ci-C 6 alkyl, a Ci-C 5 alkyl, a Ci-C 4 alkyl, a Ci-C 3 alkyl, a Ci-C 2 alkyl, or a Ci alkyl.
  • the alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an“alkenyl” or an “alkynyl”.
  • the alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as“C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -Ci 0 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • alkynyl include, but are not limited to ethynyl, 2-propynyl, 2- butynyl, l,3-butadiynyl and the like.
  • a numerical range such as“C 2 -C 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -Cio alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to lO-membered aryl.
  • the aryl is a 6- membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 - C 15 cycloalkyl), from three to ten carbon atoms (C 3 -Ci 0 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3 - to 6-membered cycloalkyl.
  • the cycloalkyl is a 5 - to 6- membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane,
  • cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
  • Halo or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
  • 2-oxopiperidinyl 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, l,l-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl.
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • a Heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5 - to l4-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaryl is a 5- to lO-membered heteroaryl.
  • the heteroaryl is a 5- to 6- membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiopheny
  • a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or - OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the terms“individual(s)”,“subject(s)” and“patient(s)” mean any mammal.
  • the mammal is a human.
  • the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker).
  • a health care worker e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker.
  • Treatment is an intervention performed with the intention of preventing the development or altering the pathology or symptoms of a disorder. Accordingly,“treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
  • a therapeutic agent may directly decrease the pathology of tumor cells, or render the tumor cells more susceptible to treatment by other therapeutic agents, e.g., radiation and/or chemotherapy.
  • “ameliorated” or“treatment” refers to a symptom which is approaches a normalized value (for example a value obtained in a healthy patient or individual), e.g., is less than 50% different from a normalized value, preferably is less than about 25% different from a normalized value, more preferably, is less than 10% different from a normalized value, and still more preferably, is not significantly different from a normalized value as determined using routine statistical tests.
  • the term“treat” or“treating” with respect to tumor cells refers to stopping the progression of said cells, slowing down growth, inducing regression, or amelioration of symptoms associated with the presence of said cells.
  • The“treatment of cancer” refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder.
  • an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate“effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • Described herein are compounds of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb) that are ENPP-l inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and infections.
  • L is a bond or -(CR 8 R 9 )-;
  • Ring A is a 5-membered heteroaryl or a 5-membered heterocycloalkyl
  • Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 8 and R 9 are taken together to form an oxo
  • each R a is hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • n 1-4;
  • p is 1-4.
  • Ring A is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, thiophenyl, furanyl, triazolyl, thiadiazolyl, or oxadiazolyl.
  • Ring A is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, or thiazolyl.
  • Ring A is imidazolyl or imidazolidinyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is imidazolyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is pyrrolyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is pyrazolyl.
  • Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is phenyl or pyridyl. In some embodiments of a compound of Formula (A), or a
  • Ring B is phenyl
  • Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is cycloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is a bicyclic cycloalkyl. In some
  • Ring B is cyclohexyl.
  • R 1 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen.
  • R 2 is hydrogen, halogen, - OR a , or Ci-C 6 alkyl optionally substituted with one or more R e .
  • R 2 is hydrogen, halogen, -OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 2 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or -OR a .
  • R 3 is hydrogen, halogen, - OR a , or Ci-C 6 alkyl optionally substituted with one or more R e .
  • R 3 is hydrogen, halogen, -OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 3 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or -OR a . In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R 2 or R 3 is not hydrogen. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R 2 or R 3 is -OR a . In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 and R 3 are -OR a .
  • R 2 is hydrogen and R 3 is -OR a .
  • R 3 is hydrogen and R 2 is -OR a .
  • R 4 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 4 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.
  • R 5 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 5 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is hydrogen.
  • L 3 is -(CR 8 R 9 )-.
  • R 8 and R 9 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 8 and R 9 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 8 and R 9 are hydrogen.
  • R 8 and R 9 are taken together to form an oxo.
  • L is a bond.
  • alkyl(NR a C( 0)NR c R d ), Ci-C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more R 8 .
  • alkyl(NR a C( 0)NR c R d ), or Ci-C 6 heteroalkyl; wherein the alkyl and heteroalkyl are independently optionally substituted with one or more R g .
  • p is 1-3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2 or 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2.
  • p is 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 4.
  • each R 6 is independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R 6 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R 6 is hydrogen.
  • two R 6 on the same carbon are taken together to form an oxo.
  • n is 1-3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2 or 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 or 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2.
  • n is 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 4.
  • L 1 is -(CR 18 R 19 )-;
  • Ring Bl is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 12 or R 13 is not hydrogen
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • pl is 1-4.
  • Ring B 1 is aryl or heteroaryl.
  • Ring Bl is phenyl.
  • Ring B 1 is cycloalkyl or heterocycloalkyl.
  • Ring Bl is cycloalkyl.
  • Ring Bl is a bicyclic cycloalkyl.
  • Ring Bl is cyclohexyl.
  • R 11 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 11 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 11 is hydrogen.
  • R 14 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 14 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 14 is hydrogen.
  • R 15 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 15 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15 is hydrogen.
  • R 18 and R 19 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 18 and R 19 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 18 and R 19 are hydrogen.
  • R 18 and R 19 are taken together to form an oxo.
  • R 12 and R 13 are independently hydrogen, halogen, - OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; provided that one of R 12 or R 13 is not hydrogen.
  • R 12 and R 13 are independently hydrogen, halogen, or -OR a ; provided that one of R 12 or R 13 is not hydrogen.
  • R 12 and R 13 are -OR a .
  • R 12 and R 13 are -OMe.
  • one ofR 12 or R 13 is -OMe.
  • R 12 is -OMe.
  • R 13 is -OMe.
  • R 13 is -OMe.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • pl is 1-3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p 1 is 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 4.
  • L 2 is a bond or -(CR 28 R 29 )-;
  • Ring A2 is imidazolyl, pyrrolyl, oxazolyl, or thiazolyl;
  • Ring B2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 28 and R 29 are taken together to form an oxo
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • n2 is 1-4;
  • Ring A2 is imidazolyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A2 is pyrrolyl.
  • Ring B2 is aryl or heteroaryl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is phenyl.
  • Ring B2 is cycloalkyl or heterocycloalkyl.
  • a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B2 is cycloalkyl or heterocycloalkyl.
  • Ring B2 is cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalky
  • Ring B2 is cyclohexyl.
  • R 21 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 21 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a
  • R 21 is hydrogen
  • R 24 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 24 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a
  • R 24 is hydrogen
  • R 25 is hydrogen, halogen, -CN, - OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 25 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a
  • R 25 is hydrogen
  • L 2 is -(CR 28 R 29 )-.
  • R 28 and R 29 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 28 and R 29 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 28 and R 29 are hydrogen. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 28 and R 29 are taken together to form an oxo.
  • L 2 is a bond.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • each R 27 is independently Ci-C 6
  • p2 is 1-3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1 or 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 2.
  • p2 is 3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 4.
  • each R 26 is independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 26 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 26 is hydrogen.
  • n2 is 1-3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 1 or 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 2.
  • n2 is 3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 4.
  • - is a single bond or a double bond
  • X is -N- or -CR 36 - when
  • X is -NR 36a - or -C(R 36 ) 2 - when
  • Y is -N- or -CR 36 - when
  • Y is -NR 36a - or -C(R 36 ) 2 - when
  • Ring B3 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 36a is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl;
  • R 38 and R 39 are taken together to form an oxo
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • p3 is 1-4.
  • Ring B3 is aryl or heteroaryl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is phenyl.
  • Ring B3 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is cycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is cyclohexyl.
  • R 31 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 31 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 31 is hydrogen.
  • R 34 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 34 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 34 is hydrogen.
  • R 35 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 35 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 35 is hydrogen.
  • L 3 is -(CR 38 R 39 )-.
  • R 38 and R 39 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 38 and R 39 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 38 and R 39 are hydrogen.
  • R 38 and R 39 are taken together to form an oxo.
  • L 3 is a bond.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • p3 is 1-3. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 1 or 2. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 1. In some embodiments of a compound of Formula (III), or a
  • p3 is 2. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 3. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 4.
  • W is .
  • X is -CR 36 - and Y is -N-.
  • X is -N- and Y is -CR 36 -.
  • X is -CR 36 - and Y is -CR 36 -.
  • X is -C(R 36 ) 2 - and Y is -NR 36a -.
  • each R 36 is independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R 36 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R 36 is hydrogen.
  • two R 36 on the same carbon are taken together to form an oxo.
  • each R 36a is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 36a are hydrogen. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 36a is independently Ci- C 6 alkyl.
  • L4 is -(CR 48 R 49 )-;
  • Ring A4 is a 5-membered heteroaryl or a 5-membered heterocycloalkyl
  • Ring B4 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • n4 is 1-4;
  • p4 is 1-4.
  • Ring A4 is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, or thiazolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is imidazolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is pyrrolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is pyrazolyl.
  • Ring B4 is aryl or heteroaryl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is phenyl.
  • Ring B4 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is cycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is cyclohexyl.
  • R 41 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 41 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 41 is hydrogen.
  • R 44 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 44 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 44 is hydrogen.
  • R 45 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 45 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 is hydrogen.
  • R 48 and R 49 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 48 and R 49 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 48 and R 49 are hydrogen.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • p4 is 1-3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 1 or 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 1. In some embodiments of a compound of Formula (IV), or a
  • p4 is 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 4.
  • each R 46 is independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 46 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 46 is hydrogen. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 46 on the same carbon are taken together to form an oxo.
  • n4 is 1-3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 1 or 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 1. In some embodiments of a compound of Formula (IV), or a
  • n4 is 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 4.
  • L 5 is a bond or -(CR 58 R 59 )-;
  • Ring B5 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 52 or R 53 independently optionally substituted with one or more R e ; provided that one of R 52 or R 53 is - OMe;
  • R 58 and R 59 are taken together to form an oxo
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • Ring B5 is aryl or heteroaryl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is phenyl.
  • Ring B5 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is cycloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is a bicyclic cycloalkyl. In some
  • Ring B5 is cyclohexyl.
  • R 51 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 51 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (V), or a
  • R 51 is hydrogen
  • R 54 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 54 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (V), or a
  • R 54 is hydrogen
  • R 55 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 55 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (V), or a
  • R 55 is hydrogen.
  • R 56 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 56 is hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (V), or a
  • R 56 is hydrogen
  • L 5 is -(CR 58 R 59 )-.
  • R 58 and R 59 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 58 and R 59 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 58 and R 59 are hydrogen. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 58 and R 59 are taken together to form an oxo.
  • L 5 is a bond.
  • R 52 is hydrogen, halogen, -OR a , Ci- C 6 alkyl, or Ci-C 6 haloalkyl; and R 53 is -OMe.
  • R 53 is hydrogen, halogen, - OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R 52 is -OMe.
  • R 52 is hydrogen, halogen, or -OR a ; and R 53 is -OMe.
  • R 53 is hydrogen, halogen, or -OR a ; and R 52 is -OMe.
  • R 52 is hydrogen or halogen; and R 53 is -OMe.
  • R 53 is hydrogen or halogen; and R 52 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 52 is hydrogen; and R 53 is -OMe. In some embodiments of a compound of Formula (V), or a
  • R 53 is hydrogen; and R 52 is -OMe.
  • R 52 is halogen; and R 53 is -OMe.
  • R 53 is halogen; and R 52 is -OMe.
  • R 52 and R 53 are -OMe.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • p5 is 1-3. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 1 or 2. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 1. In some embodiments of a compound of Formula (V), or a
  • p5 is 2. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 3. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 4.
  • L 6 is a bond or -(CR 68 R 69 )-;
  • Ring B6 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 62 or R 63 independently optionally substituted with one or more R e ; provided that one of R 62 or R 63 is - OMe;
  • R 68 and R 69 are taken together to form an oxo
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl; or R a and R c are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • p6 is 1-4.
  • Ring B6 is aryl or heteroaryl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is phenyl.
  • Ring B6 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is cycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is cyclohexyl.
  • R 61 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 61 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is hydrogen.
  • R 64 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 64 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is hydrogen.
  • R 65 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 65 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 65 is hydrogen.
  • each R 66 is independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 66 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 66 is hydrogen.
  • L 6 is -(CR 68 R 69 )-.
  • R 68 and R 69 are independently hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 68 and R 69 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 68 and R 69 are hydrogen.
  • R 68 and R 69 are taken together to form an oxo.
  • L 6 is a bond.
  • R 62 is hydrogen, halogen, -OR a , Ci- C 6 alkyl, or Ci-C 6 haloalkyl; and R 63 is -OMe.
  • R 63 is hydrogen, halogen, - OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R 62 is -OMe.
  • R 62 is hydrogen, halogen, or -OR a ; and R 63 is -OMe.
  • R 63 is hydrogen, halogen, or -OR a ; and R 62 is -OMe.
  • R 62 is hydrogen or halogen; and R 63 is -OMe.
  • R 63 is hydrogen or halogen; and R 62 is -OMe.
  • R 63 is hydrogen or halogen; and R 62 is -OMe.
  • R 62 is hydrogen; and R 63 is -OMe.
  • R 63 is hydrogen; and R 62 is -OMe.
  • R 62 is halogen; and R 63 is -OMe.
  • R 63 is halogen; and R 62 is -OMe.
  • R 62 and R 63 are -OMe.
  • alkyl(NR a C( 0)NR c R d ); wherein each alkyl is independently optionally substituted with one or more R g .
  • p6 is 1-3. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 1 or 2. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 1. In some embodiments of a compound of Formula (VI), or a
  • p6 is 2. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 3. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 4.
  • Z is -0-, -S-, or -NR 76 -;
  • L 7 is a bond or -(CR 78 R 79 )-;
  • Ring B7 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 72 or R 73 independently optionally substituted with one or more R e ; provided that one of R 72 or R 73 is - OMe;
  • R 76 is hydrogen or Ci-C 6 alkyl
  • R 78 and R 79 are taken together to form an oxo
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R b is independently Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
  • heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl;
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • p7 is 1-4.
  • Ring B7 is aryl or heteroaryl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is phenyl.
  • Ring B7 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is cycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is cyclohexyl.
  • R 71 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 71 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 71 is hydrogen.
  • R 74 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 74 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 74 is hydrogen.
  • R 75 is hydrogen, halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 75 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 75 is hydrogen.
  • Z is -0-. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is - S-. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -NR 76 -.
  • R 76 is hydrogen. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 76 is Ci-C 6 alkyl.
  • L 7 is -(CR 78 R 79 )-.
  • R 78 and R 79 are independently hydrogen, halogen, -CN, -OR a , - NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 78 and R 79 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 78 and R 79 are hydrogen. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 78 and R 79 are taken together to form an oxo.
  • L 7 is a bond.
  • R 72 is hydrogen, halogen, -OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R 73 is -OMe.
  • R 73 is hydrogen, halogen, -OR a , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R 72 is -OMe.
  • R 72 is hydrogen, halogen, or -OR a ; and R 73 is -OMe.
  • R 73 is hydrogen, halogen, or -OR a ; and R 72 is -OMe.
  • R 72 is hydrogen or halogen; and R 73 is -OMe.
  • R 73 is hydrogen or halogen; and R 72 is -OMe.
  • R 72 is hydrogen; and R 73 is -OMe.
  • R 73 is hydrogen; and R 72 is -OMe.
  • R 72 is halogen; and R 73 is -OMe.
  • R 73 is halogen; and R 72 is -OMe.
  • R 72 and R 73 are -OMe.
  • alkyl(NR a C( 0)NR c R d ), Ci-C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R g .
  • each R 77 is independently halogen, -OR a , -
  • p7 is 1-3. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 1 or 2. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 1. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 2.
  • p7 is 3. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 4.
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, Ci-C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R a is independently hydrogen, -OH, Ci-C 6 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III),
  • each R a is independently hydrogen, Ci-C 6 alkyl, or cycloalkyl.
  • each R a is independently hydrogen or Ci-C 6 alkyl.
  • each R b is independently Ci-C 6 alkyl, Ci-C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently Ci-C 6 alkyl, or cycloalkyl.
  • each R b is independently Ci-C 6 alkyl.
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R c and R d are independently hydrogen or Ci-C 6 alkyl.
  • each R c and R d are independently hydrogen or Ci-C 6 alkyl.
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH 2 , or Ci-C 6 alkyl.
  • each R e , R f , R g , and R h are independently halogen, -CN, -OR a , -NR c R d , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R e , R f , R g , and R h are independently halogen or Ci-C 6 alkyl.
  • each R e , R f , R g , and R h are independently halogen.
  • the substituents are each independently optionally substituted with 1-3 R e .
  • the substituents are each independently optionally substituted with 1 or 2 R e .
  • the substituents are each independently optionally substituted with 1 R e .
  • the substituents are each independently optionally substituted with 2 R e .
  • the substituents are each independently optionally substituted with 1-3 R f .
  • the substituents are each independently optionally substituted with 1 or 2 R f .
  • the substituents are each independently optionally substituted with 1 R f .
  • the substituents are each independently optionally substituted with 2 R f .
  • the substituents are each independently optionally substituted with 1-3 R g .
  • the substituents are each independently optionally substituted with 1 or 2 R g .
  • the substituents are each independently optionally substituted with 1 R g .
  • the substituents are each independently optionally substituted with 2 R g .
  • the substituents are each independently optionally substituted with 1-3 R h .
  • the substituents are each independently optionally substituted with 1 or 2 R h .
  • the substituents are each independently optionally substituted with 1 R h .
  • the substituents are each independently optionally substituted with 2 R h .
  • the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, disclosed herein is selected from Table 1 :
  • the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, disclosed herein is selected from:
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as H, H, C, C, N,
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a
  • salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C I-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example,“Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al,“Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O.
  • the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2 I st Ed. Mack Pub. Co., Easton, PA (2005)).
  • composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • therapeutic and/or prophylactic benefit e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 pg to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.
  • the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day.
  • the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
  • the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful as inhibitors of ENPP-l, and thereof useful in the treatment of diseases or disorders in which ENPP-l activity plays a role.
  • disclosed herein are methods of treating a subject having cancer.
  • the cancer is primed with an immunogenic cell death (ICD) inducer.
  • ICD immunogenic cell death
  • the cancer is treated with an ENPP-l inhibitor prior to administering an ICD inducer or is treated simultaneously with the ENPP-l inhibitor and an ICD inducer.
  • the method comprises administering to the subject an inhibitor of a 2’3’-cGAMP degradation polypeptide, wherein the inhibitor prevents hydrolysis of 2’3’- cGAMP and wherein the subject has an infection.
  • the ENPP-l inhibitor described herein is a competitive inhibitor. In other instances, the ENPP-l inhibitor described herein is an allosteric inhibitor. In some cases, the ENPP-l described herein is an irreversible inhibitor.
  • the ENPP-l inhibitor binds to one or more domains of ENPP-l .
  • ENPP-l comprises a catalytic domain and a nuclease-like domain.
  • the ENPP-l inhibitor binds to the catalytic domain of ENPP-l .
  • the ENPP-l inhibitor binds to the nuclease -like domain of ENPP-l .
  • the ENPP-l inhibitor selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP.
  • a PDE inhibitor selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP but interacts weakly with the region that is bound by AMP.
  • a cancer described herein is a solid tumor.
  • Solid tumor comprises neoplasms and lesions derived from cells other than blood, bone marrow, or lymphatic cells.
  • exemplary solid tumors include breast cancer and lung cancer.
  • a cancer described herein is a hematologic malignancy.
  • a hematologic malignancy comprises an abnormal cell growth of blood, bone marrow, and/or lymphatic cells.
  • an exemplary hematologic malignancy comprises multiple myeloma.
  • a hematologic malignancy is a leukemia, a lymphoma or a myeloma.
  • a hematologic malignancy is a B-cell malignancy.
  • a cancer described herein is a relapsed or refractory cancer. In some embodiments, a cancer described herein is a metastatic cancer.
  • an ICD inducer comprises radiation.
  • the radiation comprises UV radiation.
  • the radiation comprises g radiation.
  • an ICD inducer comprises a small molecule compound or a biologic.
  • an ICD small molecule inducer optionally comprises a chemotherapeutic agent.
  • the chemotherapeutic agent comprises an anthracycline. In some cases, the
  • anthracy cline is doxorubicin or mitoxantrone.
  • the chemotherapeutic agent comprises a cyclophosphamide.
  • the cyclophosphamide is mafosfamide.
  • the chemotherapeutic agent is selected from bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or a combination thereof.
  • the ICD inducer comprises digitoxin or digoxin.
  • the ICD inducer comprises septacidin.
  • the ICD inducer comprises a combination of cisplatin and thapsigargin.
  • the ICD inducer comprises a combination of cisplatin and tunicamycin.
  • an ICD inducer comprises a biologic (e.g., a protein-payload conjugate such as trastuzumab emtansine).
  • the ICD inducer comprises an activator of calreticulin (CRT) exposure.
  • CRT calreticulin
  • the method comprises an in vivo method. In some cases, the method differs from a systemic method because the production of IFNs is localized in the tumor
  • the method of enhancing type I interferon (IFN) production in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising (i) an inhibitor of a 2’3’-cGAMP degradation polypeptide to block the hydrolysis of 2’3’- cGAMP; and (ii) a pharmaceutically acceptable excipient; wherein the presence of 2’3’-cGAMP activates the STING pathway, thereby enhancing the production of type I interferons.
  • a pharmaceutical composition comprising (i) an inhibitor of a 2’3’-cGAMP degradation polypeptide to block the hydrolysis of 2’3’- cGAMP; and (ii) a pharmaceutically acceptable excipient; wherein the presence of 2’3’-cGAMP activates the STING pathway, thereby enhancing the production of type I interferons.
  • the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE) In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
  • the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
  • the cell has an elevated expression of PDE.
  • the cell has an elevated population of cytosolic DNA.
  • the elevated population of cytosolic DNA is generated by an ICD-mediated event.
  • the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
  • the inhibitor of a 2’3’-cGAMP degradation polypeptide is a PDE inhibitor.
  • the PDE inhibitor is a small molecule.
  • the PDE inhibitor is an ENPP-l inhibitor.
  • the PDE inhibitor is a reversible inhibitor.
  • the PDE inhibitor is a competitive inhibitor.
  • the PDE inhibitor is an allosteric inhibitor.
  • the PDE inhibitor is a mixed inhibitor.
  • the PDE inhibitor is an irreversible inhibitor.
  • the PDE inhibitor binds to the catalytic domain of ENPP-l.
  • the PDE inhibitor binds to the nuclease-like domain of ENPP-l.
  • the subject has been administered an immunogenic cell death (ICD) inducer prior to administering the inhibitor of a 2’3’-cGAMP degradation polypeptide.
  • the subject is administered an immunogenic cell death (ICD) inducer after administering the inhibitor of a 2’3’-cGAMP degradation polypeptide or simultaneously with the inhibitor of a 2’3’- cGAMP degradation polypeptide.
  • an ICD inducer comprises radiation. In some cases, the radiation comprises UV radiation. In other cases, the radiation comprises g radiation.
  • an ICD inducer comprises a small molecule compound or a biologic.
  • an ICD small molecule inducer optionally comprises a chemotherapeutic agent.
  • the chemotherapeutic agent comprises an anthracycline.
  • the chemotherapeutic agent comprises an anthracycline.
  • anthracy cline is doxorubicin or mitoxantrone.
  • the chemotherapeutic agent comprises a cyclophosphamide.
  • the cyclophosphamide is mafosfamide.
  • the chemotherapeutic agent is selected from bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or a combination thereof.
  • the ICD inducer comprises digitoxin or digoxin.
  • the ICD inducer comprises septacidin.
  • the ICD inducer comprises a combination of cisplatin and thapsigargin.
  • the ICD inducer comprises a combination of cisplatin and tunicamycin.
  • an ICD inducer comprises a biologic (e.g., a protein-payload conjugate such as trastuzumab emtansine).
  • the ICD inducer comprises an activator of calreticulin (CRT) exposure.
  • CRT calreticulin
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide selectively inhibits hydrolysis of 2’3’-cGAMP.
  • the therapeutically effective amount of the inhibitor of a 2’3’- cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) further reduces ATP hydrolysis in the 2’3’-cGAMP degradation polypeptide by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or by less than 1% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 50% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 40% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 30% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’- cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 20% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 10% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 5% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 4% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 3% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 2% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 1% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor.
  • the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide e.g., a ENPP-l inhibitor
  • a cancer described herein is a solid tumor.
  • exemplary solid tumors include breast cancer, lung cancer and glioblastoma (e.g., glioblastoma multiforme).
  • a cancer described herein is a hematologic malignancy.
  • a hematologic malignancy is a leukemia, a lymphoma or a myeloma.
  • a hematologic malignancy is a B-cell malignancy.
  • a cancer described herein is a relapsed or refractory cancer.
  • a cancer described herein is a metastatic cancer.
  • a method of inhibiting depletion of 2’3’-cGAMP in a cell comprises contacting a cell comprising a 2’3’-cGAMP degradation polypeptide with an inhibitor to generate a 2’3’-cGAMP degradation polypeptide -inhibitor complex, thereby inhibiting the 2’3’-cGAMP degradation polypeptide from degrading 2’3’-cGAMP to prevent the depletion of 2’3’-cGAMP in the cell.
  • the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
  • the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
  • a method of selectively inhibits a phosphodiesterase comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain- specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE.
  • a method of selectively inhibiting a phosphodiesterase comprises contacting a cell characterized with an elevated population of cytosolic DNA with a nuclease-like domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE.
  • the reduced inhibition function of ATP hydrolysis is relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor.
  • the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or to less than 1% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor.
  • the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 50% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor.
  • the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 40% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 30% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 20% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 10% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor.
  • the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 5% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 4% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 3% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 2% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor.
  • the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 1% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some cases, the PDE inhibitor does not inhibit ATP hydrolysis of the PDE.
  • the cell has an elevated expression of PDE.
  • the cell has an elevated population of cytosolic DNA.
  • the elevated population of cytosolic DNA is generated by an ICD-mediated event.
  • the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
  • the cell comprises a cancer cell.
  • the cancer cell is a solid tumor cell (e.g., a breast cancer cell, a lung cancer cell or a cancer cell from glioblastoma).
  • the cancer cell is a cell from a hematologic malignancy (e.g., from a lymphoma, a leukemia, a myeloma or a B-cell malignancy).
  • the cell comprises an effector cell.
  • the effector cell comprises a dendritic cell or a macrophage.
  • the cell comprises a non -cancerous cell residing within a tumor microenvironment in which the cell comprises an elevated population of cytosolic DNA. In some cases, the cell comprises a non-cancerous cell residing within a tumor microenvironment in which the cGAS/STING pathway is activated.
  • a subject is administered a recombinant vaccine comprising a vector that encodes a tumor antigen.
  • the subject administered a recombinant vaccine prior to administering the inhibitor of a 2’3’-cGAMP degradation polypeptide.
  • the subject is administered a recombinant vaccine after administering the inhibitor of a 2’3’-cGAMP degradation polypeptide or simultaneously with the inhibitor of a 2’3’-cGAMP degradation polypeptide.
  • a nucleic acid vector described herein comprise a circular plasmid or a linear nucleic acid.
  • the circular plasmid or linear nucleic acid is capable of directing expression of a particular nucleotide sequence in an appropriate subject cell.
  • the vector has a promoter operably linked to the tumor antigen-encoding nucleotide sequence, which is operably linked to termination signals.
  • the vector also contains sequences required for proper translation of the nucleotide sequence.
  • the vector comprising the nucleotide sequence of interest can be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components.
  • the expression of the nucleotide sequence in the expression cassette can be under the control of a constitutive promoter or of an inducible promoter, which can initiate transcription only when the host cell is exposed to some particular external stimulus.
  • the vector is a plasmid.
  • the plasmid is useful for transfecting cells with nucleic acid encoding the tumor antigen, which the transformed host cells can be cultured and maintained under conditions wherein production of the tumor antigen takes place.
  • the plasmid comprises a mammalian origin of replication in order to maintain the plasmid extrachromosomally and produce multiple copies of the plasmid in a cell.
  • the plasmid can be pVAXI, pCEP4 or pREP4 from Invitrogen (San Diego, CA).
  • the plasmid further comprises a regulatory sequence, which enables gene expression in a cell into which the plasmid is administered.
  • the coding sequence further comprises a codon that allows for more efficient transcription of the coding sequence in the host cell.
  • the vector is a circular plasmid, which transforms a target cell by integration into the cellular genome or exist extrachromosomally (e.g., autonomous replicating plasmid with an origin of replication).
  • exemplary vectors include pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing DNA encoding the antigen and enabling a cell to translate the sequence to an antigen that is recognized by the immune system.
  • the recombinant nucleic acid vaccine comprises a viral vector.
  • Exemplary viral based vectors include adenoviral based, lentivirus based, adeno-associated (AAV) based, retroviral based, or poxvirus based vectors.
  • AAV adeno-associated
  • the LEC can be any linear DNA devoid of any phosphate backbone.
  • the DNA can encode one or more microbial antigens.
  • the LEC can contain a promoter, an intron, a stop codon, and/or a polyadenylation signal. In some cases, the LEC does not contain any antibiotic resistance genes and/or a phosphate backbone. In some cases, the LEC does not contain other nucleic acid sequences unrelated to the tumor antigen.
  • further disclosed herein include methods of inhibiting depletion of 2’3’-cGAMP in a cell and selective inhibition of a 2’3’-cGAMP degradation polypeptide (e.g., ENPP- 1).
  • disclosed herein includes a method of inhibiting depletion of 2’3’ -cGAMP in a cell infected by a pathogen, which comprises contacting the cell infected by a pathogen and expressing a 2’ 3’-cGAMP degradation polypeptide with an inhibitor to generate a 2’3’ -cGAMP degradation polypeptide -inhibitor adduct, thereby inhibiting the 2’3’ -cGAMP degradation polypeptide from degrading 2’ 3’-cGAMP to prevent the depletion of 2’3’ -cGAMP in the cell.
  • disclosed herein includes a method of selectively inhibits a
  • PDE phosphodiesterase
  • a method of selectively inhibits a phosphodiesterase which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a virus.
  • PDE phosphodiesterase
  • disclosed herein includes a method of selectively inhibits a
  • PDE phosphodiesterase
  • a method of selectively inhibits a phosphodiesterase which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
  • PDE phosphodiesterase
  • a method of selectively inhibits a phosphodiesterase which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
  • PDE phosphodiesterase
  • a method of selectively inhibits a phosphodiesterase which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a nuclease-like domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
  • PDE phosphodiesterase
  • the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
  • the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
  • a method of selectively inhibits a phosphodiesterase comprises contacting a cell characterized with an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE.
  • the PDE inhibitor binds to the catalytic domain of ENPP-l.
  • the PDE inhibitor binds to the nuclease-like domain of ENPP-l.
  • the infection is a viral infection, e.g., an infection from a DNA virus or a retrovirus.
  • the viral infection is due to herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68), Kaposi’s sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomaviruses (HPV), hepatitis B virus (HBV), human
  • HSV-l herpes simplex virus 1
  • MHV68 murine gamma-herpesvirus 68
  • KSHV Kaposi’s sarcoma-associated herpesvirus
  • VACV vaccinia virus
  • HPV human papillomaviruses
  • HBV hepatitis B virus
  • HIV immunodeficiency virus
  • HCMV human cytomegalovirus
  • the infection is a bacterial infection, e.g., an infection from a Gram negative bacterium or a Gram-positive bacterium.
  • the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
  • the cytosolic DNA comprises viral DNA.
  • the elevated population of cytosolic DNA is due to a viral infection to the host cell.
  • the elevated population of the cytosolic DNA is due to delivery of viral DNA through a virus-like particle (VLP).
  • VLP virus-like particle
  • the elevated population of cytosolic DNA is due to a recombinant DNA vaccine, which comprises a DNA vector encoding a viral antigen.
  • the viral antigen is derived from a DNA virus. In other cases, the viral antigen is derived from a retrovirus.
  • the viral antigen is derived from herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68), Kaposi’s sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomaviruses (HPV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), or human cytomegalovirus (HCMV).
  • HSV-l herpes simplex virus 1
  • MHV68 murine gamma-herpesvirus 68
  • KSHV Kaposi’s sarcoma-associated herpesvirus
  • VACV vaccinia virus
  • HPV human papillomaviruses
  • HBV hepatitis B virus
  • HMV human immunodeficiency virus
  • HCMV human cytomegalovirus
  • the recombinant DNA vaccine comprise a DNA vector that encodes a bacterial antigen, e.g., derived from a Gram-negative bacterium or a Gram-positive bacterium.
  • a bacterial antigen e.g., derived from a Gram-negative bacterium or a Gram-positive bacterium.
  • the bacterial antigen is derived from Listeria monocytogenes, Mycobacterium
  • tuberculosis Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
  • a DNA vector described herein comprise a circular plasmid or a linear nucleic acid.
  • the circular plasmid or linear nucleic acid is capable of directing expression of a particular nucleotide sequence in an appropriate subject cell.
  • the vector has a promoter operably linked to the microbial antigen-encoding nucleotide sequence, which is operably linked to termination signals.
  • the vector also contains sequences required for proper translation of the nucleotide sequence.
  • the vector comprising the nucleotide sequence of interest can be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components.
  • the expression of the nucleotide sequence in the expression cassette can be under the control of a constitutive promoter or of an inducible promoter, which can initiate transcription only when the host cell is exposed to some particular external stimulus.
  • the vector is a plasmid.
  • the plasmid is useful for transfecting cells with nucleic acid encoding the microbial antigen, which the transformed host cells can be cultured and maintained under conditions wherein production of the microbial antigen takes place.
  • the plasmid comprises a mammalian origin of replication in order to maintain the plasmid extrachromosomally and produce multiple copies of the plasmid in a cell.
  • the plasmid can be pVAXI, pCEP4 or pREP4 from Invitrogen (San Diego, CA).
  • the plasmid further comprises a regulatory sequence, which enables gene expression in a cell into which the plasmid is administered.
  • the coding sequence further comprises a codon that allows for more efficient transcription of the coding sequence in the host cell.
  • the vector is a circular plasmid, which transforms a target cell by integration into the cellular genome or exist extrachromosomally (e.g., autonomous replicating plasmid with an origin of replication).
  • exemplary vectors include pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing DNA encoding the antigen and enabling a cell to translate the sequence to an antigen that is recognized by the immune system.
  • the recombinant nucleic acid vaccine comprises a viral vector.
  • Exemplary viral based vectors include adenoviral based, lentivirus based, adeno-associated (AAV) based, retroviral based, or poxvirus based vectors.
  • AAV adeno-associated
  • the LEC can be any linear DNA devoid of any phosphate backbone.
  • the DNA can encode one or more microbial antigens.
  • the LEC can contain a promoter, an intron, a stop codon, and/or a polyadenylation signal. In some cases, the LEC does not contain any antibiotic resistance genes and/or a phosphate backbone. In some cases, the LEC does not contain other nucleic acid sequences unrelated to the microbial antigen.
  • a method of stabilizing a stimulator of interferon genes (STING) protein dimer in a cell comprises (a) contacting a cell characterized with an elevated expression of a phosphodiesterase (PDE) or an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3’-cGAMP; and (b) interacting 2’3’-cGAMP to a STING protein dimer to generate a 2’3’-cGAMP-STING complex, thereby stabilizing the STING protein dimer.
  • PDE phosphodiesterase
  • interacting of 2’3’-cGAMP to a STING protein dimer to generate a 2’3’-cGAMP-STING complex further activates the STING protein dimer.
  • activation of the STING protein dimer further leads to upregulating the production of type I interferon (IFN).
  • IFN type I interferon
  • the production of IFNs is localized in a tumor microenvironment.
  • the cell has an elevated population of cytosolic DNA.
  • the elevated population of cytosolic DNA is generated by an ICD-mediated event.
  • the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
  • the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
  • the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
  • the cell comprises a cancer cell.
  • the cancer cell is a solid tumor cell (e.g., a breast cancer cell, a lung cancer cell or a cancer cell from glioblastoma).
  • the cancer cell is a cell from a hematologic malignancy (e.g., from a lymphoma, a leukemia, a myeloma or a B-cell malignancy).
  • the cell comprises an effector cell.
  • the effector cell comprises a dendritic cell or a macrophage.
  • the cell comprises a non -cancerous cell residing within a tumor microenvironment in which the cell comprises an elevated population of cytosolic DNA. In some cases, the cell comprises a non-cancerous cell residing within a tumor microenvironment in which the cGAS/STING pathway is activated.
  • the ENPP-l inhibitor described herein is administered for therapeutic applications.
  • the ENPP-l inhibitor is administered once per day, twice per day, three times per day or more.
  • the ENPP-l inhibitor is administered daily, every day, every alternate day, five days a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month, three times per month, or more.
  • the ENPP-l inhibitor is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more.
  • the administration of the ENPP-l inhibitor is given continuously; alternatively, the dose of the ENPP-l inhibitor being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
  • the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday is from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the amount of the ENPP-l inhibitor varies depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless is routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated.
  • the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the ENPP-l inhibitor is administered to a subject at least 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36 or 48 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 0.5 hour after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1 hour after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1.5 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 hours after administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 3 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 hours after administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 9 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 18 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 24 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 36 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 48 hours after administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to a subject at least 1, 2, 3, 4,
  • the ENPP-l inhibitor is administered to the subject at least 1 day after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 days after administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 7 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 days after administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 13 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 14 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 28 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 30 days after administration of the ICD inducer. [0374] In some embodiments, the ENPP-l inhibitor is administered to a subject at least 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36 or 48 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 0.5 hour prior to
  • the ENPP-l inhibitor is administered to the subject at least 1 hour prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1.5 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 hours prior to administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 6 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 hours prior to
  • the ENPP-l inhibitor is administered to the subject at least 11 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 18 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 24 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 36 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 48 hours prior to administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to a subject at least 1, 2, 3, 4,
  • the ENPP-l inhibitor is administered to the subject at least 1 day prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 days prior to administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 6 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 days prior to administration of the ICD inducer.
  • the ENPP-l inhibitor is administered to the subject at least 12 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 13 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 14 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 28 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 30 days prior to administration of the ICD inducer.
  • the ENPP-l inhibitor is administered simultaneously with an ICD inducer.
  • the ENPP-l inhibitor is administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 1 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 2 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 3 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 4 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 5 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 6 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 7 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 8 or more days.
  • the ENPP-l inhibitor is administered continuously for 9 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 10 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 14 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 15 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 28 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 30 or more days.
  • the ENPP-l inhibitor is administered at predetermined time intervals for 1,
  • the ENPP-l inhibitor is administered at predetermined time intervals for 1 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 2 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 3 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 4 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 5 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 6 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 7 or more days.
  • the ENPP-l inhibitor is administered at predetermined time intervals for 8 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 9 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 10 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 14 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 15 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 28 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 30 or more days.
  • the ENPP-l inhibitor is administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 1 or more month. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 2 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 3 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 4 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 5 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 6 or more months.
  • the ENPP-l inhibitor is administered at predetermined time intervals for 7 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 8 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 9 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 10 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 11 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 12 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 24 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 36 or more months.
  • the ENPP-l inhibitor is administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. In some instances, the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered
  • the ENPP-l inhibitor is administered intennitently for 14 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 15 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 28 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 30 or more days.
  • the ENPP-l inhibitor is administered for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or more. In some embodiments, the ENPP-l inhibitor is administered for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles or more. In some cases, the ENPP-l inhibitor is administered for at least 1 cycle. In some cases, the ENPP-l inhibitor is administered for at least 2 cycles. In some cases, the ENPP-l inhibitor is administered for at least 3 cycles. In some cases, the ENPP-l inhibitor is administered for at least 4 cycles. In some cases, the ENPP-l inhibitor is administered for at least 5 cycles. In some cases, the ENPP-l inhibitor is administered for at least 6 cycles.
  • the ENPP-l inhibitor is administered for at least 7 cycles. In some cases, the ENPP-l inhibitor is administered for at least 8 cycles. In some instances, a cycle comprises 14 to 28 days. In some cases, a cycle comprises 14 days. In some cases, a cycle comprises 21 days. In some cases, a cycle comprises 28 days.
  • the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or more. In some embodiments, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles or more. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 2 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 3 cycles.
  • the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 4 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 5 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 6 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 7 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 8 cycles. In some instances, a cycle comprises 14 to 28 days. In some cases, a cycle comprises 14 days. In some cases, a cycle comprises 21 days. In some cases, a cycle comprises 28 days.
  • the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1, 5, 10, 14, 15, 20, 21, 28, 30, 60, or 90 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 day. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 5 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 10 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 14 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 15 days.
  • the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 20 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 21 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 28 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 30 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 60 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 90 days.
  • the ENPP-l inhibitor is administered to a subject at a therapeutically effective amount.
  • the therapeutically effective amount is optionally administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 1 dose.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 2 or more doses.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 3 or more doses.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 4 or more doses.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 5 or more doses.
  • the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 6 or more doses.
  • the therapeutically effective amount of the ENPP-l inhibitor selectively inhibits hydrolysis of 2’3’-cGAMP.
  • the therapeutically effective amount of the ENPP-l inhibitor further reduces ATP hydrolysis in ENPP-l by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or by less than 1% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 50% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor.
  • the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 40% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 30% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 20% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor.
  • the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 10% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 5% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 4% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor.
  • the therapeutically effective amount of the ENPP- 1 inhibitor reduces ATP hydrolysis in ENPP-l by less than 3% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 2% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 1% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor does not induce ATP hydrolysis in ENPP-l.
  • one or more methods described herein further comprising administering an additional therapeutic agent.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • the additional therapeutic agent is an immune checkpoint inhibitor.
  • Exemplary immune checkpoint inhibitor comprises an inhibitor of PD1, an inhibitor of PD- Ll, an inhibitor of TIM or an inhibitor of TIGIT.
  • the subject has a resistance to an immune checkpoint inhibitor prior to the administration of the inhibitor of PDE.
  • the ENPP-l inhibitor and the additional therapeutic agent is administered simultaneously.
  • the ENPP-l inhibitor and the additional therapeutic agent is administered sequentially.
  • the ENPP-l inhibitor is administered before administering the additional therapeutic agent.
  • the ENPP-l inhibitor is administered after administering the additional therapeutic agent.
  • kits and articles of manufacture for use with one or more methods described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the container(s) include the ENPP-l inhibitor, optionally with one or more additional therapeutic agents disclosed herein.
  • kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Step 3 tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4-l)amino)methyl)phenyl)carbamate
  • Step 4 1 -(4-aminobenzyl)-7,8-dimethoxy-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one hydrochloride
  • Step 5 N-(4-((7,8-dimethoxy-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)sulf amide
  • Step 1 tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl) carbamate
  • Step 3 N-(4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)sulfamide
  • Step 1 tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)benzyl)carbamate
  • Step 4 (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)methanamine hydrochloride
  • Step 1 tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)phenyl)carbamate
  • Step 2 tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)phenyl)carbamate
  • Step 4 4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)aniline 2,2,2-trifluoroacetate
  • Step 1 methyl (trans)-4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino) cyclohexane-l-carboxylate
  • Step 2 methyl (trans)-4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)cyclohexane-l- carboxylate
  • Step 3 methyl (trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l- carboxylate
  • Step 4 ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methanol
  • Step 5 ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methyl methanesulfonate
  • Step 6 ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methanamine
  • Step 7 ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)sulfamide
  • reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 c 50 mL). Organic layer was dried over sodium sulphate, filtered and distilled under vacuum. The crude residue was purified by gradient column chromatography using methanol in dichloromethane to afford N-(4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)benzyl)cyclopropanesulfonamide as an off white solid (0.042 g , 24 %).
  • Potassium hydroxide (1.09 g, 19.49 mmol) was taken in 4 mL of dry MeOH at room temperature. This mixture was heated at 50 °C for 10 minutes until it became clear solution and later cooled to room temperature. Hydroxylamine hydrochloride (1.35 g, 19.49 mmol) was taken in 8 mL of dry MeOH at room temperature. This mixture was heated at 50 °C for 10 minutes until it became clear solution and later cooled to room temperature. This solution was added slowly to the already prepared Potassium hydroxide solution at 0 °C.
  • reaction mixture was stirred at room temperature for 10 minutes and added through a sodium sulphate bed to a stirring solution of to methyl (trans)-4- (7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l-carboxylate (0.4 g, 1.08 mmol) in dry MeOH (4 mL).
  • the resulting reaction mixture was stirred for 2 h at room temperature.
  • the progress of the reaction was monitored by TLC using 10% MeOH in DCM as eluent. Excess methanol was evaporated under reduced pressure using rotavapor to get crude which was adjusted to pH- 6 using saturated citric acid solution.
  • Step 1 fc/7-butyl (6,7-dimethoxyquinolin-4-yl)carbamate
  • the reaction mixture was cooled to room temparature and directly evaporated under reduced pressure to get the crude compound.
  • the crude residue was dissolved in water and nuetralised with saturated sodium bicarbonate solution , then Extracted with ethylacetate (2 x 10 mL), The combined organic layer were washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound.
  • Step 6 tert- butyl (4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)carbamate:

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Abstract

Disclosed herein are methods and compounds of augmenting and enhancing the production of type I IFNs in vivo. In some embodiments, the compounds disclosed herein are ENPP-1 inhibitors, pharmaceutical compositions, and methods for the treatment of cancer or a viral infection.

Description

ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE 1 (ENPP-1)
INHIBITORS AND USES THEREOF
CROSS-REFERENCE
[0001] This patent application claims the benefit of U.S. Provisional Application No. 62/641,937, filed March 12, 2018 which is incorporated herein by reference in their entirety.
BACKGROUND OF THE DISCUOSURE
[0002] Cancer immunotherapy comprises the use of the patient’s immune system to combat tumor cells. In some instances, cancer immunotherapy utilizes the presence of tumor antigens (e.g., tumor- specific antigens) to facilitate the recognition of the tumor cells by the immune system. In other instances, cancer immunotherapy utilizes immune system components such as lymphocytes and cytokines to coordinate a general immune response.
[0003] Microorganisms that are capable of causing disease are termed pathogens. Pathogenic microorganisms include bacteria, viruses, fungi, protozoa, and helminths. In some instances, antimicrobials such as broad spectrum fluoroquinolones and oxazolidinones fight infection by inhibiting microbial reproduction within a host. In other instances, antimicrobials enhance or strengthen a host’s immune response to the pathogenic infection.
SUMMARY OF THE DISCUOSURE
[0004] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000002_0001
L1 is -(CR18R19)-;
Ring B1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R11, R14, and R15 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -OC(=0)Rb, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re;
R12 and R13 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re; provided that one of R12 or R13 is not hydrogen;
each
Figure imgf000003_0001
Ci-Ce alkyl(S(=0)2NRcRd), C,-C(, alkyl(NRaC(=0)NRcRd), C ,-C(, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R18 and R19 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
pl is 1-4. [0005] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000004_0001
Formula (II);
wherein
L2 is a bond or -(CR28R29)-;
Ring A2 is imidazolyl, pyrrolyl, oxazolyl, or thiazolyl;
Ring B2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R21, R24, and R25 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
each R26 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C ,-C(, alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
or two R26 on the same carbon are taken together to form an oxo;
each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Rg;
R28 and R29 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R28 and R29 are taken together to form an oxo; each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
n2 is 1-4; and
p2 is 1-4.
[0006] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
[0007] Also disclosed herein is a method of treating cancer in a subject in need thereof comprising administering a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein. In some embodiments of a method of treating cancer, the cancer is a solid tumor. In some embodiments of a method of treating cancer, the solid tumor is breast cancer, lung cancer, or glioblastoma. In some embodiments of a method of treating cancer, the cancer is a hematologic malignancy. In some embodiments of a method of treating cancer, the hematologic malignancy is a leukemia, a lymphoma, or a myeloma. In some embodiments of a method of treating cancer, the hematologic malignancy is a B-cell malignancy. In some embodiments of a method of treating cancer, the hematologic malignancy is multiple myeloma. In some embodiments of a method of treating cancer, the cancer is a relapsed or refractory cancer. In some embodiments of a method of treating cancer, the cancer is a metastatic cancer.
[0008] Also disclosed herein is a method of treating an infection in a subject in need thereof comprising administering a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein. In some embodiments of a method of treating an infection, the infection is a viral infection. In some embodiments of a method of treating an infection, the viral infection is due to a DNA virus. In some embodiments of a method of treating an infection, the viral infection is a due to a herpesvirus. In some embodiments of a method of treating an infection, the herpesvirus is selected from herpes simplex viruses 1 (HSV-l), herpes simplex viruses 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6A (HHV-6A), human herpesvirus 6B (HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma- associated herpesvirus (KSHV). In some embodiments of a method of treating an infection, the herpesvirus is herpes simplex viruses 1 (HSV-l). In some embodiments of a method of treating an infection, the viral infection is a due to a retrovirus. In some embodiments of a method of treating an infection, the retrovirus is human immunodeficiency virus (HIV). In some embodiments of a method of treating an infection, the viral infection is a due to a hepatitis virus. In some embodiments of a method of treating an infection, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV). In some embodiments of a method of treating an infection, the viral infection is due to vaccinia virus (VACV), adenovirus, or human papillomaviruses (HPV). In some embodiments of a method of treating an infection, the viral infection is due to a RNA virus. In some embodiments of a method of treating an infection, the viral infection is due to dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0009] In some embodiments, the immunophenotype of a tumor microenvironment modulates the responsiveness of the tumor to a cancer therapy. In some instances, tumor-infiltrating lymphocytes are correlated with favorable prognosis in different types of tumors and are correlated with positive clinical outcome in response to several lines of immunotherapy.
[0010] In some cases, innate immune sensing in the tumor microenvironment promotes T-cell priming and subsequent infiltration of tumor-infiltrating lymphocytes. For example, transcriptional profiling analyses of melanoma patients have shown that tumors containing infiltrating activated T cells are characterized by a type I IFN transcriptional signature. Furthermore, mice lacking the IFN- a/b receptor in dendritic cells are unable to reject immunogenic tumors and the CD8a+ dendritic cells from these mice are defective in antigen cross-presentation to CD8+ T cells.
[0011] In some embodiments, systemic delivery of type I IFNs has shown efficacy in cancer settings. Indeed, systemic injection of IFN-b in a mouse xenograft model of human colorectal cancer liver metastases has shown tumor regression and improved survival.
[0012] In some instances, systemic delivery of type I IFNs requires high doses to achieve therapeutic benefit. In such cases, desensitization of the immune system and issues with tolerability have also been observed.
[0013] The innate immune system is the first line of defense to a microbial infection. The host innate immunity is activated through recognition of conserved microbial signatures termed pathogen- associated molecular patterns (PAMPs) and host damage-associated molecular patterns (DAMPs). Upon sensing of microbial PAMPs and DAMPs, signal cascades are activated to produce type I interferons and/or multiple cytokines and chemokines, culminating in the synthesis of antiviral proteins. The presence of antiviral proteins and cytokines (e.g., interferons or chemokines) subsequently promote apoptosis, inhibits cellular protein translation, and recruit immue cells to the site of infection to further initiate adaptive immune response.
[0014] Pattern recognition receptors (PRRs) are germ-line encoded receptors that recognize PAMPs and DAMPs and faciliate the rapid and efficient innate immune response. Cytosolic DNA sensor is a type of PRRthat detects the intracellular presence of pathogenic DNA. DNA-dependent activator of IFN -regulatory factors (DAI), a cytosolic DNA sensor, utilizes the cGAS-STING pathway for production of type I interferons.
[0015] In some embodiments, disclosed herein are methods of enhancing and/or augmenting the production of type I IFNs in vivo, without the need of systemic delivery of type I IFNs. In such instances, the IFN production is localized in the tumor microenvironment. In some cases, the methods comprise activating and enhancing the cGAS-STING response. In some cases, the methods comprise priming a cancer with an immunogenic cell death inducer prior to stimulating the cGAS-STING pathway. In other cases, the methods comprise blocking the degradation of a STING activating substrate prior to priming a cancer with an immunogenic cell death inducer. In additional cases, the methods comprise use of an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., an inhibitor of a phosphodiesterase) with an immunogenic cell death inducer for the treatment of a cancer.
[0016] In additional embodiments, disclosed herein include methods of designing inhibitors of 2’3’-cGAMP degradation polypeptides and assays for evaluating the enzyme activity of the GMP degradation polypeptides.
cGAS-STING Pathway, immunogenic cell death, and the production of type I IFNs
[0017] Cytosolic DNA can signal the presence of cellular damage and/or the presence of cancerous cells and/or an infection within a cell or at a nearby cell. These cytosolic DNAs (e.g., double stranded DNAs) are surveyed by DNA sensors such as RNA pol III, DAI, IFI16, DDX41, LSml4A, cyclic- GMP-AMP synthase, LRRFIP1, Sox2, DHX9/36, Ku70 and AIM2. Cyclic-GMP-AMP synthase (cGAS or cGAMP synthase) is a 522 amino acid protein that belongs to the nucleotidyltransferase family of cytosolic DNA sensors. Upon cytosolic DNA stimulation, cGAS synthesizes cGAMP, which comprises a first bond between the 2’-OH of GMP and the 5’-phosphate of AMP and a second bond between the 3’-OH of AMP and the 5’-phosphate of GMP. cGAMP (also known as cyclic GMP- AMP, 2’3’-cGAMP, cGAMP (2’-5’) or cyclic Gp(2’-5’)Ap(3’-5’)) serves as a ligand to STING, thereby activating the STING-mediated IFN (e.g., PTΊb) production.
[0018] STING (also known as stimulator of interferon genes, TMEM173, MITA, ERIS, or MPYS) is a 378 amino acid protein that comprises aN-terminal region containing four trans -membrane domains and a C-terminal domain that comprises a dimerization domain. Upon binding to 2’3’- cGAMP, STING undergoes a conformational rearrangement enclosing the 2’ 3’-cGAMP molecule. [0019] Binding of 2’3’-cGAMP activates a cascade of events whereby STING recruits and activates IKB kinase (IKK) and TANK-binding kinase (TBK1), which following their
phosphorylation, respectively activate nuclear transcription factor KB (NF-KB) and interferon regulatory factor 3 (IRF3). In some instances, the activated proteins translocate to the nucleus to induce transcription of the genes encoding type I IFN and cytokines for promoting intercellular host immune defense. In some cases, the production of type I IFNs further drives the development of cytolytic T cell response and enhances expression of MHC, thereby increasing antigen processing and presentation within a tumor microenvironment. In such cases, enhanced type I IFN production further renders the tumor cells to be more vulnerable by enhancing their recognition by the immune system.
[0020] In some instances, STING is capable of directly sensing bacterial cyclic dinucleotides (CDNs) such as c[di-GMP] In some cases, 2’3’-cGAMP acts as a second messenger binding to STING in response to cells exposed to cytosolic DNA.
[0021] In some embodiments, cytosolic DNA is generated through“self-DNA” or endogenous DNA from the host through the DNA structure-specific endonuclease methyl methane -sulphonate (MMS) and ultraviolet-sensitive 81 (MUS81). The DNA structure-specific endonuclease MUS81 is a member of the XPF family of endonucleases that forms a heterodimeric complex with essential meiotic endonuclease 1 (EME1). In some instances, the MUS81-EME1 complex cleaves DNA structures at stalled replication forks. In some cases, MUS81 cleavage of self-DNA leads to accumulation of cytosolic DNA and activation of the STING pathway.
[0022] In other instances, cytosolic DNA is generated through immunogenic cell death (ICD)- mediated events, activation of the STING-pathway, production of type I INFs, and further priming of the tumor cell microenvironment.
Immunogenic Cell Death
[0023] In some embodiments, immunogenic cell death (ICD), or immunogenic cancer cell death, is a cell death modality which further stimulates an immune response against tumor expressed antigens. In some cases, tumor expressed antigens are tumor neoantigens or antigens that are formed by mutated proteins and unique to the tumor. In other cases, tumor expressed antigens comprise overexpressed proteins such as MUC1, CA-125, MART-l or carcinoembyonic antigen (CEA). In some instances, ICD is characterized by a series of biochemical events that comprises: 1) the cell surface translocation of calreticulin (CALR or CRT), an endoplasmic reticulum (ER) resident chaperone protein and a potent DC "eat me" signal; 2) the extracellular release of high mobility group box 1 (HMGB1), a DNA binding protein and toll-like receptor 4 (TLR-4) mediated DC activator; and 3) the liberation of adenosine-5 '-triphosphate (ATP), a cell-cell signaling factor in the extracellular matrix (ECM) that serves to activate P2X7 purinergic receptors on DCs, triggering DC inflammasome activation, secretion of IL-Ib, and subsequent priming of interferon-g (IFNy) producing CD8+ T cells. In some embodiments, the cumulative effects of the 3 arms of ICD and in particular CRT exposure (or the surface translocation of CRT) act to promote DC phagocytosis of tumor cells, thereby facilitating DC processing of tumor-expressed antigens and subsequent DC-associated cross-priming of CD8+ cytotoxic T lymphocytes.
[0024] Calreticulin, also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60), is a protein that in humans is encoded by the CALR gene. Calreticulin is a multifunctional protein that binds Ca2+ ions (a second messenger in signal transduction), rendering it inactive. In some instances, calreticulin is located in the lumen of the endoplasmic reticulum, where it interacts with misfolded proteins, inhibits their export from the endoplasmic reticulum into the Golgi apparatus and subsequently tags these misfolded proteins for degradation. In some cases, calreticulin further serves as a signaling ligand to recruit DCs to initiate phagocytosis.
[0025] In some embodiments, ICD is further sub-categorized into different types of ICD based on the ICD inducer. In some instances, an ICD inducer initiates the process of immunogenic cell death.
In some cases, an ICD inducer comprises radiation. Exemplary types of radiation include UV radiation and g radiation. In some cases, an ICD inducer comprises UV radiation. In some cases, an ICD inducer comprises g radiation.
[0026] In other cases, an ICD inducer comprises a small molecule. In some cases, the small molecule comprises a chemotherapeutic agent. Exemplary chemotherapeutic agents include, but are not limited to, an anthracycline such as doxorubicin or mitoxantrone; a cyclophosphamide such as mafosfamide; bortezomib, daunorubicin, docetaxel, oxaliplatin or paclitaxel. In some instances, an ICD inducer comprises doxorubicin, mitoxantrone, mafosfamide, bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or any combinations thereof. In some instances, an ICD inducer comprises digitoxin or digoxin. In some instances, an ICD inducer comprises digitoxin. In some instances, an ICD inducer comprises digoxin. In some instances, an ICD inducer comprises septacidin. In some cases, an ICD inducer comprises a combination of cisplatin and thapsigargin. In some cases, an ICD inducer comprises a combination of cisplatin and tunicamycin.
[0027] In some embodiments, the ICD inducer is a PARP inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, or E7016.
[0028] In additional cases, an ICD inducer comprises a biologic. In such cases, a biologic comprises a protein or functional fragments thereof, a polypeptide, an oligosaccharide, a lipid, a nucleic acid (e.g., DNA or RNA) or a protein-payload conjugate. In some cases, a protein or functional fragments thereof comprises an enzyme, a glycoprotein, or a protein capable of inducing ICD. In some cases, a protein or functional fragments thereof comprises a humanized antibody or binding fragment thereof, a chimeric antibody or binding fragment thereof, a veneer antibody or binding fragment thereof, a monoclonal antibody or binding fragment thereof, a bispecific antibody or binding fragment thereof, an Fab, an Fab’, an F(ab’)2, an F(ab’)3, an scFv, an sc(Fv)2, a dsFv, a diabody, a minibody, or a nanobody or binding fragments thereof. In some cases, a protein-payload conjugate comprises a protein or functional fragments thereof conjugated to a payload (e.g., a small molecule payload). In some cases, an exemplary protein-payload conjugate is trastuzumab emtansine.
[0029] In some embodiments, CRT exposure leads to phagocytosis by dendritic cells, leading to generating a population of cytosolic DNA. In some cases, cytosolic DNA sensor such as cyclic GMP- AMP synthase detects the presence of the cytosolic DNA and subsequently triggers inflammatory responses (e.g., generation of type I IFNs) via the STING-mediated pathway.
Pathogens
[0030] As described above, the presence of intracellular nucleic acid from a pathogen activates cGAS, leading to production of 2’3’-cGAMP, and subsequent activation of the STING pathway. In some instances, the pathogen is a virus, e.g., a DNA virus or an RNA virus. In some cases, the pathogen is a retrovirus. Exemplary viruses capable of subsequent activation of STING include, but are not limited to, herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68),
Kaposi’s sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomaviruses (HPV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), or human cytomegalovirus (HCMV). In other instances, the pathogen is a bacterium. Exemplary bacteria include, but are not limited to, Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
[0031] In some embodiments, the pathogen is a DNA virus. In some instances, the DNA virus is a single-stranded DNA virus. In other instances, the DNA virus is a double -stranded DNA virus. In some cases, the virus utilizes a DNA-dependent DNA polymerase for replication.
[0032] In some embodiments, the pathogen is an RNA virus. In some instances, the RNA virus is a single-stranded RNA virus (e.g., single-stranded-positive sense or single -stranded-negative sense). In other instances, the RNA virus is a double -stranded RNA virus. Exemplary RNA viruses include vesicular stomatitis virus (VSV), sendai virus, hepatitis C virus, dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus. In some embodiments, the RNA virus is dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
[0033] In some embodiments, the pathogen is a retrovirus. Retroviruses are single -stranded RNA viruses with a DNA intermediate. In most viruses, DNA is transcribed into RNA, and then RNA is translated into protein. However, retroviruses function differently, as their RNA is reverse -transcribed into DNA. Upon infection of a cell by a retrovirus, the retroviral RNA genome is transcribed into its corresponding double-stranded DNA by a reverse transcriptase enzyme which is coded for by the viral genome, which is the reverse of the usual pattern, thus retro (backwards). This DNA then enters the nucleus and integrates into the host DNA using an integrase enzyme which is also coded for by the viral genome. The integrated viral DNA ("proviral" DNA) becomes a component of the host genome, replicating with it and producing the proteins required in assembling new copies of the virus. It is difficult to detect the virus until it has infected the host. The information contained in a retroviral gene is thus used to generate the corresponding protein via the sequence: RNA DNA RNA polypeptide.
[0034] The genome of a retrovirus (in either the RNA or DNA form) is divided conceptually into two parts. The first, or "trans-acting," category consists of the regions coding for viral proteins. These include the group specific antigen ("gag") gene for synthesis of the core coat proteins, the "pol" gene for the synthesis of various enzymes (such as reverse transcriptase), and the envelope ("env") gene for the synthesis of envelope glycoproteins. The full-length RNA transcript is packaged by the viral proteins into a viral particle which then buds off in a piece of cell membrane, in which are embedded env-derived peptides. This membrane-coated viral particle is a fully competent viral particle and go on to infect other cells.
[0035] In general, the second part of the retroviral genome is referred to as the "cis-acting" portion and consists of the regions which must be on the genome to allow its packaging and replication. This includes the packaging signal on an RNA molecule, such as the viral RNA, which identifies that RNA molecule to viral proteins as one to be encapsidated, Long Terminal Repeats ("LTRs") with promoters and polyadenylation sites, and two start sites for DNA replication. The promoters, enhancers, and other regions of the LTRs are also capable of conferring tissue specificity such that the virus will only be "expressed" (i.e., transcribed and translated) in specific cell types even though it infects others. Exemplary Viruses
Herpes simplex virus 1 (HSV-1)
[0036] HSV-l is a highly contagious infection, which is common and endemic throughout the world. Most HSV-l infections are acquired during childhood. The vast majority of HSV-l infections are oral herpes (infections in or around the mouth, sometimes called orolabial, oral-labial or oral- facial herpes), but a proportion of HSV-l infections are genital herpes (infections in the genital or anal area). HSV-l is mainly transmitted by oral-to-oral contact to cause oral herpes infection, via contact with the HSV-l virus in sores, saliva, and surfaces in or around the mouth. However, HSV-l is also transmitted to the genital area through oral -genital contact to cause genital herpes.
Murine gamma-herpesvirus 68 (MHV68)
[0037] MHV-68 is a rodent pathogen and a member of the gammaherpesvirus subfamily. MHV-68 has the ability to establish latent infections within lymphocytes and make close associations with cell tumors. MHV-68 establishes latency unless the host immune system is compromised, and this latency is regulated by multiple cellular controls, such as virus-specific open reading frames that result in gene products promoting the maintenance of latency or activation of lytic cycles. One of the major consequences of MHV-68 in mice is infectious mononucleosis. MHV-68 infection sites consist of primarily lung epithelial cells, adrenal glands, and heart tissue, with latent infection in B lymphocytes. Kaposi’s sarcoma-associated herpesvirus (KSHV)
[0038] KSHV or human herpesvirus 8 (HHV8) is a human rhadinovirus (gamma-2 herpesvirus) belonging to the family of herpesviruses. KSHV is a large double -stranded DNA virus with a protein covering that packages its nucleic acids, called the capsid, which is then surrounded by an amorphous protein layer called the tegument, and finally enclosed in a lipid envelope derived in part from the cell membrane. This virus is transmitted both sexually and through body fluids, for example, saliva and blood). KSHV causes a blood vessel cancer called Kaposi's sarcoma (KS), a lymphoma (a cancer of the lymphocyte) called body cavity -based lymphoma and some forms of severe lymph node enlargement, called Castleman's disease.
Vaccinia virus (VACV)
[0039] Vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. The poxviruses are the largest known DNA viruses and are distinguished from other viruses by their ability to replicate entirely in the cytoplasm of infected cells. Poxviruses do not require nuclear factors for replication and, thus, replicate with little hindrance in enucleated cells. VACV has a linear, double-stranded DNA genome of approximately 190 kb in length, which encodes for around 250 genes. The genome is surrounded by a lipoprotein core membrane. Vaccinia virus is well-known for its role as a vaccine that eradicated the smallpox disease. The natural host of Vaccinia virus is unknown, but the virus replicates in cows and humans. During its replication cycle, Vaccinia virus produces four infectious forms which differ in their outer membranes: intracellular mature virion (IMV), the intracellular enveloped virion (IEV), the cell-associated enveloped virion (CEV) and the extracellular enveloped virion (EEV).
Adenovirus
[0040] Adenoviruses are double -stranded DNA viruses and are now known to be a common cause of asymptomatic respiratory tract infection. An extremely hardy virus, adenovirus is ubiquitous in human and animal populations, survives long periods outside a host, and is endemic throughout the year. Possessing 52 serotypes, adenovirus is recognized as the etiologic agent of various diverse syndromes. It is transmitted via direct inoculation to the conjunctiva, a fecal -oral route, aerosolized droplets, or exposure to infected tissue or blood. The virus is capable of infecting multiple organ systems; however, most infections are asymptomatic.
Human papillomaviruses (HPV)
[0041] Human papillomaviruses (HPV), DNA virus from the papillomavirus family, are common viruses that cause warts. There are more than 100 types of HPV. Most are harmless, but about 30 types put you at risk for cancer. These types affect the genitals and you get them through sexual contact with an infected partner. They are either low-risk or high-risk. Low -risk HPV causes genital warts. High-risk HPV leads to cancers of the cervix, vulva, vagina, and anus in women and cancers of the anus and penis in men.
Hepatitis B virus (HBV)
[0042] HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and integrates into the host genome. Hepatitis B is one of a few known non -retroviral viruses which use reverse transcription as a part of its replication process. The features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection is either asymptomatic or presents with symptomatic acute hepatitis. About 5%— 10% of population infected is unable to clear the virus and becomes chronically infected. Many chronically infected persons have mild liver disease. Other individuals with chronic HBV infection develop active disease, which progresses to cirrhosis and liver cancer.
Hepatitis D virus (HDV)
[0043] hepatitis D virus (HDV) is a small spherical enveloped viroid. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV).
Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.
Human immunodeficiency virus (HIV)
[0044] The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of retrovirus) that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS). AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including but not limited to, pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell -mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. Human cytomegalovirus (HCMV)
[0045] Human cytomegalovirus (HCMV) is a beta-herpesvirus that causes lifelong infection in humans. HCMV has a prevalence of 55-100% within the human population. Primary HCMV infection is generally asymptomatic in healthy hosts but causes severe and sometimes fatal disease in immunocompromised individuals, organ transplant recipients, and neonates. HCMV is the leading infectious cause of congenital abnormalities in the Western world, affecting 1-2.5% of all live births. After infection, HCMV remains latent within the body throughout life and is reactivated at any time. Eventually, it causes mucoepidermoid carcinoma and other malignancies such as prostate cancer. Although they are found throughout the body, HCMV infections are frequently associated with the salivary glands. The mode of HCMV transmission from person to person is entirely unknown but is presumed to occur through bodily fluids. Infection requires close, intimate contact with a person secreting the virus in their saliva, urine, or other bodily fluids. HCMV is transmitted sexually and via breast milk, and also occurs through receiving transplanted organs or blood transfusions.
Dengue fever virus
[0046] Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. It is transmitted by arthropods (mosquitoes or ticks), and is therefore also referred to as an arbovirus (arthropod-borne virus). Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus but it also circulates in nonhuman primates. A female mosquito that takes a blood meal from a person infected with dengue fever, during the initial 2- to lO-day febrile period, becomes itself infected with the virus in the cells lining its gut. About 8- 10 days later, the virus spreads to other tissues including the mosquito's salivary glands and is subsequently released into its saliva. The virus seems to have no detrimental effect on the mosquito, which remains infected for life.
Ebola virus
[0047] Ebola virus (EBOV) is one of five known viruses within the genus Ebolavirus. Four of the five known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD). The EBOV genome is a single - stranded RNA approximately 19,000 nucleotides long. It encodes seven structural proteins:
nucleoprotein (NP), polymerase cofactor (VP35), (VP40), GP, transcription activator (VP30), VP24, and RNA-dependent RNA polymerase (L).
Marburg virus
[0048] Marburg virus is a hemorrhagic fever virus of the Filoviridae family of viruses and a member of the species Marburg marburgvirus, genus Marburgvirus. Marburg virus (MARV) causes Marburg virus disease in humans and nonhuman primates, a form of viral hemorrhagic fever. The virus is considered to be extremely dangerous. Zika virus
[0049] Zika virus (ZIKV) is a member of the virus family Flaviviridae. It is spread by daytime - active Aedes mosquitoes, such as A. aegypti and A. albopictus. Zika virus is related to the dengue, yellow fever, Japanese encephalitis, and West Nile viruses. Since the 195 Os, it has been known to occur within a narrow equatorial belt from Africa to Asia. The infection, known as Zika fever or Zika virus disease, often causes no or only mild symptoms, similar to a very mild form of dengue fever. While there is no specific treatment, paracetamol (acetaminophen) and rest may help with the symptoms. Zika can spread from a pregnant woman to her baby. This can result in microcephaly, severe brain malformations, and other birth defects. Zika infections in adults may result rarely in Guillain-Barre syndrome.
Bacteria
[0050] In some embodiments, a pathogen described herein is a bacterium. Bacteria are microscopic single-celled microorganisms that exist either as independent (free-living) organisms or as parasites (dependent on another organism for life) and thrive in diverse environments. As prokaryotes, the organism consists of a single cell with a simple internal structure. Bacterial DNA floats free, in a twisted thread-like mass called the nucleoid. Bacterial cells also contain separate, circular pieces of DNA called plasmids. Bacteria lack membrane -bound organelles, specialized cellular structures that are designed to execute a range of cellular functions from energy production to the transport of proteins. However, both bacterial cells contain ribosomes. A few different criteria are used to classify bacteria. They are distinguished by the nature of their cell walls, by their shape, or by differences in their genetic makeup.
Exemplary Bacteria
Listeria monocytogenes
[0051] Listeria monocytogenes is the species of pathogenic bacteria that causes the infection listeriosis. L monocytogenes is a motile, non-spore-forming, gram-positive bacillus that has aerobic and facultative anaerobic characteristics making it capable of surviving in the presence or absence of oxygen. It grows best at neutral to slightly alkaline pH and is capable of growth at a wide range of temperatures, from l-45°C. It is beta-hemolytic and has a blue-green sheen on blood-free agar. It exhibits characteristic tumbling motility when viewed with light microscopy. It grows and reproduces inside the host's cells and is one of the most virulent foodbome pathogens, with 20 to 30% of food borne listeriosis infections in high-risk individuals are fatal. Most infections occur after oral ingestion, with access to the systemic circulation after intestinal penetration. CNS infection manifests as meningitis, meningoencephalitis, or abscess. Endocarditis is another possible presentation. Localized infection manifests as septic arthritis, osteomyelitis, and, rarely, pneumonia.
Mycobacterium tuberculosis [0052] Mycobacterium tuberculosis is an obligate pathogenic bacterial species in the family Mycobacteriaceae and the causative agent of tuberculosis. M. tuberculosis has an unusual, waxy coating on its cell surface (primarily due to the presence of mycolic acid), which makes the cells impervious to Gram staining. The physiology ofM tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. Francisella novicida
[0053] Francisella novicida is a bacterium of the Francisellaceae family, which consist of Gram negative pathogenic bacteria. These bacteria vary from small cocci to rod-shaped, and are most known for their intracellular parasitic capabilities. Some of the main symptoms associated with this infection include pneumonia, muscle pain, and fever.
Legionella pneumophila
[0054] Legionella pneumophila is a thin, aerobic, pleomorphic, flagellated, nonspore-forming, Gram-negative bacterium of the genus Legionella. L. pneumophila infection causes Legionnaires' disease, a severe form of pneumonia. The symptoms of Legionnaire's disease include confusion, headache, diarrhea, abdominal pain, fever, chills, and myalgia as well as a non-productive cough. Pontiac fever is a non-pneumonic form of L. pneumophila infection. Symptoms are flu-like, including fever, tiredness, myalgia, headache, sore throat, nausea, and sometimes cough. L. pneumophila is transmitted by aerosols and aspiration of contaminated water.
Chlamydia trachomatis
[0055] Chlamydia trachomatis is a gram-negative bacterium that infects the columnar epithelium of the cervix, urethra, and rectum, as well as nongenital sites such as the lungs and eyes. The bacterium is the cause of the most frequently reported sexually transmitted disease in the United States. Most persons with this infection are asymptomatic. Untreated infection results in serious complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy in women, and epididymitis and orchitis in men. Men and women experience chlamydia-induced reactive arthritis. In neonates and infants, the bacterium causes conjunctivitis and pneumonia. Adults also experience conjunctivitis caused by chlamydia. Trachoma is a recurrent ocular infection caused by chlamydia. Streptococcus pneumoniae
[0056] Streptococcus pneumoniae, or pneumococcus is a Gram-positive, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), facultative anaerobic member of the genus Streptococcus, that is responsible for the majority of community-acquired pneumonia. It is a commensal organism in the human respiratory tract, meaning that it benefits from the human body, without harming it. However, infection by pneumococcus is dangerous, causing not only pneumonia, but also bronchitis, otitis media, septicemia, and meningitis. Pneumococcal pneumonia causes fever and chills, coughs, difficulty breathing, and chest pain. If the infection spreads to the brain and spinal cord, it causes pneumococcal meningitis, characterized by a stiff neck, fever, confusion, and headaches. S. pneumoniae primarily spreads through the air in the form of aerosol droplets from coughing and sneezing.
Neisseria gonorrhoeae
[0057] Neisseria gonorrhoeae, also known as gonococci (plural), or gonococcus (singular), is a species of Gram-negative, fastidious, coffee bean-shaped diplococci bacteria responsible for the sexually transmitted infection gonorrhea. Neisseria gonorrhoeae grow and rapidly multiply in the mucous membranes, especially the mouth, throat, and anus of males and females, and the cervix, fallopian tubes, and uterus of the female reproductive tract. N. gonorrhoeae is transmitted from person to person via oral, vaginal, and anal sexual contact. During childbirth, infants contract the infection in the birth canal resulting in bilateral conjunctivitis.
Phosphodiesterases
[0058] In some embodiments, tumor cells circumvent the STING-mediated type I IFN production through overexpression of a phosphodiesterase. In some instances, phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication.
Phosphodiesterases comprise a class of enzymes that catalyze the hydrolysis of a phosphodiester bond. In some instances, this class comprises cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small-molecule phosphodiesterases .
[0059] Cyclic nucleotide phosphodiesterases (PDEs) regulate the cyclic nucleotides cAMP and cGMP. In some instances, cAMP and cGMP function as intracellular second messengers to transduce a variety of extracellular signals including hormones, light, and neurotransmitters. In some cases, PDEs degrade cyclic nucleotides to their corresponding monophosphates, thereby regulating the intracellular concentrations of cyclic nucleotides and their effects on signal transduction.
[0060] In some embodiments, cGAMP (or 2’2-cGAMP) acts as a second messenger binding to STING. In some instances, the cGAMP acts as an intracellular second messenger. In other instances, the cGAMP acts as an extracellular second messenger. In such cases, the extracellular second messenger cGAMP is transferred between cells through, e.g., gap junctions and/or viral particles, and enables activation of the STING pathway in a paracrine fashion.
[0061] In some embodiments, PDEs are classified into classes I, II and III. In some cases, mammalian PDEs, which belong to Class I PDEs, are further divided into 12 families (PDE1-PDE12) based on their amino acid sequences, substrate specificity and affinity, sensitivity to cofactors, and sensitivity to inhibitory agents. In some cases, the different families of mammalian PDEs further contain splice variants that can be unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association proteins. [0062] PDE1 family comprises Ca2+/calmodulin-dependent PDEs. In some cases, PDE1 is encoded by at least three different genes (PDE1A, PDE1B, and PDE1C), each having at least two different splice variants, e.g. PDE1C1 and PDE1C3. In some cases, PDE1 isozymes are regulated in vitro by phosphorylation/dephosphorylation. For example, phosphorylation decreases the affinity of PDE for calmodulin, decreases the activity of PDE1, and increases steady state levels of cAMP. In some cases, PDE1 is observed in the lung, heart, and brain.
[0063] PDE2s are cGMP-stimulated PDEs that have been observed in the cerebellum, neocortex, heart, kidney, lung, pulmonary artery, and skeletal muscle. In some cases, PDE2 mediates the effects of cAMP on catecholamine secretion, participate in the regulation of aldosterone, and play a role in olfactory signal transduction.
[0064] The family of PDE3s has a high affinity for both cGMP and cAMP. PDE3 plays a role in stimulating myocardial contractility, inhibiting platelet aggregation, relaxing vascular and airway smooth muscle, inhibiting proliferation of T-lymphocytes and cultured vascular smooth muscle cells, and regulating catecholamine-induced release of free fatty acids from adipose tissue. In some instances, isozymes of PDE3 are regulated by cAMP -dependent protein kinase, or by insulin- dependent kinases.
[0065] In some embodiments, PDE4s are specific for cAMP and are activated by cAMP -dependent phosphorylation. In some cases, PDE4s are localized to airway smooth muscle, the vascular endothelium, and all inflammatory cells. PDE4 plays a role in regulation of immune cell function.
[0066] PDE5s exert selective recognition for cGMP as a substrate and comprise two allosteric cGMP-specific binding sites. In some cases, binding of cGMP to these allosteric binding sites modulate phosphorylation of PDE5 by cGMP -dependent protein kinase. In some cases, elevated levels of PDE5 are found in vascular smooth muscle, platelets, lung, and kidney. PDE5 plays a role in regulating vascular resistance and responsivity to the vasodilating mediator nitric oxide.
[0067] PDE6s, the photoreceptor cyclic nucleotide phosphodiesterases, are involved in the phototransduction cascade. In association with the G-protein transducin, PDE6s hydrolyze cGMP to regulate cGMP -gated cation channels in photoreceptor membranes. In addition to the cGMP -binding active site, PDE6s also have two high-affinity cGMP-binding sites which may further play a regulatory role in PDE6 function.
[0068] The PDE7 family of PDEs is cAMP specific and comprises one known member having multiple splice variants. Although mRNAs encoding PDE7s are found in skeletal muscle, heart, brain, lung, kidney, and pancreas, expression of PDE7 proteins is restricted to specific tissue types. Further, PDE7s shares a high degree of homology to the PDE4 family.
[0069] PDE8s are cAMP specific. In some cases, PDE8s are expressed in thyroid gland, testis, eye, liver, skeletal muscle, heart, kidney, ovary, and brain. [0070] PDE9s are cGMP specific. In some cases, PDE9s are expressed in kidney, liver, lung, brain, spleen, and small intestine.
[0071] PDElOs are dual-substrate PDEs, hydrolyzing both cAMP and cGMP. In some instances, PDElOs are expressed in brain, thyroid, and testis.
[0072] PDE1 ls, similar to PDElOs, are dual -substrate PDEs that hydrolyze both cAMP and cGMP. In some instances, PDE1 ls are expressed in the skeletal muscle, brain, lung, spleen, prostate gland, and testis.
[0073] PDEl2s hydrolyze cAMP and oligoadenylates (e.g., 2’,5’-oligoadenylate). In some cases, although PDE12 hydrolyzes the 2’5’ linkage, PDE12 does not exhibit activity toward 2’3’-cGAMP.
Ecto-nucleotide Pyrophosphatase/Phosphodiesterase
[0074] In some embodiments, the class of phosphodiesterases also comprises an ecto-nucleotide pyrophosphatase/phosphodiesterase. Ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP) or nucleotide pyrophosphatase/phosphodiesterases (NPP) are a subfamily of ectonucleotidases which hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to nucleoside 5’- monophosphates. In some embodiments, ENPP (or NPP) comprises seven members, ENPP-l, ENPP- 2, ENPP-3, ENPP-4, ENPP-5, ENPP-6 and ENPP-7.
[0075] The ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP-l) protein (also known as PC-l) is a type II transmembrane glycoprotein comprising two identical disulfide -bonded subunits. In some instances, ENPP-l is expressed in precursor cells and promotes osteoblast differentiation and regulates bone mineralization. In some instances, ENPP-l negatively regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates (NTPs) to produce inorganic pyrophosphate (PPi). In some cases, expression of ENPP-l has been observed in pancreas, kidney, bladder, and the liver. In some cases, ENPP-l has been observed to be overexpressed in cancer cells, e.g., in breast cancer cells and glioblastoma cells.
[0076] In some embodiments, ENPP-l has a broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. In some instances, ENPP-l functions to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and also hydrolyze diadenosine polyphosphates. In some cases, ENPP-l hydrolyzes the 2’5’ linkage of cyclic nucleotides. In some cases, ENPP-l degrades 2’3’-cGAMP, an activator of STING.
[0077] In some embodiments, ENPP-l comprises two N-terminal somatomedin B (SMB)-like domains (SMB1 and SMB2), a catalytic domain and a C-terminal nuclease-like domain. In some cases, the two SMB domains are connected to the catalytic domain by a first flexible linker, while the catalytic domain is further connected to the nuclease-like domain by a second flexible linker. In some instances, the SMB domains facilitate ENPP-l dimerization. In some cases, the catalytic domain contains the NTP and cGAMP binding sites. In some cases, the nuclease-like domain contains an EF- hand motif, which binds Ca+2 ion.
[0078] In some cases, ENPP-2 and ENPP-3 are type II transmembrane glycoproteins that share a similar architecture with ENPP-l, for example, comprising the two N-terminal SMB-like domains, a catalytic domain, and a nuclease-like domain. In some instances, ENPP-2 hydrolyzes
lysophospholipids to produce lysophosphatidic acid (LPA) or sphingosylphosphorylcholine (SPC) to produce sphingosine-l phosphate (S1P). In some cases, ENPP-3 is identified to regulate N- acetylglucosaminyltransferase GnT-IX (GnT-Vb).
[0079] In some embodiments, ENPP-4-ENPP-7 are shorter proteins compared to ENPP-l -ENPP-3 and comprise a catalytic domain and lack the SMB-like and nuclease-like domains. ENPP-6 is a choline-specific glycerophosphodiesterase, with lysophospholipase C activity towards
lysophosphatidylcholine (LPC). ENPP-7 is an alkaline sphingomyelinase (alk-SMase) with no detectable nucleotidase activity.
Inhibitor of 2’3’-cGAMP Degradation Polypeptide
[0080] In some embodiments, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a reversible inhibitor. A reversible inhibitor interacts with an enzyme via non-covalent interactions, e.g., hydrogen bonds, hydrophobic interactions, and/or ionic bonds. In some instances, a reversible inhibitor is further classified as a competitive inhibitor, a noncompetitive inhibitor, an allosteric inhibitor or a mixed inhibitor. In competitive inhibition, both the inhibitor and the substrate compete for the same active site. In noncompetitive inhibition, the inhibitor and the substrate bind simultaneously to the enzyme and the inhibitor decreases the enzyme’s activity. In allosteric inhibition, the inhibitor binds to the enzyme at a site distant from the active site, which binding reduces the enzyme’s activity. Some inhibitors act via a combination of competitive, noncompetitive, and/or allosteric mechanisms: these are referred to as mixed inhibitors.
[0081] In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a competitive inhibitor. In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a noncompetitive inhibitor. In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is an allosteric inhibitor. In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is a mixed inhibitor. In some instances, an ENPP-l inhibitor described herein is a competitive inhibitor. In other instances, a ENPP-l inhibitor described herein is a noncompetitive inhibitor In other instances, a ENPP-l inhibitor described herein is an allosteric inhibitor. In other instances, a ENPP-l inhibitor described herein is a mixed inhibitor. [0082] In some embodiments, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) described herein is an irreversible inhibitor. Irreversible inhibitors interact with an enzyme with covalent interaction. In some cases, the ENPP-l is an irreversible inhibitor.
[0083] In some embodiments, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) binds to one or more domains of a PDE described herein. In some cases, a PDE inhibitor binds to one or more domains of ENPP-l. As described above, ENPP-l comprises a catalytic domain and a nuclease-like domain. In some instances, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) binds to the catalytic domain of ENPP-l. In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) binds to the nuclease like domain of ENPP-l.
[0084] In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP. In some cases, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP but interacts weakly with the region that is bound by AMP. In some instances, an inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) does not inhibit, or only weakly inhibits, the ATP hydrolysis function of PDE.
Definitions
[0085] As used herein and in the appended claims, the singular forms“a,”“and,” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“an agent” includes a plurality of such agents, and reference to“the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
The term“comprising” (and related terms such as“comprise” or“comprises” or“having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein,“consist of’ or“consist essentially of’ the described features.
[0086] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0087] “Alkyl” refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples of saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2- methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2- methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2 -pentyl, 2, 2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as“Ci-C6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Ci0 alkyl, a Ci-C9 alkyl, a Ci-C8 alkyl, a Ci-C7 alkyl, a Ci-C6 alkyl, a Ci-C5 alkyl, a Ci-C4 alkyl, a Ci-C3 alkyl, a Ci-C2 alkyl, or a Ci alkyl. When the alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an“alkenyl” or an “alkynyl”. The alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples of alkenyls include, but are not limited to ethenyl (-CH=CH2), l-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, l,3-butadienyl and the like. Whenever it appears herein, a numerical range such as“C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-Ci0 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Examples of alkynyl include, but are not limited to ethynyl, 2-propynyl, 2- butynyl, l,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as“C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-Cio alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, - CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
[0088] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
[0089] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
[0090] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to lO-membered aryl. In some embodiments, the aryl is a 6- membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
[0091] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3- C15 cycloalkyl), from three to ten carbon atoms (C3-Ci0 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3 - to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6- membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.l]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
[0092] “Halo” or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0093] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like.
[0094] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, l,l-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
[0095] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C6 heteroalkyl. Unless stated otherwise specifically in the specification, a Heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
[0096] “Heteroaryl” refers to a 5 - to l4-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to lO-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, l-oxidopyridinyl, l-oxidopyrimidinyl, l-oxidopyrazinyl, 1 -oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
[0097] As used herein, the terms“individual(s)”,“subject(s)” and“patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker).
[0098] “Treatment” is an intervention performed with the intention of preventing the development or altering the pathology or symptoms of a disorder. Accordingly,“treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. In tumor (e.g., cancer) treatment, a therapeutic agent may directly decrease the pathology of tumor cells, or render the tumor cells more susceptible to treatment by other therapeutic agents, e.g., radiation and/or chemotherapy. As used herein,“ameliorated” or“treatment” refers to a symptom which is approaches a normalized value (for example a value obtained in a healthy patient or individual), e.g., is less than 50% different from a normalized value, preferably is less than about 25% different from a normalized value, more preferably, is less than 10% different from a normalized value, and still more preferably, is not significantly different from a normalized value as determined using routine statistical tests. For example, the term“treat” or“treating” with respect to tumor cells refers to stopping the progression of said cells, slowing down growth, inducing regression, or amelioration of symptoms associated with the presence of said cells.
[0099] The“treatment of cancer”, refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder. [0100] The terms‘"effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate“effective” amount in any individual case is determined using techniques, such as a dose escalation study.
Compounds
[0101] Described herein are compounds of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb) that are ENPP-l inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and infections.
[0102] Disclosed herein is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000027_0001
Formula (A)
wherein
L is a bond or -(CR8R9)-;
Ring A is a 5-membered heteroaryl or a 5-membered heterocycloalkyl;
Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R'-R are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C ,-C(, alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re;
each R6 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf; or two R6 on the same carbon are taken together to form an oxo
R7 is halogen, -ORa, -CN, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, - C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Rg;
R8 and R9 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R8 and R9 are taken together to form an oxo;
each Ra is hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl
n is 1-4; and
p is 1-4.
[0103] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, thiophenyl, furanyl, triazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, or thiazolyl. In some
embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is imidazolyl or imidazolidinyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is imidazolyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is pyrrolyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is pyrazolyl.
[0104] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is phenyl or pyridyl. In some embodiments of a compound of Formula (A), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is phenyl.
[0105] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is cycloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is a bicyclic cycloalkyl. In some
embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is cyclohexyl.
[0106] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R1 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R1 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R1 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R1 is hydrogen.
[0107] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 heteroalkyl; wherein the alkyl and heteroalkyl are independently optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, - ORa, or Ci-C6 alkyl optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, -ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen or -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl; wherein the alkyl and heteroalkyl are independently optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, - ORa, or Ci-C6 alkyl optionally substituted with one or more Re. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, -ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen or -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R2 or R3 is not hydrogen. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R2 or R3 is -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 and R3 are -ORa.
[0108] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R2 is hydrogen and R3 is -ORa. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is hydrogen and R2 is -ORa.
[0109] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R4 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R4 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R4 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R4 is hydrogen.
[0110] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R5 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R5 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R5 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R5 is hydrogen.
[0111] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L3 is -(CR8R9)-.
[0112] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R8 and R9 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R8 and R9 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R8 and R9 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R8 and R9 are hydrogen. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R8 and R9 are taken together to form an oxo.
[0113] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is a bond.
[0114] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently halogen, -ORa, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)ORa, -C(=0)NRaORa, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6
alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6
alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more R8. [0115] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently halogen, -ORa, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6
alkyl(NRaC(=0)NRcRd), or Ci-C6 heteroalkyl; wherein the alkyl and heteroalkyl are independently optionally substituted with one or more Rg.
[0116] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently halogen, -ORa, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-Ce alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), or C,-C(, alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0117] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, or C,-C(, alkyl(NRaS(=0)2NRcRd), C ,-C(, alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0118] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently halogen, -ORa, -CN, -SRa, -S(=0)Rb, -
Figure imgf000032_0001
[0119] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently halogen, -ORa, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0120] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl( S (=0)2NRcRd) .
[0121] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R7 is independently Ci-C6 alkyl(S(=0)2NRcRd).
[0122] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1-3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2 or 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 4.
[0123] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R6 is independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R6 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R6 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R6 is hydrogen. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R6 on the same carbon are taken together to form an oxo.
[0124] In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1-3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2 or 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 or 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 3. In some embodiments of a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 4.
[0125] Also disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000034_0001
Formula (I);
wherein
L1 is -(CR18R19)-;
Ring Bl is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R11, R14, and R15 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
R12 and R13 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re; provided that one of R12 or R13 is not hydrogen;
each
Figure imgf000034_0002
Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R18 and R19 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
pl is 1-4.
[0126] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B 1 is aryl or heteroaryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring Bl is phenyl.
[0127] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B 1 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring Bl is cycloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring Bl is a bicyclic cycloalkyl. In some
embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring Bl is cyclohexyl.
[0128] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R11 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
[0129] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R11 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R11 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R11 is hydrogen.
[0130] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R14 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R14 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R14 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R14 is hydrogen.
[0131] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R15 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R15 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R15 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R15 is hydrogen.
[0132] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R18 and R19 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R18 and R19 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R18 and R19 are hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R18 and R19 are taken together to form an oxo.
[0133] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 and R13 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; provided that one of R12 or R13 is not hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 and R13 are independently hydrogen, halogen, - ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; provided that one of R12 or R13 is not hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 and R13 are independently hydrogen, halogen, or -ORa; provided that one of R12 or R13 is not hydrogen. In some embodiments of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 and R13 are -ORa. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 and R13 are -OMe. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one ofR12 or R13 is -OMe. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R12 is -OMe. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R13 is -OMe.
[0134] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6
alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), or C,-C(,
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0135] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C C6 alkyl, C ,- C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0136] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently -OH, -S(=0)2NRcRd, -C(=0)NRa0Ra, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C ,-C(, alkyl(NRaS(=0)2NRcRd), or C,-C(, alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0137] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently -OH, -S(=0)2NRcRd, -C(=0)NRaORa, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C ,-C(, alkyl(NRaS(=0)2NRcRd), or C,-C(, alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0138] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)ORa, -C(=0)NRaORa, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6 alkyl(NRaC(=0)NRcRd) .
[0139] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0140] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently -OH, -S(=0)2NRcRd, -C(=0)NRaORa, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl( S (=0)2NRcRd) .
[0141] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently - S(=0)2NRcRd. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R17 is independently Ci-C6 alkyl(S(=0)2NRcRd).
[0142] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 1-3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p 1 is 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pl is 4.
[0143] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000038_0001
Formula (II);
wherein
L2 is a bond or -(CR28R29)-;
Ring A2 is imidazolyl, pyrrolyl, oxazolyl, or thiazolyl;
Ring B2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R21, R24, and R25 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re;
each R26 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
or two R26 on the same carbon are taken together to form an oxo;
each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0) 0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(= 0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, C ,-C(, alkyl, C,-C(, alkyl(NRaS(=0)2NRcRd), C ,-C(, alkyl(S(=0)2NRcRd), C,-C(, alkyl(
Figure imgf000039_0001
i-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Rg;
R28 and R29 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R28 and R29 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
n2 is 1-4; and
p2 is 1-4. [0144] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A2 is imidazolyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A2 is pyrrolyl.
[0145] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B2 is aryl or heteroaryl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is phenyl.
[0146] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
Ring B2 is cycloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is a bicyclic cycloalkyl. In some
embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B2 is cyclohexyl.
[0147] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R21 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R21 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R21 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R21 is hydrogen.
[0148] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R24 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R24 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R24 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R24 is hydrogen.
[0149] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R25 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R25 is hydrogen, halogen, -CN, - ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R25 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R25 is hydrogen.
[0150] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L 2 is -(CR 28 R 29 )-.
[0151] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R28 and R29 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R28 and R29 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R28 and R29 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R28 and R29 are hydrogen. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R28 and R29 are taken together to form an oxo.
[0152] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L2 is a bond.
[0153] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -NRcRd, -
Figure imgf000041_0001
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0154] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci- C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0155] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently -OH, -S(=0)2NRcRd, -C(=0)NRaORa, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0156] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6
alkyl(NRaC(=0)NRcRd) .
[0157] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd 6 alkyl, Ci- C6 haloalkyl,
Figure imgf000042_0001
[0158] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently -OH, -S(=0)2NRcRd, -C(=0)NRa0Ra, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C ,-C(, alkyl(NRaS(=0)2NRcRd), or C,-C(, alkyl( S (=0)2NRcRd) .
[0159] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently - S(=0)2NRcRd. Iln some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently Ci-C6
alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R27 is independently Ci-C6 alkyl(S(=0)2NRcRd).
[0160] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1-3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1 or 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 4.
[0161] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R26 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, - C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R26 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R26 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R26 is hydrogen.
[0162] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R26 on the same carbon are taken together to form an oxo.
[0163] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 1-3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 1 or 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 2. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 3. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n2 is 4.
[0164] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000043_0005
- is a single bond or a double bond;
X is -N- or -CR36- when
Figure imgf000043_0001
X is -NR36a- or -C(R36)2- when
Figure imgf000043_0002
Y is -N- or -CR36- when
Figure imgf000043_0003
Y is -NR36a- or -C(R36)2- when
Figure imgf000043_0004
Ring B3 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R31, R34, and R35 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
each R36 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C ,-C(, alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
or two R36 on the same carbon are taken together to form an oxo;
each R36a is independently hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl;
each R37 is independently halogen, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Rg;
R38 and R39 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R38 and R39 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
p3 is 1-4.
[0165] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B3 is aryl or heteroaryl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is phenyl.
[0166] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is cycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B3 is cyclohexyl.
[0167] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R31 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R31 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R31 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R31 is hydrogen.
[0168] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R34 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R34 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R34 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R34 is hydrogen.
[0169] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R35 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R35 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R35 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R35 is hydrogen.
[0170] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L 3 is -(CR 38 R 39 )-.
[0171] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R38 and R39 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R38 and R39 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R38 and R39 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R38 and R39 are hydrogen. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R38 and R39 are taken together to form an oxo.
[0172] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L3 is a bond.
[0173] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently halogen, -ORa, -SRa, -S(=0)Rb, - NRcRd, -
Figure imgf000046_0001
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0174] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently halogen, -ORa, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0175] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg. [0176] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently halogen, -ORa, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6 alkyl (NRaC(=0)NRcRd) .
[0177] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently halogen, -ORa, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0178] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or C C6 alkyl( S (=0)2NRcRd) .
[0179] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (III), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R37 is independently Ci-C6 alkyl( S (=0)2NRcRd) .
[0180] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 1-3. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 1 or 2. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 1. In some embodiments of a compound of Formula (III), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 2. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 3. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p3 is 4.
[0181] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is
Figure imgf000047_0001
. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -CR36- and Y is -N-. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -N- and Y is -CR36-. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -CR36- and Y is -CR36-.
[0182] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable
Figure imgf000048_0001
some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -C(R36)2- and Y is -NR36a-.
[0183] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36 is independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36 is hydrogen. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R36 on the same carbon are taken together to form an oxo.
[0184] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36a is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36a are hydrogen. In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R36a is independently Ci- C6 alkyl.
[0185] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000048_0002
Formula (IV);
wherein
L4 is -(CR48R49)-;
Ring A4 is a 5-membered heteroaryl or a 5-membered heterocycloalkyl;
Ring B4 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R41, R44, and R45 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
each R46 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C ,-C(, alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
or two R46 on the same carbon are taken together to form an oxo;
each R47 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R48 and R49 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
n4 is 1-4; and
p4 is 1-4.
[0186] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, oxazolyl, or thiazolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is imidazolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is pyrrolyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A4 is pyrazolyl.
[0187] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B4 is aryl or heteroaryl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is phenyl.
[0188] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is cycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B4 is cyclohexyl.
[0189] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R41 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R41 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R41 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R41 is hydrogen.
[0190] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R44 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R44 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R44 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R44 is hydrogen.
[0191] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R45 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R45 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R45 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R45 is hydrogen.
[0192] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R48 and R49 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R48 and R49 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R48 and R49 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R48 and R49 are hydrogen.
[0193] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)ORa, -C(=0)NRaORa, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6
alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0194] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently halogen, -OH, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0195] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently -OH, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg. [0196] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6
alkyl(NRaC(=0)NRcRd) .
[0197] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently halogen, -OH, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0198] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently -OH, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or C C6 alkyl( S (=0)2NRcRd) .
[0199] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (IV), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R47 is independently Ci-C6 alkyl( S (=0)2NRcRd) .
[0200] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 1-3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 1 or 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 1. In some embodiments of a compound of Formula (IV), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p4 is 4.
[0201] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R46 is independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R46 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R46 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R46 is hydrogen. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R46 on the same carbon are taken together to form an oxo.
[0202] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 1-3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 1 or 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 1. In some embodiments of a compound of Formula (IV), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 2. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 3. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n4 is 4.
[0203] Also disclosed is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000053_0001
L5 is a bond or -(CR58R59)-;
Ring B5 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R51, R54, and R55 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -OC(=0)Rb, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
R52 and R53 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -OC(=0)Rb, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re; provided that one of R52 or R53 is - OMe;
R56 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C,-C(, alkyl, C ,-C(, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
each
Figure imgf000054_0001
Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R58 and R59 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R58 and R59 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
p5 is 1-4. [0204] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B5 is aryl or heteroaryl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is phenyl.
[0205] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is cycloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is a bicyclic cycloalkyl. In some
embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B5 is cyclohexyl.
[0206] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R51 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R51 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R51 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R51 is hydrogen.
[0207] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R54 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R54 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R54 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R54 is hydrogen.
[0208] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R55 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R55 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R55 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R55 is hydrogen. [0209] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R56 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R56 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R56 is hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R56 is hydrogen.
[0210] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L5 is -(CR58R59)-.
[0211] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R58 and R59 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R58 and R59 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R58 and R59 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R58 and R59 are hydrogen. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R58 and R59 are taken together to form an oxo.
[0212] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L5 is a bond.
[0213] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; and R52 is -OMe. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is hydrogen, halogen, -ORa, Ci- C6 alkyl, or Ci-C6 haloalkyl; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is hydrogen, halogen, - ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; and R52 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is hydrogen, halogen, or -ORa; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is hydrogen, halogen, or -ORa; and R52 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is hydrogen or halogen; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is hydrogen or halogen; and R52 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is hydrogen; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is hydrogen; and R52 is -OMe.
In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 is halogen; and R53 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R53 is halogen; and R52 is -OMe. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R52 and R53 are -OMe.
[0214] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently hydrogen, -ORa, -CN, -SRa, -S(=0)Rb, -N02, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, - C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl(NRcRd), Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg.
[0215] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -CN, -SRa, -S(=0)Rb, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0216] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 haloalkyl, C^Q, alkyl(NRaS(=0)2NRcRd), or C,-C(, alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0217] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or C C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg. [0218] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -CN, -SRa, -S(=0)Rb, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6
alkyl(NRaC(=0)NRcRd) .
[0219] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0220] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -ORa, -S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or C C6 alkyl( S (=0)2NRcRd) .
[0221] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R57 is independently Ci-C6 alkyl(S(=0)2NRcRd).
[0222] In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 1-3. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 1 or 2. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 1. In some embodiments of a compound of Formula (V), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 2. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 3. In some embodiments of a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p5 is 4.
[0223] Also disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000059_0001
Formula (VI);
wherein
L6 is a bond or -(CR68R69)-;
Ring B6 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R61, R64, and R65 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
R62 and R63 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re; provided that one of R62 or R63 is - OMe;
each R66 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, -C(=0)NRcRd, - 0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, -NRaC(=0)0Ra, C ,-C(, alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
each R67 is independently hydrogen, halogen, -ORa, -CN, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg; R68 and R69 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R68 and R69 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
p6 is 1-4.
[0224] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B6 is aryl or heteroaryl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is phenyl.
[0225] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is cycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B6 is cyclohexyl.
[0226] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R61 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R61 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R61 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R61 is hydrogen.
[0227] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R64 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R64 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R64 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R64 is hydrogen.
[0228] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R65 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R65 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R65 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R65 is hydrogen.
[0229] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R66 is independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R66 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R66 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R66 is hydrogen.
[0230] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L6 is -(CR68R69)-.
[0231] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R68 and R69 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R68 and R69 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R68 and R69 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R68 and R69 are hydrogen. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R68 and R69 are taken together to form an oxo.
[0232] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L6 is a bond.
[0233] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci- C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R63 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, C,-C(, alkyl, C ,-C(, haloalkyl, or C C6 heteroalkyl; and R62 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 is hydrogen, halogen, -ORa, Ci- C6 alkyl, or Ci-C6 haloalkyl; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R63 is hydrogen, halogen, - ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; and R62 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 is hydrogen, halogen, or -ORa; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R63 is hydrogen, halogen, or -ORa; and R62 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 is hydrogen or halogen; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R63 is hydrogen or halogen; and R62 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R62 is hydrogen; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R63 is hydrogen; and R62 is -OMe.
In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 is halogen; and R63 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R63 is halogen; and R62 is -OMe. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R62 and R63 are -OMe.
[0234] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently hydrogen, halogen, -CN, -SRa, - S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, - C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, - NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R8.
[0235] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -CN, -SRa, -S(=0)Rb, - NRcRd, -
Figure imgf000063_0002
alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0236] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C C6 alkyl, C ,- C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0237] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -S(=0)2NRcRd, - C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more R8.
[0238] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -CN, -SRa, -S(=0)Rb, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)ORa, -C(=0)NRaORa, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), or Ci-C6 alkyl(NRaC(=0)NRcRd) .
[0239] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -S(=0)2Rb, -NRaS(=0)2Rb, - S(=0)2NRcRd, -C(=0)NRaORa, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci- C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
[0240] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently halogen, -S(=0)2NRcRd, -
Figure imgf000063_0001
[0241] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (VI), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R67 is independently Ci-C6 alkyl( S (=0)2NRcRd) .
[0242] In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 1-3. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 1 or 2. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 1. In some embodiments of a compound of Formula (VI), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 2. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 3. In some embodiments of a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p6 is 4.
[0243] Also disclosed herein is a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000064_0001
;
wherein
Z is -0-, -S-, or -NR76-;
L7 is a bond or -(CR78R79)-;
Ring B7 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R71, R74, R75 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re;
R72 and R73 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -0C(=0)0Ra, - C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Rb, - NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
independently optionally substituted with one or more Re; provided that one of R72 or R73 is - OMe;
R76 is hydrogen or Ci-C6 alkyl;
each R77 is independently hydrogen, halogen, -ORa, -CN, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R78 and R79 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R78 and R79 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; or Ra and Rc are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Re, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
p7 is 1-4.
[0244] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof Ring B7 is aryl or heteroaryl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is phenyl.
[0245] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is cycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is a bicyclic cycloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B7 is cyclohexyl.
[0246] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R71 is hydrogen, halogen, -CN, -ORa, -NRcRd, - C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R71 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R71 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R71 is hydrogen.
[0247] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R74 is hydrogen, halogen, -CN, -ORa, -NRcRd, - C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R74 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R74 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R74 is hydrogen.
[0248] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R75 is hydrogen, halogen, -CN, -ORa, -NRcRd, - C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R75 is hydrogen, halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R75 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R75 is hydrogen.
[0249] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -0-. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is - S-. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -NR76-.
[0250] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R76 is hydrogen. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R76 is Ci-C6 alkyl.
[0251] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L 7 is -(CR 78 R 79 )-.
[0252] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R78 and R79 are independently hydrogen, halogen, - CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R78 and R79 are independently hydrogen, halogen, -CN, -ORa, - NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R78 and R79 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R78 and R79 are hydrogen. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R78 and R79 are taken together to form an oxo.
[0253] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L7 is a bond.
[0254] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 is hydrogen, halogen, -CN, -ORa, -NRcRd, - C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; and R73 is -OMe. In some
embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)ORa, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
R72 is hydrogen, halogen, -ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; and R73 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is hydrogen, halogen, -ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 is hydrogen, halogen, or -ORa; and R73 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is hydrogen, halogen, or -ORa; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 is hydrogen or halogen; and R73 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is hydrogen or halogen; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 is hydrogen; and R73 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is hydrogen; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 is halogen; and R73 is -OMe. In some
embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R73 is halogen; and R72 is -OMe. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R72 and R73 are -OMe.
[0255] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently hydrogen, halogen, -ORa, - CN, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, - 0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, -0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, C C6 haloalkyl, C ,-C(, alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), C C6
alkyl(NRaC(=0)NRcRd), Ci-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg.
[0256] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, -CN, -SRa, - S(=0)Rb, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, - C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, C,-C(, haloalkyl, Ci-Ce alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), or C,-C(, alkyl(NRaC(=0)NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg. [0257] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0258] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, - S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd); wherein each alkyl is independently optionally substituted with one or more Rg.
[0259] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, -CN, -SRa, - S(=0)Rb, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, - C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, C,-C(, haloalkyl, Ci-Ce alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), or C,-C(, alkyl(NRaC(=0)NRcRd) .
[0260] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, -S(=0)2Rb, -NRaS(=0)2Rb, - Ci-Ce haloalkyl,
Figure imgf000069_0001
[0261] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently halogen, -ORa, -
Figure imgf000069_0002
[0262] In some embodiments of a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently -NRaS(=0)2NRcRd, Ci-C6
alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd). In some embodiments of a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently -NRaS(=0)2NRcRd. In some embodiments of a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently Ci-C6 alkyl(NRaS(=0)2NRcRd). In some embodiments of a compound of Formula (VII), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R77 is independently Ci-C6 alkyl( S (=0)2NRcRd) .
[0263] In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 1-3. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 1 or 2. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 1. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 2. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 3. In some embodiments of a compound of Formula (Vila) or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p7 is 4.
[0264] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen, -OH, Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen, -OH, Ci-C6 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III),
(IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen, Ci-C6 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen or Ci-C6 alkyl.
[0265] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently Ci-C6 alkyl, or cycloalkyl.
In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently Ci-C6 alkyl.
[0266] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV),
(V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl.
[0267] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Re, Rf, Rg, and Rh are independently halogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Re, Rf, Rg, and Rh are independently halogen.
[0268] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1-3 Re. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 or 2 Re. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 Re. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 2 Re.
[0269] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1-3 Rf. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 or 2 Rf. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 Rf. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 2 Rf.
[0270] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1-3 Rg. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 or 2 Rg. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 Rg. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 2 Rg.
[0271] In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1-3 Rh. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 or 2 Rh. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 1 Rh. In some embodiments of a compound of Formula (A), (I), (II), (III), (IV), (V), (VI), (Vila), or (Vllb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the substituents are each independently optionally substituted with 2 Rh.
[0272] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, disclosed herein is selected from Table 1 :
TABLE 1
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0002
[0273] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, disclosed herein is selected from:
Figure imgf000076_0001
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[0274] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
Labeled compounds
[0275] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as H, H, C, C, N,
180, 170, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-l4, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e. , 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
[0276] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[0277] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[0278] In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
[0279] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate,
dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate,
hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalene sulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.
[0280] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, l,2-ethanedisulfonic acid, 2 -hydroxyethane sulfonic acid, benzene sulfonic acid, 2- naphthalene sulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[0281] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a
pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-4 alkyl)4, and the like.
[0282] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
Solvates
[0283] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[0284] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers
[0285] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Preparation of the Compounds
[0286] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.“Commercially available chemicals” are obtained from standard commercial sources including Acres Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[0287] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example,“Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al,“Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O.
House,“Modem Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March,
“Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G.“Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V.“Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, 19 ISBN 0-19-509618-5; Larock, R. C.“Comprehensive Organic Transformations: A Guide to
Functional Group Preparations” 2nd Edition (1999) Wiley -VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor)“Modem Carbonyl Chemistry” (2000) Wiley - VCH, ISBN: 3-527-29871-1; Patai, S.“Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G.“Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C.,“Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals:
Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes;“Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and“Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.
[0288] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth“Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.
Pharmaceutical Compositions
[0289] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2 Ist Ed. Mack Pub. Co., Easton, PA (2005)).
[0290] Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and a pharmaceutically acceptable excipient.
[0291] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0292] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
[0293] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
[0294] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 pg to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.
[0295] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
Methods of Treatment
[0296] The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful as inhibitors of ENPP-l, and thereof useful in the treatment of diseases or disorders in which ENPP-l activity plays a role. In some embodiments, disclosed herein are methods of treating a subject having cancer. In some instances, the cancer is primed with an immunogenic cell death (ICD) inducer. In other instances, the cancer is treated with an ENPP-l inhibitor prior to administering an ICD inducer or is treated simultaneously with the ENPP-l inhibitor and an ICD inducer.
[0297] In some embodiments, disclosed herein are methods of treating a subject having a pathogenic infection. In some instances, the method comprises administering to the subject an inhibitor of a 2’3’-cGAMP degradation polypeptide, wherein the inhibitor prevents hydrolysis of 2’3’- cGAMP and wherein the subject has an infection.
[0298] In some instances, the ENPP-l inhibitor described herein is a competitive inhibitor. In other instances, the ENPP-l inhibitor described herein is an allosteric inhibitor. In some cases, the ENPP-l described herein is an irreversible inhibitor.
[0299] In some cases, the ENPP-l inhibitor binds to one or more domains of ENPP-l . As described above, ENPP-l comprises a catalytic domain and a nuclease-like domain. In some instances, the ENPP-l inhibitor binds to the catalytic domain of ENPP-l . In some cases, the ENPP-l inhibitor binds to the nuclease -like domain of ENPP-l .
[0300] In some cases, the ENPP-l inhibitor selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP. In some cases, a PDE inhibitor selectively binds to a region on PDE (e.g., ENPP-l) also recognized by GMP but interacts weakly with the region that is bound by AMP.
[0301] In some embodiments, a cancer described herein is a solid tumor. Solid tumor comprises neoplasms and lesions derived from cells other than blood, bone marrow, or lymphatic cells. In some cases, exemplary solid tumors include breast cancer and lung cancer.
[0302] In some embodiments, a cancer described herein is a hematologic malignancy. A hematologic malignancy comprises an abnormal cell growth of blood, bone marrow, and/or lymphatic cells. For instances, an exemplary hematologic malignancy comprises multiple myeloma. In some instances, a hematologic malignancy is a leukemia, a lymphoma or a myeloma. In some cases, a hematologic malignancy is a B-cell malignancy.
[0303] In some embodiments, a cancer described herein is a relapsed or refractory cancer. In some embodiments, a cancer described herein is a metastatic cancer.
[0304] In some embodiments, an ICD inducer comprises radiation. In some cases, the radiation comprises UV radiation. In other cases, the radiation comprises g radiation.
[0305] In some embodiments, an ICD inducer comprises a small molecule compound or a biologic. As described above, an ICD small molecule inducer optionally comprises a chemotherapeutic agent.
In some cases, the chemotherapeutic agent comprises an anthracycline. In some cases, the
anthracy cline is doxorubicin or mitoxantrone. In some instances, the chemotherapeutic agent comprises a cyclophosphamide. In some instances, the cyclophosphamide is mafosfamide. In some embodiments, the chemotherapeutic agent is selected from bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or a combination thereof. In some cases, the ICD inducer comprises digitoxin or digoxin. In some cases, the ICD inducer comprises septacidin. In some cases, the ICD inducer comprises a combination of cisplatin and thapsigargin. In some cases, the ICD inducer comprises a combination of cisplatin and tunicamycin.
[0306] In some embodiments, an ICD inducer comprises a biologic (e.g., a protein-payload conjugate such as trastuzumab emtansine). In some cases, the ICD inducer comprises an activator of calreticulin (CRT) exposure.
Method of Enhancing and/or Augmenting Type I IFN Production
[0307] Also described herein are methods of enhancing and/or augmenting type I interferon (IFN) production. In some instances, the method comprises an in vivo method. In some cases, the method differs from a systemic method because the production of IFNs is localized in the tumor
microenvironment. In some cases, the method of enhancing type I interferon (IFN) production in a subject in need thereof, comprises administering to the subject a pharmaceutical composition comprising (i) an inhibitor of a 2’3’-cGAMP degradation polypeptide to block the hydrolysis of 2’3’- cGAMP; and (ii) a pharmaceutically acceptable excipient; wherein the presence of 2’3’-cGAMP activates the STING pathway, thereby enhancing the production of type I interferons.
[0308] In some cases, the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE) In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
pyrophosphatase/phosphodiesterase (ENPP) protein. In some cases, the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
[0309] In some instances, the cell has an elevated expression of PDE.
[0310] In some instances, the cell has an elevated population of cytosolic DNA. In some cases, the elevated population of cytosolic DNA is generated by an ICD-mediated event. In other cases, the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
[0311] In some embodiments, the inhibitor of a 2’3’-cGAMP degradation polypeptide is a PDE inhibitor. In some instances, the PDE inhibitor is a small molecule. In some instances, the PDE inhibitor is an ENPP-l inhibitor. In some cases, the PDE inhibitor is a reversible inhibitor. In some cases, the PDE inhibitor is a competitive inhibitor. In some cases, the PDE inhibitor is an allosteric inhibitor. In some cases, the PDE inhibitor is a mixed inhibitor. In other cases, the PDE inhibitor is an irreversible inhibitor. In some embodiments, the PDE inhibitor binds to the catalytic domain of ENPP-l. In other embodiments, the PDE inhibitor binds to the nuclease-like domain of ENPP-l.
[0312] In some embodiments, the subject has been administered an immunogenic cell death (ICD) inducer prior to administering the inhibitor of a 2’3’-cGAMP degradation polypeptide. In other instances, the subject is administered an immunogenic cell death (ICD) inducer after administering the inhibitor of a 2’3’-cGAMP degradation polypeptide or simultaneously with the inhibitor of a 2’3’- cGAMP degradation polypeptide. In some embodiments, an ICD inducer comprises radiation. In some cases, the radiation comprises UV radiation. In other cases, the radiation comprises g radiation.
[0313] In some embodiments, an ICD inducer comprises a small molecule compound or a biologic. As described above, an ICD small molecule inducer optionally comprises a chemotherapeutic agent. In some cases, the chemotherapeutic agent comprises an anthracycline. In some cases, the
anthracy cline is doxorubicin or mitoxantrone. In some instances, the chemotherapeutic agent comprises a cyclophosphamide. In some instances, the cyclophosphamide is mafosfamide. In some embodiments, the chemotherapeutic agent is selected from bortezomib, daunorubicin, docetaxel, oxaliplatin, paclitaxel, or a combination thereof. In some cases, the ICD inducer comprises digitoxin or digoxin. In some cases, the ICD inducer comprises septacidin. In some cases, the ICD inducer comprises a combination of cisplatin and thapsigargin. In some cases, the ICD inducer comprises a combination of cisplatin and tunicamycin.
[0314] In some embodiments, an ICD inducer comprises a biologic (e.g., a protein-payload conjugate such as trastuzumab emtansine). In some cases, the ICD inducer comprises an activator of calreticulin (CRT) exposure.
[0315] In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) selectively inhibits hydrolysis of 2’3’-cGAMP.
[0316] In some embodiments, the therapeutically effective amount of the inhibitor of a 2’3’- cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) further reduces ATP hydrolysis in the 2’3’-cGAMP degradation polypeptide by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or by less than 1% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 50% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 40% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 30% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’- cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 20% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 10% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 5% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 4% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 3% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 2% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’- cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) reduces ATP hydrolysis in 2’3’-cGAMP degradation polypeptide by less than 1% relative to the ATP hydrolysis of a 2’3’-cGAMP degradation polypeptide in the absence of the 2’3’-cGAMP degradation polypeptide inhibitor. In some cases, the therapeutically effective amount of the inhibitor of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l inhibitor) does not induce ATP hydrolysis in 2’3’-cGAMP degradation polypeptide.
[0317] In some embodiments, a cancer described herein is a solid tumor. In some cases, exemplary solid tumors include breast cancer, lung cancer and glioblastoma (e.g., glioblastoma multiforme).
[0318] In some embodiments, a cancer described herein is a hematologic malignancy. In some instances, a hematologic malignancy is a leukemia, a lymphoma or a myeloma. In some cases, a hematologic malignancy is a B-cell malignancy.
[0319] In some embodiments, a cancer described herein is a relapsed or refractory cancer.
[0320] In some embodiments, a cancer described herein is a metastatic cancer.
Method of Inhibiting 2’3’-cGAMP Depletion
[0321] In some embodiments, further disclosed herein include methods of inhibiting depletion of 2’3’-cGAMP in a cell and selective inhibition of a 2’3’-cGAMP degradation polypeptide (e.g., a ENPP-l). In some instances, a method of inhibiting depletion of 2’3’-cGAMP in a cell comprises contacting a cell comprising a 2’3’-cGAMP degradation polypeptide with an inhibitor to generate a 2’3’-cGAMP degradation polypeptide -inhibitor complex, thereby inhibiting the 2’3’-cGAMP degradation polypeptide from degrading 2’3’-cGAMP to prevent the depletion of 2’3’-cGAMP in the cell.
[0322] In some cases, the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
pyrophosphatase/phosphodiesterase (ENPP) protein. In some cases, the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
[0323] In other instances, a method of selectively inhibits a phosphodiesterase (PDE) comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain- specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE.
[0324] In additional instances, a method of selectively inhibiting a phosphodiesterase (PDE) comprises contacting a cell characterized with an elevated population of cytosolic DNA with a nuclease-like domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE.
[0325] In some cases, the reduced inhibition function of ATP hydrolysis is relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some cases, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or to less than 1% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 50% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 40% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 30% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 20% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 10% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 5% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 4% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 3% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 2% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some instances, the PDE inhibitor reduces ATP hydrolysis in the PDE by less than 1% relative to the ATP hydrolysis of a PDE in the absence of the PDE inhibitor. In some cases, the PDE inhibitor does not inhibit ATP hydrolysis of the PDE.
[0326] In some embodiments, the cell has an elevated expression of PDE.
[0327] In some embodiments, the cell has an elevated population of cytosolic DNA. In some cases, the elevated population of cytosolic DNA is generated by an ICD-mediated event. In other cases, the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
[0328] In some instances, the cell comprises a cancer cell. In some instances, the cancer cell is a solid tumor cell (e.g., a breast cancer cell, a lung cancer cell or a cancer cell from glioblastoma). In other instances, the cancer cell is a cell from a hematologic malignancy (e.g., from a lymphoma, a leukemia, a myeloma or a B-cell malignancy).
[0329] In some embodiments, the cell comprises an effector cell. In some instances, the effector cell comprises a dendritic cell or a macrophage.
[0330] In some embodiments, the cell comprises a non -cancerous cell residing within a tumor microenvironment in which the cell comprises an elevated population of cytosolic DNA. In some cases, the cell comprises a non-cancerous cell residing within a tumor microenvironment in which the cGAS/STING pathway is activated.
[0331] In some embodiments, a subject is administered a recombinant vaccine comprising a vector that encodes a tumor antigen. In some instances, the subject administered a recombinant vaccine prior to administering the inhibitor of a 2’3’-cGAMP degradation polypeptide. In other instances, the subject is administered a recombinant vaccine after administering the inhibitor of a 2’3’-cGAMP degradation polypeptide or simultaneously with the inhibitor of a 2’3’-cGAMP degradation polypeptide.
[0332] In some embodiments, a nucleic acid vector described herein comprise a circular plasmid or a linear nucleic acid. In some cases, the circular plasmid or linear nucleic acid is capable of directing expression of a particular nucleotide sequence in an appropriate subject cell. In some cases, the vector has a promoter operably linked to the tumor antigen-encoding nucleotide sequence, which is operably linked to termination signals. In some instances, the vector also contains sequences required for proper translation of the nucleotide sequence. The vector comprising the nucleotide sequence of interest can be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components. The expression of the nucleotide sequence in the expression cassette can be under the control of a constitutive promoter or of an inducible promoter, which can initiate transcription only when the host cell is exposed to some particular external stimulus.
[0333] In some instances, the vector is a plasmid. In some cases, the plasmid is useful for transfecting cells with nucleic acid encoding the tumor antigen, which the transformed host cells can be cultured and maintained under conditions wherein production of the tumor antigen takes place. [0334] In some instances, the plasmid comprises a mammalian origin of replication in order to maintain the plasmid extrachromosomally and produce multiple copies of the plasmid in a cell. The plasmid can be pVAXI, pCEP4 or pREP4 from Invitrogen (San Diego, CA).
[0335] In some instances, the plasmid further comprises a regulatory sequence, which enables gene expression in a cell into which the plasmid is administered. In some cases, the coding sequence further comprises a codon that allows for more efficient transcription of the coding sequence in the host cell.
[0336] In some instances, the vector is a circular plasmid, which transforms a target cell by integration into the cellular genome or exist extrachromosomally (e.g., autonomous replicating plasmid with an origin of replication). Exemplary vectors include pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing DNA encoding the antigen and enabling a cell to translate the sequence to an antigen that is recognized by the immune system.
[0337] In some instances, the recombinant nucleic acid vaccine comprises a viral vector.
Exemplary viral based vectors include adenoviral based, lentivirus based, adeno-associated (AAV) based, retroviral based, or poxvirus based vectors.
[0338] In some instances, the recombinant nucleic acid vaccine is a linear DNA vaccine, or linear expression cassette ("LEC"), that is capable of being efficiently delivered to a subject via
electroporation and expressing one or more polypeptides disclosed herein. The LEC can be any linear DNA devoid of any phosphate backbone. The DNA can encode one or more microbial antigens. The LEC can contain a promoter, an intron, a stop codon, and/or a polyadenylation signal. In some cases, the LEC does not contain any antibiotic resistance genes and/or a phosphate backbone. In some cases, the LEC does not contain other nucleic acid sequences unrelated to the tumor antigen.
Methods of Inhibiting 2’3’-cGAMP Depletion
[0339] In some embodiments, further disclosed herein include methods of inhibiting depletion of 2’3’-cGAMP in a cell and selective inhibition of a 2’3’-cGAMP degradation polypeptide (e.g., ENPP- 1). In some embodiments, disclosed herein includes a method of inhibiting depletion of 2’3’ -cGAMP in a cell infected by a pathogen, which comprises contacting the cell infected by a pathogen and expressing a 2’ 3’-cGAMP degradation polypeptide with an inhibitor to generate a 2’3’ -cGAMP degradation polypeptide -inhibitor adduct, thereby inhibiting the 2’3’ -cGAMP degradation polypeptide from degrading 2’ 3’-cGAMP to prevent the depletion of 2’3’ -cGAMP in the cell.
[0340] In some instances, disclosed herein includes a method of selectively inhibits a
phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3 -cGAMP, wherein the PDE inhibitor has a reduced function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a virus. [0341] In some instances, disclosed herein includes a method of selectively inhibits a phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a virus.
[0342] In some instances, disclosed herein includes a method of selectively inhibits a
phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a nuclease-like domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a virus.
[0343] In some embodiments, disclosed herein includes a method of selectively inhibits a phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
[0344] In some embodiments, disclosed herein includes a method of selectively inhibits a phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a catalytic domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
[0345] In some embodiments, disclosed herein includes a method of selectively inhibits a phosphodiesterase (PDE), which comprises contacting a cell characterized with an elevated population of cytosolic DNA with a nuclease-like domain-specific PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE, and wherein the elevated population of cytosolic DNA is generated by a recombinant DNA vaccine.
[0346] In some cases, the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
pyrophosphatase/phosphodiesterase (ENPP) protein. In some cases, the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
[0347] In some instances, a method of selectively inhibits a phosphodiesterase (PDE) comprises contacting a cell characterized with an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3-cGAMP, wherein the PDE inhibitor has a reduced inhibition function of ATP hydrolysis of the PDE. In some cases, the PDE inhibitor binds to the catalytic domain of ENPP-l. In some cases, the PDE inhibitor binds to the nuclease-like domain of ENPP-l. [0348] In some embodiments, the infection is a viral infection, e.g., an infection from a DNA virus or a retrovirus. In some cases, the viral infection is due to herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68), Kaposi’s sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomaviruses (HPV), hepatitis B virus (HBV), human
immunodeficiency virus (HIV), or human cytomegalovirus (HCMV).
[0349] In some instances, the infection is a bacterial infection, e.g., an infection from a Gram negative bacterium or a Gram-positive bacterium. In some cases, the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
[0350] In some instances, the cytosolic DNA comprises viral DNA. In some cases, the elevated population of cytosolic DNA is due to a viral infection to the host cell. In other cases, the elevated population of the cytosolic DNA is due to delivery of viral DNA through a virus-like particle (VLP).
[0351] In some instances, the elevated population of cytosolic DNA is due to a recombinant DNA vaccine, which comprises a DNA vector encoding a viral antigen. In some cases, the viral antigen is derived from a DNA virus. In other cases, the viral antigen is derived from a retrovirus. In some cases, the viral antigen is derived from herpes simplex virus 1 (HSV-l), murine gamma-herpesvirus 68 (MHV68), Kaposi’s sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomaviruses (HPV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), or human cytomegalovirus (HCMV).
[0352] In some cases, the recombinant DNA vaccine comprise a DNA vector that encodes a bacterial antigen, e.g., derived from a Gram-negative bacterium or a Gram-positive bacterium. In some cases, the bacterial antigen is derived from Listeria monocytogenes, Mycobacterium
tuberculosis , Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
[0353] In some embodiments, a DNA vector described herein comprise a circular plasmid or a linear nucleic acid. In some cases, the circular plasmid or linear nucleic acid is capable of directing expression of a particular nucleotide sequence in an appropriate subject cell. In some cases, the vector has a promoter operably linked to the microbial antigen-encoding nucleotide sequence, which is operably linked to termination signals. In some instances, the vector also contains sequences required for proper translation of the nucleotide sequence. The vector comprising the nucleotide sequence of interest can be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components. The expression of the nucleotide sequence in the expression cassette can be under the control of a constitutive promoter or of an inducible promoter, which can initiate transcription only when the host cell is exposed to some particular external stimulus.
[0354] In some instances, the vector is a plasmid. In some cases, the plasmid is useful for transfecting cells with nucleic acid encoding the microbial antigen, which the transformed host cells can be cultured and maintained under conditions wherein production of the microbial antigen takes place.
[0355] In some instances, the plasmid comprises a mammalian origin of replication in order to maintain the plasmid extrachromosomally and produce multiple copies of the plasmid in a cell. The plasmid can be pVAXI, pCEP4 or pREP4 from Invitrogen (San Diego, CA).
[0356] In some instances, the plasmid further comprises a regulatory sequence, which enables gene expression in a cell into which the plasmid is administered. In some cases, the coding sequence further comprises a codon that allows for more efficient transcription of the coding sequence in the host cell.
[0357] In some instances, the vector is a circular plasmid, which transforms a target cell by integration into the cellular genome or exist extrachromosomally (e.g., autonomous replicating plasmid with an origin of replication). Exemplary vectors include pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing DNA encoding the antigen and enabling a cell to translate the sequence to an antigen that is recognized by the immune system.
[0358] In some instances, the recombinant nucleic acid vaccine comprises a viral vector.
Exemplary viral based vectors include adenoviral based, lentivirus based, adeno-associated (AAV) based, retroviral based, or poxvirus based vectors.
[0359] In some instances, the recombinant DNA vaccine is a linear DNA vaccine, or linear expression cassette ("LEC"), that is capable of being efficiently delivered to a subject via
electroporation and expressing one or more polypeptides disclosed herein. The LEC can be any linear DNA devoid of any phosphate backbone. The DNA can encode one or more microbial antigens. The LEC can contain a promoter, an intron, a stop codon, and/or a polyadenylation signal. In some cases, the LEC does not contain any antibiotic resistance genes and/or a phosphate backbone. In some cases, the LEC does not contain other nucleic acid sequences unrelated to the microbial antigen.
Method of Activating a STING Protein Dimer
[0360] In some embodiments, a method of stabilizing a stimulator of interferon genes (STING) protein dimer in a cell comprises (a) contacting a cell characterized with an elevated expression of a phosphodiesterase (PDE) or an elevated population of cytosolic DNA with a PDE inhibitor to inhibit hydrolysis of 2’3’-cGAMP; and (b) interacting 2’3’-cGAMP to a STING protein dimer to generate a 2’3’-cGAMP-STING complex, thereby stabilizing the STING protein dimer. In some instances, interacting of 2’3’-cGAMP to a STING protein dimer to generate a 2’3’-cG AMP-STING complex further activates the STING protein dimer. In some cases, activation of the STING protein dimer further leads to upregulating the production of type I interferon (IFN). In some cases, the production of IFNs is localized in a tumor microenvironment. [0361] In some instances, the cell has an elevated population of cytosolic DNA. In some cases, the elevated population of cytosolic DNA is generated by an ICD-mediated event. In other cases, the elevated population of cytosolic DNA is generated by DNA structure -specific endonuclease MUS81.
[0362] In some cases, the 2’3’-cGAMP degradation polypeptide is a phosphodiesterase (PDE). In some cases, the 2’3’-cGAMP degradation polypeptide is an ectonucleotide
pyrophosphatase/phosphodiesterase (ENPP) protein. In some cases, the 2’3’-cGAMP degradation polypeptide is ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-l).
[0363] In some instances, the cell comprises a cancer cell. In some instances, the cancer cell is a solid tumor cell (e.g., a breast cancer cell, a lung cancer cell or a cancer cell from glioblastoma). In other instances, the cancer cell is a cell from a hematologic malignancy (e.g., from a lymphoma, a leukemia, a myeloma or a B-cell malignancy).
[0364] In some embodiments, the cell comprises an effector cell. In some instances, the effector cell comprises a dendritic cell or a macrophage.
[0365] In some embodiments, the cell comprises a non -cancerous cell residing within a tumor microenvironment in which the cell comprises an elevated population of cytosolic DNA. In some cases, the cell comprises a non-cancerous cell residing within a tumor microenvironment in which the cGAS/STING pathway is activated.
Dosing regiment
[0366] In some embodiments, the ENPP-l inhibitor described herein is administered for therapeutic applications. In some embodiments, the ENPP-l inhibitor is administered once per day, twice per day, three times per day or more. The ENPP-l inhibitor is administered daily, every day, every alternate day, five days a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month, three times per month, or more. The ENPP-l inhibitor is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more.
[0367] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the ENPP-l inhibitor is given continuously; alternatively, the dose of the ENPP-l inhibitor being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). In some instances, the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday is from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
[0368] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
[0369] In some embodiments, the amount of the ENPP-l inhibitor varies depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless is routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In some instances, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[0370] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages is altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
[0371] In some embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage varies within this range depending upon the dosage form employed and the route of administration utilized.
[0372] In some embodiments, the ENPP-l inhibitor is administered to a subject at least 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36 or 48 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 0.5 hour after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1 hour after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1.5 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 18 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 24 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 36 hours after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 48 hours after administration of the ICD inducer.
[0373] In some embodiments, the ENPP-l inhibitor is administered to a subject at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 28, 30 or 40 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1 day after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 13 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 14 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 28 days after administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 30 days after administration of the ICD inducer. [0374] In some embodiments, the ENPP-l inhibitor is administered to a subject at least 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36 or 48 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 0.5 hour prior to
administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1 hour prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1.5 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 hours prior to
administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 18 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 24 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 36 hours prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 48 hours prior to administration of the ICD inducer.
[0375] In some embodiments, the ENPP-l inhibitor is administered to a subject at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 28, 30 or 40 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 1 day prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 2 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 3 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 4 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 5 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 6 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 7 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 8 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 9 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 10 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 11 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 12 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 13 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 14 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 28 days prior to administration of the ICD inducer. In some cases, the ENPP-l inhibitor is administered to the subject at least 30 days prior to administration of the ICD inducer.
[0376] In some cases, the ENPP-l inhibitor is administered simultaneously with an ICD inducer.
[0377] In some cases, the ENPP-l inhibitor is administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 1 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 2 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 3 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 4 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 5 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 6 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 7 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 8 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 9 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 10 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 14 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 15 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 28 or more days. In some instances, the ENPP-l inhibitor is administered continuously for 30 or more days.
[0378] In some cases, the ENPP-l inhibitor is administered at predetermined time intervals for 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 1 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 2 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 3 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 4 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 5 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 6 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 7 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 8 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 9 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 10 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 14 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 15 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 28 or more days. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 30 or more days.
[0379] In some embodiments, the ENPP-l inhibitor is administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 1 or more month. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 2 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 3 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 4 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 5 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 6 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 7 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 8 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 9 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 10 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 11 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 12 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 24 or more months. In some instances, the ENPP-l inhibitor is administered at predetermined time intervals for 36 or more months.
[0380] In some cases, the ENPP-l inhibitor is administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 1 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 2 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 3 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 4 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 5 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 6 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 7 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 8 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 9 or more days. In some instances, the ENPP-l inhibitor is administered
intermittently for 10 or more days. In some instances, the ENPP-l inhibitor is administered intennitently for 14 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 15 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 28 or more days. In some instances, the ENPP-l inhibitor is administered intermittently for 30 or more days.
[0381] In some embodiments, the ENPP-l inhibitor is administered for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or more. In some embodiments, the ENPP-l inhibitor is administered for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles or more. In some cases, the ENPP-l inhibitor is administered for at least 1 cycle. In some cases, the ENPP-l inhibitor is administered for at least 2 cycles. In some cases, the ENPP-l inhibitor is administered for at least 3 cycles. In some cases, the ENPP-l inhibitor is administered for at least 4 cycles. In some cases, the ENPP-l inhibitor is administered for at least 5 cycles. In some cases, the ENPP-l inhibitor is administered for at least 6 cycles. In some cases, the ENPP-l inhibitor is administered for at least 7 cycles. In some cases, the ENPP-l inhibitor is administered for at least 8 cycles. In some instances, a cycle comprises 14 to 28 days. In some cases, a cycle comprises 14 days. In some cases, a cycle comprises 21 days. In some cases, a cycle comprises 28 days.
[0382] In some embodiments, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or more. In some embodiments, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles or more. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 cycle. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 2 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 3 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 4 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 5 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 6 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 7 cycles. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 8 cycles. In some instances, a cycle comprises 14 to 28 days. In some cases, a cycle comprises 14 days. In some cases, a cycle comprises 21 days. In some cases, a cycle comprises 28 days.
[0383] In some embodiments, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1, 5, 10, 14, 15, 20, 21, 28, 30, 60, or 90 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 1 day. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 5 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 10 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 14 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 15 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 20 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 21 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 28 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 30 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 60 days. In some cases, the ENPP-l inhibitor is administered simultaneously or sequentially with an ICD inducer for at least 90 days.
[0384] In some instances, the ENPP-l inhibitor is administered to a subject at a therapeutically effective amount. For example, the therapeutically effective amount is optionally administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 1 dose. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 2 or more doses. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 3 or more doses. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 4 or more doses. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 5 or more doses. In some instances, the therapeutically effective amount of the ENPP-l inhibitor is administered to a subject in 6 or more doses.
[0385] In some cases, the therapeutically effective amount of the ENPP-l inhibitor selectively inhibits hydrolysis of 2’3’-cGAMP.
[0386] In some embodiments, the therapeutically effective amount of the ENPP-l inhibitor further reduces ATP hydrolysis in ENPP-l by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or by less than 1% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 50% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 40% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 30% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 20% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 10% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 5% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 4% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP- 1 inhibitor reduces ATP hydrolysis in ENPP-l by less than 3% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 2% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor reduces ATP hydrolysis in ENPP-l by less than 1% relative to the ATP hydrolysis of the ENPP-l in the absence of the ENPP-l inhibitor. In some cases, the therapeutically effective amount of the ENPP-l inhibitor does not induce ATP hydrolysis in ENPP-l.
Additional Therapeutic Agents
[0387] In some embodiments, one or more methods described herein further comprising administering an additional therapeutic agent. In some instances, the additional therapeutic agent is a chemotherapeutic agent. In some instances, the additional therapeutic agent is an immune checkpoint inhibitor. Exemplary immune checkpoint inhibitor comprises an inhibitor of PD1, an inhibitor of PD- Ll, an inhibitor of TIM or an inhibitor of TIGIT. In some cases, the subject has a resistance to an immune checkpoint inhibitor prior to the administration of the inhibitor of PDE. In some cases, the ENPP-l inhibitor and the additional therapeutic agent is administered simultaneously. In other cases, the ENPP-l inhibitor and the additional therapeutic agent is administered sequentially. In some instances, the ENPP-l inhibitor is administered before administering the additional therapeutic agent. In other instances, the ENPP-l inhibitor is administered after administering the additional therapeutic agent.
Kits/Article of Manufacture
[0388] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic. [0389] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
[0390] For example, the container(s) include the ENPP-l inhibitor, optionally with one or more additional therapeutic agents disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
[0391] A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
[0392] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
[0393] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
EXAMPLES
[0394] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Example 1: N-(4-((7,8-dimethoxy-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)sulfamide:
Figure imgf000103_0001
Step 1: 4-chloro-6,7-dimethoxy-3-nitroquinoline
[0395] Procedure: To a stirred solution of 6,7-dimethoxyquinolin-4-ol (5 g, 24.3 mmol) in propionic acid (150 mL) was added fuming nitric acid (2.5 mL) and the resulting reaction mixture was stirred at 100° C for 6 h. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Then the reaction mixture was cooled to 0 °C. The solid was filtered and washed with pentane, then triturated with methanol-diethyl ether (1:5), flitered and dried under vaccum pressure to afford 6,7-dimethoxy-3-nitroquinolin-4-ol as yellow solid (4.7 g, 77%). 1HNMR (400 MHz, DMSO-d6): d 12.71 (s, 1H), 9.04 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H).
To a stirred solution of 6,7-dimethoxy-3-nitroquinolin-4-ol (3.6 g, 14.3 mmol) in dichloromethane (50 mL) was added thionyl chloride (2.6 mL, 35.9) at 0 °C followed by addition of catalytic amount of dimethylformamide (0.4 mL) and the resulting reaction mixture was stirred at 40° C for 12 h. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. The reaction mixture was cooled to room temperature then evaporated under reduced pressure. To the residue obtained was added ice water and stirred for 10 minutes. The precipitated solid was filtered and washed with hexane and dried under vaccum pressure to afford 4-chloro-6,7-dimethoxy-3- nitroquinoline as yellow solid (3.5 g, 91%). 1HNMR (400 MHz, DMSO-d6): d 9.18 (s, 1H), 7.56 (d, J = 7.2 Hz, 2H), 4.01 (s, 6H). LC-MS (ES) m/z = 269.0 [M+H]+.
Step 2: N-(4-aminobenzyl)-6,7-dimethoxy-3-nitroquinolin-4-amine
[0396] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (3.1 g, 11.5 mmol) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (5.8 mL, 33.3 mmol) at room temperature followed by addition of 4-(aminomethyl)aniline (1.51 mL, 13.4 mmol) and the resulting reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC using 40% ethylacetate in hexane as eluent. To the reaction mixture was added ice water and the resulting solid filtered and washed with hexane, then dried under vacuum pressure to afford N-(4- aminobenzyl)-6,7-dimethoxy-3-nitroquinolin-4-amine as yellow solid (4 g, 98%). 1HNMR (400 MHz, DMSO-d6): d 9.05-9.15 (m, 1H), 8.88 (s, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 6.97 (d, J= 7.2 Hz, 2H), 6.50 (d, J= 7.6 Hz, 2H), 5.04 (s, 2H), 4.70-4.80 (m, 2H), 3.91 (s, 3H), 3.77 (s, 3H).
Step 3: tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4-l)amino)methyl)phenyl)carbamate
[0397] Procedure: To a stirred solution of N-(4-aminobenzyl)-6,7-dimethoxy-3-nitroquinolin-4- amine (4 g, 11.2 mmol) in tetrahydrofuran (50 mL) was added Boc anhydride (5.1 mL, 22.5 mmol) at room temperature and the resulting reaction mixture stirred at 60° C for 12 h. The progress of the reaction was monitored by TLC using 50% ethylacetate in hexane as eluent. To the reaction mixture was added water (40 mL) and extracted with ethylacetate (2 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under vacuum pressure to obtain the desired crude compound. The crude product was purified by combiflash purifier to afford tert-butyl (4-(((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)methyl)phenyl)carbamate as yellow solid (3.95 g, 77%). 1HNMR (400 MHz, DMSO-d6): d 9.32 (s, 1H), 9.08-9.16 (m, 1H), 8.86-8.92 (m, 1H), 7.68 (s, 1H), 7.40 (d, J= 6.4 Hz, 2H), 7.30 (s, 1H), 7.20 (d, J= 6.8 Hz, 2H), 4.81-4.82 (m, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 1.45 (s, 9H). LC-MS (ES) m/z = 455.2 [M+H]+.
[0398] To a stirred solution of tert-butyl (4-(((6,7-dimethoxy-3-nitroquinolin-4- yl)amino)methyl)phenyl)carbamate (3.9 g, 8.50 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added palladium on carbon (0.5 g) at room temperature and the resulting reaction mixture stirred for 7 h at room temperature under hydrogen atmosphere. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture was filtered through diatomaceous earth and the filterate evaporated under reduced pressure to obtain the desired crude compound. The crude product was purified by combiflash purifier to afford tert-butyl (4-(((3- amino-6,7-dimethoxyquinolin-4-yl)amino)methyl)phenyl)carbamate as pale brown solid (3.18 g, Impure). 1HNMR (400 MHz, DMSO-d6): d 9.17 (s, 1H), 8.13 (s, 1H), 7.29 (d, J= 8 Hz, 2H), 7.23 (s, 1H), 7.20 (d, J= 5.2 Hz, 2H), 7.04 (s, 1H), 5.27 (t, J= 7.2 Hz, 1H), 4.70 (s, 2H), 4.24 (d, J= 7.2 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 1.43 (s, 9H). LC-MS (ES) m/z = 425.2 [M+H]+
Step 4: 1 -(4-aminobenzyl)-7,8-dimethoxy-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one hydrochloride
[0399] Procedure: To a stirred solution of tert-butyl (4-(((3-amino-6,7-dimethoxyquinolin-4- yl)amino)methyl)phenyl)carbamate (0.5 g, 1.10 mmol) in tetrahydrofuran (10 mL) was added triethylamine (0.46 mL, 3.30 mmol) at 0 °C followed by addition of 20% phosgene solution in toluene (0.8 mL, 2.30 mmol) and the resulting reaction mixture stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture quenched with ice followed by addition of saturated aqueous NaHC03 solution and extracted with ethylacetate (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the desired crude compound. The crude product was purified by combiflash purifier to afford tert-butyl (4-((7,8- dimethoxy-2 -oxo -2,3 -dihydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)methyl)phenyl)carbamate as pale yellow solid (0.28 g, 54%). 1HNMR (400 MHz, DMSO-d6): d 11.45 (s, 1H), 9.26 (s, 1H), 8.46 (s, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.27 (s, 1H), 7.11 (d, J= 7.6 Hz, 2H), 7.05 (s, 1H), 5.42 (s, 2H), 3.81 (s, 3H),
3.63 (s, 3H), 1.41 (s, 9H). LC-MS (ES) m/z = 451.4 [M+H]+.
[0400] To a stirred solution oftert-butyl (4-((7,8-dimethoxy-2-oxo-2,3-dihydro-lH-imidazo[4,5- c]quinolin-l-yl)methyl)phenyl)carbamate (0.27 g, 0.77 mmol) in dichloromethane (10 mL) was added 4M HC1 in dioxane (2.0 mL) at room temperature and the resulting reaction mixture was stirred for 4 h at room tempertaure. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture was concentrated under reduced pressure to get the solid product. The solid obtained was triturated with diethyl ether, dried under vacuum pressure to afford 1 - (4-aminobenzyl) -7,8 -dimethoxy- 1 , 3 -dihydro-2H-imidazo [4, 5 -c] quinolin-2 -one hydrochloride as pale yellow solid (0.25 g, Crude). 1HNMR (400 MHz, DMSO-d6): d 12.43 (s, 1H), 8.83 (s, 1H), 7.53 (s, 1H), 7.23 (s, 1H), 7.16 (d, J= 6.8 Hz, 2H), 6.86-6.94 (m, 2H), 5.56 (s, 2H), 4.8-5.7 (m, 2H), 3.96 (s, 3H), 3.66 (s, 3H). LC-MS (ES) m/z = 351.0 [M+H-HC1]+
Step 5: N-(4-((7,8-dimethoxy-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)sulf amide
[0401] Procedure: To a stirred solution of l-(4-aminobenzyl)-7,8-dimethoxy-l,3-dihydro-2H- imidazo[4,5-c]quinolin-2-one hydrochloride (0.2 g, 0.51 mmol) in acetonitrile (15 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.53 mmol) at 0° C followed by addition of 4-nitrophenyl sulfamate (0.22 g, 1.03 mmol) and the resulting reaction mixture stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. The solid formed in the reaction mixture was filtered off and dried under vacuum pressure. The solid was triturated with tetrahydrofuran-water ( 1 : 0.5 ratio), filtered, dried under vacuum pressure to afford N-(4-((7,8-dimethoxy-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)sulfamide as an off white solid (0.035 g, 16%). 1HNMR (400 MHz, DMSO-d6): d 11.47 (s, 1H), 9.45 (s, 1H),
8.46 (s, 1H), 7.28 (s, 1H), 7.14 (d, J= 8 Hz, 2H), 7.02-7.06-7.09 (m, 3H), 7.01 (s, 2H), 5.44 (s, 2H),
3.82 (s, 3H), 3.63(s, 3H). LC-MS (ES) m/z = 430.1 [M+H]+. HPLC purity 99.14% at 220nm.
Example 2: N-(4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)sulfamide:
Figure imgf000105_0001
Step 1: tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl) carbamate
[0402] Procedure: To a stirred solution of tert-butyl (4-(((3-amino-6,7-dimethoxyquinolin-4- yl)amino)methyl)phenyl)carbamate (0.5 g, 1.10 mmol) in l,4-dioxane (10 mL) was added triethylorthoformate (0.39 mL, 2.30 mmol) at room temperature and the resulting reaction mixture was stirred for 12 h at 100 °C. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. To the reaction mixture was added water and and extracted with ethylacetate (2 x 40 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the desired crude compound. The obtained crude product was purified by combiflash purifier to afford tert-butyl (4-((7,8- dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)carbamate as an off-white solid (0.46 g, 90%). 1HNMR (400 MHz, DMSO-d6): d 9.29 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 7.47 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.26 (s, 1H), 7.01 (d, J= 8.4 Hz, 2H), 5.89 (s, 2H), 3.85 (s, 3H), 3.70 (s, 3H), 1.41 (s, 9H). LC-MS (ES) m/z = 435.2 [M+H]+.
Step 2: 4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)aniline hydrochloride
[0403] Procedure: To a stirred solution of tert-butyl (4-((7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)methyl)phenyl)carbamate (0.46 g, 1.0 mmol) in dichloromethane (10 mL) was added 4M HC1 in dioxane (2.0 mL) at room temperature and the resulting reaction mixture was stirred for 12 h at room tempertaure. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture was concentrated under reduced pressure to get the solid product which was triturated with diethyl ether, dried under vacuum pressure to afford 4-((7,8- dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)aniline hydrochloride as off-white solid (0.45 g, Crude). 1HNMR (400 MHz, DMSO-d6): d 9.69 (s, 1H), 8.97 (s, 1H), 7.87 (s, 1H), 7.34 (s, 1H), 7.22- 7.30 (m, 4H), 6.18 (s, 2H), 4.8-5.7 (m, 2H), 3.93 (s, 3H), 3.75 (s, 3H). LC-MS (ES) m/z = 335.2
[M+H-HC1] .
Step 3: N-(4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)sulfamide
[0404] Procedure: To a stirred solution of 4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)aniline hydrochloride (0.1 g, 0.26 mmol) in acetonitrile (30 mL) was added N,N- diisopropylethylamine (0.22 mL, 1.34 mmol) at 0° C followed by added 4-nitrophenyl sulfamate (0.29 g, 1.34 mmol) and the resulting reaction mixture was stirred for 12 h at 100° C. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture was cooled to room temperature and the solid formed filtered and dried under reduced pressure. The solid was triturated with tetrahydrof iran (2 x 2 mL), filtered, dried under reduced pressure to afford N-(4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)sulfamide as off-white solid (0.035 g, 28%). 1HNMR (400 MHz, DMSO-d6): d 9.49 (s, 1H), 9.06 (s, 1H), 8.50 (s, 1H), 7.48 (s,
1H), 7.28 (s, 1H), 7.02-7.09 (m, 6H), 5.87 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H). LC-MS (ES) m/z =
414.3 [M+H]+. HPLC purity 98.32% at 225nm. Example-3: N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)benzyl)sulfamide
Figure imgf000107_0001
Step 1: tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)benzyl)carbamate
[0405] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (2 g, 7.46mmol) in dimethyl formamide (20 mL) was added potassium carbonate (3 g, 22.38mmol) followed by tert-butyl (4-aminobenzyl)carbamate (1.8 g, 8.20 mmol) and heated into 100 °C for 6 h. The progress of the reaction was monitored by TLC. Then the reaction was added ice cold water (100 mL) and extracted with ethyl acetate (3 c 100 mL), combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column
chromatography using 48% ethyl acetate in hexane to afford tert-butyl (4-((6,7-dimethoxy-3- nitroquinolin-4-yl)amino)benzyl)carbamate (1 g, 30 %) as yellow solid. 1HNMR (400 MHz, DMSO- d6): d 9.78 (s, 1H), 8.95 (s, 1H), 7.43 (s, 1H), 7.36 (s, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.03 (d, J= 8.4 Hz, 2H), 4.06-4.07 (m, 2H), 3.93(s, 3H), 3.64 (s, 3H), 1.37 (s, 9H).LC-MS (ES) m/z = 455.2 [M+H]+. Step 2: tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)benzyl)carbamate
[0406] Procedure: To a stirred solution of tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4- yl)amino)benzyl)carbamate (1 g, 2.20mmol) in methanol (30 mL) and water (10 mL) was added Iron powder (0.60 g, 11.01 mmol) followed by ammonium chloride (1.16 g, 22.02 mmol) and the reaction mixture heated to and stirred at 60 °C for 5 h. The progress of the reaction was monitored by TLC. Then the reaction mixture was filtered through celite, rinsed using methanol and the solvent evaporated under reduced pressure. Water (100 mL) was added then extracted with ethyl acetate (2 c 100 mL) and the combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to afford tert-butyl (4-((3- amino-6,7-dimethoxyquinolin-4-yl)amino)benzyl)carbamate (0.85 g, 91%) as Yellow solid. LC-MS (ES) m/z = 425.2 [M+H]+. Step 3: tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)benzyl)carbamate
[0407] Procedure: To a stirred solution of tert-butyl (4-((3 -amino-6, 7-dimethoxy quinolin-4- yl)amino)benzyl)carbamate (0.4 g, 0.94mmol) in acetonitrile (50 mL) was added triethylorthoformate (0.47 mL, 2.83 mmol) and the reaction mixture heated to 90 °C then stirred for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, water (100 mL) was added and extracted with ethyl acetate (2 c 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to afford tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)benzyl)carbamate (0.4g, crude) as a yellow solid.1HNMR (400 MHz, DMSO-d6): d 9.28 (s, 1H), 8.59 (s, 1H), 7.69 (d, J= 8 Hz, 2H), 7.56-7.58 (m, 4H), 6.58 (s, 1H), 4.25-4.27 (m, 2H), 3.86 (s, 3H), 3.41 (s, 3H), 1.40 (s, 9H). LC-MS (ES) m/z = 435.2 [M+H]+.
Step 4: (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)methanamine hydrochloride
[0408] Procedure: A stirred solution of tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)benzyl)carbamate (0.4 g, 0.92mmol) in dichloromethane (3 mL) was cooled to 0 °C and 4M HC1 in dioxan (0.56 mL) added then the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure to afford (4- (7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)p henyl)methanamine hydrochloride salt (0.35 g, crude) as an off-white solid. The crude product was used in next reaction step without further purification 1HNMR (400 MHz, DMSO-d6): d 9.75 (s, 1H), 8.95 (s, 1H), 8.65 (bs, 3H), 7.87-7.90 (m, 5H), 6.68 (s, 1H), 4.20-4.22 (m, 2H), 3.97 (s, 3H), 3.49 (s, 3H).LC-MS (ES) m/z = 335.1 [M+H]+. Step 5: N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)benzyl)sulfamide
[0409] Procedure: To a stirred solution of (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)methanamine hydrochloride salt (0.15 g, 0.40 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.2 mL, 1.21 mmol) at 0 °C and 4-nitrophenyl sulfamate (0.096 g, 0.44 mmol) the reaction mixture was stirred at room temperaturefor 3 h. The progress of the reaction was monitored by TLC. Then the reaction mixture was added water (100 mL) and extracted with ethyl acetate (3 c 100 mL), combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered andevaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography using 8%methanol in dichloromethane to afford N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)benzyl)sulfamide (0.070 g, 44%) as an Off white solid. 1HNMR (400 MHz, DMSO-d6): d 9.10 (s, 1H), 8.45 (s, 1H), 7.60-7.67 (m, 4H), 7.53 (s, 1H), 7.24-7.27 (m, 1H), 6.64-6.68 (m, 2H), 6.58 (s, 1H), 4.23-4.24 (m,
2H), 3.89 (s, 3H), 3.41 (s, 3H).LC-MS (ES) m/z = 414.0 [M+H]+. HPLC purity 99.65% at 254 nm. Example-4: N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)sulfamide
Figure imgf000109_0001
Step 1: tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)phenyl)carbamate
[0410] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (0.5 g, 1.86 mmol) in dimethylformamide (20 mL) was added sodium carbonate (0.57 g, 5.40 mmol) followed by addition of tert-butyl (4-aminophenyl)carbamate (0.41 g, 1.98 mmol) and let stir at room temperature for 16 h. The progress of the reaction was monitored by TLC. Ice cold water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (3 x 50 mL), combined organic layers washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography to afford tert- butyl (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)phenyl)carbamate (0.55 g, 67 %). 1HNMR (400 MHz, DMSO-d6): d 9.76 (s, 1H), 9.34 (s, 1H), 8.91 (s, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H), 7.01 (d, J= 8.8 Hz, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 1.46 (s, 9H). LC-MS (ES) m/z = 441.2 [M+H]+.
Step 2: tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)phenyl)carbamate
[0411] Procedure: To a stirred solution of tert-butyl (4-((6,7-dimethoxy-3-nitroquinolin-4- yl)amino)phenyl)carbamate (0.5 g, 1.13 mmol) in ethanol (25 mL) and water (10 mL) was added Iron powder (0.63 g, 11.35 mmol) followed by addition of ammonium chloride (1.21 g, 22.70 mmol) and the reaction mixture heated at 90 °C for 2 h. The progress of the reaction was monitored by TLC. Then the reaction mixture was filtered through celite, rinsed using ethanol and evaporated under reduced pressure. Water (50 mL) was added and the product extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to afford tert-butyl (4-((3-amino-6,7-dimethoxyquinolin-4- yl)amino)phenyl)carbamate (0.4 g, Crude). LC-MS (ES) m/z = 411.2 [M+H]+. Step 3: tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)carbamate
[0412] Procedure: To a stirred solution of tert-butyl (4-((3 -amino-6, 7-dimethoxy quinolin-4- yl)amino)phenyl)carbamate (0.3 g, 0.94 mmol) in acetonitrile (15 mL) was added triethylorthoformate (0.36 mL, 2.19 mmol) and the reaction mixture heated at 110 °C for 4 h. The progress of the reaction was monitored by TLC. Then the reaction mixture was evaporated under reduced pressure, water (50 mL) added and extracted with ethyl acetate (2 x 50 mL), combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain the desired crude compound. The obtained crude was further purified by combiflash purifier to afford tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)carbamate (0.21 g, 69%). 'H NMR (400 MHz, DMSO-d6) d ppm 9.70 (s, 1H), 9.08 (s, 1H), 8.39 (s, 1H), 7.73 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.8 Hz, 2H), 7.53 (s, 1H), 6.70 (s, 1H), 3.86 (s, 3H), 3.45 (s, 3H), 1.50 (s, 9H). LC-MS (ES) m/z = 421.1 [M+H]+.
Step 4: 4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)aniline 2,2,2-trifluoroacetate
[0413] Procedure: To a stirred solution of tert-butyl (4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)phenyl)carbamate (0.21 g, 0.49 mmol) in dichloromethane (5 mL) was added 30% trifluroacetic acid in dichloromethane (10 mL) dropwise at 0 °C and the resulting reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure to afford (4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)aniline 2,2,2-trifluoroacetate salt (0.14 g, 95 %). LC-MS (ES) m/z = 321.1 [M+H]+. Step 5: N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)sulfamide
[0414] Procedure: To a stirred solution of (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)aniline 2,2,2-trifluoroacetate (0.12 g, 0.40 mmol) in acetonitrile (5 mL) was added N,N- diisopropylethylamine (0.14 mL, 0.81 mmol) at 0 °C followed by addition of 4-nitrophenyl sulfamate (0.064 g, 0.29 mmol). The reaction mixture was then stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. To the reaction mixture was added water (50 mL) and extracted with ethyl acetate (3 c 50 mL), combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography to afford N-(4-(7,8- dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)sulfamide (0.030 g, 27%). 1HNMR (400 MHz, DMSO-d6): d 9.93 (s, 1H), 9.08 (s, 1H), 8.41 (s, 1H), 7.62 (d, J= 8.8 Hz, 2H), 7.53 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.30 (s, 2H), 6.65 (s, 1H), 3.89 (s, 3H), 3.45 (s, 3H).LC-MS (ES) m/z = 400.0 [M+H]+. HPLC purity: 97.81%. Example 5: ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)sulfamide
Figure imgf000111_0001
Step 1: methyl (trans)-4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino) cyclohexane-l-carboxylate
[0415] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (2 g, 7.44 mmol) in N,N-Dimethylformamide (15 mL) was added potassium carbonate (2.05 g, 14.88 mmol) at room temperature followed by added methyl (trans)-4-aminocyclohexane-l-carboxylate (1.053 g,
6.70 mmol) and the resulting reaction mixture was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC using 30% ethylacetate in hexane as eluent. To the reaction mixture was added ice water (150 mL) and yellow solid precipitated out. It was filtered and washed with hexane, dried under vacuum pressure to afford methyl (trans)-4-((6,7-dimethoxy-3-nitroquinolin- 4-yl)amino)cyclohexane-l-carboxylate (1.3 g, 46.4 %). LC-MS (ES) m/z = 390.2 [M+H]+
Step 2: methyl (trans)-4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)cyclohexane-l- carboxylate
[0416] Procedure: To a stirred solution of (trans)-4-((6,7-dimethoxy-3-nitroquinolin-4- yl)amino)cyclohexane-l-carboxylate (1.2 g, 3.08 mmol) in ethyl acetate (20 mL) under argon atmosphere was added carefully Pd/C (10 % on carbon) at room temperature. The resulting reaction mixture was degasified under vaccum and kept under hydrogen ballon bladder pressure, stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC using 50% ethylacetate in hexane as eluent. The reaction mixture was filtered through celite bed and the filterate was evaporated to remove solvents under reduced pressure to to afford methyl (trans)-4-((3-amino- 6,7-dimethoxyquinolin-4-yl)amino)cyclohexane-l-carboxylate (1.2 g, crude) as brown solid. LC-MS (ES) m/z = 360.1 [M+H]+
Step 3: methyl (trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l- carboxylate
[0417] Procedure: To a stirred solution of methyl (trans)-4-((3-amino-6,7-dimethoxyquinolin-4- yl)amino)cyclohexane-l-carboxylate (1.2 g, 3.33 mmol) in acetonitrile (15 mL) in sealed tube was added trimethyl orthoformate (1.84 mL, 16.69 mmol). The reaction mixture was stirred at 100 °C for 6 h at room temperature under hydrogen atmosphere. The progress of the reaction was monitored by TLC using 10 % methanol in dichloromethane as eluent. Solvents were evaporated from reaction mixture under reduced pressure get crude compound. Further obtained crude was purified by combiflash purifier in silica gel coloumn using methanol in dichloromethane to afford methyl (trans)- 4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l-carboxylate (1 g, 81.3 %) as off- white solid. LC-MS (ES) m/z = 370.2 [M+H]+
Step 4: ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methanol
[0418] Procedure: To a stirred solution of tert-butyl methyl (trans)-4-(7,8-dimethoxy-lH- imidazo[4,5-c]quinolin-l-yl)cyclohexane-l-carboxylate (0.5 g, 1.35 mmol) in tetrahydrofuran (15 mL) was added diisobutylaluminium hydride (1 M in toluene) ( 2.7 mL, 2.70 mmol) at -78 °C and stirred for 1 h. Reaction mixture stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture cooled to 0 °C and quenched with saturated ammonium chloride solution (10 mL) and extracted with ethylacetate (2 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the desired crude compound. Further obtained crude was purified by combiflash purifier to afford ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methanol (0.3 g, 64.9%) as off-white solid.LC-MS (ES) m/z = 342.2 [M+H]+
Step 5: ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methyl methanesulfonate
[0419] Procedure: To a stirred solution of ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin- l-yl)cyclohexyl)methanol (0.2 g, 0.58 mmol) in dichloromethane (10 mL) were added triethylamine (0.248 mL, 1.75 mmol) and methane sulfonyl chloride (0.068 mL, 0.878 mmol) at room temperature. The resulting reaction mixture was stirred for 2 h at room tempertaure. The progress of the reaction was monitored by TLC using 5% methanol in dichloromethane as eluent. Reaction mixture was diluted with dichloromethane (60 mL) and saturated sodium bicarbonate solution (50 mL) was added. The organic layer separated and the aqueous was extracted with dichloromethane (2 x 20 mL). The combined organic layer was seperated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the desired ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methyl methanesulfonate (0.12 g, Crude) as brown solid. It was taken to next step with out purification. LC-MS (ES) m/z = 420.2 [M+H]+.
Step 6: ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methanamine
[0420] Procedure: To solution of ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methyl methanesulfonate (0.12 g, 0.286 mmol) in methanol (10 mL) in autoclave was saturated methanolic ammomnia (12 mL) at room temperature. The autoclave was sealed and heated at 100 °C for 16 h. Reaction mixture cooled to room temperature and carefully released pressure from autoclave. Reaction mixture methanol was evaporated to remove excess methanol and ammonia. The obtained crude was then was diluted with DMwater (60 mL) and extracted with dichloromethane (2 x 60 mL). The combined organic layer was seperated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the desired compound ((trans)-4-(7,8-dimethoxy-lH- imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methanamine (0.06 g, crude) as yellow solid. It was then taken forward to next step with out further purification. LC-MS (ES) m/z = 341.2 [M+H]+.
Step 7: ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)sulfamide
[0421] Procedure: To a stirred solution of ((trans)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin- l-yl)cyclohexyl)methanamine (0.04 g, 0.117 mmol) in Acetonitrile (10 mL) were added N,N- diisopropylethylamine (0.081 mL, 0.468 mmol) and 4-nitrophenyl sulfamate (0.028 g, 0.129 mmol) at room temperature. The resulting reaction mixture was stirred for 6 h at room temperature. The progress of the reaction was monitored by TLC using 10% methanol in dichloromethane as eluent. Acetonitrile was removed from reaction under reduced pressure. The obtained crude was then was diluted with DMwater (40 mL) and extracrted with methanol in dichloromethane (2 x 40 mL). The combined organic layer was seperated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude compound further obtained crude was purified by combiflash purifier in silica gel coloumn with methanol and dichloromethane as eluents to afford ((trans)-4-(7,8- dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)sulfamide (0.005 g, 10.1%) as white solid. 1HNMR (400 MHz, DMSO-d6): d 9.04 (s, 1H), 8.48 (s, 1H), 7.55 (d, J= 10.8 Hz, 2H), 6.60 - 6.51 (m, 1H), 6.45 (s, 2H), 4.95 - 4.85 (m, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 2.82 (t, J= 6.2 Hz, 2H), 2.36 - 2.31 (m, 2H), 2.03 - 2.01 (m, 2H), 1.95 - 1.89 (m, 2H), 1.70 - 1.58 (m, 1H), 1.37 - 1.31 (m, 2H). LC- MS (ES) m/z = 420.4 [M+H]+. HPLC purity 99.4 %.
Example 6: Synthesis of N-(4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)benzyl)cyclopropanesulfonamide
Figure imgf000113_0001
Yield: 24 %
[0422] Procedure: To a stirred solution of compound (4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinohn-l-yl)phenyl)methanamine hydrochloride (0.15 g, 0.404 mmol) in acetonitrile (10 mL) was added N,N-isopropyl ethylamine (0.211 mL, 1.213 mmol) and 3-methoxybenzoyl chloride (0.082 ml, 0.808 mmol). The resulting mixture was stirred at 70 °C for 12 h. The progress of the reaction was monitored by TLC (5 % Methanol in dichloromethane). Then the reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 c 50 mL). Organic layer was dried over sodium sulphate, filtered and distilled under vacuum. The crude residue was purified by gradient column chromatography using methanol in dichloromethane to afford N-(4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)benzyl)cyclopropanesulfonamide as an off white solid (0.042 g , 24 %). 1HNMR (400 MHz, DMSO-d6): d 9.09 (s, 1H), 8.44 (s, 1H), 7.79 (t, J= 6.2 Hz, 1H), 7.71 - 7.66 (m, 4H), 7.53 (s, 1H), 6.64 (s, 1H), 4.35 (d, J= 6.8 Hz, 2H), 3.89 (s, 3H), 3.42 (s, 3H), 2.61 - 2.56 (m, 1H), 0.95 - 0.93 (m, 4H). LC-MS (ES) m/z = 439.4 [M+H]+. HPLC purity 99.56% at 254 nm.
Example 7: Synthesis of (lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-N- hydroxycyclohexane-l-carboxamide
Figure imgf000114_0001
[0423] Potassium hydroxide (1.09 g, 19.49 mmol) was taken in 4 mL of dry MeOH at room temperature. This mixture was heated at 50 °C for 10 minutes until it became clear solution and later cooled to room temperature. Hydroxylamine hydrochloride (1.35 g, 19.49 mmol) was taken in 8 mL of dry MeOH at room temperature. This mixture was heated at 50 °C for 10 minutes until it became clear solution and later cooled to room temperature. This solution was added slowly to the already prepared Potassium hydroxide solution at 0 °C. The reaction mixture was stirred at room temperature for 10 minutes and added through a sodium sulphate bed to a stirring solution of to methyl (trans)-4- (7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l-carboxylate (0.4 g, 1.08 mmol) in dry MeOH (4 mL). The resulting reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC using 10% MeOH in DCM as eluent. Excess methanol was evaporated under reduced pressure using rotavapor to get crude which was adjusted to pH- 6 using saturated citric acid solution. The aqueous was extracted with 10 % Methanol/DCM, but the compound was higly soluble in water. The aqeous layer was then cooled and lyophilized for 16 h to get crude as pale yellow solid. 10 % MeOH/DCM was added to the crude and stirred for 30 minutes. The Organic layer decanted and evaporated under reduced pressure to get crude further obtained crude was purified by combiflash purifier in silica gel coloumn with methanol and dichloromethane as eluents to afford product as mixture, this was once again purified using Prep TLC plate with 10 % MeOH/DCM as mobile phase. The obtained compound was then washed with 5 % MeOH/DCM (2 x 5 mL) and chilled Acetonitrile (5 mL) washing. The compound was the dissolved in
acetonitrile/water, cooled to -78 °C to freeze completely. It was then kept in lyophilizer for 16 h to afford (lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-N-hydroxycyclohexane-l- carboxamide (0.030 g, 7.4%) as white solid. 1HNMR (400 MHz, DMSO-d6): d 10.48 (s, 1H), 9.01 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.99 - 4.92 (m, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 2.38 - 2.36 (m, 2H), 2.21 - 2.11 (m, 1H), 1.93 - 1.81 (m, 6H). LC-MS (ES) m/z = 371 [M+H]+ HPLC purity 95.06 %.
Example 8: Synthesis of N-(4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)sulfamide
Figure imgf000115_0001
Step 1 : fc/7-butyl (6,7-dimethoxyquinolin-4-yl)carbamate
[0424] Procedure: To a stirred solution of compound 4-chloro-6,7-dimethoxy quinoline (5 g, 22.421 mmol) in toluene (50 mL) was added cesium carbonate (14.6 g, 44.842 mmol), tert-butyl carbamate (3.2 g, 26.905 mmol). The mixture was purged with argon gas for 15 minutes, then added X-phos (1 g, 2.242 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1 g, 1.121 mmol) at room temparature, Reaction mixture was stirred for 16 h at 100 °C. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temparature, Reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 4% methanol in dichloroethane as eluent to afford tert-butyl (6,7-dimethoxyquinolin-4-yl) carbamate as an off white solid (4.6 g, 68%). LC-MS (ES) m/z = 305.2 [M+H] +.
Step 2 : 6,7-dimethoxyquinolin-4-amine
[0425] Procedure: To a stirred solution of compound tert-butyl (6,7-dimethoxyquinolin-4- yl)carbamate (4.5 g, 14.802 mmol) in DCM (30 mL), was added 4M HC1 in dioxane (15 mL) at 0 °C. Reaction mixture was stirred for 5 h at room temparature. Progress of the reaction was monitored by TLC. Reaction mixture was concentrated under reduced pressure to get the solid, the solid was dissolved in water and basified with 1N NaOH upto pH ~ 8.0, then extracted with DCM (2 x 50 mL). The combined organic layer were washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by diethyl ether to afford 6,7-dimethoxyquinolin-4-amine as an off white solid (2.5 g, 83%). LC-MS (ES) m/z = 205.1 [M+H] +. Step 3: 3-bromo-6,7-dimethoxyquinolin-4-amine
[0426] Procedure: To a stirred solution of compound 6,7-dimethoxyquinolin-4-amine (2.5 g, 12.254 mmol) in Aceticacid(lO mL) was added Bromine (0.7 mL, 13.480 mmol), at 0 °C. Reaction mixture was stirred at room temparature for 2 h. Progress of the reaction was monitored by TLC. The reaction mixture was added diethyl ether (30 mL), and stirred for 15 minutes, solid was precepitated, the solid compound was filtered. Taken the solid and dissolved in water and basified with 1N NaOH upto 8.0 pH, then extracted with DCM (2 x 30 mL), The combined organic layer were washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was washed with diethyl ether and n-pentane to afford 3-bromo-6,7-dimethoxyquinolin-4-amine as an off white solid (3 g, 86%). LC-MS (ES) m/z = 285 [M+H] +.
Step 4: (E)-3-(2-ethoxyvinyl)-6,7-dimethoxyquinolin-4-amine
[0427] Procedure: To a stirred solution of compound 3-bromo-6,7-dimethoxyquinolin-4-amine (1.5 g, 5.319 mmol) in ACN:Water (4: 1), was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (2.1 g, 10.0638 mmol) and potasium phosphate (2.25 g, 10.638 mmol) at room temparature. The mixture was purged with argon gas for 15 minutes, then added S-phos (0.160 g,
0.398 mmol), Palladium(II) acetate (0.036 g, 0.159 mmol) at room temparature, Reaction mixture was stirred for 16 h at 110 °C, Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temparature, Reaction mixture was filtered through celite and filterate was cocentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 7% methanol in dichloroethane as eluent to afford (E)-3-(2-ethoxyvinyl)-6,7- dimethoxyquinolin-4-amine as an off white solid (0.750 g, Crude). LC-MS (ES) m/z = 275.3 [M+H] +. Step 5: 7,8-dimethoxy-lH-pyrrolo [3, 2-c] quinoline
[0428] Procedure: To a stirred solution of compound (E)-3-(2-ethoxyvinyl)-6,7- dimethoxyquinolin-4-amine (0.350 g, 1.276 mmol) in 4M HC1 in MeOH (5 mL) in sealed tube at room temperature. Reaction mixture was stirred at 75 °C for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temparature and directly evaporated under reduced pressure to get the crude compound.The crude residue was dissolved in water and nuetralised with saturated sodium bicarbonate solution , then Extracted with ethylacetate (2 x 10 mL), The combined organic layer were washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was washed with diethyl ether and n-pentane to afford 7,8-dimethoxy-lH-pyrrolo[3,2-c]quinoline as an off white solid (0.200 g, Crude), LC-MS (ES) m/z = 229.0 [M+H] +.
Step 6: tert- butyl (4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)carbamate:
[0429] Procedure: To a stirred solution of compound 7,8-dimethoxy-lH-pyrrolo[3,2-c]quinoline (0.150 g, 0.657 mmol ) in l,4-Dioxane (4 mL) was added tert-butyl (4-bromobenzyl)carbamate (0.281 g, 0.986 mmol), Cs2C03 (0.643 g, 1.971 mmol) at room temperature. The mixture was purged with argon gas for 15 minutes, then added Xantphos(0.0l9 g, 0.032 mmol),
Tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.032 mmol) at room temparature, Reaction mixture was stirred for 16 h at 110 °C. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temparature, Reaction mixture was filtered through celite and filterate was cocentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 30% Ethylacetate in hexane as eluent to afford tert-butyl (4-(7,8- dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)carbamate as an colourless liquid (0.080 g, 28%), LC-MS (ES) m/z = 434.4 [M+H] +.
Step 7: (4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)phenyl)methanamine:
[0430] Procedure: To a stirred solution of compound tert-butyl (4-(7,8-dimethoxy-lH- pyrrolo[3,2-c]quinolin-l-yl)benzyl)carbamate(0.l00 g, 0.230 mmol ) in DCM(5 mL), was added 4M HC1 in Dioxane (2 mL) at 0 °C. Reaction mixture was stirred for 12 h at room temparature. Progress of the reaction was monitored by TLC. Reaction mixture was concentrated under reduced pressure to get the crude compound, The obtained crude was washed with diethyl ether and n-pentane to afford (4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)phenyl)methanamine.HCl as an off white solid (0.090 g, Crude). LC-MS (ES) m/z = 334.0 [M+H] +
Step 8: N-(4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)sulfamide:
[0431] Procedure: To a stirred solution of compound (4-(7,8-dimethoxy-lH-pyrrolo[3,2- c]quinolin-l-yl)phenyl)methanamine.HCl (0.090 g crude, 0.270 mmol ) in acetonitrile (5 mL) was added Di isopropyl ethylamine (0.1 mL, 0.54 mmol) and stirred for 5 minutes. Then 4-nitrophenyl sulfamate (0.064 g, 0.297 mmol) was added at RT, and stirred for 3 h at room temparature. The progress of the reaction was monitored by TLC. Then the reaction was quenched with water and the compound was extracted with ethyl acetate (2 x 10 mL), combined organic layer were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 5% methanol in dichloroethane as eluent to afford N-(4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)sulfamide as an off white solid (0.015 g, 13%). 1HNMR (400 MHz, DMSO-d6): d 9.0 (s, 1H), 7.62 (d, J= 8.4 Hz, 2H), 7.55(d, J= 8.4 Hz, 2H), 7.49 (d, J= 2.8 Hz, 1H), 7.46 (s, 1H), 7.23 (t, J= 6 Hz, lH),6.90 (d, J= 3.2 Hz, lH),6.66 (s, 2H), 6.56 (s, 1H), 4.2l(d, J= 6.8 Hz, 2H), 3.86 (s, 3H), 3.33(s, 3H). LC-MS (ES) m/z = 4l3.3[M-H]+ , HPLC purity 99.65% at 220 nm. Example 9: Synthesis of N-(4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)phenyl)sulfamide
Figure imgf000118_0001
Step 1 : 7,8-dimethoxy-l-(4-nitrophenyl)-lH-pyrrolo [3,2-c] quinoline:
[0432] Procedure: To a stirred solution of 7,8-dimethoxy-lH-pyrrolo[3,2-c]quinoline (0.2 g, 0.876 mmol ) in l,4-Dioxane(5 mL) was added l-bromo-4-nitrobenzene (0.210 g, 1.052 mol), and Cesium carbonate (0.857 g, 2.628 mmol) at room temparature, under argon condition and purged for 15 minutes then added Xantphos (0.025 g, 0.043 mmol), Tris(dibenzylideneacetone)dipalladium(0)
(0.040 g, 0.043 mmol) at room temperature. Reaction mixture was stirred for 16 h at 110 °C. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature, filtered through celite and filterate cocentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 2% methanol in dichloroethane as eluent to afford 7,8-dimethoxy-l-(4-nitrophenyl)-lH-pyrrolo[3,2-c]quinoline as an off white solid (0.160 g, 52%). LC-MS (ES) m/z = 350.1 [M+H]+.
Step 2: 4-(7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)aniline:
[0433] Procedure: To a stirred solution of 7,8-dimethoxy-l-(4-nitrophenyl)-lH-pyrrolo[3,2- c]quinolone (0.140 g, 0.401 mmol ) in methanol and water (4: 1) was added Zinc dust (0.131 g, 2.005 mmol) and ammonium chloride (0.107 g, 2.005 mmol) at room temperature. Reaction mixture was stirred for 3 h at 80 °C. Progress of the reaction was monitered by TLC. Reaction mixture was cooled to room temperature, filtered through celite and filterate was cocentrated under reduced pressure to get the crude compound. The obtained crude was washed with diethyl ether and n-pentane to afford 4- (7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)aniline as an off white solid (0.1 g, 78%). LC-MS (ES) m/z = 320.1 [M+H]+.
Step 3: N-(4-(7,8-dimethoxy-lH-pyrrolo [3,2-c] quinolin-l-yl)benzyl)sulf amide:
[0434] Procedure: To a stirred solution of compound 4-(7,8-dimethoxy-lH-pyrrolo[3,2- c]quinolin-l-yl)aniline(0.l g, 0.313 mmol ) in acetonitrile (5 mL) was added DIPEA (0.1 mL, 0.626 mmol) and stirred for 5 min. Then 4-nitrophenyl sulfamate(0.075 g, 0.344 mmol) was added at room temparature, and stirred for 4 h at room temparature. The progress of the reaction was monitored by TLC. Then the reaction was quenched with water and the compound was extracted with ethyl acetate (2 x 10 mL), combined organic layer were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash purifier using 9% methanol in dichloroethane as eluent to afford N-(4-(7,8-dimethoxy-lH-pyrrolo[3,2- c]quinolin-l-yl)benzyl)sulfamide as an off white solid (0.010 g, 8%). 1HNMR (400 MHz, DMSO-d6): d 9.87(s, 1H), 8.97(s, 1H), 7.48 (q, J= 8.4 Hz, 4H), 7.39(d, J= 8.4 Hz, 2H), 7.27(s, 2H), 6.86 (d, J =3.2Hz, 1H), 6.57(s, 1H), 3.85(s, 3H), 3.37(s, 3H). LC-MS (ES) m/z = 399.2[M+H]+ , HPLC purity 99.87% at 220 nm.
Example 10: N-(4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)-N- hydroxyform amide
Figure imgf000119_0001
Step 1 : 4-((7-methoxy-lH-imidazo [4,5-c] quinolin-l-yl)methyl)aniline
[0435] Procedure: To a stirred solution of tert-butyl (4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)carbamate (5.5 g, 13.613 mmol) in DCM (50 mL) was added 4M HC1 in Dioxane (50 mL) at room temperature and the resulting reaction mixture was stirred for 12 h at room tempertaure. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. Reaction mixture was concentrated under reduced pressure to get the solid. Th solid was basified with saturated aqueous NaHC03 solution (100 mL) and extracted with DCM (300 mL). The organic layer was dried over Na2S04, filtered and concentrated under vacuum pressure to afford 4-((7-methoxy-lH- imidazo[4,5-c]quinohn-l-yl)methyl)anihne as yellow colour solid (3.4 g, Crude). LC-MS (ES) m/z = 305.1 [M+H]+.
Step 2: 7-methoxy-l-(4-nitrosobenzyl)-lH-imidazo[4,5-c]quinoline
[0436] Procedure: To a stirred solution of 4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)aniline (0.5 g, 1.644 mmol, 1 eq) in DCM (40 mL) was added m-CPBA (0.73 g, 3.2894 mmol, 2 eq) at 0° C and the resulting reaction mixture was stirred for 3.5 h at roomtemparature. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. Reaction mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHC03 solution ( 100 mL).
The organic layer was dried over Na2S04, filtered and concentrated under vacuum pressure to afford 7-methoxy-l-(4-nitrosobenzyl)-lH-imidazo[4,5-c]quinolone as off white solid (0.42 g, crude). LC- MS (ES) m/z = 319.1 [M+H]+.
Step 3: N-(4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l-yl)methyl)phenyl)-N-hydroxyformamide
[0437] Procedure: To a stirred solution of 50 % aq glyoxylic acid (1.95 g, 26.415 mmol, 20 eq)) in water (50 mL) was adjusted to pH ~ 6 with 10 M NaOH and heated to 40 °C. To this solution 7- methoxy-l-(4-nitrosobenzyl)-lH-imidazo[4,5-c]quinolone (0.42g, 1.320 mmol, leq) in EtOH (20 mL) was added and the reaction was stirred for 2 h and then treated with 10 g of NaCl. The aqueous reaction was extracted twice with 300 mL of EtOAc, and the combined EtOAc extract was dried with Na2S04 and evaporated to give a pale yellow solid. The crude was purified by preparative TLC using 5% MeOH in DCM as eluent to afford N-(4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)-N-hydroxyformamide (2 mg). 1HNMR (400 MHz, DMSO-d6): d 10.35 - 10.42 (m, 1H), 9.16 (s, 1H), 8.65 - 8.60 (m, 1H), 8.48 (s, 1H), 8.03 (d, J= 9.2 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.52 (d, J= 2.8 Hz, 1H), 7.40 - 7.25 (m, 1H), 7.20 - 7.10 (m, 3H), 5.93 (s, 2H), 3.86 (s, 3H). LC-MS (ES) m/z = 349.1 [M+H|+. HPLC purity: 99.13% at 220 nm.
Example 11: (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)methanesulfonamide
Figure imgf000120_0001
Step 1: (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)phenyl)methanesulfonamide
[0438] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (1 g, 3.72 mmol) in N,N-Dimethylformamide (10 mL) was added potassium carbonate (0.77 g, 5.58 mmol) at room temperature followed by addition of (4 -aminophenyl)methane sulfonamide (0.74 g, 3.72 mmol) and the resulting reaction mixture was stirred for 24 h at room temperature. The progress of the reaction was monitored by TLC using 5 % methanol in dichloromethane as eluent. To the reaction mixture was added ice water (100 mL) and yellow solid precipitated out. It was then extracted with ethylacetate (2 x 50 mL). The combined organic layer washed with water (50 mL). Organic layer separated dried over sodium sulphate and evaporated under reduced pressure to get crude. The crude was then purified using combiflash purifier in silicagel coloumn using 4 % methanol in
dichloromethane to afford (4-((6,7-dimethoxy-3-nitroquinolin-4-yl)
amino)phenyl)methanesulfonamide (0.7 g, 47.2 %). LC-MS (ES) m/z = 419.3 [M+H]+
Step 2: (4-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)phenyl)methanesulfonamide
[0439] Procedure: To a stirred solution of (4-((6,7-dimethoxy-3-nitroquinolin-4- yl)amino)phenyl)methanesulfonamide (0.7 g, 1.76 mmol) in methanol/water (16 mL/4 mL) were added zinc dust (0.46 g, 7.04 mmol) and ammonium chloride (0.37 g, 7.04 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC using 10% methanol in dichloromethane as eluent. The reaction mixture was filtered through celite bed and the filterate was evaporated to remove solvents under reduced pressure to obtain yellow solid as crude. The crude was then purified using combiflash purifier in silicagel coloumn, desired product eluted in methanol/dichloromethane/triethylamine (4.5 % / 95%/0.5%) to afford (4-((3- amino-6, 7-dimethoxyquinolin-4-yl)amino)phenyl)methanesulfonamide (0.35 g, 51.1 %). LC-MS (ES) m/z = 389.3 [M+H]+
Step 3: (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)methanesulfonamide
[0440] Procedure: To a stirred solution of (4-((3-amino-6,7-dimethoxyquinolin-4- yl)amino)phenyl)methanesulfonamide (0.15 g, 0.38 mmol) in ethanol (10 mL) in sealed tube was added triethyl orthoformate (0.32 mL, 1.93 mmol). The reaction mixture was stirred at 80 °C for 16 h in sealed tube. The progress of the reaction was monitored by TLC using 10 % methanol in dichloromethane as eluent. Solvents were evaporated from reaction mixture under reduced pressure get crude compound. The obtained crude was washed with acetonitrile (2 x 5 mL) and with diethyl ether (2 x 5 mL) to get pure compound which was dried under vacuum. It was then dissolved in 5 % dichloromethane in t- butanol / water (10 mL/5mL) cooled to -78 °C to freeze and lypholysized for 16 h to afford (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)methanesulfonamide (0.03 g, 19.5 %) as off-white solid.1HNMR (400 MHz, DMSO-d6): d 9.10 (s, 1H), 8.46 (s, 1H), 7.74 (d, J= 8 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.52 (s, 1H), 6.95 (s, 2H), 6.63 (s, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.40 (s, 3H). LC-MS (ES) m/z = 399.2 [M+H]+ HPLC purity 99.22 % at 220 nm.
Example 12-17: The following examples were synthesized as described in examples 1-11
Figure imgf000121_0001
Figure imgf000122_0002
Example 18: Synthesis of N-(4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)sulfamide
Figure imgf000122_0001
Step 1: Synthesis of l-(4-bromobenzyl)-7,8-dimethoxy-lH-pyrrolo[3,2-c]quinoline:
[0441] To a stirred solution of 7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolone (0.3 g, 1.315 mmol) in DMF (10 mL) was added sodium hydride (0.15 g, 3.945 mmol) at 0 °C. Reaction mixture was stirred for 20 minutes at same temperature and l-bromo-4-(bromomethyl)benzene (0.35 g, 1.446 mmol) was added at 0 °C. Reaction mixture was allowed to stir at room temperature for lh. Progress of the reaction was monitored by TLC. Reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Combined organic layer were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 5% methanol in dichloroethane as eluent to afford l-(4-bromobenzyl)-7,8-dimethoxy- lH-pyrrolo[3,2-c]quinolone as an off white solid (0.32 g, 61%), LC-MS (ES) m/z = 399[M+H] +. Step 2: Synthesis of tert-butyl (4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)carbamate:
[0442] To a stirred solution of compound l-(4-bromobenzyl)-7,8-dimethoxy-lH-pyrrolo[3,2- c]quinoline (0.3 g, 0.1.010 mmol ) in toluene (10 mL) was added tert-butyl carbamate (0.14 g, 1.212 mmol), Cs2C03 (0.98 g, 3.03 mmol) at room temperature. The mixture was purged with argon gas for 15 minutes, then added X-phos (0.048 g, 0.101 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.046 g, 0.05 mmol). Reaction mixture was stirred for 16 h at 110 °C. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature and filtered through celite. Filtrate was concentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 7% methanol in dichloromethane as eluent to afford tert-butyl (4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)methyl)phenyl)carbamate as off white solid (0.2 g, 61%), LC-MS (ES) m/z = 434.4 [M+H] +.
Step 3: Synthesis of 4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)methyl)aniline hydrochloride:
[0443] To a stirred solution oftert-butyl (4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)carbamate (0.15 g, 0.346 mmol ) in DCM (5 mL), was added 4M HC1 in Dioxane (5 mL) at 0 °C. Reaction mixture was stirred for l2h at room temperature. Progress of the reaction was monitored by TLC. Reaction mixture was concentrated under reduced pressure to get the crude compound, The obtained crude was washed with diethyl ether and n-pentane to afford (4-(7,8- dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)phenyl)methanamine.HCl as off white solid (0.11 g, crude). LC-MS (ES) m/z = 334.0 [M+H] +
Step 4: Synthesis of N-(4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)sulfamide:
[0444] To a stirred solution of 4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l-yl)methyl)aniline hydrochloride (0.11 g crude, 0.298 mmol ) in acetonitrile (5 mL) was added diisopropyl ethylamine (0.13 mL, 0.74 mmol) and stirred for 5 minutes. 4-nitrophenyl sulfamate (0.078 g, 0.357 mmol) was added and stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate (2 x 10 mL), combined organic layers were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 5% methanol in dichloromethane as eluent to afford N-(4-((7,8-dimethoxy-lH-pyrrolo[3,2-c]quinolin-l - yl)methyl)phenyl) sulfonic amide as off white solid (0.02 g, 16 %). 1HNMR (400 MHz, DMSO-d6): d 9.45 (s, 1H), 9.07 (s, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.06 (d, J= 8.4 Hz, 2H), 7.00 (s, 2H), 6.96 - 6.91 (m, 3H), 5.91 (s, 2H), 3.87 (s, 3H), 3.69 (s, 3H); LC-MS (ES) m/z = 413.3[M-H] +; HPLC purity 99.32% at 220 nm.
Example 19: Synthesis of N-(4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)sulfamide
Figure imgf000123_0001
Step 1: Synthesis of 7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinoline:
[0445] To a stirred solution of 7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinoline (0.3 g, 1.315 mmol) in ethanol (20 mL), was added Pd/C (0.5g) and cone. HC1 (0.7 mL) at rt in autoclave. Reaction mixture was degassed with hydrogen gas and heated to 70 °C under 90 psi. Reaction mixture was stirred for 16 h. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature, Reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 9- 15 % methanol in dichloromethane as eluent to afford 7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2- c]quinoline as off white solid (0.12 g, crude). LC-MS (ES) m/z = 231 [M+H]+
Step 2: Synthesis of l-(4-bromobenzyl)-7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinoline
[0446] To a stirred solution of compound 7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinoline (0.1 g, 0.43 mmol ) in DMF (5 mL) was added sodium hydride (0.052 g, 1.30 mmol) at 0 °C.
Reaction mixture was stirred for 20 minutes at same temperature and l-bromo-4- (bromomethyl)benzene (0.129 g, 0.52 mmol) was added at 0 °C. Reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC. Reaction mixture was quenched with ice-cold water and extracted with ethyl acetate combined organic layers were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 7-9% methanol in dichloromethane as eluent to afford l-(4-bromobenzyl)-7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinolone as off white solid (0.12 g, crude), LC-MS (ES) m/z = 399.0 [M+H] +.
Step 3: Synthesis of tert-butyl (4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)carbamate
[0447] To a stirred solution of l-(4-bromobenzyl)-7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2- c]quinolone (0.12 g, 0.301 mmol ) in toluene (5 mL) was added tert-butyl carbamate (0.042 g, 0.36 mmol) & t-BuONa (0.087 g, 0.903 mmol) at room temperature. The mixture was purged with argon gas for 15 minutes, then added Ru-phos (0.007 g, 0.01 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.008 g, 0.009 mmol) at room temperature. Reaction mixture was stirred for 16 h at 110 °C. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature, Reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to get the crude compound. The obtained crude was purified by combiflash purifier using 7% methanol in dichloromethane as eluent to afford tert-butyl (4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2- c]quinolin-l-yl)methyl)phenyl)carbamate as off white solid (0.09 g, crude); LC-MS (ES) m/z = 436.2 [M+H] +. Step 4: Synthesis of 4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)aniline hydrochloride
[0448] To a stirred solution of tert-butyl (4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2- c]quinolin-l-yl)methyl)phenyl)carbamate (0.09 g, 0.206 mmol ) in DCM (5 mL), was added 4M HC1 in Dioxane (3 mL) at 0 °C. Reaction mixture was stirred for l2h at room temperature. Progress of the reaction was monitored by TLC. Reaction mixture was concentrated under reduced pressure to give the crude compound, The obtained crude was washed with diethyl ether and n-pentane to afford 4- ((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]qumolm-l-yl)methyl)aniline hydrochloride as off white solid (0.07 g, Crude). LC-MS (ES) m/z = 336.1 [M+H] +
Step 5: Synthesis of N-(4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2-c]quinolin-l- yl)methyl)phenyl)sulfamide:
[0449] To a stirred solution of compound 4-((7,8-dimethoxy-2,3-dihydro-lH-pyrrolo[3,2- c]quinolin-l-yl)methyl)aniline hydrochloride (0.070 g crude, 0. 208 mmol ) in acetonitrile (5 mL) was added diisopropyl ethylamine (0.1 mL, 0.624 mmol) and stirred for 5 minutes. Then 4-nitrophenyl sulfamate (0.055 g, 0.250 mmol) was added at RT, and stirred for 12 h, at room temperature. The progress of the reaction was monitored by TLC. Then the reaction was quenched with water and the compound was extracted with ethyl acetate (2 x 10 mL), combined organic layer were dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude compound. The obtained crude was purified by preparative HPLC to afford N-(4-((7,8-dimethoxy-2,3-dihydro-lH- pyrrolo[3,2-c]quinolin-l-yl)methyl)phenyl)sulfonic amide as off white solid (0.006 g). 1HNMR (400 MHz, DMSO-d6): d 9.40 (s, 1H), 8.16 (s, 1H), 7.27 (d, J= 8.4 Hz, 2H), 7.13 - 7.11 (m, 3H), 7.02 - 6.99 (m, 3H), 4.80 (s, 2H), 3.81 - 3.77 (m, 5H), 3.47 (s, 3H), 3.11 (t, J= 9.2 Hz, 2H); LC-MS (ES) m/z = 415 [M-H]+ ; HPLC purity 99.73% at 225 nm.
Example 20: Synthesis of N-(4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l- yl)benzyl)sulf amide
Figure imgf000125_0001
Step 1: Synthesis of 3-iodo-6,7-dimethoxyquinolin-4-ol
[0450] To a stirred solution of 6,7-dimethoxyquinolin-4-ol (4 g, 19.51 mmol) in AcOH (50 mL) was added N-iodosuccinimide (NIS, 4.39 g, 19.51 mmol) at room temperature. The resulting reaction mixture stirred for 3h at RT. The progress of the reaction was monitored by TLC. The precipitated solid filtered and washed with EtOAc (2 x 50 mL) and dried to afford 3-iodo-6,7-dimethoxyquinolin- 4-ol (5.3 g, 82 %) as off-white solid. LC-MS (ES) m/z = 331.9 [M+H]+.
Step 2: Synthesis of 4-chloro-3-iodo-6,7-dimethoxyquinoline
[0451] A solution of 3-iodo-6,7-dimethoxyquinolin-4-ol (5.3 g, 16.01 mmol) in POCl3 (50 mL) was heated at reflux for 3 h. The progress of the reaction was monitored by TLC. Reaction mixture concentrated under reduced pressure. Ice-cooled water (100 mL) was added. The precipitated solid was filtered to afford 4-chloro-3-iodo-6,7-dimethoxyquinoline (5.56 g, 99%) as brown solid. LC-MS (ES) m/z = 349.9 [M+H]+.
Step 3: Synthesis of 4-((3-iodo-6,7-dimethoxyquinolin-4-yl)amino)benzonitrile
[0452] To a stirred solution of 4-chloro-3-iodo-6,7-dimethoxyquinoline (2 g, 5.73 mmol) and 4- aminobenzonitrile (0.8 g, 6.87 mmol) in 1 -methoxy-2 -propanol (20 mL) was added pTSA (0.54 g, 2.86 mmol) and heated the reaction mixture at 120 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure. The crude residue was purified by gradient column chromatography using 30% EtOAc in hexane to afford desired product (2.1 g, 70 %) as off-white solid. LC-MS (ES) m/z = 432 [M+H]+.
Step 4: Synthesis of 4-(allyl(3-iodo-6,7-dimethoxyquinolin-4-yl)amino)benzonitrile
[0453] A stirred solution of 4-((3-iodo-6,7-dimethoxyquinolin-4-yl)amino)benzonitrile (1 g, 2.32 mmol) in DML (15 mL) was cooled to 0 °C and added NaH (0.11 g, 2.78 mmol). The reaction mixture was stirred for 15 min. Then allyl bromide (0.36 g, 3.01 mmol) was added at 0 °C and stirred for 30 min. The progress of the reaction was monitored by TLC. Reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL), combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain desired product (0.95 g, 87%) as yellow solid. LC-MS (ES) m/z = 472 [M+H]+.
Step 5: Synthesis of 4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l-yl)benzonitrile
[0454] To a stirred solution 4-(allyl(3-iodo-6,7-dimethoxyquinolin-4-yl)amino)benzonitrile (1.55 g, 3.29 mmol) in DML (15 mL) was added Pd(OAc)2 (0.036 g, 0.16 mmol), KOAc, (0.64 g, 6.58 mmol), sodium formate (0.44 g, 6.58 mmol) and LiCl (0.13 g, 3.29 mmol) at RT. The reaction mixture was heated at 100 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 c 100 mL), combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography using 2% methanol in dichloromethane to afford 4- (7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l-yl)benzonitrile (0.96 g, 85%) as off white solid. LC-MS (ES) m/z = 344.1 [M+H]+. Step 6: Synthesis of (4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l- yl)phenyl)methanamine
[0455] To a stirred solution 4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l- yl)benzonitrile (0.4 g, 1.16 mmol) in THF (10 mL) was added BH3.DMS (3.5 mL, 3.49 mmol) at RT. The reaction mixture was heated at 60 °C for 3 h. The progress of the reaction was monitored by TLC. Reaction mixture was quenched with MeOH and concentrated to give (4-(7,8-dimethoxy-3-methyl- lH-pyrrolo[3,2-c]quinolin-l-yl)phenyl)methanamine (0.4 g, Crude). LC-MS (ES) m/z = 348.1
[M+H]+.
Step 7: Synthesis of N-(4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l- yl)benzyl)sulf amide
[0456] To a stirred solution of (4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l- yl)phenyl)methanamine (0.4 g, 1.15 mmol) in acetonitrile (20 mL) was added N,N -diisopropyl ethylamine (0.6 mL, 3.45 mmol) and 4-nitrophenyl sulfamate (0.326 g, 1.49 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 c 100 mL), combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography using 2% methanol in dichloromethane to afford N-(4-(7,8-dimethoxy-3-methyl-lH-pyrrolo[3,2-c]quinolin-l-yl)benzyl)sulfamide (0.055 g,
11%) as an Off white solid. 1HNMR (400 MHz, DMSO-d6): d 8.95 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 8 Hz, 2H), 7.45 (s, 1H), 7.24 - 7.22 (m, 2H), 6.66 (s, 2H), 6.56 (s, 1H), 4.20 (d, J= 6.8 Hz, 2H), 3.85 (s, 3H), 3.33 (s, 3H), 2.41 (s, 3H). LC-MS (ES) m/z = 427.4 [M+H]+. HPLC purity 99.35% at 220 nm.
Example 21: Synthesis of N-cyclopropyl-N-(((lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5- c]quinolin-l-yl)cyclohexyl)methyl)sulfamide
Figure imgf000127_0001
Step 1: Synthesis of (lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l- carbaldehyde
[0457] To a stirred solution of ((lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methanol (0.55 g, 1.61 mmol) in DCM (20 mL) was added Dess-martin periodinane (1.16 g, 2.738 mmol) portion wise at room temperature. The resulting reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. Reaction mixture was diluted with dichloromethane (60 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was separated and the aqueous was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford (lR,4R)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l- carbaldehyde (0.43 g, crude) as yellow solid. It was taken to next step without purification. LC-MS (ES) m/z = 340.4 [M+H]+
Step 2: Synthesis of N-(((lr,4r)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methyl)cyclopropanamine
[0458] To solution of (lR,4R)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexane-l- carbaldehyde (0.25 g, 0.736 mmol) and cyclopropylamine (0.21 g, 3.68 mmol) in methanol (10 mL) was added acetic acid (0.1 mL) at room temperature. The resulting reaction mixture was stirred for 1 h at room temperature. Then NaCNBH3 (0.046 g, 0.736 mmol) was added portion wise at RT. The progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (30 mL) and extracted with 10 % MeOH and DCM (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure further obtained crude was purified by combiflash purifier using methanol and dichloromethane as eluents to afford N-(((lR,4R)-4-(7,8- dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)cyclohexyl)methyl)cyclopropanamine (0.23 g, 82.14 %) as Brown solid. LC-MS (ES) m/z = 381.5 [M+H]+.
Step 3: Synthesis of N-cyclopropyl-N-(((lR,4R)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methyl)sulfamide
[0459] To a stirred solution of N-(((lR,4R)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)cyclohexyl)methyl)cyclopropanamine (0.2 g, 0.52 mmol) in acetonitrile (5 mL) was added diisopropyl ethylamine (0.29 mL, 1.57 mmol) and 4-nitrophenyl sulfamate (0.148 g, 0.68 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was added water (50 mL) and extracted with ethyl acetate (2 x 50 mL), combined organic layers were washed with brine (30 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound. The crude residue was purified by gradient column chromatography using 2%methanol in
dichloromethane to obtain N-cyclopropyl-N-(((lR,4R)-4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin- l-yl)cyclohexyl)methyl)sulfamide (0.04 g, 16%) as off white solid. 1HNMR (400 MHz, DMSO-d6): d 8.99 (s, 1H), 8.43 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 6.79 (s, 2H), 4.89 (bs, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 2.99-2.97 (m, 2H), 2.31 (bs, 4H), 1.97- 1.88 (m, 4H), 1.32-1.21 (m, 2H), 0.71- 0.65 (m, 4H). LC- MS (ES) m/z = 460.1 [M+H]+. HPLC purity 99.3% at 225nm. Example 22: Synthesis of N-(4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5-c]quinolin-2-yl)phenyl) sulf amide
Figure imgf000129_0001
Step 1: Synthesis of 6,7-dimethoxy-3-nitroquinolin-4-ol
[0460] To a stirred solution of 6,7-dimethoxyquinolin-4-ol (5 g, 24.3 mmol) in propionic acid (150 mL) was added fuming nitric acid (2.5 mL) and the resulting reaction mixture was stirred at 100° C for 6 h. The progress of the reaction was monitored by TLC using 5% methanol in DCM as eluent. Then the reaction mixture was cooled to 0 °C. The solid formed was filtered and washed with pentane. The solid was triturated with methanol-diethyl ether (1:5), filtered and dried under vacuum to afford 6,7-dimethoxy-3-nitroquinolin-4-ol as yellow solid (4.7 g, 77%). 1HNMR (400 MHz, DMSO- d6): d 12.71 (s, 1H), 9.04 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H).
Step 2: Synthesis of 4-chloro-6,7-dimethoxy-3-nitroquinoline
[0461] To a stirred solution of 6,7-dimethoxy-3-nitroquinolin-4-ol (3.6 g, 14.3 mmol) in DCM (50 mL) at 0 °C was added thionyl chloride (2.6 mL, 35.9 mmol) & catalytic amount of DMF (0.4 mL). The resulting reaction mixture was stirred at 40° C for 12 h. The progress of the reaction was monitored by TLC using 5% methanol in DCM as eluent. Then the reaction mixture was cooled to room temperature then evaporated under reduced pressure. To the residue obtained was added ice water and stirred for 10 minutes. Further solid precipitated was filtered and washed with hexane and dried under vacuum to afford 4-chloro-6,7-dimethoxy-3-nitroquinoline as yellow solid (3.5 g, 91%). 1HNMR (400 MHz, DMSO-d6): d 9.18 (s, 1H), 7.56 (d, J= 7.2 Hz, 2H), 4.01 (s, 6H). LC-MS (ES) m/z = 269.0 [M+H|+
Step 3: Synthesis of 6,7-dimethoxy-N-methyl-3-nitroquinolin-4-amine
[0462] To a stirred solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (2 g, 7.44 mmol) in Toluene/IPA (40mL/8 mL) was added 2M Methylamine in THF (l8.6mL, 37.23 mmol) the resulting mixture was stirred in an autoclave at 70° C for 1 h. The progress of the reaction was monitored by TLC using 5% methanol in DCM as eluent. Then the reaction mixture was cooled to room
temperature, evaporated under reduced pressure to get crude. The obtained crude was purified by combiflash chromatography using methanol in dichloromethane to afford 6,7-dimethoxy-N-methyl-3- nitroquinolin-4-amine as yellow solid (1.65 g, 95%). 1HNMR (400 MHz, DMSO-d6): d 8.18 (s, 1H), 8.6l(bs, 1H), 7.75(s, 1H), 7.27(s, 1H), 3.9l(s, 6H), 3.07 (d, J= 5.2 Hz, 3H). LC-MS (ES) m/z = 264.1 [M+H]+
Step 4: Synthesis of 6, 7-dimethoxy-N4-methylquinoline-3, 4-diamine
[0463] To a stirred solution of 6,7-dimethoxy-N-methyl-3-nitroquinolin-4-amine (1.65 g, 6.26 mmol) in MeOH/DCM (50 mL / 50 mL) under argon atmosphere was added Pd/C (10 % on carbon) at room temperature. The resulting reaction mixture was degasified under vacuum and kept under hydrogen balloon bladder pressure, stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. The reaction mixture was filtered through celite bed and the filtrate was evaporated to remove solvents under reduced pressure to afford 6,7- dimethoxy-N4-methylquinoline-3, 4-diamine as greenish yellow solid (1.5 g, crude). 1HNMR (400 MHz, DMSO-d6): d 8.04 (s, 1H), 7.43(s, 1H), 7.09(s, 1H), 4.74(bs, 2H), 3.87(s, 3H), 3.83(s, 3H), 3.09 (s, 3H). LC-MS (ES) m/z = 234.1 [M+H]+
Step 5: Synthesis of N-(6,7-dimethoxy-4-(methylamino)quinolin-3-yl)-4-nitrobenzamide
[0464] To a stirred solution of 6, 7-dimethoxy-N4-methylquinoline-3 ,4-diamine (1.5 g, 6.43 mmol) in HMPA/CH3CN (8 mL/ 2 mL) was added 4-nitrobenzoyl chloride (1.78 g, 9.64 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC using 5% methanol in DCM as eluent. Then the reaction mixture was diluted with 10% MeOH in DCM (200 mL) and washed with NaHC03 solution followed by water. The organic layer was dried over Na2S04 and filtered. The filtrate was evaporated under reduced pressure to obtain N-(6,7-dimethoxy-4-(methylamino)quinolin-3-yl)-4-nitrobenzamide as brown liquid (1 g, crude). LC-MS (ES) m/z = 381.0 [M-H]+
Step 6: Synthesis of 7,8-dimethoxy-l-methyl-2-(4-nitrophenyl)-lH-imidazo[4,5-c]quinoline
[0465] To a stirred solution of N-(6,7-dimethoxy-4-(methylamino)quinolin-3-yl)-4-nitrobenzamide (1 g, 2.61 mmol) in HMPA (4 mL) was added glacial acetic acid (3 mL) and the resulting reaction mixture was stirred at 180 °C for 2 h. The progress of the reaction was monitored by TLC using 10% methanol in DCM as eluent. The reaction mixture was cooled to room temperature, the solid precipitated was washed with DCM and dried under high vacuum to obtain 7,8-dimethoxy-l-methyl- 2-(4-nitrophenyl)-lH-imidazo[4,5-c]quinolone as yellow solid (0.9 g, 94%). 1HNMR (400 MHz, DMSO-d6): d 9.07 (s, 1H), 8.44(d, J= 8.8 Hz, 2H), 8.13 (d, J= 8.8 Hz, 2H), 7.81 (s, 1H), 7.59(s, 1H), 4.3 l(s, 3H), 4.0l(s, 3H), 3.94(s, 3H). LC-MS (ES) m/z = 365.1 [M+H]+ Step 7: Synthesis of 4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5-c]quinolin-2-yl)aniline
[0466] To a stirred solution of 7,8-dimethoxy-l-methyl-2-(4-nitrophenyl)-lH-imidazo[4,5- c]quinoline (0.9 g, 2.47 mmol) in MeOH/DCM(l00 mL / 100 mL) under argon atmosphere was added Pd/C (10 % on carbon) at room temperature. The resulting reaction mixture was degasified under vacuum and kept under hydrogen balloon bladder pressure, stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. The reaction mixture was filtered through celite bed and the filtrate was evaporated to remove solvents under reduced pressure to afford 4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5-c]quinohn-2-yl)aniline as yellow solid (0.75 g, 90%). 1HNMR (400 MHz, DMSO-d6): d 8.95 (s, 1H), 7.76(s, 1H), 7.53(s, 1H), 7.48(d, J= 8.0 Hz, 2H), 6.7l(d, J= 8.4 Hz, 2H), 5.60(s, 2H), 4.23(s, 3H), 3.99(s, 3H), 3.92(s, 3H). Step 8: Synthesis of N-(4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5-c]quinolin-2- yl)phenyl)sulf amide
[0467] To a stirred solution of 4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5-c]quinolin-2-yl)aniline (0.1 g, 0.29 mmol ) in acetonitrile/THF (20 mL/20 mL) at 0 °C was added DIPEA (0.15 mL,
0.897mmol) followed by 4-nitrophenyl sulfamate (0.084 g, 0.388 mmol) and the resulting reaction mixture was stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. The solid precipitated was filtered and dried under high vacuum to give crude. The crude was dissolved in Aq.NH3 and washed with 30 % MeOH/DCM. The aqueous layer was evaporated, residue was washed with n-Pentane, diethyl ether to obtain N-(4-(7,8-dimethoxy-l-methyl-lH-imidazo[4,5- c]quinolin-2-yl)phenyl)sulfonamide as off white solid(0.005 g, 4%). 1HNMR (400 MHz, DMSO-d6): d 9.9l(s, 1H), 9.00(s, 1H), 7.78(s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.56(s, 1H), 7.34(d, J=8.4 Hz, 2H), 7.27(s, 2H), 4.25(s, 3H), 4.00(s, 3H), 3.93(s, 3H). m/z = 414.1 [M+H] + HPLC purity 99.72 %.
Example 23: Synthesis of (4-((7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)phenyl)methanesulfonamide
Figure imgf000131_0001
[0468] 1HNMR (400 MHz, DMSO-d6): d 9.03 (s, 1H), 8.50 (s, 1H), 7.53 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 7.14 (d, J= 8.0 Hz, 2H), 6.77 (s, 2H), 6.00 (s, 2H), 4.17 (s, 2H), 3.86 (s, 3H), 3.66 (s, 3H); LC-MS (ES) m/z = 413.3 [M+H] +; HPLC purity 96.23% at 244 nm. Example 24: Synthesis of (4-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)methanamine
Figure imgf000132_0001
[0469] 1HNMR (400 MHz, DMSO-d6): d 9.75 (s, 1H), 8.95 (s, 1H), 8.65 (bs, 3H), 7.87-7.90 (m, 5H), 6.68 (s, 1H), 4.20-4.22 (m, 2H), 3.97 (s, 3H), 3.49 (s, 3H).LC-MS (ES) m/z = 335.1 [M+H]+.
Example 25: Synthesis of 4-((7-methoxy-lH-imidazo[4,5-c]quinolin-l- yl)methyl)benzenesulfonamide
Figure imgf000132_0002
[0470] 1HNMR (400 MHz, DMSO-d6): d 9.18 (s, 1H), 8.50 (s, 1H), 7.96 (d, J= 9.2 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 2.8 Hz, 1H), 7.26 - 7.24 (m, 4H), 7.16 - 7.14 (m, 1H), 6.04 (s, 2H), 3.86 (s, 3H). LC-MS (ES) m/z = 368.9 [M+H]+.
Example 26: Synthesis of 7-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide
Figure imgf000133_0001
Step 1: Synthesis of benzyl 7-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate.
[0471] To a stirred solution of benzyl 7-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.7 g, 2.47 mmol) in acetonitrile (10 mL) was added N,N-diisopropyl ethylamine (1.29 mL, 7.43 mmol) and 4-chloro-6,7-dimethoxy-3-nitroquinoline (0.66 mL, 2.47 mmol ) and the resulting reaction mixture was stirred for 20 h at room temperature. The progress of the reaction was monitored by TLC using 50% ethyl acetate in hexane as eluent. To the reaction mixture was added ice water and solid formed was filtered and washed with diethyl ether, dried under vacuum to afford benzyl 7-((3 -amino-6, 7- dimethoxyquinolin-4-yl)amino)-3,4-dihydroisoquinoline-2(lH)-carboxylate as yellow solid (0.73 g, crude). MS (ES) m/z = 515.1 [M+H]+
Step 2: Synthesis of benzyl 7-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate.
[0472] To a stirred solution of benzyl 7-((6,7-dimethoxy-3-nitroquinolin-4-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate (0.5 g, 0.97 mmol) in methanol/water (10 mL/3 mL) was added iron (0.27 g, 4.85 mmol) and ammonium chloride (0.51 g, 9.71 mmol). The resulting mixture was stirred at 80 °C for 2 h. The progress of the reaction was monitored by TLC using 5 % methanol in dichloromethane as eluent. The reaction mixture was filtered through celite bed and the filtrate was evaporated to remove solvents under reduced pressure to obtain solid as crude. The crude was then purified using combiflash, desired product eluted in 4% methanol/dichloromethane, fraction containing product were evaporated to afford benzyl 7-((3 -amino-6, 7-dimethoxy quinolin-4- yl)amino)-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.4 g, 85 %). LC-MS (ES) m/z = 485.2
[M+H]+ Step 3: Synthesis of benzyl 7-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate.
[0473] To a stirred solution of benzyl 7-((3-amino-6,7-dimethoxyquinolin-4-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate (0.4 g, 0.82 mmol) in ethanol (3 mL) was added
triethylorthoformate (1.5 mL, 8.25 mmol). The resulting reaction mixture was stirred for 16 h at 120 °C. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. The reaction mixture was cooled to room temperature; solvent was evaporated under reduced pressure.
The solid obtained was washed with diethyl ether and dried to afford benzyl 7-(7,8-dimethoxy-lH- imidazo[4,5-c]quinolin-l-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate as solid (0.5 g, crude). MS (ES) m/z = 495.1 [M+H]+
Step 4: Synthesis of 7,8-dimethoxy-l-(l,2,3,4-tetrahydroisoquinolin-7-yl)-lH-imidazo[4,5- c] quinoline.
[0474] To a stirred solution of benzyl 7-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (0.4 g, 0.20 mmol) in MeOH (10 mL) was added palladium on carbon (0.1 g) at room temperature and the resulting reaction mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. Reaction mixture was filtered through celite and filtrate was evaporated under reduced pressure to afford 7,8-dimethoxy-l-(l,2,3,4-tetrahydroisoquinolin-7-yl)-lH- imidazo[4,5-c]quinoline as solid (0.37 g, crude). LC-MS (ES) m/z = 361.1 [M+H]+.
Step5: Synthesis of 7-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-3,4-dihydroisoquinoline- 2(lH)-sulfonamide.
[0475] To a stirred solution of 7,8-dimethoxy-l-(l,2,3,4-tetrahydroisoquinolin-7-yl)-lH- imidazo[4,5-c]quinoline (0.37 g, 1.02 mmol) in acetonitrile (10 mL) was added N,N -diisopropyl ethylamine (0.53 mL, 3.07 mmol) & 4-nitrophenyl sulfamate (0.26 g, 1.23 mmol) and the resulting mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC using 5% MeOH in DCM as eluent. To the reaction mixture, water (200 ml) was added and extracted with dichloromethane (2x100 ml), combined organic layers were dried over sodium sulphate, filtered and evaporated to give crude compound. The crude compound was purified using combiflash chromatography, desired product eluted in 7% methanol/dichloromethane, the fractions containing product were concentrated to afford 7-(7,8-dimethoxy-lH-imidazo[4,5-c]quinolin-l-yl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide as off white solid (0.08 g, 17%).
[0476] 1HNMR (400 MHz, DMSO-d6): d 8.97 (s, 1H), 8.43 (s, 1H), 7.60 (s, 1H), 7.53 - 7.48 (m, 3H), 6.95 (s, 2H), 6.66 (s, 1H), 4.31 (s, 2H), 3.88 (s, 3H), 3.44 (s, 3H), 3.34 (t, J= 5.6 Hz, 2H), 3.04 (bs, 2H). LC-MS (ES) m/z = 440.0 [M+H]+. Biological Assays:
Example Bl: ENPP1 Enzyme Assay with cGAMP substrate:
[0477] Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP-l) is a transmembrane glycoprotein that hydrolyzes nucleotides and nucleotide derivatives with the formation of nucleoside s’ -monophosphates. ENPP-l hydrolyzes 2’3’ -cGAMP (cGAMP), breaking it down into 5’-AMP and 5’-GMP. The 5’-AMP formed from the reaction is detected using the AMP-Glo® Kit (Promega). The assay kit contains two reagents. The first reagent terminates the enzymatic reaction, removes ATP (using adenylyl cyclase), and converts 5’-AMP produced into ADP (using polyphosphate: AMP phosphotransferase). The second reagent converts ADP to ATP (using adenylate kinase) and generates light from ATP using the luciferin/luciferase reaction. The amount of light measured is proportional to the amount of 5’-AMP produced by ENPP1.
[0478] Different concentrations of ENPP1 inhibitors were pre-incubated with 5 ng/well of human ENPP-l enzyme (R&D Systems) for 15 minutes at 37°C. The reaction volume was 18 pL. The reaction was initiated by adding 20 mM 2’3’-cGAMP and incubating for 30 minutes at 37°C. The final assay reaction mixture contains a buffer of 50 mM Tris pH 8.0, 250 mM NaCl, 0.5 mM CaCl2, 1 mM ZnCl2 and 1% DMSO. At the end of the incubation, the reaction was stopped by adding 12 mΐ of AMP-Glo reagent- 1 and mixing the reaction uniformly for 5 minutes, followed by incubation at room temperature for one hour. Then 25 mΐ of AMP Glo reagent-2 was added to the reaction, mixed uniformly with a pipette, and incubated at room temperature for one hour to convert the ADP formed from reagent- 1 to ATP and light. The generated light was measured in a Perkin Elmer Victor® instrument. Maximal activity control samples (containing enzyme, substrate, and buffer in the absence of ENPP1 inhibitors: MAX) and background control samples (containing enzyme, substrate, and buffer plus a fully inhibitory concentration (3 mM) of the reference ENPP1 Inhibitor, (N-(2-(l-(6,7- dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfamide): MIN) were simultaneously evaluated in order to calculate the percent inhibition at each compound concentration as follows:
% inhibition = (([MAX -MIN] - [COMPOUND-MIN])/[MAX-MIN])* 100
[0479] The IC50 values for percent inhibition versus compound concentration were determined by fitting the inhibition curves using a four-parameter variable slope model in GraphPad Prism® software. Ki values were derived from the IC50 values using the Cheng -Prusoff equation (Cheng Y, PmsoffWH. Biochem Pharmacol. 1973 Dec l;22(23):3099-l08) Relationship between the inhibition constant (Kl) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction):
Ki = IC50/ (1 + [cGAMP]/Km), where routinely [cGAMP] = 20 mM and Km = 16 mM Example B2: ENPP1 Enzyme Assay with AMP-pNP substrate:
[0480] ENPP1 is an ectonucleotidase that hydrolyzes both the STING activator 2’,3’-cGAMP and 5’ ATP (ATP). In some instances, an inhibitor of ENPP-l is capable of selectively blocking the hydrolysis of 2’,3’-cGAMP while only minimally inhibiting the hydrolysis of ATP. The ATP analog p Nitrophenyl 5 '-Adenosine Monophosphate (AMP-pNP) has been demonstrated to accurately reflect the response of ATP itself to different classes of ENPP1 inhibitors 1 and was synthesized as described in Lee at al (Lee SY, Sarkar S, Bhattarai S, Namasivayam V, De longhe S, Stephan H, Herdewijn P, El-Tayeb A, Miiller CE. Substrate-Dependence of Competitive Nucleotide
Pyrophosphatase/Phosphodiesterasel (NPP1) Inhibitors. Front Pharmacol. 2017 Feb l5;8:54). The ENPP1 assay with AMP-pNP substrate was conducted in a buffer containing 50 mM Tris-HCl (pH 8.5)/ 250 mM NaCl/0.5 mM CaCl2/l mM ZnCl2/0.1% DMSO. Inhibitors were added at final concentrations ranging between 10 mM and 30 pM depending on the compound. Duplicate wells were run at each inhibitor concentration. The final assay volume was 40 pL and human recombinant ENPP1 is present at 60 ng/well. The assay was initiated by the addition of substrate (300 mM AMP- pNP final concentration), and incubated for 20 minutes at 37°C. The absorbance at 405 nm was then read in a Tecan® plate reader. Each assay plate also included wells with no enzyme added (MIN OD) and wells with no inhibitor added (MAX OD). The percent inhibition of ENPP1 for each sample was then calculated as:
% inhibition = {[Average of (MAX OD-MIN OD) - (sample OD - Average MIN OD)]/Average of (MAX OD - MIN OD)} x 100%.
[0481] IC50 values of compounds were calculated by entering the percent inhibition values into a sigmoidal variable slope nonlinear regression model in GraphPad Prism® software. IC50 values were converted to Ki values using the Cheng -Prusoff equationi, where the Km was 151 mM, based on internal determinations: Ki = IC50/ (1 + [AMP-pNP]/Km).
[0482] The data for select compounds is shown in Table 2:
TABLE 2
Figure imgf000136_0001
Figure imgf000137_0001
Ki: A < 100 nM; 100 nM < B < 1 mM; and 1 mM < C. ND = Not Determined

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000138_0001
Formula (I);
wherein
L1 is -(CR18R19)-;
Ring Bl is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R11, R14, and R15 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Rb, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re;
R12 and R13 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Rb, -NRaC(=0)0Ra, C,-C(, alkyl, C ,-C(, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re; provided that one of R12 or R13 is not hydrogen;
each
Figure imgf000138_0002
C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg; R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R18 and R19 are taken together to form an oxo;
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Ra and Rc are taken together with the atoms to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; and
pl is 1-4.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring Bl is aryl or heteroaryl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring Bl is phenyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring Bl is cycloalkyl or heterocycloalkyl.
5 The compound of claim 1 or 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring Bl is cyclohexyl.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R11 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R11 is hydrogen.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R14 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, C,-C(, alkyl, C,-C(, haloalkyl, or Ci-C6 heteroalkyl.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R14 is hydrogen.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R15 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R15 is hydrogen.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R18 and R19 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R18 and R19 are hydrogen.
14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R18 and R19 are taken together to form an oxo.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R12 and R13 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl; provided that one of R12 or R13 is not hydrogen.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R12 and R13 are independently hydrogen, halogen, -ORa, Ci-C6 alkyl, or Ci-C6 haloalkyl; provided that one of R12 or R13 is not hydrogen.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R12 and R13 are independently hydrogen, halogen, or -ORa; provided that one of R12 or R13 is not hydrogen.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R12 and R13 are -ORa.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R17 is independently halogen, -OH, -CN, -SRa, -S(=0)Rb, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, - NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRcRd), Ci-C6 alkyl(NRaS(=0)2NRcRd), Ci-C6
alkyl(S(=0)2NRcRd), or Ci-C6 alkyl(NRaC(=0)NRcRd).
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R17 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -
C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
21. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R17 is independently -OH, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, - NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl(NRaS(=0)2NRcRd), or C,-C(, alkyl( S (=0)2NRcRd) .
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
pl is 1 or 2.
23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
pl is 1.
24. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000142_0001
Formula (II);
wherein
L2 is a bond or -(CR28R29)-;
Ring A2 is imidazolyl, pyrrolyl, oxazolyl, or thiazolyl;
Ring B2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R21, R24, and R25 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, - NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Rb, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Re;
each R26 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rb, -N02, -NRcRd, - S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Rb, -NRaC(=0)0Ra, C,-C(, alkyl, C ,-C(, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rf;
or two R26 on the same carbon are taken together to form an oxo;
each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -N02, -NRcRd, -S(=0)2Rb, - NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)Rb, -0C(=0)Rb, -C(=0)0Ra, -C(=0)NRa0Ra, - 0C(=0)0Ra, -C(=0)NRcRd, -0C(=0)NRcRd, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, Ci-C6 alkyl, Ci-C6 alkyl(NRcRd), Ci-C6
alkyl(NRaS(=0)2NRcRd), Ci-C6 alkyl(S(=0)2NRcRd), Ci-C6 alkyl(NRaC(=0)NRcRd), Ci- C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more Rg;
R28 and R29 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more Rh;
or R28 and R29 are taken together to form an oxo; each Ra is independently hydrogen, -OH, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Rb is independently Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl; each Rc and Rd are independently hydrogen, Ci-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
or Ra and Rc are taken together with the atoms to which they are attached to form a
heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl;
each Re, Rf, Rg, and Rh are independently halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
n2 is 1-4; and
p2 is 1-4.
25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring A2 is imidazolyl.
26. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring A2 is pyrrolyl.
27. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B2 is aryl or heteroaryl.
28. The compound of any one of claims 24-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B2 is phenyl.
29. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B2 is cycloalkyl or heterocycloalkyl.
30. The compound of any one of claims 24-26 or 29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B2 is cyclohexyl.
31. The compound of any one of claims 24-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R21 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
32. The compound of any one of claims 24-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R21 is hydrogen.
33. The compound of any one of claims 24-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R24 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, C,-C(, alkyl, C,-C(, haloalkyl, or Ci-C6 heteroalkyl.
34. The compound of any one of claims 24-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R24 is hydrogen.
35. The compound of any one of claims 24-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R25 is hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
36. The compound of any one of claims 24-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R25 is hydrogen.
37. The compound of any one of claims 24-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
L2 is -(CR28R29)-.
38. The compound of any one of claims 24-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 and R29 are independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
39. The compound of any one of claims 24-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 and R29 are hydrogen.
40. The compound of any one of claims 24-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 and R29 are taken together to form an oxo.
41. The compound of any one of claims 24-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
L2 is a bond.
42. The compound of any one of claims 24-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R27 is independently halogen, -OH, -SRa, -S(=0)Rb, -NRcRd, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -C(=0)0Ra, -C(=0)NRa0Ra, -C(=0)NRcRd, -NRaC(=0)NRcRd, - NRaS(=0)2NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, C,-C(, alkyl, C,-C(, haloalkyl, C ,-C(, alkyl(NRcRd), C ,-C(, alkyl(NRaS(=0)2NRcRd), C,-C(, alkyl(S(=0)2NRcRd), or C,-C(, alkyl(NRaC(=0)NRcRd) .
43. The compound of any one of claims 24-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R27 is independently halogen, -OH, -S(=0)2Rb, -NRaS(=0)2Rb, -S(=0)2NRcRd, -
C(=0)NRa0Ra, -NRaC(=0)NRcRd, -NRaS(=0)2NRcRd, -NRaC(=0)Ra, C,-C(, alkyl, C ,-C(, haloalkyl, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
44. The compound of any one of claims 24-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R27 is independently -OH, -S(=0)2NRcRd, -C(=0)NRa0Ra, -NRaC(=0)NRcRd, - NRaS(=0)2NRcRd, -NRaC(=0)Ra, Ci-C6 alkyl(NRaS(=0)2NRcRd), or Ci-C6 alkyl(S(=0)2NRcRd).
45. The compound of any one of claims 24-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
p2 is 1 or 2.
46. The compound of any one of claims 24-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
p2 is 1.
47. The compound of any one of claims 24-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R26 is independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=0)0Ra, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl.
48. The compound of any one of claims 24-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R26 is hydrogen.
49. The compound of any one of claims 24-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
two R26 on the same carbon are taken together to form an oxo.
50. The compound of any one of claims 24-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
n2 is 1 or 2.
51. The compound of any one of claims 24-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
n2 is 1.
52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or
heterocycloalkyl.
53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra is independently hydrogen, -OH, Ci-C6 alkyl, or cycloalkyl.
54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra is independently hydrogen or Ci-C6 alkyl.
55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rb is independently Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or heterocycloalkyl.
56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rb is independently Ci-C6 alkyl or cycloalkyl.
57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rb is independently Ci-C6 alkyl.
58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, cycloalkyl, or heterocycloalkyl.
59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rc and Rd are independently hydrogen or Ci-C6 alkyl.
60. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more halogen, -OH, -NH2, or Ci-C6 alkyl.
61. A pharmaceutical composition comprising a compound of any one of claims 1 -60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
62. A method of treating cancer in a subject in need thereof comprising administering a
compound of any one of claims 1 -60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 61.
63. The method of claim 62, wherein the cancer is a solid tumor.
64. The method of claim 63, wherein the solid tumor is breast cancer, lung cancer, or
glioblastoma.
65. The method of claim 62, wherein the cancer is a hematologic malignancy.
66. The method of claim 65, wherein the hematologic malignancy is a leukemia, a lymphoma, or a myeloma.
67. The method of claim 66, wherein the hematologic malignancy is a B-cell malignancy.
68. The method of claim 66, wherein the hematologic malignancy is multiple myeloma.
69. The method of any one of the claims 62-68, wherein the cancer is a relapsed or refractory cancer.
70. The method of any one of the claims 62-69, wherein the cancer is a metastatic cancer.
71. A method of treating an infection in a subject in need thereof comprising administering a compound of any one of claims 1 -60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 61.
72. The method of claim 71, wherein the infection is a viral infection.
73. The method of claim 72, wherein the viral infection is due to a DNA virus.
74. The method of claim 71 or 72, wherein the viral infection is a due to a herpesvirus.
75. The method of claim 74, wherein the herpesvirus is selected from herpes simplex viruses 1
(HSV-l), herpes simplex viruses 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6A (HHV-6A), human herpesvirus 6B (HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV).
76. The method of claim 74 or 75, wherein the herpesvirus is herpes simplex viruses 1 (HSV-l).
77. The method of claim 71 or 72, wherein the viral infection is a due to a retrovirus.
78. The method of claim 77, wherein the retrovirus is human immunodeficiency virus (HIV).
79. The method of claim 71 or 72, wherein the viral infection is a due to a hepatitis virus.
80. The method of claim 79, wherein the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV).
81. The method of claim 71 or 72, wherein the viral infection is due to vaccinia virus (VACV), adenovirus, or human papillomaviruses (HPV).
82. The method of claim 81, wherein the viral infection is due to a RNA virus.
83. The method of claim 81 or 82, wherein the viral infection is due to dengue fever virus, yellow fever virus, ebola virus, Marburg virus, Venezuelan encephalitis virus, or zika virus.
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