Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • 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
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
  • C07D513/20—Spiro-condensed systems

Definitions

• Described herein are compounds that modulate the activity of certain proteins involved in apoptotic pathways, or signaling pathways associated with inflammation and/or autoimmune diseases and/or cell division and/or angiogenesis.
• the compounds described herein are antagonists of inhibitor of apoptosis (IAP) proteins.
• the compounds described herein are pan-IAP antagonists.
• the compounds described herein are useful for the treatment of cancer, inflammatory diseases, and/or autoimmune diseases as described herein.
• a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
• a method of treating a hyperproliferative disorder in an individual in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, to the individual.
• the hyperproliferative disorder is a cancer or an autoimmune disease.
• the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.
• Also disclosed herein is a method of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, to the individual.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• AML acute myelogenous leukemia
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma.
• the cancer is glioblastoma.
• the cancer is gastric carcinoma.
• the cancer is esophageal squamous cell carcinoma.
• the cancer is a lung cancer.
• the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma.
• the cancer is pancreatic cancer.
• the cancer is breast cancer.
• Also disclosed herein is a method of treating a disease associated with unwanted angiogenesis in an individual in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, to the individual.
• the disease associated with unwanted angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, Osler-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma or hypertrophic scarring.
• the disease associated with unwanted angiogenesis is cancer.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• AML acute myelogenous leukemia
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is glioblastoma. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is gastric carcinoma. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is esophageal squamous cell carcinoma. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is a lung cancer. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is pancreatic cancer. In some embodiments of a method of treating a disease associated with unwanted angiogenesis, the cancer is breast cancer.
• HAV Human Immunodeficiency Virus
• HIV Human Immunodeficiency Virus
• a method of reversing a latency of Human Immunodeficiency Virus (HIV) in a mammal comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, to the individual.
• the latency of HIV is reversed without activation of T cells.
• the method further comprises administering an additional latency reversal agent, a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents.
• the additional latency reversal agent is a histone deacetylase inhibitor (HDACi), a bromodomain and extra terminal domain inhibitors (BETi), or a Protein Kinase C (PKC) agonist.
• FIG.1 illustrates comparative data of Compound 18a and various known compounds in their potency and efficacy in HIV latency reversal in latently infected cell line 2D10.
• FIG.2 shows the effect of Compound 18a and various control conditions on the activation of resting CD4+ T cells isolated from a healthy donor, assessed by measuring CD69 expression.
• FIG.3 shows the effect of Compound 18a and various control conditions on cytokine release in peripheral blood mononuclear cell and resting CD4+ T cells isolated from healthy donors.
• FIG.4 shows cIAP1 degradation, p100 cleavage, and the induction of GPF expression in the latently infected Jurkat 2D10 cell line upon treatment with Compound 18a.
• FIG.5 shows the effects of Compound 18a in combination with other latency reversing agents on activating HIV transcription in latently infected Jurkat 2D10 cells. Heatmaps indicate excess over Bliss (EOB) score where a score greater than zero indicates synergy between compounds.
• FIG.6 shows the effect of Compound 18m compared with other IAP antagonists in their potency and efficacy in patient derived AML samples.
• AML-IAP inhibitors available as either tools or potential drugs to treat cancer and other medical conditions. Genetic silencing of ML-IAP shows efficacy in various tumors as well as xenograft studies. By advancing the development of IAP antagonists, the survival of cancer patients including AML patients will be increased, giving new hope to the severely ill. This will lead to a major advancement in the treatment of cancers, in particular AML cancers.
• AML is a diverse collection of hematological cancers characterized by the bone marrow’s excessive production of immature myeloid blood cells. This acute proliferation of abnormal progenitors results in impairment of normal blood and bone marrow functions.
• Leukemia is the fourth most common cancer among 17-34 year old age group, but AML is more fatal in older patients. AML is considered to be a “late effect” disease, and exposure to ionizing radiation and/or chemical agents has been implicated in the development of leukemias and other blood cancers. Leukemia is curable in approximately 30% of patients under age 60, but in older patients the cure rate is only about 10%. In fact, elderly patients unable to tolerate aggressive chemotherapies only survive an average of ⁇ 7 months.
• Apoptosis a form of programmed cell death, is often dysregulated in malignant cells, and the evasion of apoptosis is a hallmark of cancer. As cancer cells divide and proliferate, normal control of cell death is impaired and tumor formation occurs.
• the IAP protein family is involved in blocking and attenuating programmed cell death pathways, predominantly through modulation of the caspase cascade (Fig.1). IAP proteins are often upregulated in cancers and are believed to underlie the resistance of many malignant cells to chemotherapeutics. Ablation or antagonism of IAP proteins is therefore an attractive therapeutic strategy for the treatment of cancer.
• Proteins and genes are ascribed to the IAP family if they possess a baculovirus IAP protein repeat (BIR) domain. Of the eight IAP proteins, five also contain a RING E3 ligase domain, with cIAP1 and cIAP2 also containing a caspase recruitment domain (CARD).
• the prototypical IAP family member is XIAP, which is a potent binder and inhibitor of caspase-3, one of the proteases that effects apoptosis.
• Another highly relevant member of the IAP protein family is ML-IAP, also known as Livin or KIAP, which was first identified as a member of the IAP protein family due to its single BIR domain (49, 50).
• the ML-IAP BIR domain is also responsible for apoptosis inhibition, and small molecule antagonists have significant potential for development as therapeutic agents.
• the RING domain of ML-IAP has been shown to function as an E3 ligase, facilitating the ubiquitination and subsequent degradation of itself and, more importantly, the natural caspase antagonist that modulates apoptotic signaling - the second mitochondria-derived activator of caspases (SMAC).
• SMAC second mitochondria-derived activator of caspases
• both protein and mRNA levels of ML-IAP are low to undetectable in most adult tissues but are highly expressed in a number of cancers including hematologic malignancies.
• AML cells have been shown to overexpress multiple antiapoptotic proteins, including Bcl2 and IAP protein family members, and it is believed this may underlie their resistance to therapies and eventual relapse.
• IAP protein family members can be potential therapeutic targets for AML, and the expression levels of IAP proteins have been shown to be prognostic.
• Provided herein is a new series of highly potent, bivalent IAP antagonists with single agent malignant cell-killing activity in culture. IAP antagonists can also be effective against AML.
• IAP apoptosis pathway
• BIR baculovirus IAP repeat
• IAP protein family Five human members of the IAP protein family include: XIAP, cIAPl (also, BIRC 2 ), cIAP2 (also, BIRC 3 ), NAIP, and survivin.
• XIAP inhibits apoptosis by binding to and inhibiting the activity of caspase-9, caspase-3 and caspase 7.
• Alterations in IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis. When the IAP pathway is upregulated, the IAP proteins bind to and prevent initiator and effector caspases from cleaving downstream cellular proteins.
• the proteolytic action of caspases is required to allow the cell death cascade to progress normally.
• the compounds described herein are nonpeptidic second mitochondria- derived activator of caspase (SMAC) mimetics and induce apoptosis (e.g., in cancer cells).
• the compounds described herein are IAP antagonists.
• IAP proteins not only regulate caspases and apoptosis, but also modulate inflammatory signaling and immunity, mitogenic kinase signaling, proliferation and mitosis, as well as cell invasion and metastasis.
• IAP Inhibitor of apoptosis proteins have emerged as regulators of innate immune signaling downstream of Pattern Recognition Receptors (PRRs) such as Toll-like receptor 4 (TLR4), Nucleotide-Binding Oligomerization Domain 1 (NOD1) and NOD2 receptors, and Retinoic Acid-Inducible Gene (RIG)-I Receptor.
• PRRs Pattern Recognition Receptors
• TLR4 Toll-like receptor 4
• NOD1 Nucleotide-Binding Oligomerization Domain 1
• NOD2 Nucleotide-Binding Oligomerization Domain 1
• ROG Retinoic Acid-Inducible Gene
• cIAP1 Cellular Inhibitor of Apoptosis Protein-1
• cIAP2 Cellular Inhibitor of Apoptosis Protein-2
• XIAP X-linked Inhibitor of Apoptosis
• the compounds described herein are also useful in the treatment of non-neoplastic diseases and/or inflammatory diseases and/or autoimmune diseases.
• ART combinatorial antiretroviral therapy
• HIV human immunodeficiency virus
• antiretroviral therapy only targets actively replicating HIV and not the dormant, replication competent HIV that resides in certain types of cells. These dormant HIV viruses can reactivate and trigger new rounds of viral replication upon discontinuation of antiretroviral therapy.
• a strategy for improving HIV treatment is to also target the dormant, replication competent HIV virus residing in latently infected cells, which are cells that are infected with HIV but are not actively producing HIV. These latently infected cells are not undergoing active virus replication and the viral genome has been integrated into the host DNA in such a manner that the virus DNA is indistinguishable from the host’s DNA. Latently infected cells are not recognized by the immune system and are not susceptible to antiretroviral therapy (ART). Thus, the dormant virus and latently infected cells can remain hidden and persist indefinitely.
• One approach for targeting latently infected cells is to develop new therapeutic agents or drugs that can reverse latency in infected cells by inducing active HIV replication. Once the dormant HIV virus is “awakened”, the infected cells become susceptible to immune system clearance or the effects of additional treatments such as killer agents to eliminate infected cells. Concurrent treatment with antiretroviral drugs will prevent the spread of the reactivated virus and suppress new rounds of HIV infection.
• the combination of therapeutic agents that can reverse the latency of HIV-infected cells and drugs to eradicate the awakened HIV virus is termed the “shock and kill” or “kick and kill” approach. IAP inhibition has been implicated in the reversal of HIV latency.
• the IAP antagonists may be used alone or in combination with other therapeutic agents, such as those that are used to treat HIV.
• other therapeutic agents that could be used in combination with IAP antagonists include therapeutic agents that activate HIV transcription in latently infected cells, therapeutic agents that inhibit active HIV replication, or any combination thereof.
• the additional therapeutic agents that inhibit active HIV replication include antiretroviral therapy drugs.
• the pharmaceutical compositions are described comprising IAP antagonists, alone or in combination with one or more additional therapeutics agents that are useful for the treatment of HIV in a mammal.
• the mammal is a human.
• Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms.
• Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl- 1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl
• C 1 -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 C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, aC 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
• an alkyl group is optionally substituted, 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 -NO 2 .
• the alkyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, or -OMe.
• alkyl is optionally substituted with halogen.
• alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
• 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 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C8 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.
• an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
• alkenyl is optionally substituted with halogen.
• Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
• 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 -C 10 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 -C4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
• an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, or -OMe.
• alkynyl is optionally substituted with halogen.
• Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, 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 -NO 2 .
• 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, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 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. [0038] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine.
• the alkyl is substituted with one, two, or three amines.
• Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
• 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 10-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.
• the aryl is phenyl.
• an aryl may be optionally substituted, 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 -NO 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), bridged, spirocyclic ring systems.
• Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 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, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
• Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, 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 -NO 2 .
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
• the cycloalkyl is optionally substituted with halogen.
• “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms.
• the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms.
• Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 . [0042] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms.
• the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens.
• Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
• Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
• 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 C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , - CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH(CH 3 )OCH 3 .
• a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
• “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls.
• Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
• “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. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen.
• the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non- aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
• the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
• the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
• heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, t
• heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. 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, 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 -NO 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 C 1 -C 6 heteroalkyl.
• a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
• Heteroaryl refers to a 5- to 14-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 quaternized.
• the heteroaryl is a 5- to 10-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][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• a heteroaryl is optionally substituted, 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 -NO 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.
• An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a subject (e.g. a mammal, such as a human), either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
• “Treatment” of a subject includes any type of intervention used in an attempt to alter the natural course of the subject.
• treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen, e.g., cancer does not metastasize and the like) or alleviation of the condition (e.g., reduction in tumor size, remission of cancer, absence of symptoms of autoimmune disease and the like).
• treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein).
• prophylactic treatment e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein.
• a 1 and A 2 are independently C 1 -C 6 alkylene, C 3 -C 10 cycloalkylene, C 5 -C 10 arylene, C 2 -C 10 heterocycloalkylene, or 4- to 10-membered heteroarylene, wherein each alkylene, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene is independently optionally substituted with one, two, or three R c ;
• L is -X 5 -(CH 2 ) n1 -Q 1 -(CH 2 ) n2 -X 5 -; each X 5 is independently O, S, or absent; each n 1 and n 2 is independently 0-5;
• Q 1 is -C 1 -C 6 alkylene-, -C 2 -C 6 alkenylene-, -C 2 -C 6 alkynylene-, -C(O)NH-C 1 -C 6 alkylene-NHC(O)-, -SO 2
• each n is 1. In some embodiments of a compound of Formula (I), each n is 2. [0055] In some embodiments of a compound of Formula (I), each R 7 is independently H or OH. In some embodiments of a compound of Formula (I), each R 7 is H. [0056] In some embodiments, the compounds described herein or pharmaceutically acceptable salt, N- oxide, racemate, or stereoisomer thereof, has the structure of Formula II: Formula II [0057] In some embodiments, the compounds described herein or pharmaceutically acceptable salt, N- oxide, racemate, or stereoisomer thereof, has the structure of Formula III: Formula III.
• each R 2a and R 2b is independently H, OH, C 1 -C 6 alkyl, or C 2 -C 6 alkene; or R 2a and R 2b taken together form a C 3 -C 6 cycloalkyl.
• each R 2a and R 2b is independently OH or C 2 -C 6 alkene; or R 2a and R 2b taken together form a C 3 -C 6 cycloalkyl.
• each R 2a or R 2b is independently H or OH.
• R 2a is OH.
• R 2b is H.
• R 2a is H and R 2b is OH.
• R 2a is OH and R 2b is H.
• each R 2a and R 2b is independently C 1 -C 6 alkyl or C 2 -C 6 alkene. In some embodiments of a compound of Formula (I), (II), or (III), each R 2a and R 2b is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 2a and R 2b is independently C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 2a and R 2b is independently C 2 -C 3a lkenyl.
• R 2a and R 2b taken together form a C 3 -C 6 cycloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), R 2a and R 2b taken together form a x 3 - C 5 cycloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), R 2a and R 2b taken together form a C 5 cycloalkyl.
• R 2a and R 2b taken together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.
• R 2a and R 2b taken together form a cyclopentyl or cyclopentenyl.
• each R 1a and R 1b is independently H, OH, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 1a and R 1b is H. [0063] In some embodiments of a compound of Formula (I), (II), or (III), each R 1 is independently H or C 1 -C 3 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 1 is H.
• each R 1 is independently C 1 -C 6 alkyl independently optionally substituted with one, two, or three R a .
• each R 2 is independently – NR 5 R 6 .
• each R 5 and R 6 is independently H or C 1 -C 6 alkyl.
• each R 2 is independently -NH 2 or -NHCH 3 .
• each R 3 is independently H or C 1 -C 3 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 3 is independently H or CH 3 . In some embodiments of a compound of Formula (I), (II), or (III), each R 3 is independently H or C 2 -C 3 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), R 3 is CH 2 CH 3 . In some embodiments of a compound of Formula (I), (II), or (III), each R 3 is H.
• each R 3 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 3 is independently C 3 -C 6 cycloalkyl. [0066] In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is independently H or C 1 -C 3 alkyl. In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is independently H or CH 3 . In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is independently H or C 2 -C 3 alkyl.
• R 4 is CH 2 CH 3 . In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is CH 3 . In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is H. In some embodiments of a compound of Formula (I), (II), or (III), each R 4 is independently C 1 -C 6 alkyl independently optionally substituted with one, two, or three R a .
• each R 4 is independently C 3 - C 6 cycloalkyl independently optionally substituted with one, two, or three R a .
• each R 3 is independently C 1 -C 3 alkyl and each R 4 is independently C 1 -C 3 alkyl.
• each R 3 is CH 3 and each R 4 is CH 3 .
• each is independently or In some embodiments of a compound of Formula (I), (II), or (III), each is independently In some embodiments of a compound of Formula (I), (II), or (III), each is In some embodiments of a compound of Formula (I), (II), or (III), each is In some embodiments of a compound of Formula (I), (II), or (III), each is .
• a 1 and A 2 are independently C 1 -C 6 alkylene independently optionally substituted with one, two, or three R c .
• a 1 and A 2 are independently C 3 -C 10 cycloalkylene independently optionally substituted with one, two, or three R c . In some embodiments of a compound of Formula (I), (II), or (III), A 1 and A 2 are independently C 5 -C10 arylene independently optionally substituted with one, two, or three R c . In some embodiments of a compound of Formula (I), (II), or (III), A 1 and A 2 are independently 4-10 membered heterocycloalkylene independently optionally substituted with one, two, or three R c .
• a 1 and A 2 are independently 4-10 membered heteroarylene independently optionally substituted with one, two, or three R c .
• a 1 and A 2 are independently C 1 -C 6 alkylene or C 3 -C 10 cycloalkylene, wherein each alkylene and cycloalkylene is independently optionally substituted with one, two, or three R c .
• a 1 and A 2 are .
• a 1 and A 2 are .
• a compound of Formula (I), (II), or (III) are .
• each X 5 is O.
• each X 5 is S.
• each X 5 is absent.
• each n 1 and n 2 is independently 1-3.
• each n 1 and n 2 is independently 0- 3. In some embodiments of a compound of Formula (I), (II), or (III), each n 1 and n 2 is independently 0-2. In some embodiments of a compound of Formula (I), (II), or (III), each n 1 and n 2 is independently 1-2. In some embodiments of a compound of Formula (I), (II), or (III), each n 1 and n 2 is 1. In some embodiments of a compound of Formula (I), (II), or (III), each n 1 and n 2 is 2.
• each n 1 and n 2 is 0.
• Q 1 is -C 1 -C 6 alkylene-, -C 2 - C 6 alkynylene-, -C 2 -C 6 alkynylene-C 6 -C 10 arylene-, -C 2 -C 6 alkynylene-C 6 -C 10 arylene-C 2 -C 6 alkynylene-, or - C 6 -C 10 arylene-C 6 -C 10 arylene-; wherein each alkylene, C 2 -C 6 alkynylene, and C 6 -C 10 arylene is independently optionally substituted with one, two, or three R d .
• Q 1 is -C 2 -C 6 alkynylene-optionally substituted with one, two, or three R d .
• Q 1 is -C 1 -C 6 alkylene.
• Q 1 is -C 2 -C 6 alkenylene.
• Q 1 is -C 2 -C 6 alkynylene.
• Q 1 is -C(O)NH-C 1 -C 6 alkylene-NHC(O)-.
• Q 1 is -SO 2 -. In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is -C 2 -C 6 alkynyl-C 6 -C10arylene-. In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is - C 2 -C 6 alkynylene-C 6 -C10arylene- C 2 -C 6 alkynylene.
• Q 1 is - C 6 -C10arylene-C 6 -C10arylene
• Q 1 is -C 4 alkylene-, , , , , -C(O)NH-(CH 2 ) 1-3 -NHC(O)-,or -SO 2 -.
• Q 1 is , , , , -C(O)NH-(CH 2 )1-3- NHC(O)-, or -SO 2 -.
• Q 1 is - C(O)NH-(CH 2 )1-3-NHC(O)-, or -SO 2 -. In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is -C 4 alkylene-. In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is .
• Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is . In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is -C(O .
• Q 1 is -C(O)NH-(CH 2 ) 2 -NHC(O)-. In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is -SO 2 -. [0075] In some embodiments of a compound of Formula (I), (II), or (III), Q 1 is and X 1 is -O-. In some embodiments of a compound of Formula (I), (II), or (III), is In some embodiments of a compound of Formula (I), (II), or (III), each R c is independently C 6 aryl.
• each R , R , R, and R is independently halogen, OH, NH 2 , CN, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 - C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl.
• each R a , R b , R c , and R d is independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• each R a , R b , R c , and R d is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• any combination of the groups described above or below for the various variables is contemplated herein.
• groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
• Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [0080]
• the compounds described herein exist as geometric isomers.
• the compounds described herein possess one or more double bonds.
• the compounds presented herein include all cis, trans, syn, anti,
• the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
• the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
• the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
• dissociable complexes are preferred.
• the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
• Labeled compounds [0081] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
• the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
• isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
• the 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.
• Pharmaceutically acceptable salts [0083] 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.
• 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, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
• those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0089] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
• 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. 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 [0091] 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.
• Synthesis of Compounds [0092] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.
• the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
• the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols.
• the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
• Therapeutically effective amounts of compound of Formula I, II, or III may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
• the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
• a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day.
• the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
• the compositions are preferably provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
• the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
• compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration.
• routes e.g., oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration.
• parenteral e.g., intramuscular, intravenous, intrathecal, or intraperitoneal
• compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, liposomes, exosomes, nanoparticles, or any other appropriate compositions.
• formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
• pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
• U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
• compositions are comprised of in general, a compound of Formula I, II, or III in combination with at least one pharmaceutically acceptable excipient.
• Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula I, II, or III.
• excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
• Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
• Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
• Compressed gases may be used to disperse a compound of this invention in aerosol form.
• Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
• Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
• the level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula I, II, or III based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
• the compound is present at a level of about 1-80 wt %.
• the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
• Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
• a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred.
• the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
• the pharmaceutical compositions of the present invention also include those that contain one or more other active ingredients, in addition to a compound of the present invention.
• the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
• compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
• Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
• a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
• the pharmaceutical compositions of the present invention also include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
• the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient.
• an effective dose of each will be used.
• the administration of a compound described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
• the length of the drug holiday optionally 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 includes 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%.
• a maintenance dose is administered if necessary.
• the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
• patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
• a compound described herein is administered in combination with a second anti- cancer agent.
• anti-cancer agents for use in combination with a compound of Formula I, II, or III include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
• anti-cancer agents that can be employed in combination with a compound of Formula I, II, or III include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetime
• anti-cancer agents that can be employed in combination with a compound of Formula I, II, or III include: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; a
• anticancer agents that can be employed in combination with a compound of Formula I, II, or III include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.).
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
• alkyl sulfonates e.g., busulfan
• nitrosoureas e.g., carmustine, lomusitne, etc.
• triazenes decarbazine, etc.
• antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
• folic acid analog e.g., methotrexate
• pyrimidine analogs e.g., Cytarabine
• purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
• Examples of natural products useful in combination with a compound of Formula I, II, or III include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
• vinca alkaloids e.g., vinblastin, vincristine
• epipodophyllotoxins e.g., etoposide
• antibiotics e.g., daunorubicin, doxorubicin, bleomycin
• enzymes e.g., L-asparaginase
• biological response modifiers e.g., interferon alpha
• alkylating agents that can be employed in combination a compound of Formula I, II, or III include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
• nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
• ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
• antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
• folic acid analog e.g., methotrexate
• pyrimidine analogs e.g., fluorouracil, floxuridine, Cytarabine
• purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
• hormones and antagonists useful in combination a compound of Formula I, II, or III include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
• adrenocorticosteroids e.g., prednisone
• progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
• platinum coordination complexes e.g., cisplatin, carboblatin
• anthracenedione e.g., mitoxantrone
• substituted urea e.g., hydroxyurea
• methyl hydrazine derivative e.g., procarbazine
• adrenocortical suppressant e.g., mitotane, aminoglutethimide
• Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible EGFR tyrosine kinase inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistat
• a compound described herein e.g., a compound of Formula I, II, or III
• TNF-alpha and/or TNF-related apoptosis-inducing ligand TRAIL shows homology to other members of the TNF-alpha family of proteins.
• a compound described herein e.g., a compound of Formula I, II, or III
• a TNF-alpha modulator and/or a TNF-alpha analogue e.g., lenalidomide, revlimid, CC-5013; CC-4047, ACTIMID. Tthalidomide and the like.
• a compound described herein e.g., a compound of Formula I, II, or III
• an adjuvant, hormone therapy, immunotherapy or any combination thereof e.g., a compound described herein is administered in combination with antiretroviral therapy (ART).
• ART antiretroviral therapy
• antiretroviral therapy for use in combination with a compound of Formula I, II, or III include Combivir, Kaletra, Aluvia, Trizivir, Epzicom, Kivexa, Triomune, Duovir-N, Truvada, Atripla, Complera, Eviplera, Stribild, Triumeq, Evotaz, Prezcobix, Rezolsta, Dutrebis, Genvoya, Odefsey, Descovy, Juluca, Symfi, Symfi Lo, Biktarvy, Cimduo, Symtuza, Delstrigo, and Dovato.
• a compound described herein is administered in combination with a latency reversal agent (LRA) with or without antiretroviral therapy (ART).
• LRA latency reversal agent
• examples of latency reversal agent (LRA) for use in combination with a compound of Formula I, II, or III include histone deacetylase inhibitors (HDACi), bromodomain and extra terminal domain inhibitors (BETi), Protein Kinase C (PKC) agonists, activators of positive transcription elongation factor b (P-TEFb), Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, tetraethylthiuram disulfide (Disulfiram), benzotriazole derivatives, quinolines, cytokines, methyltransferase inhibitors, and methylation inhibitors.
• HDACi histone deacetylase inhibitors
• BETi bromodomain and extra terminal domain inhibitors
• PKC Protein Kinase
• a compound described herein is administered in combination with a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents. Additional latency reversal agents can be found in Stoszko et al., Curr Opin Virol.2019 Jul 16; 38:37-53 which is hereby incorporated by reference for such disclosures.
• Methods of Use Disclosed herein, in certain embodiments, are methods of inhibiting the activity of an inhibitor of apoptosis (IAP) protein in an individual in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein to the individual.
• IAP apoptosis
• the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP, survivin, NAIP, apollon, ILP2, or any combinations thereof.
• a hyperproliferative disorder in an individual in need thereof comprising administration of a therapeutically effective amount of a compound of any one described herein, to the individual in need thereof.
• the hyperproliferative disorder is cancer or an autoimmune disease.
• the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.
• the cancer is an epithelial cancer, a carcinoma, a neoplasm, a sarcoma, a chondrosarcoma, a blastoma, a cancer of the central nervous system, or a hematological cancer.
• the cancer is an epithelial cancer or a carcinoma.
• the cancer is a neoplasm or a sarcoma or a chondrosarcoma or a blastoma or a cancer of the central nervous system. In some embodiments, the cancer is a hematological cancer. [00128] Also provided herein are methods of treating a disease associated with angiogenesis in an individual in need thereof comprising administration of a therapeutically effective amount of a compound of any one of Formula described herein to the individual in need thereof.
• the disease associated with angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, Osler-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma or hypertrophic scarring.
• IAP inhibitor of apoptosis
• methods of inhibiting the activity of inhibitor of apoptosis (IAP) proteins in an individual in need thereof comprising administration of a therapeutically effective amount of a compound of any one of Formula described herein to the individual in need thereof.
• the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP, survivin, NAIP, apollon, or ILP2.
• methods of inducing apoptosis in a cell comprising contacting the cell with a therapeutically effective amount of a compound of any one of Formula described herein.
• the compound of any one of Formula described herein binds a XIAP BIR3 domain, thus antagonizing the action of IAPs.
• inhibiting the activity of an IAP protein induces apoptosis in a plurality of cells.
• the cells are cancerous cells.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• AML acute myelogenous leukemia
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma.
• the cancer is glioblastoma.
• the cancer is gastric carcinoma.
• the cancer is esophageal squamous cell carcinoma.
• the cancer is a lung cancer.
• the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma.
• the cancer is pancreatic cancer.
• the cancer is breast cancer.
• the cancer is a cancer of oral cavity and pharynx.
• the cancer is a cancer of tongue, mouth, pharynx, or other oral cavity.
• the cancer is a cancer of digestive system.
• the cancer is esophagus cancer, stomach cancer, small intestine cancer, colon cancer, rectum cancer, anus cancer, anal canal cancer, anorectum cancer, liver cancer, intrahepatic bile duct cancer, gallbladder cancer, biliary cancer, pancreatic cancer, or cancers of other digestive organs.
• the cancer is a cancer of the respiratory system.
• the cancer is a larynx cancer, lung cancer, bronchus cancer, or cancers of other respiratory organs.
• the cancer is a skin cancer.
• the cancer is melanoma of the skin or a cancer of other nonepithelial skin.
• the cancer is a cancer of the genital system selected from uterine corpus, uterine cervix, uterine corpus, ovary, vulva, vagina, other female genital, prostate, testis, penis, and other male genital.
• the cancer is a cancer of the urinary system selected from urinary bladder, kidney, renal pelvis, ureter, and other urinary organs.
• the cancer is a cancer of the endocrine system selected from thyroid, other endocrine. In some embodiments, the cancer is a hematologic cancers. In some embodiments, the cancer is Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia. [00136] In some embodiments, inhibiting the activity of an IAP protein treats a hyperproliferative disorder. In some embodiments, the hyperproliferative disorder is a cancer or an autoimmune disease.
• the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma.
• the cancer is glioblastoma.
• the cancer is gastric carcinoma.
• the cancer is esophageal squamous cell carcinoma.
• the cancer is a lung cancer.
• the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma.
• the cancer is pancreatic cancer.
• the cancer is breast cancer.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• AML acute myelogenous leukemia
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma.
• the cancer is glioblastoma.
• the cancer is gastric carcinoma.
• the cancer is esophageal squamous cell carcinoma.
• the cancer is a lung cancer.
• the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma.
• the cancer is pancreatic cancer.
• the cancer is breast cancer.
• the disease associated with unwanted angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, Osler-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma or hypertrophic scarring.
• the disease associated with unwanted angiogenesis is a cancer.
• the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinations thereof.
• the cancer is a skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combinations thereof.
• the cancer is acute myelogenous leukemia (AML).
• the cancer is renal cell carcinoma.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the cancer is renal cell carcinoma.
• the cancer is glioblastoma.
• the cancer is gastric carcinoma.
• the cancer is esophageal squamous cell carcinoma.
• the cancer is a lung cancer.
• the lung cancer is non-small cell lung carcinoma or small cell lung cancer.
• the cancer is multiple myeloma.
• the cancer is pancreatic cancer.
• the cancer is breast cancer.
• Some embodiments relate to a method of reversing a latency of Human Immunodeficiency Virus (HIV) in a mammal, wherein the method comprises administering a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, to the individual.
• HIV Human Immunodeficiency Virus
• the latency of HIV is reversed without activation of T cells.
• CHEMISTRY EXAMPLES [00140] The following examples are intended to illustrate but not limit the disclosed embodiments. All solvents were used as purchased from commercial sources or dried over 4 ⁇ molecular sieves prior to use in the case of moisture sensitive reactions. Reactions conducted under microwave irradiation were performed in a CEM Discover microwave reactor using either CEM 10 mL reaction vessels or a ChemGlass heavy wall pressure vessel (100 mL, 38 mm x 190 mm). Reaction progress was monitored by reverse-phase HPLC and/or thin-layer chromatography (TLC).
• TLC thin-layer chromatography
• High resolution mass spectrometry was performed using ESI-TOFMS, EI-MS (reference: perfluorokerosene) and APCI-MS.
• TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography was performed using silica gel (32-63 ⁇ m particle size) or aluminum oxide (activated, basic, ⁇ 150 mesh size). All products were purified to homogeneity by TLC analysis (single spot, unless stated otherwise), using a UV lamp and/or iodine and/or CAM or basic KMnO 4 for detection purposes.
• NMR spectra were recorded on 400 MHz and 500 MHz spectrometers at ambient temperature.
• alanine (Ala), 1- hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM), N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide (EDC), palladium on carbon (Pd-C), dichloromethane (DCM), diethyl ether (Et2O), ethyl acetate (EtOAc), 2,2,2-trifluoroethanol (TFE), methanol (MeOH), homoserine (HSer), tetrahydrofuran (THF), trifluoroacetic acid (TFA), diisobutylaluminum hydride (DIBAL).
• Al alanine
• HOBT 1- hydroxybenzotriazole
• NMM N-methylmorpholine
• EDC N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide
• Pd-C palladium on carbon
• Divinyl sulfone (33 ⁇ L, 0.334 mmol, 1.00 eq) was added and the resulting mixture was stirred at rt for 24 h. Upon completion, all volatiles were removed in vacuo and the resulting residue was purified by fc (hexanes/ethyl acetate). Colorless solid, yield 150 mg (73%).
• Example 34 Preparation of 4 ⁇ [(tert ⁇ Butyldimethylsilyl)oxy]but ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl 4 ⁇ methylbenzene ⁇ 1 ⁇ sulfonate (42) [00180]
• the compound 42 was prepared according to the established literature procedure; see Köpfer, A.; Breit, B. Angew. Chem.2015, 54 (23), 6913-6917.
• Example 35 Preparation of tert ⁇ Butyl [(1S,2R) ⁇ 2 ⁇ ( ⁇ 4 ⁇ [(tert ⁇ butyldimethylsilyl)oxy]but ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl ⁇ oxy) ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamate (43) [00181] Under N 2 atmosphere, alcohol 2 (70 mg, 0.281 mmol, 1.00 eq.) was dissolved in dry DMF (567 ⁇ L) and the solution was cooled down to 0 °C. Tosylate 42 (110 mg, 0.309 mmol, 1.10 eq.) was added.
• Example 36 Preparation of tert ⁇ Butyl [(1S,2R) ⁇ 2 ⁇ [(4 ⁇ hydroxybut ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamate (44) [00182] Compound 43 (60 mg,0.139 mmol, 1.00 eq.) was dissolved in THF (153 ⁇ L) and TBAF in THF (1.00 M, 153 ⁇ L, 0.153 mmol, 1.10 eq.) was added. After the mixture was stirred for 16 h at rt, sat.
• Example 37 Preparation of tert ⁇ Butyl [(1S,2R) ⁇ 2 ⁇ ( ⁇ 4 ⁇ [(4 ⁇ methylbenzenesulfonyl)oxy]but ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl ⁇ oxy) ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamate (45) [00183] Alcohol 44 (85 mg, 0.267 mmol, 1.00 eq.) was dissolved in diethyl ether (415 ⁇ L) and the mixture was cooled down to 0 °C. Tosyl chloride (71 mg, 0.373 mmol, 1.40 eq.) and powdered KOH (80 mg, 1.43 mmol, 5.35 eq.) were added.
• Example 38 Preparation of tert ⁇ Butyl [(1S,2R) ⁇ 2 ⁇ [(4 ⁇ [(1S,2R) ⁇ 1 ⁇ [(tert ⁇ butoxy)carbonyl]amino ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ but ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamate (5j) [00184] Under N 2 atmosphere, alcohol 2 (42 mg, 0.170 mmol, 1.20 eq.) was dissolved in dry DMF (560 ⁇ L) and the solution was cooled down to 0 °C.
• Tosylate 45 (67 mg, 0.142 mmol, 1.00 eq.) was added.
• the resulting solution was treated with powdered KOH (16 mg, 0.291 mmol, 2.05 eq.) and stirring was continued at 0 °C.
• water (10 mL) was added and the resulting mixture was extracted with ethyl acetate (4 x 10 mL).
• the combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.
• the residue was purified by fc (hexanes/ethyl acetate). White solid, yield 41 mg (53%).
• Example 39 Preparation of 1S,2R) ⁇ 2 ⁇ [(4 ⁇ [(1S,2R) ⁇ 1 ⁇ (chloroamino) ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ but ⁇ 2 ⁇ yn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ ammonium dichloride (6j) [00185]
• the compound was prepared according to general procedure A. White solid, yield 27 mg (86%).
• LC-MS: m/z 349.25 (calcd.349.19 for C 22 H 25 N 2 O 2 + [M+H + ]).
• Example 56 2-(2,2-Dimethoxyethyl)-2-(prop-2-en-1-yl)pent-4-enal (47) [00207] Under N 2 atmosphere, DIBAL-H in hexanes (1 M, 6.21 mL, 6.21 mmol, 1.30 eq.) was added dropwise to a solution of nitrile 46 (1.00 g, 4.78 mmol, 1.00 eq.) in dry CH 2 Cl 2 (1.00 mL) at -78 °C over 45 min. After stirring at -78 °C for 2 h, stirring was continued for 2 h at 0 °C. Afterwards, sat. NH 4 Cl solution (7.5 mL), sat.
• Example 62 Benzyl (2S,3S) ⁇ 2 ⁇ amino ⁇ 4 ⁇ (1,3 ⁇ dioxan ⁇ 2 ⁇ yl) ⁇ 3 ⁇ hydroxybutanoate (62) [00218] The compound 62 was prepared according to the established literature procedure; see Boger, D. L.; Schüle G. J. Org.
• Example 80 Preparation of tert ⁇ Butyl N ⁇ [(1S) ⁇ 1 ⁇ [(4S,7S,8S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,8S,9aS) ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ [(tert ⁇ butoxy)carbonyl](methyl)amino ⁇ propanamido] ⁇ 8 ⁇ hydroxy ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thiazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydr
• Example 89 Preparation of (1R)-1- ⁇ [(4S,7S,9aS)-7- ⁇ [(1S,2R)-2-[(6- ⁇ [(1S,2R)-1-[(4S,7S,9aS)-4-[(1R)- 1-formamido-1-methylpropan-2-ylium]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine- 7-amido]-2,3-dihydro-1H-inden-2-yl]oxy ⁇ hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1- yl]carbamoyl ⁇ -8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl ⁇ -1- methylpropan-2-y
• Example 91 [(1S) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 8,8 ⁇ Dimethyl ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ (methylazaniumyl)butanamido] ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thiazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamoyl ⁇ 8,8 ⁇ dimethyl ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thiazepin ⁇ 4 ⁇ yl]carbamoyl ⁇ propyl](
• Example 92 (2S) ⁇ 2 ⁇ [(4S,7S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ (Methylamino)propanamido] ⁇ 5 ⁇ oxo ⁇ 8,8 ⁇ bis(prop ⁇ 2 ⁇ en ⁇ 1 ⁇ yl) ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thiazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamoyl ⁇ 5 ⁇ oxo ⁇ 8,8 ⁇ bis(prop ⁇ 2 ⁇ en ⁇ 1 ⁇ yl) ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thi
• Example 94 [(1S) ⁇ 1 ⁇ [(4S,7S,8S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,8S,9aS) ⁇ 8 ⁇ Hydroxy ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ (methylazaniumyl)propanamido] ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]thiazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamoyl ⁇ 8 ⁇
• Example 102 Preparation of Methyl (4S,7S,9aS) ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ [(tert ⁇ butoxy)carbonyl](methyl)amino ⁇ propanamido] ⁇ 8,8 ⁇ dimethyl ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]oxazepine ⁇ 7 ⁇ carboxylate (70) [00258] Under N 2 atmosphere, the amine 69, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (349 mg, 1.72 mmol, 1.20 eq.), 1-hydroxybenzotriazole hydrate (206 mg, 1.01 mmol, 1.20 eq.) and 4- methylmorpholine (279 ⁇ L, 2.53 mmol, 3.00 eq.) were dissolved in dry DMF (3.9 mL) and cooled to 0 °C.
• Example 104 Preparation of tert ⁇ Butyl N ⁇ [(1S) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ [(tert ⁇ butoxy)carbonyl](methyl)amino ⁇ propanamido] ⁇ 8,8 ⁇ dimethyl ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]oxazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamoyl ⁇ 8,8 ⁇ dimethyl ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1
• Example 105 Preparation of [(1S) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 7 ⁇ [(1S,2R) ⁇ 2 ⁇ [(6 ⁇ [(1S,2R) ⁇ 1 ⁇ [(4S,7S,9aS) ⁇ 8,8 ⁇ Dimethyl ⁇ 4 ⁇ [(2S) ⁇ 2 ⁇ (methylazaniumyl)propanamido] ⁇ 5 ⁇ oxo ⁇ octahydropyrrolo[2,1 ⁇ b][1,3]oxazepine ⁇ 7 ⁇ amido] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 2 ⁇ yl]oxy ⁇ hexa ⁇ 2,4 ⁇ diyn ⁇ 1 ⁇ yl)oxy] ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ inden ⁇ 1 ⁇ yl]carbamoyl ⁇ 8,8 ⁇ dimethyl ⁇
• Example 107 Preparation of 2-[(5,5-Dimethyl-1,3-dioxan-2-yl)methyl]-2-(prop-2-en-1-yl)pent-4- enenitrile (73) [00262] The compound 73 was prepared according to Example 42 from dimethyl acetal 55 and the appropriate 2,2-dimethylpropane-1,3-diol. Yield (76%).
• Example 108 Preparation of 1-[(5,5-Dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-ene-1- carbonitrile (74) [00263] The compound 74 was prepared according to Example 59 from intermediate 73. Yield (100%).
• Example 109 Preparation of 1-[(5,5-Dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-ene-1- carbaldehyde (75) [00265] The compound 75 was prepared from nitrile 74 and DIBAL-H in hexanes, according to Example 43. Yield (70%).
• Example 110 Preparation of 1- ⁇ 1-[(5,5-Dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-en-1-yl ⁇ -2- nitroethan-1-ol (76) [00266] The compound 76 was prepared from aldehyde 75, nitromethane and NEt 3 , according to Example 44.
• Example 111 Preparation of 5,5-Dimethyl-2-( ⁇ 1-[(E)-2-nitroethenyl]cyclopent-3-en-1-yl ⁇ methyl)- 1,3-dioxane (77) [00267] The compound 77 was prepared from nitroaldol 76, nitromethane and NEt 3 , according to Example 45. Yield (94%).
• Example 112 Preparation of (4S,5R)-3-[(1S)-1- ⁇ 1-[(5,5-Dimethyl-1,3-dioxan-2-yl)methyl]cyclopent- 3-en-1-yl ⁇ -2-nitroethyl]-4,5-diphenyl-1,3-oxazolidin-2-one (78) [00268] The compound 78 was prepared from nitroalkene 77, according to Example 46. Yield (64%).
• Example 113 Preparation of (S)-2-(1-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)cyclopent-3-en-1-yl)-2- ((4S,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl)acetic acid (79) [00269] Under N 2 atmosphere, sodium nitrite (2.08 g, 30.2 mmol, 3.00 eq) and dry acetic acid (5.76 mL, 101 mmol, 10.0 eq) were added to a solution of nitro derivative 78 (5.10 g, 10.1 mmol, 1.00 eq) suspended in dry DMSO (25 mL).
• Example 114 Preparation of Methyl (2S)-2- ⁇ 1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3- en-1-yl ⁇ -2-[(4S,5R)-2-oxo-4,5-diphenyl-1,3-oxazolidin-3-yl]acetate (80) [00270] The crude carboxylic acid 79 was dissolved in dry DMF (20 mL) and cooled to 0 °C. K 2 CO 3 (1.53 g, 11.1 mmol, 1.10 eq) was added and stirred for 10 minutes.
• Example 116 Preparation of Methyl (2S)-2-[(2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -4- [(triphenylmethyl)sulfanyl]butanamido]-2- ⁇ 1-[(5,5-dimethyl-1,3-dioxan-2- yl)methyl]cyclopentyl ⁇ acetate (82) [00272] Under N 2 atmosphere, amine 81, carboxylic acid 7 (945 mg, 1.98 mmol, 1.00 eq), 1- hydroxybenzotriazole hydrate (363 mg, 2.37 mmol, 1.20 eq.) and N-methylmorpholine (654 ⁇ L, 5.93 mmol, 3.00 eq.) were dissolved in a mixture of dry THF (7.1 mL) / DMF (1.0 mL) and cooled to 0 °C.
• Example 118 Preparation of Methyl (4'S,7'S,9'aS)-4'-[(2S)-2- ⁇ [(tert- butoxy)carbonyl](methyl)amino ⁇ propanamido]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'- pyrrolo[2,1-b][1,3]thiazepine]-7'-carboxylate (84) [00274] Under N 2 atmosphere, the amine 83, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (327 mg, 1.61 mmol, 1.20 eq.), 1-hydroxybenzotriazole hydrate (247 mg, 1.61 mmol, 1.20 eq.) and 4- methylmorpholine (444 ⁇ L, 4.00 mmol, 3.00 eq.) were dissolved in dry DMF (6.2 mL) and
• Example 120 Preparation of tert-Butyl N-[(1S)-1- ⁇ [(4'S,7'S,9'aS)-7'- ⁇ [(1S,2R)-2-[(6- ⁇ [(1S,2R)-1- ⁇ [(4'S,7'S,9'aS)-4'-[(2S)-2- ⁇ [(tert-butoxy)carbonyl](methyl)amino ⁇ propanamido]-5'-oxo-hexahydro- 2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepin]-7'-yl]amido ⁇ -2,3-dihydro-1H-inden-2- yl]oxy ⁇ hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl ⁇ -5'-oxo-hexahydr
• Example 121 Preparation of [(1S)-1- ⁇ [(4'S,7'S,9'aS)-7'- ⁇ [(1S,2R)-2-[(6- ⁇ [(1S,2R)-1- ⁇ [(4'S,7'S,9'aS)- 4'-[(2S)-2-(Methylazaniumyl)propanamido]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'- pyrrolo[2,1-b][1,3]thiazepin]-7'-yl]amido ⁇ -2,3-dihydro-1H-inden-2-yl]oxy ⁇ hexa-2,4-diyn-1-yl)oxy]- 2,3-dihydro-1H-in
• Example B [00279] One thousand seven hundred cells per well were plated in a 384 well plate and incubated overnight at 37 °C / 5% CO 2 .
• Binding of compounds to ML-IAP and BIR3 domain of cIAP1, cIAP2 and XIAP was determined by fluorescence polarization.
• Assay buffer was 100 mM KH 2 PO 4 at pH 7.5, 50 ⁇ M ZnSO 4 , 1 mM TCEP (Tris(2-carboxyethyl)phosphine hydrochloride) and 50 nM SMAC-FITC probe (AbuRPF-K(5-Fam)-NH 2 ) as described by Z. Nikolovska-Coleska et al. 9 .
• cIAP1 and XIAP were present at 800 nM while cIAP2 and MLIAP were present at 1.5 ⁇ M.
• Jurkat 2D10 cells were treated with different doses of the compounds, or one of the following compounds: BV-6, SM-164, Birinapant, LCL-161, GDC-0152, AT- 406 for 48 hours. Reversal of HIV latency was evaluated by analyzing GFP expression using flow cytometry. Induction of GFP expression was compared to baseline GFP levels detected in the absence of treatment. The results are shown in Table 5 and FIG.1. Compound 18a has higher efficacy in activating the latently infected cell line than many known compounds (FIG.1). Table 5.
• AA is ⁇ 1nM; 1nM ⁇ A ⁇ 10nM; 10nM ⁇ B ⁇ 100nM; 100nM ⁇ C ⁇ 1000nM; 1000nM ⁇ D ⁇ 10 ⁇ M; E is > 10 ⁇ M.
• Compound 18a was also tested for its impact on T cell activation and cytokine release.
• Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll density gradient centrifugation (Histopaque, Sigma Aldrich) from buffy coats of three healthy human donors (San Diego Blood Bank).
• CD4+ T cells were subsequently isolated by negative selection using magnetic beads (Miltenyi Biotec). Cells were treated with compound 18a, or 50 ng/ml Phorbol myristate acetate (PMA) and 1 ⁇ M Ionomycin, or Dynabeads Human T-Activator CD3/CD28 (ThermoFisher Scientific) at a bead-to-cell ratio of 1:1, or left untreated.
• PMA Phorbol myristate acetate
• Ionomycin 1 ⁇ M Ionomycin
• Dynabeads Human T-Activator CD3/CD28 Dynabeads Human T-Activator CD3/CD28
• CD69 and CD25 expression of the early and late activation markers CD69 and CD25 on CD4+ T cells was assessed by flow cytometry using a Phycoerythrin-labeled anti-CD69 antibody (BioLegend; Cat# 310906) and an Allophycocyanin-labeled anti-CD25 antibody (BioLegend; Cat# 302610). Cytokine expression levels in cultures of PBMC or resting CD4+ T cells were analyzed using the LEGENDplex Human Inflammation Panel 13-plex (BioLegend). As shown in FIG.2 and FIG.3, treatment using compound 18a did not induce activation of resting CD4+ T cells or cytokine release in PBMC or resting CD4+ T cells.
• FIG.4 shows the cIAP1degradation and NF ⁇ B pathway activation by the compound.
• JLat 10.6 cells were treated with different concentrations of compound 18a for 24 hours.
• GFP expression indicating latency reversal was measured by flow cytometry.
• cIAP1 degradation and p100 cleavage were assessed by western blot using the antibodies AF8181 (R&D Systems) and #4882 (Cell Signaling Technology), respectively.
• AF8181 R&D Systems
• #4882 Cell Signaling Technology
• Compound 18a was also tested in combination with other LRA reagents for synergistic activation of the latently infected cell line Jurkat 2D10.
• Jurkat 2D10 cells were treated with combinations of compound 18a and BET inhibitors (JQ1, I-BET 151) or PKC agonists (Bryostatin, Ingenol-3-angelate) for 48 hours. Reversal of HIV latency was evaluated by analyzing GFP expression using flow cytometry.
• mice Compounds were formulated in 5% DMSO, 10% Tween-80, and 85% dH2O and injected intraperitoneally (i.p.) into mice at doses of 10 mg/kg.
• i.p. intraperitoneally
• blood samples were collected retro-orbitally one hour after injection and for the time course PK study, blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 24 h time points.
• plasma was separated by centrifugation. Plasma samples were extracted with acetonitrile:water 4:1 with 0.1% formic acid containing indometacin as an internal standard.

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