WO2020176868A1 - Promédicaments lipidiques d'inhibiteurs de btk et leurs utilisations - Google Patents

Promédicaments lipidiques d'inhibiteurs de btk et leurs utilisations Download PDF

Info

Publication number
WO2020176868A1
WO2020176868A1 PCT/US2020/020433 US2020020433W WO2020176868A1 WO 2020176868 A1 WO2020176868 A1 WO 2020176868A1 US 2020020433 W US2020020433 W US 2020020433W WO 2020176868 A1 WO2020176868 A1 WO 2020176868A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
independently selected
nitrogen
sulfur
oxygen
Prior art date
Application number
PCT/US2020/020433
Other languages
English (en)
Inventor
Joseph BOLEN
Daniel Kenneth BONNER
Ketki KARANAM
Christopher John Porter
Jamie SIMPSON
Natalie TREVASKIS
Dan Zheng
Nathania LEONG
Garima SHARMA
Mitchell MCINERNEY
Tim QUACH
Sefei HAN
Original Assignee
Puretech Lyt, Inc.
Monash University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Puretech Lyt, Inc., Monash University filed Critical Puretech Lyt, Inc.
Publication of WO2020176868A1 publication Critical patent/WO2020176868A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Inhibitors of Bruton’s tyrosine kinase possess anticancer, immunosuppressive, and anti-inflammatory properties, with selective activity on immune cells, particularly B cells.
  • Exemplary BTK inhibitors ibrutinib and acalabrutinib are indicated for the treatment of a wide variety of cancers (e.g., chronic lymphocytic leukemia and mantle cell lymphoma) and for the treatment of certain autoimmune diseases, disorders, or conditions (e.g., graft versus host disease).
  • the lymphatic system consists of a specialized network of vessels, nodes and lymphoid tissues that are distributed throughout the body in close proximity to the vascular system.
  • the lymphatic system plays a number of key roles in immune response, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been suggested as a means to improve both pharmacokinetic and pharmacodynamic profiles.
  • Lymphatic drug transport has the potential to enhance oral bioavailability through avoidance of first pass metabolism, to alter systemic drug disposition, and to enhance efficacy against lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection.
  • lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection.
  • enters into the lymph since their size precludes ready diffusion across the vascular endothelium lining the blood capillaries that drain the small intestine. Instead, these large colloidal structures enter the lymphatic capillaries since the lymphatic endothelium is considerably more permeable than that of the vascular endothelium.
  • testosterone undecanoate is a marketed drug for hypogonadism and other conditions.
  • Oral administration of testosterone itself is problematic because of its extensive first pass metabolism in the liver and resulting very low bioavailability.
  • the undecanoate ester of testosterone redirects a small proportion of the absorbed dose into the lymphatic system, thereby avoiding hepatic first pass metabolism and increasing the oral bioavailability of testosterone.
  • this process is still very inefficient, and the bioavailability of testosterone after oral administration of the undecanoate ester is thought to be ⁇ 5%.
  • BTK inhibitors and their analogues are administered of a prodrug tailored to more specifically target a BTK inhibitor to its site of action.
  • Lymphatic vessels are critical to host immune function.
  • Antigens foreign or autoantigens
  • dendritic cells presenting such antigens, migrate through afferent lymphatic vessels and reach the draining lymph nodes.
  • Antigen presentation in the draining lymph nodes results in priming, activation, polarization, and expansion to activate T cells, initiating an inflammatory response, e.g., against the foreign or self antigen.
  • B cells are also activated, leading to antibody production against the foreign or self-antigen.
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(0)R 3 ;
  • each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted Ci-37 hydrocarbon chain;
  • Y is absent or is -C(O)-, -C(NR)-, or -C(S)-;
  • -SR a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci- 6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 4 or R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen
  • n 0-18;
  • A is a therapeutic agent selected from a BTK inhibitor or a derivative, analogue, or prodrug thereof.
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a disclosed lipid prodrug, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • lipid prodrug may exist in the form of a pharmaceutically acceptable salt.
  • a reference to a“lipid prodrug” is also a disclosure of “lipid prodrug or a pharmaceutically acceptable salt thereof.” It follows that such a lipid prodrug or pharmaceutically acceptable salt thereof may be used in a pharmaceutical composition and a method of use, such as those disclosed herein.
  • Typical use of prodrug strategies to improve a therapeutic agent’s (active pharmaceutical agent’s) pharmacokinetic properties relies on cleavage in vivo of the parent agent via non-specific degradation or enzymatic cleavage, thus allowing the agent to exert its biological activity.
  • the present invention in one aspect, provides modified glyceride-based compounds (lipid prodrugs) that direct lymphatic transport of a therapeutic agent and improve cleavage of the lipid prodrug to the therapeutic agent.
  • lipids including triglycerides, follow a particular metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates.
  • dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides.
  • Lipid prodrugs are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system to reach the systemic circulation without interacting with the liver.
  • the lipid prodrugs are cleaved, releasing the therapeutic agent, after the prodrugs have reached the systemic circulation, or after reaching a target tissue.
  • the lipid prodrugs release the therapeutic agent by destruction of a self-immolative linker that attaches the therapeutic agent to the glyercol-derived group, or by enzymatic cleavage of a linker.
  • the target tissue is the lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor, such as a lymph node site of metastasis.
  • the target tissue is the brain or CNS.
  • the present invention provides a compound of Formula I:
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(0)R 3 ;
  • each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted Ci-37 hydrocarbon chain;
  • X is -0-, -NR-, -S-, -0(Ci- 6 aliphatic)-0-, -0(Ci- 6 aliphatic)-S-, -0(Ci- 6 aliphatic)-NR-, -S(Ci- 6 aliphatic)-0-, -S(Ci- 6 aliphatic)-S-, -S(Ci- 6 aliphatic)-NR-, -NR(CI- 6 aliphatic)-0-, - NR(C I-6 aliphatic)-S-, or -NR(C I-6 aliphatic)-NR-, wherein 0-2 methylene units of the Ci- 6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S- and the Ci- 6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
  • each R is independently hydrogen or an optionally substituted group selected from Ci- 6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Y is absent or is -C(O)-, -C(NR)-, or -C(S)-;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent Ci-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -0-, -NR-, -S-, -OC(O)-, -C(0)0-, -C(0)-, -S(O)-, -S(0) 2 -
  • each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R 4 and R 5 is independently hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci- 6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbo
  • R 4 or R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • n 0-18;
  • each m is independently 0-6;
  • A is a therapeutic agent selected from a BTK inhibitor or a derivative, analogue, or prodrug thereof.
  • R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid such as a fatty acid, or -C(0)R 3 .
  • R 1 is hydrogen. In some embodiments, R 1 is an acid-labile group. In some embodiments, R 1 is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(0)R 3 . In some embodiments, R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen. In some embodiments, R 2 is an acid-labile group. In some embodiments, R 2 is a lipid. In some embodiments, R 2 is a fatty acid. In some embodiments, R 2 is -C(0)R 3 . In some embodiments, R 2 is selected from those depicted in Table 1, below.
  • each of R 1 and R 2 is independently a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail below.
  • each of R 1 and R 2 is independently a saturated or unsaturated medium-chain or long-chain fatty acid.
  • each of R 1 and R 2 is a fatty acid, each independently having a C2-C40 chain.
  • each of R 1 and R 2 is a fatty acid, each independently having a C 6 - C20, C8-C20, C10-C20, C10-C18, C12-C18, C14-C18, C16-C18, or C10-C16 chain.
  • each of R 1 and R 2 is a fatty acid independently selected from oleic acid, palmitic acid, EPA, and DHA. In some embodiments, each of R 1 and R 2 is a fatty acid independently selected from butyric acid, oleic acid, palmitic acid, EPA, and DHA. In some embodiments, each of R 1 and R 2 is a fatty acid independently selected from butyric acid, oleic acid, and palmitic acid.
  • R 1 and R 2 are each independently selected from an acid labile group such as tert- butoxycarbonyl (Boc), an amino acid, PEG group, -C(0)0R, -C(0)NR 2 , - CH2OR, -C(NR)R, or -P(0) 2 0R.
  • an acid labile group such as tert- butoxycarbonyl (Boc)
  • an amino acid PEG group, -C(0)0R, -C(0)NR 2 , - CH2OR, -C(NR)R, or -P(0) 2 0R.
  • R 1 or R 2 is defined as a fatty acid
  • R 1 or R 2 is the acyl residue of the fatty acid.
  • R 1 is the acyl portion of palmitic acid, i.e. -C(0)Ci 5 H 3i .
  • each R 3 is independently a saturated or unsaturated, straight or branched, optionally substituted Ci-37 hydrocarbon chain.
  • R 3 is a saturated, straight, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, straight, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, branched, optionally substituted Ci-37 hydrocarbon chain. In some embodiments, R 3 is selected from those depicted in Table 1, below.
  • X is -0-, -NR-, -S-, -0(Ci- 6 aliphatic)-0-, - 0(Ci-6 aliphatic)-S-, -0(Ci-6 aliphatic)-NR-, -S(Ci-6 aliphatic)-0-, -S(Ci-6 aliphatic)-S-, -S(Ci-6 aliphatic)-NR-, -NR(CI-6 aliphatic)-0-, -NR(CI-6 aliphatic)-S-, or -NR(CI-6 aliphatic)-NR-, wherein 0-2 methylene units of the Ci- 6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S- and the Ci- 6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms.
  • X is -0-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -0(Ci- 6 aliphatic)-0-. In some embodiments, X is -0(Ci- 6 aliphatic)-S-. In some embodiments, X is -0(Ci- 6 aliphatic)-NR-. In some embodiments, X is -S(Ci- 6 aliphatic)-0-. In some embodiments, X is -S(Ci- 6 aliphatic)-S-. In some embodiments, X is -S(Ci-6 aliphatic)-NR-.
  • X is -NR(CI-6 aliphatic)- 0-. In some embodiments, X is -NR(CI-6 aliphatic)-S-. In some embodiments, X is -NR(CI-6 aliphatic)-NR-. In any of the foregoing embodiments, 0-2 methylene units of the bivalent Ci- 6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S- and the bivalent Ci- 6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Table 1, below.
  • Y is absent or is -C(O)-, -C(NR)-, or -C(S)-.
  • Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-. In some embodiments, Y is selected from those depicted in Table 1, below.
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C i-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -0-, -NR-, -S-, -OC(O)-, -C(0)0-, - C(O)-, -S(O)-, -S(0) 2 -, -C(S)-, -NRS(0) 2 -, -NRC(O)-, -C(0)NR-, -OC(0)NR-, - NRC(0)0-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-;
  • L is a covalent bond.
  • L is a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent Ci-30 (e.g., C3-30, C5- 30, C7-3O, C3-25, C5-25, C7-25, C3-2O, C5-2O, C7-2O, C8-18, C6-18, C7-17, C8-16, Cs-15, Cs-14, C7-I3, C6-12, etC.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -0-, -NR-, -S-, -OC(O)-, -C(0)0-, -C(0)-, -S(O)-, -S(0) 2 -, -C(S)-
  • Ci-30 e.g., C3-30, C5- 30, C7-3O, C3-25, C5-25, C7-25, C3-2O,
  • L is
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent Ci-30 (e.g., C3-30, C5-30, C7-30, C3-25, C5-25, C7- 25, C3-20, C5-20, C7-20, C8-18, C6-18, C7-17, Cs-i6, Cs-i5, Cs-i4, C7-13, C6-12, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -
  • L is a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent Ci-20 (e.g., C3-20, C5-20, C7-20, Cs-is, C6-18, C7-17, Cs-i6, Cs-is, Cs-i4, C7- 13, C6-12, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -0-, -NR-, -S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, - C(S)-, -NRS(0) 2 -, -S(0) 2 NR-, or a naturally-
  • Ci-20 e.g., C3-20, C5-20, C7-20, Cs-is, C6-18, C7-17, Cs-i6, Cs-is,
  • R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -OR. In some embodiments, R 4 is -NR2. In some embodiments, R 4 is -SR. In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is a Ci- 6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is a Ci- 6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • each R 4 is independently hydrogen, deuterium, halogen, -CN, or Ci- 4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • at least one instance of R 4 is not hydrogen.
  • R 4 is Ci-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 4 is Ci-4 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is selected from those depicted in Table 1, below.
  • R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -OR. In some embodiments, R 5 is -NR2. In some embodiments, R 5 is -SR. In some embodiments, R 5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is an 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is a Ci- 6 aliphatic group optionally substituted with -CN, -OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 5 is a Ci- 6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • each R 5 is independently hydrogen, deuterium, halogen, -CN, or Ci- 4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • At least one instance of R 5 is not hydrogen.
  • R 5 is Ci-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 5 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 is isobutyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 is selected from those depicted in Table 1, below.
  • -M- is a self-immolative group.
  • -M- is an acetal, an o-benzyl alcohol, a /i-benzyl alcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction.
  • -M- is selected from a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative group, carboxy(methylacetal) self-immolative group, p- hydroxybenzyl self-immolative group, para-hydroxybenzyl carbonyl self-immolative group, flipped ester self-immolative group, trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self- immolative group.
  • -M- is:
  • each R 6 is independently selected from hydrogen, deuterium, Ci-io aliphatic, halogen, or -CN;
  • each R 6 is independently selected from hydrogen, deuterium, Ci-io aliphatic, halogen, or -CN.
  • R 6 is hydrogen.
  • R 6 is deuterium.
  • R 6 is C1-5 aliphatic.
  • R 6 is halogen.
  • R 6 is -CN.
  • R 7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7 is or a Ci- 6 aliphatic group optionally substituted with -CN, - OR, -NR2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7 is a Ci- 6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • R 7 is hydrogen, deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a Ci-4 alkyl group optionally substituted with -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the Ci-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
  • R 7 is hydrogen, halogen, -CN, -OR, or Ci-4 alkyl.
  • R is hydrogen or Ci-4 alkyl.
  • R 7 is selected from those depicted in Table 1, below.
  • each Z 1 is independently selected from -0-, -NR-, or -S-. In some embodiments, Z 1 is -0-. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S. In some embodiments, Z 1 is -NH- or -NMe-.
  • Z 1 is selected from those depicted in Table 1, below.
  • each Z 2 is independently selected from -0-, -NH-, -NMe-, -S-, -OC(O)-, -NHC(0)0-, -NMeC(0)0-, -OC(0)NH-, or -OC(0)NMe-.
  • Z 2 is covalently bound to A. In some embodiments, Z 2 is -O- or -0C(0)0-.
  • Z 2 is selected from those depicted in Table 1, below.
  • Z 1 is -O- and Z 2 is -O- or -0C(0)0-.
  • Z 3 is selected from those depicted in Table 1, below.
  • each Z 4 is independently selected from -O-, -NR-, -S-, -C(R 6 )2-, or a covalent bond.
  • Z 4 is -O-.
  • Z 4 is -NR-.
  • Z 4 is -S-.
  • Z 4 is -C(R 6 ) 2 - .
  • Z 4 is a covalent bond.
  • Z 4 is selected from those depicted in Table 1, below.
  • -M- is selected from those depicted in Table 1, below.
  • n is 0-18.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-3, 2-
  • A is a derivative or analogue of tirabrutinib.
  • a tirabrutinib “derivative” as used herein generally refers to a tirabrutinib molecule that has been functionalized or chemically altered.
  • Exemplary tirabrutinib derivatives include, without limitation, deuterated tirabrutinib, tirabrutinib with a modified ynone side chain (e.g. by conjugate addition of a nucleophile, e.g.
  • A is spebrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, A is spebrutinib. Spebrutinib has the following structure:
  • A is a derivative or analogue of spebrutinib.
  • a spebrutinib “derivative” as used herein generally refers to a spebrutinib molecule that has been functionalized or chemically altered.
  • Exemplary spebrutinib derivatives include, without limitation, deuterated spebrutinib, spebrutinib with a modified acrylamide side chain (e.g. by conjugate addition of a nucleophile, e.g.
  • A is a prodrug of spebrutinib.
  • A is a pharmaceutically acceptable salt of spebrutinib, such as the hydrochloride salt.
  • A is a prodrug of zanubrutinib.
  • A is a pharmaceutically acceptable salt of zanubrutinib, such as the hydrochloride salt.
  • A is selected from those in Table 1, Table 2, and Table 3, below; or a pharmaceutically acceptable salt thereof. In some embodiments, A is selected from those depicted in Table 1, below; or a pharmaceutically acceptable salt thereof. In some embodiments, A is selected from those depicted in Table 2, below; or a pharmaceutically acceptable salt thereof. In some embodiments, A is selected from those in Table 3, below; or a pharmaceutically acceptable salt thereof. In some embodiments, A is selected from those depicted in Table 1 and Table 2, below; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula I-a, I- b, I-c, or I-d:
  • the present invention provides a compound of Formula Ill-d, wherein at least one instance of R 4 or R 5 is other than hydrogen; a compound of Formula Ill-b; or a compound of Formula III-c; or a pharmaceutically acceptable salt of any of the foregoing.
  • the present invention provides a compound of Formula III-e, Ill-f, Ill-g, or Ill-h:
  • the present invention provides a compound of Formula IV-a, IV-b, IV-c, or IV-d:
  • the present invention provides a compound of Formula V-a or
  • R 1 , R 2 , R 4 , and -M- is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula Vl-a,
  • the present invention provides a compound of Formula Vl-i, wherein at least one instance of R 4 or R 5 is other than hydrogen, or a compound of Formula Vl-h, or a pharmaceutically acceptable salt of either of the foregoing. In some embodiments, the present invention provides a compound of Formula Vl-i, wherein at least one instance of R 4 or R 5 is other than hydrogen, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula Vll-a or VII-b:
  • R 1 , R 2 , R 4 , R 5 , and -M- is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a lipid prodrug compound, shown in Table 1, or a pharmaceutically acceptable salt thereof:
  • the present invention provides a compound in Table 1, above, wherein the compound is denoted as having a cumulative lymphatic transport of“A”, as reported in Example 6. In some embodiments, the present invention provides a compound in Table 1, above, wherein the compound is denoted as having a cumulative lymphatic transport of“A” or “B”. In some embodiments, the present invention provides a compound in Table 1, above, wherein the compound is denoted as having a cumulative lymphatic transport of“A” or“B” or“C”. In some embodiments, the present invention provides a compound in Table 1, above, wherein the compound is denoted as having a cumulative lymphatic transport of“A” or“B” or“C” or“D”.
  • Lipids Including Fatty Acids, Phospholipids, Lipid-Processing Mimetics, and Mixtures Thereof, for Use in Disclosed Lipid Prodrugs
  • Lipid prodrugs according to the present disclosure mimic the lipid-processing that takes place in the human body.
  • the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g. phophatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidyl serine or analogue or portion thereof, such as a partially hydrolyzed portion thereof), or other lipid-processing mimetic (e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing).
  • a fatty acid phosphatide, phospholipid, or analogue thereof
  • lipid-processing mimetic e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing.
  • the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof at the R 1 or R 2 position in the formulae depicted above and herein.
  • the fatty acid is a short-chain, medium-chain, or long-chain fatty acid.
  • the fatty acid is a saturated fatty acid.
  • the fatty acid is an unsaturated fatty acid.
  • the fatty acid is a monounsaturated fatty acid.
  • the fatty acid is a polyunsaturated fatty acid, such as an co-3 (omega-3) or co- 6 (omega-6) fatty acid.
  • the lipid e.g., fatty acid
  • the lipid has a C2, C3, C4, C5, C6, C7, Cs, C9, C10, Cn, C12, Cl3, Cl4, Cl5, Cl6, Cl7, Cl8, Cl9, C20, C2I, C22, C23, C24, C25, C26, C27, C28, C29, C30, C3I, C32, C33, C34, C35, C36, C37, C38, C39, C40, C4I, C42, C43, C44, C45, C46, C47, C48, C49, C50, C5I, C52, C53, C54, C55, C56, C57, C58, C59, or C60 chain.
  • the lipid prodrug comprises two fatty acids, each of which is independently selected from a fatty acid having a chain with any one of the foregoing ranges or numbers of carbon atoms.
  • one of the fatty acids is independently a fatty acid with a C6-C21 chain and one is independently a fatty acid with a C12-C36 chain.
  • each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.
  • Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.
  • saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, i sol auric acid, 11-methyldodecanoic acid, isomyri Stic acid, 13 -methyl -tetradecanoic acid, isopalmitic acid, 15-methyl -hexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyl-eicosanoic acid, a-ethyl- hexanoic acid, a-hexyldecanoic acid, a-heptylundecanoic acid, 2-decyltetradecanoic acid, 2- undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2-undecylpentadecanoic acid, and Fine oxocol 1800 acid (product of Nissan Chemical Industries
  • polycarboxylic acids examples include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L- malic acid, and the like.
  • each fatty acid is independently selected from Propionic acid, Butyric acid, Valeric acid, Caproic acid, Enanthic acid, Caprylic acid, Pelargonic acid, Capric acid, Undecylic acid, Why acid, Tridecylic acid, Myristic acid, Pentadecylic acid, Palmitic acid, Margaric acid, Stearic acid, Nonadecylic acid, arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.
  • one or both of the fatty acids is an essential fatty acid.
  • the therapeutic benefits of disclosed lipid prodrugs may be increased by including such fatty acids in the lipid prodrug.
  • each fatty acid is independently selected from al 1 - v.s-7, 10, 13- hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, or lipoic acid.
  • Fatty acid chains differ greatly in the length of their chains and may be categorized according to chain length, e.g. as short to very long.
  • Short-chain fatty acids are fatty acids with chains of about five or less carbons (e.g. butyric acid).
  • each of the fatty acids is independently a SCFA.
  • one of the fatty acids is independently a SCFA.
  • VLCFA Very long chain fatty acids
  • fatty acids with chains of 22 or more carbons, such as 22-60, 22-50, or 22-40 carbons.
  • each of the fatty acids is independently a VLCFA.
  • one of the fatty acids is independently a VLCFA.
  • one of the fatty acids is independently a MCFA and one is independently a LCFA.
  • a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g. triglyceride scaffolds, described herein.
  • the present invention provides enhanced desirable properties of the therapeutic agent such as improving oral bioavailability, minimizing destruction of the agent in the gut, avoiding liver first-pass effect, improving therapeutic agent delivery to a target tissue, or increasing the solubility and stability of the therapeutic agents, including the solubility and stability of the agents in vivo.
  • BTK inhibitor refers to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK).
  • Exemplary BTK inhibitors include those described above: ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, tirabrutinib, spebrutinib, and zanubrutinib.
  • Further examples of BTK inhibitors, and conditions treatable by compounds of this invention can be found in WO 2008/039218 and WO 2011/090760, the entirety of which are incorporated herein by reference.
  • BTK inhibitors and related derivatives, analogues, prodrugs, and pharmaceutically acceptable salts such as those described herein are broad-spectrum acting drugs having activity against cancer, immune, and inflammatory diseases, disorders, and conditions.
  • Ibrutinib (sold, e.g., under the trade name Imbruvica®) and acalabrutinib (sold, e.g., under the trade name Calquence®) are indicated for the treatment of a wide variety of cancers and for the treatment of certain autoimmune diseases, disorders, or conditions (e.g., graft versus host disease).
  • Disclosed lipid prodrugs are therefore useful in treating the foregoing and other diseases, disorders, or conditions, such as those disclosed herein.
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug disclosed herein, modulates the immune system of a patient after administration.
  • BTK inhibitors produce anticancer and immunosuppressive effects by binding (irreversibly, in many instances) to Bruton’s tyrosine kinase, which is involved in signaling pathways for the maturation, proliferation, and apoptosis of B-cells, for example, by interaction with the B-cell receptor (BCR), STAT3 transcription factor, and phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks).
  • BCR B-cell receptor
  • STAT3 transcription factor STAT3 transcription factor
  • PIP5Ks phosphatidylinositol 4-phosphate 5-kinases
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug disclosed herein, is taken up selectively into the lymphatic system of a patient after oral administration.
  • the lipid prodrug interacts with immune cells in the lymphatic system.
  • a disclosed lipid prodrug is delivered selectively to B lymphocytes.
  • a disclosed lipid prodrug modulates the activity of B lymphocytes.
  • a disclosed lipid prodrug modulates the activity of one or more of B cells, dendritic cells, granulocytes, innate lymphoid cells (ILCs), megakaryocytes, monocytes/macrophages, myeloid-derived suppressor cells (MDSC), natural killer (NK) cells, platelets, red blood cells (RBCs), T cells, or thymocytes.
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug disclosed herein, exhibits increased delivery at a given dose or more selective delivery at a given dose to B lymphocytes as compared with a corresponding dose of a non-lipid prodrug form of the BTK inhibitor, or a derivative, analogue, or prodrug thereof.
  • a given dose of a disclosed lipid prodrug more effectively modulates the activity of one or more of B cells, dendritic cells, granulocytes, innate lymphoid cells (ILCs), megakaryocytes, monocytes/macrophages, myeloid-derived suppressor cells (MDSC), natural killer (NK) cells, platelets, red blood cells (RBCs), T cells, or thymocytes, as compared with a corresponding dose of a non-lipid prodrug form of the BTK inhibitor, or a derivative, analogue, or prodrug thereof.
  • B cells dendritic cells
  • granulocytes granulocytes
  • ILCs innate lymphoid cells
  • MSC myeloid-derived suppressor cells
  • NK natural killer cells
  • RBCs red blood cells
  • T cells or thymocytes
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, e.g., a BTK inhibitor lipid prodrug.
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor lipid prodrug is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the disease, disorder, or condition is a cancer or an autoimmune disease, disorder, or condition.
  • the disease, disorder, or condition is selected from autoimmune encephalomyelitis; B-cell acute lymphoblastic leukemia; B-cell lymphoma; breast tumor; carcinoid tumor; central nervous system tumor; chronic lymphocytic leukemia; colorectal tumor; diffuse large B-cell lymphoma; follicle center lymphoma; glioblastoma; graft versus host disease; hairy cell leukemia; hematological neoplasm; lymphoplasmacytic lymphoma; macroglobulinemia; mantle cell lymphoma; marginal zone B-cell lymphoma; metastatic bladder cancer; metastatic head and neck cancer; metastatic non small cell lung cancer; metastatic pancreas cancer; metastatic renal cell carcinoma; multiple myeloma; multiple sclerosis; myelodysplastic syndrome; neuroendocrine tumor; non-Hodgkin lymphoma; ovary tumor; primary mediastinal large B-cell lympho
  • the present invention provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, e.g., a BTK inhibitor lipid prodrug.
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor lipid prodrug is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the cancer is metastatic.
  • the cancer is a B-cell cancer.
  • the cancer is selected from B- cell acute lymphoblastic leukemia; B-cell lymphoma; breast tumor; carcinoid tumor; central nervous system tumor; chronic lymphocytic leukemia; colorectal tumor; diffuse large B-cell lymphoma; follicle center lymphoma; glioblastoma; hairy cell leukemia; hematological neoplasm; lymphoplasmacytic lymphoma; mantle cell lymphoma; marginal zone B-cell lymphoma; metastatic bladder cancer; metastatic head and neck cancer; metastatic non small cell lung cancer; metastatic pancreas cancer; metastatic renal cell carcinoma; multiple myeloma; myelodysplastic syndrome; neuroendocrine tumor; non-Hodgkin lymphoma; ovary tumor; primary mediastinal large B-cell lymphoma; renal cell carcinoma; stomach tumor; systemic mastocytosis; T-cell lymphoma; and transitional cell carcinoma.
  • the present invention provides a method of treating an autoimmune disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, e.g., a BTK inhibitor lipid prodrug.
  • a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor lipid prodrug is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease, disorder, or condition is graft versus host disease or macroglobulinemia.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor lipid prodrug is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease, disorder, or condition is selected from Beh et’s disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, retroperitoneal fibrosis, idiopathic thrombocytopenic purpura (ITP), scleroderma (systemic sclerosis or SSc), pemphigus vulgaris, granulomatosis with polyangiitis, immunoglobulin A nephropathy, small vessel vasculitis, retroperitoneal fibrosis, and psoriasis.
  • Beh et’s disease pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, retroperitoneal fibrosis, idiopathic thrombocytopenic purpura (ITP), scleroderma (systemic sclerosis or SSc), pemphigus vulgaris, granulomatosis with polyangiitis, immunoglobul
  • the present invention provides a method of treating or preventing organ transplant rejection, graft-versus-host disease, or implant rejection, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug.
  • the present invention provides a method of treating or preventing organ transplant rejection, graft-versus-host disease, or implant rejection, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug e.g., a BTK inhibitor lipid prodrug.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor lipid prodrug is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the organ transplant is selected from a skin, liver, heart, kidney, pancreas, thymus, small intestine, large intestine, uterus, a vascularized composite allograft (VCA) such as face or hand, bone marrow, allogenic blood and marrow transplant (BMT), cornea, and lung transplant.
  • VCA vascularized composite allograft
  • BMT allogenic blood and marrow transplant
  • cornea and lung transplant.
  • lung transplant is acute or chronic transplant rejection.
  • idiopathic nephrotic syndrome or minimal change nephropathy including idiopathic nephrotic syndrome or minimal change nephropathy), idiopathic membranous nephropathy, congenital urological abnormality, chronic inflammatory demyelinating polyradiculopathy, immune thrombocytopenia, microscopic polyangiitis, MPO-ANCA vasculitis, Takayasu arteritis, hyperkalemia, Bronchiolitis Obliterans, polycystic liver disease, polyomavirus infection, amyotrophic lateral sclerosis (ALS), familial lipoprotein lipase deficiency, Hurler Syndrome, Fanconi Anemia, Glanzmann Thrombasthenia, severe congenital neutropenia, leukocyte adhesion deficiency, Shwachman- Diamond Syndrome, Diamond-Blackfan Anemia, Dyskeratosis-congenita, Chediak-Higashi Syndrome, histiocytosis, DO
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a disclosed lipid prodrug such as a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from end stage renal disease (ESRD), allogeneic peripheral haematopoietic stem cell transplant, neuroepithelial tumor, multiple myeloma, agnogenic myeloid metaplasia, leukemia, malignant lymphoma, Smith-Magenis Syndrome, a congenital haemoglobinopathy, a sickle cell disorder, a thalassemic disorder such as beta-thalassemia, type 1 diabetes, severe systemic sclerosis, a myelodysplastic syndrome or neoplasm, antibody-mediated rejection, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia, adult acute myeloid leukemia with l lq23
  • ESRD end stage renal
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is an autoimmune disorder, an inflammatory disorder, a cancer, or transplant rejection.
  • a disclosed lipid prodrug such as a compound of formula I, or a pharmaceutically acceptable salt thereof
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is celiac disease, refractory celiac disease, enteropathy-associated T-cell lymphoma, cutaneous T-cell lymphoma, a lymphoproliferative disorder of granular lymphocytes, T-cell leukemia, B-cell chronic lymphocytic leukemia, hairy cell leukemia, acute myelogenous leukemia, solid cancer, inflammatory bowel disease, non-alcoholic fatty liver disease, Epstein-Barr viral infection, eosinophilia, transplant rejection, rheumatoid arthritis, sarcoidosis, or multiple sclerosis.
  • a disclosed lipid prodrug such as a compound of formula I, or a pharmaceutically acceptable salt thereof
  • the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is a cancer.
  • the cancer is a cancer of the blood or cells of the immune system.
  • the cancer is a lymphoma or leukemia.
  • the cancer is selected from enteropathy-associated T-cell lymphoma, cutaneous T-cell lymphoma, a lymphoproliferative disorder of granular lymphocytes, T-cell leukemia, B-cell chronic lymphocytic leukemia, hairy cell leukemia, acute myelogenous leukemia, and a solid cancer, such as a cancer comprising a solid tumor.
  • the lipid prodrug is administered in combination with one or more additional immunomodulatory (e.g., immunosuppressive) agents or other co-administered agents such as tacrolimus, everolimus, sirolimus, a steroid such as prednisone, prednisolone, or dexamethasone, cyclophosphamide, azathioprine, methotrexate, or the like.
  • additional immunomodulatory e.g., immunosuppressive
  • agents such as tacrolimus, everolimus, sirolimus, a steroid such as prednisone, prednisolone, or dexamethasone, cyclophosphamide, azathioprine, methotrexate, or the like.
  • the lipid prodrug e.g., a BTK inhibitor lipid prodrug disclosed herein
  • one or more additional immunomodulatory (e.g., immunosuppressive) agents or other co-administered agents such as tacrolimus, everolimus, sirolimus, a steroid such as prednisone, prednisolone, or dexamethasone, cyclophosphamide, azathioprine, methotrexate, or the like.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical.
  • the term“long chain triglycerides” (or“LCT”) means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids,“LCFA”), whereas the term“medium chain triglycerides” (or“MCT”) means both a simple and mixed triglyceride containing fatty acids with 4 to 12 carbon atoms.
  • ECN or“equivalent carbon number” means the sum of the number of carbon atoms in the acyl chains of a glyceride molecule.
  • tripalmitin tripalmitic glycerol
  • ECN electroactive glycerol
  • Naturally occurring oils are frequently“mixed” with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone.
  • triacylglycerols with ECNs of 24-30 typically contain predominately medium chain fatty acids, while triacylglycerols with ECNs of greater than 43 typically contain predominantly long chain fatty acids.
  • Triacylglycerols having an ECNs of 32-42 typically contain one or two MCFA in combination with one or two LCFAs to “fill” the triglyceride.
  • Triacylglycerols with ECNs in the range of greater than 30 to less than 48 typically represent mixed triacylglycerol species that are absent from or are present in significantly lower concentrations in physical mixtures.
  • the fatty acids that occur in foods usually contain an even number of carbon atoms in an unbranched chain, e.g., lauric or dodecanoic acid.
  • the term“self-immolative group,” as used herein, refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond.
  • self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methylacetal) self-immolative groups, /i-hydroxybenzyl self- immolative groups, para-hydroxybenzyl carbonyl self-immolative groups, flipped ester self- immolative groups, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative groups.
  • a number of other suitable self-immolative groups are known in the art as described, for example, in C. A. Blencowe et al ., Polym. Chem. 2011, 2, 773-790 and F.
  • the therapeutic agent is covalently attached to the lymphatic drug-release moiety (i.e., the remaining portion of the lipid prodrug besides the therapeutic agent) by the use of“click” chemistry.
  • “click-ready group” refers to a chemical moiety capable of undergoing a click reaction, such as an azide or alkyne.
  • Click reactions tend to involve high-energy (“spring-loaded”) reagents with well- defined reaction coordinates that give rise to selective bond-forming events of wide scope.
  • Examples include nucleophilic trapping of strained-ring electrophiles (epoxide, aziridines, aziridinium ions, episulfonium ions), certain carbonyl reactivity (e.g., the reaction between aldehydes and hydrazines or hydroxylamines), and several cycloaddition reactions.
  • the azide- alkyne 1,3-dipolar cycloaddition and the Diels- Alder cycloaddition are two such reactions.
  • gew-difluorinated cyclooctynes from Codelli, et al.; ./. Am.
  • the term“therapeutic agent,”“active pharmaceutical agent,”“active agent,” or“pharmaceutical agent” includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g. of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.
  • the therapeutic agent is a small molecule.
  • the small molecule has a molecular weight of less than 800; or less than 700, 600, 500, 400, or 300. In some embodiments, the molecular weight is about 300 to about 800; or about 400-700, 300-600, or 400-500.
  • Lipid prodrug compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, Handbook of Chemistry and Physics, 98 th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , M. B. Smith and J. March, 7 th Edition, John Wiley & Sons, 2013, the entire contents of which are hereby incorporated by reference.
  • aliphatic or“aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as“carbocycle,”“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc.
  • a bicyclic group has 7- 12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term“bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • Exemplary bridged bicyclics include:
  • heteroatom means one or more of boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2//-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • alkylene refers to a bivalent alkyl group.
  • An“alkylene chain” is a polymethylene group, i.e., -(CH2) n- , wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • aryl used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • the term“aryl” may be used interchangeably with the term“aryl ring.”
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and“heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyri do[2,3 -/?]- 1 ,4-oxazin-3(4H)-one.
  • a heteroaryl group may be mono- or bicyclic.
  • the term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted.
  • the term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2//-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in A -substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
  • the term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • a disclosed lipid prodrug exhibits at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% lymphatic transport when administered orally. In some embodiments, a disclosed lipid prodrug exhibits about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by either w/w% of the lipid prodrug administered or w/w% of the therapeutic agent in its lipid prodrug form vs. the unmodified therapeutic agent.
  • the present disclosure provides a method of increasing transport of an immune suppressant, e.g., of a BTK inhibitor, to the lymph, the method comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug form of the BTK inhibitor.
  • the compositions described herein comprising a prodrug form of a BTK inhibitor are useful for increasing transport of an immune suppressant, e.g., of the BTK inhibitor, to the lymph.
  • the present disclosure provides a method of reducing the activation of macrophages, or eliminating or reducing the production of activated macrophages, the method comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug form of a BTK inhibitor.
  • the present disclosure provides a method of suppressing antibody formation by B-lymphocytes, the method comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug form of a BTK inhibitor.
  • the present disclosure provides a method for reducing infiltration of circulating monocytes and lymphocytes to a site of inflammation, the method comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug form of a BTK inhibitor.
  • a BTK inhibitor lipid prodrug Any of the BTK inhibitor lipid prodrugs described herein can be used in any of the methods described herein.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof, or combinations thereof.
  • the BTK inhibitor lipid prodrug is selected from the compounds depicted in Table 1 or a pharmaceutically acceptable salt thereof, or combinations thereof.
  • Such lipid prodrugs can be used for treating diseases associated with hyperinflammation.
  • the invention provides a method of treating a disease, disorder, or condition selected from inflammatory disorders, autoimmune disorders autoinflammatory diseases (such as IBD), metabolic disease, neurological disorders, transplant rejection, graft-versus-host disease, and/or cancers, and/or B cell malignancies, such as B cell lymphoma, and others described herein, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug.
  • a disease, disorder, or condition selected from inflammatory disorders, autoimmune disorders autoinflammatory diseases (such as IBD), metabolic disease, neurological disorders, transplant rejection, graft-versus-host disease, and/or cancers, and/or B cell malignancies, such as B cell lymphoma, and others described herein, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug.
  • the present disclosure provides methods for reducing, ameliorating, or eliminating one or more symptom(s) associated with inflammatory disorders, autoimmune disorders, autoinflammatory diseases (such as IBD), metabolic disease, neurological disorders, transplant rej ection, graft-versus-host disease and/or cancers and/or B cell malignancies, such as B cell lymphoma, and others described herein, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug.
  • the disclosure provides a method for treating, reducing, ameliorating, or eliminating one or more symptom(s) associated with inflammatory disorders, autoimmune disorders, autoinflammatory diseases (such as IBD), metabolic disease, neurological disorders, transplant rejection and/or graft-versus-host disease, and others described herein in a patient, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug.
  • compositions comprising at least one lipid prodrug form of a BTK inhibitor, e.g., as described herein and uses of such for treating, reducing, ameliorating, or eliminating one or more symptom(s) associated with inflammatory disorders, autoimmune disorders, autoinflammatory diseases (such as IBD), metabolic disease, neurological disorders, transplant rejection graft-versus-host disease, and/or cancers and/or B cell malignancies, such as B cell lymphoma, and others described herein in a patient.
  • the BTK inhibitor lipid prodrug is selected from a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor lipid prodrug is selected from a compound depicted in Table 1 or a pharmaceutically acceptable salt thereof.
  • IBD is characterized by dysregulated immune responses, leading to abnormal cytokine production and cellular inflammation, and consequently injury to the distal small intestine and the colonic mucosa.
  • a large amount of evidence points to involvement of T cell and T cell trafficking to the gut and associated lymphoid tissue as a key part in disease pathogenesis.
  • Chronic gut inflammation in IBD is a consequence of dysregulated immune response to commensal gut bacteria.
  • intravascular naive T cells To mount a protective immune response to pathogenic bacteria in the gut, intravascular naive T cells must home to the inductive sites of the intestinal tract, the gut-associated lymphoid tissue (GALT) and the gut-draining MLNs, where they undergo antigen-driven priming, activation, polarization, and expansion to yield Thl and/or Thl7 effector cells.
  • GALT gut-associated lymphoid tissue
  • the effector cells leave the lymphoid tissue through the efferent lymphatics, enter the systemic circulation, and then arrive at the gut, where they help to destroy the pathogenic bacteria.
  • the disclosure provides a method for treating or reducing, ameliorating, or eliminating symptoms for diseases and conditions associated with gut inflammation in a subject.
  • the disclosure provides a method for treating a disease associated with gut inflammation in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein, e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, including but not limited to, a compound depicted in Table 1 or a pharmaceutically acceptable salt thereof.
  • the disease associated with gut inflammation is ulcerative colitis.
  • lipid prodrugs of BTK inhibitors described herein which are predominantly targeted to the lymphatic system, may provide further benefit in the treatment of celiac disease over the BTK inhibitor alone, e.g., by reducing side effects and increasing efficacy, as described herein.
  • the disclosure provides a method for the treatment of celiac disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein.
  • the disclosure provides a method for the treatment of refractory celiac disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein.
  • the disclosure provides a method for the treatment of enteropathy-associated T-cell lymphoma in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein.
  • CD8+ T cells For example, in CD4 T cells from active SLE patients T cell calcium flux is faster and cellular signaling is altered (Maria and Davidson, Emerging areas for therapeutic discovery in SLE; Current Opinion in Immunology 2018, 55: 1-8, and references therein). More recently, a role for CD8+ T cells is also described (Ling et ah, Clq restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism; Science. 2018 May 4;360(6388): 558-563).
  • Immunosuppressive agents are used to treat the renal- immune- complex-mediated injuries responsible for the occurrence of immune complex-mediated glomerulonephritis, lupus nephritis flares (LN), (characterized by reduced renal function, hematuria, and proteinuria; Meliambro et ah, Therapy for Proliferative Lupus Nephritis; Rheum Dis Clin N Am 44 (2016) 545-560).
  • targeting a BTK inhibitor to the lymphatic system may provide further benefit in the treatment of SLE and LN over the BTK inhibitor alone.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament for the treatment of SLE and/or LN, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein.
  • MS Multiple sclerosis
  • CNS chronic inflammation, primary demyelination, axonal damage, perivascular infiltration of lymphocytes, and plasma cells in the white substance of the brain and spinal cord, loss of blood brain barrier integrity as well as astrocyte and microglia activation (Negi and Das, CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid Organ; International Reviews Of Immunology 2017, Vol. 0, No. 0, 1-12, and references therein).
  • the DCs and macrophages presenting myelin antigens leave the CNS and reach the cervical lymph nodes (LNs) where they present the myelin antigen to auto-reactive T and B lymphocytes, which then differentiate into effector cells. Once activated, these auto-reactive lymphocytes home in the CNS and begin the inflammatory process.
  • LNs cervical lymph nodes
  • Immunosuppressive therapy such as cyclophosphamide
  • cyclophosphamide is commonly used in the treatment of MS. Accordingly, targeting a BTK inhibitor, which has immunosuppressive activity, to the lymphatic system using a lipid prodrug form of the BTK inhibitor described herein may provide further benefit in the treatment of MS over the BTK inhibitor alone.
  • the disclosure provides a method for treating a neurodegenerative disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein or antigen binding fragment thereof.
  • the neurodegenerative disease is multiple sclerosis.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament for the treatment of a neurodegenerative disorder, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein, and wherein the neurodegenerative disease is multiple sclerosis.
  • Rheumatoid arthritis is an immune-inflammatory disorder that mainly targets the synovium of diarthrodial joints.
  • Cell-cell and cytokine networks established within the inflamed RA synovium promote disease chronicity, amplify autoimmune responses and cause cartilage and bone destruction (Guo et ah, Rheumatoid arthritis: pathological mechanisms and modem pharmacologic therapies Bone Res. 2018; 6: 15).
  • RA Several clinical observations implicate the lymphatic system in RA pathogenesis. RA takes several years to develop, and the early steps of the disease process in RA occur in lymphoid organs, where lymphocytes are primed and differentiate into effector and memory cells.
  • T cells and B cells are continuously activated and proliferate, resulting in the production of cytokines and autoantibodies.
  • the T cells and B cells invade the synovium, by forming novel lymphoid structures and producing defective repair mechanisms. New blood vessels formed as a result of inflammation allow the immune cells to easily migrate into the synovial lesion.
  • the longevity of the pathologic immune response depends on the specific interactions between the immune cells and the non lymphoid cells, and determines the level of tissue damage associated with RA (as reviewed in Weyand and Goronzy,“Immunometabolism in early and late stages of rheumatoid arthritis,” Nature Reviews Rheumatology, 13(5), 291-301(2017)).
  • targeting the lymphoid organs with an agent that can suppress the activation of immune cells within the lymphoid tissue, such as the lipid prodrugs described herein may be useful for the treatment of RA, in particular in the early stages of RA.
  • the disclosure provides a method for treating rheumatoid arthritis in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament for the treatment of an immune-inflammatory disorder, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein and wherein the immune- inflammatory disorder is rheumatoid arthritis.
  • Asthma is an inflammatory disease characterized by reversible, and at times irreversible, airflow obstruction and pulmonary symptoms of variable severity. Chronic inflammation in patients with asthma leads to mucosal edema, subepithelial fibrosis, and alterations in the extracellular matrix (Stump et al., Lymphatic Changes in Respiratory Diseases: More than Just Remodeling of the Lung?; Am J Respir Cell Mol Biol. 2017 Sep; 57(3): 272-279.). Allergen-specific CD4+ T cells play a key role in asthma (reviewed in Ling and Luster, Allergen- Specific CD4+ T Cells in Human Asthma; Ann Am Thorac Soc. 2016 Mar; 13(Suppl 1): S25- S30).
  • the disclosure provides a method for treating asthma in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament for the treatment of an immune-inflammatory disorder, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein and wherein the immune- inflammatory disorder is asthma.
  • Alloimmune T cells are the key component of the human adaptive immune response to transplants of organs, cells, and tissues from other humans, which are referred to as allogeneic.
  • This alloimmune response is the central immune response in solid organ transplantation and hematopoietic stem cell transplantation (HSCT), in both host-versus-graft and graft-versus-host responses (DeWolf and Sykes Alloimmune T cells in transplantation; J Clin Invest. 2017 Jun 30; 127(7): 2473-2481).
  • HSCT hematopoietic stem cell transplantation
  • the success of HSCT is dependent on potent nonspecific immunosuppressive therapy to prevent graft rejection and graft-versus-host disease (GVHD).
  • the disclosure provides a method for providing immunosuppressive therapy to prevent host-versus- graft-disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a BTK inhibitor lipid prodrug described herein or antigen binding fragment thereof.
  • the transplant is a heart, lung, heart-lung or liver transplant.
  • the transplant is a hematopoietic stem cell transplant.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament to prevent transplant rejection in a subject, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein, and wherein the transplant is selected from a heart, lung, heart-lung or liver transplant.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament to prevent graft-versus-host disease in a subject, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein, and wherein the transplant is a hematopoietic stem cell transplant.
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament to prevent host-versus-graft disease in a subject, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein, and wherein the transplant is a hematopoietic stem cell transplant.
  • the BTK inhibitor lipid prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof, or the BTK inhibitor lipid prodrug is selected from the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • Btk inhibitors have demonstrated anti-tumor activity, in animal models and in clinical studies.
  • the orally administered irreversible BTK inhibitor has shown high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), Waldenstrom macroglobulinemia, and other B-cell malignancies.
  • CLL chronic lymphocytic leukemia
  • MCL mantle-cell lymphoma
  • Waldenstrom macroglobulinemia and other B-cell malignancies.
  • BTK may be involved in the development and progression of other malignancies, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, multiple myeloma, and marginal zone lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • follicular lymphoma multiple myeloma
  • marginal zone lymphoma marginal zone lymphoma.
  • the B cell malignancy is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, B-cell chronic lymphocytic leukemia (CLL), and Waldenstrom macroglobulinemia.
  • DLBCL diffuse large B-cell lymphoma
  • CLL B-cell chronic lymphocytic leukemia
  • the disclosure provides the use of a BTK inhibitor lipid prodrug as a medicament for the treatment of a B cell lymphoma, wherein the BTK inhibitor lipid prodrug is any of the compounds described herein.
  • Inflammatory markers include measurement of CD8+ and CD4+ (conventional) T-cell activation (in an in vitro or in vivo assay, e.g., by measuring inflammatory cytokine levels, e.g., IFNgamma, TNF alpha, CD44, ICOS granzymeB, Perforin, IL2 (upregulation); CD26L and IL-10 (downregul ati on)) .
  • inflammatory cytokine levels e.g., IFNgamma, TNF alpha, CD44, ICOS granzymeB, Perforin, IL2 (upregulation); CD26L and IL-10 (downregul ati on)
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Lipid vehicles, and the resulting lipid formulations may contain oil/lipids and/or surfactants, optionally with co-solvents.
  • Type I formulations include oils or lipids which require digestion, such as mono, di and tri-glycerides and combinations thereof.
  • Type II formulations are water-insoluble self emulsifying drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations, with additional water insoluble surfactants.
  • SEDDS water-insoluble self emulsifying drug delivery systems
  • Suitable surfactants for use in the lipid formulations include propylene glycol mono- and di-esters of Cx-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters including, but not limited to, polyoxyl 40 stearate and
  • a polymer may also be used in the formulation to inhibit drug precipitation or to alter the rate of drug release.
  • a range of polymers have been shown to impart these properties and are well known to those skilled in the art.
  • Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the Eudragit series of polymers, including Eudragit E100, polyvinylpyrrolidone, or others as described in, e.g. Warren et al., Mol. Pharmaceutics 2013, 10, 2823-2848.
  • formulations may take the form of large monolithic dose forms or may be present as micro or nano-particulate matrices as described in, for example, in Mishra, Handbook of Encapsulation and Controlled Release , CRC Press, Boca Raton, (2016) ISBN 978-1-4822-3234-9, Wilson and Crowley, Controlled Release in Oral Drug Delivery , Springer, NY, ISBN 978-1-4614-1004-1 (2011) or Wise, Handbook of Pharmaceutical Controlled Release Technology , Marcel Dekker, NY, ISBN 0-82467-0369-3 (2000).
  • the present invention provides a method of treating COPD comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednis
  • beta-2 agonists such as
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a disclosed lipid prodrug and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.
  • the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation
  • ulcerative colitis and Crohn’s disease endocrine opthalmopathy
  • Grave’s disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • Fadrozole is marketed under the trade name AfemaTM.
  • Anastrozole is marketed under the trade name ArimidexTM.
  • Letrozole is marketed under the trade names FemaraTM or FemarTM.
  • Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • topoisom erase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CamptosarTM.
  • Topotecan is marketed under the trade name HycamptinTM.
  • histone deacetylase inhibitors or“HD AC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • c-Met receptor compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • the term“mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • the term“inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZamestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase enzyme, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • MMP matrix metalloproteinase inhibitor
  • collagen peptidomimetic and nonpeptidomimetic inhibitors tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -b-D-arabinofuransyl cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DMl, erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PR064553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • a disclosed lipid prodrug can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • a disclosed lipid prodrug can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl) ⁇ 2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy include treatment with compounds, such as VisudyneTM and porfimer sodium.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • Disclosed lipid prodrugs are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a disclosed lipid prodrug may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • Amisulpride amitriptyline, amprenavir, anastrozole, Apomorphine, apremilast, Arbutamine, Argatroban, Arsenic trioxide, aspirin, Atazanavir/cobicistat, Atorvastatin, Avibactam/ceftazidime, Azacitidine, azathioprine, Azithromycin, Belinostat, bendamustine, Bexarotene, Biapenem, Bicalutamide, Bortezomib, Bosentan, bosutinib, Bromfenac, Buprenorphine, Bupropion, Busulfan, Cl esterase inhibitor, Caffeine, calcium levofolinate, Cangrelor, capecitabine, capsaicin, Carfilzomib, Carvedilol, Cefepime, Ceftaroline fosamil, Ceftazidime, Ceftibuten, Ce
  • a disclosed lipid prodrug may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a disclosed lipid prodrug is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • the disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition such as cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder.
  • a disease, disorder, or condition such as cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • drug unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a disclosed lipid prodrug or composition thereof and any co-administered additional therapeutic agents will be decided by the attending physician within the scope of sound medical judgment.
  • lipid prodrug compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • the therapeutic agents comprised in disclosed lipid prodrugs may be purchased commercially or prepared by organic synthesis, semi synthesis, fermentation (e.g. with viral vectors), and like methods known in the art.
  • protecting groups can be used to manipulate therapeutic agents in preparation for conjugation to the remainder of the lipid prodrug structure, for example, to prevent undesired side reactions from taking place.
  • LG includes, but is not limited to, halogens (e.g, fluoride, chloride, bromide, iodide), sulfonates (e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • halogens e.g, fluoride, chloride, bromide, iodide
  • sulfonates e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate
  • diazonium and the like.
  • the phrase“oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis , P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethyl silyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis , P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups , Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (Boc), ethyl oxy carbonyl, methyloxycarbonyl, tri chi oroethyl oxy carbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • compounds of the present invention may be synthesized via one of the following routes:
  • acid-TG iii can be generated by ring opening with diglyceride ii in the presence of pyridine or another appropriate base (Scheme 2).
  • This method works best when R 4 and R 5 of acid anhydride i-a are identical, e.g. both Me, but will result in a regioisomeric mixture of acid-TG products iv when R 4 and R 5 differ from each other. Consequently, other methods, such as that outlined in Scheme 3, can advantageously be employed in this circumstance.
  • a modified version of the acetal self-immolative group can be used where an additional carboxy group is included.
  • Reaction of the parent drug with a chloroalkyl chloroformate gives chloroalkyl carbonates (shown) or carbamates xi (see Scheme 5).
  • Displacement of the halide leaving group is then accomplished by treatment with the carboxylate derived from acid-TG iv in an appropriate solvent such as refluxing toluene to afford the target compound xii.
  • primary alcohol xxii can be activated by treatment with /;-nitrophenyl (PNP) chloroformate to give PNP carbonate xxiii. Displacement of the PNP group is then achieved by reaction with a pharmaceutical agent (A-OH shown) under basic conditions to give the desired compound xxiv.
  • PNP /;-nitrophenyl
  • DIPEA diisopropylethylamine
  • EDCI, EDC, or EDAC l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • TEA triethylamine
  • THF tetrahydrofuran
  • TBS lerl-b uty 1 dimethyl silyl
  • NBS N-bromosuccinimide
  • PCC Pyridinium chlorochromate
  • PE petroleum ether
  • HATU l-[Bis(dimethylamino)methylene]-lii-l,2,3-triazolo[4,5-3 ⁇ 4]pyridinium 3-oxid Hexafluorophosphate
  • Int-1 (220 g, 388 mmol) was dissolved in a solution of THF (3000 mL) and water (200 mL) at 0 °C. Sodium borohydride (22 g, 579 mmol) was added portion wise. After addition, the mixture was filtered to afford a cake, which was dried to afford compound Int-2 (1,3-DG) (177 g, 311 mmol, 80% yield) as a white solid.
  • Int-7 (68 g, 86.5 mmol) and palladium on carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under hydrogen atmosphere at 30 °C for 16 h, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to afford Int-4 (C5pMe-acid-2-TG) (51 g, 73.2 mmol, 84% yield) as a white solid.
  • Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 98.3 pL, 98.3 miho ⁇ ) was added to a solution of TBDPS ether Int-22 (39.0 mg, 39.3 miho ⁇ ) in THF (2.5 mL) at 0 °C and the mixture stirred at room temperature for three hours. The reaction was diluted with water (10 mL), extracted with ethyl acetate (3 x 15 mL), and the organic extracts washed with brine (30 mL), dried (MgSCL) and concentrated under reduced pressure to give the crude product.
  • TBDPS ether Int-22 39.0 mg, 39.3 miho ⁇
  • n-Butyllithium (n-BuLi, 1.6 M in hexanes, 4.01 mL, 6.42 mmol) was added slowly to a solution of TMS-acetylene (1.02 mL, 7.22 mmol) in THF (9 mL) at -78 °C and the mixture stirred at -78 °C for five minutes then warmed to room temperature and stirred for a further 15 minutes.
  • Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 1.61 mL, 1.61 mmol) was added dropwise to silylalkyne Int-40 (463 mg, 1.34 mmol) in THF (12 mL) at 0 °C and the mixture stirred at room temperature for 40 minutes.
  • the reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 c 20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSCh) and concentrated under reduced pressure to give the crude product.
  • a suspension of PdCl 2 (PPh3) 2 (32.2 mg, 0.0459 mmol) in DMF (4 mL) was degassed using a stream of N 2 gas for five minutes, and then Cul (35.0 mg, 0.184 mmol), Et3N (256 pL, 1.84 mmol) and a degassed solution of alkyne Int-41 (250 mg, 0.918 mmol) and enol triflate Int- 17 (313 mg, 1.19 mmol) in DMF (6 mL) were added.
  • the mixture was degassed using a stream of N 2 for a further five minutes and then heated at 70 °C for one hour.
  • TBDPS ether Int-46 (65.7 mg, 0.0619 mmol) in THF (3 mL) at 0 °C and the mixture stirred at room temperature for 19 hours.
  • the reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with sat. aq. NaHCCh and brine (30 mL each), dried (MgSCh) and concentrated under reduced pressure to give the crude product.
  • compound Int-177 (C8 Me-OH-2-TG-oleate) was prepared from l -(/tvV-butyl diphenyl si lyloxy)-pent-4-yne, benzyl (Z)-3-(((trifluorom ethyl) sulfonyl)oxy)but-2-enoate (Int-198; prepared similarly to Int-17), and Int-112.
  • Compound lnt-232 was prepared from Int-45 and Int-112 according to the procedures described for the conversion of Int-45 to Int-47. Oxidation of lnt-232 to Int-233 was conducted using the Jones’ reagent according to the procedure described for preparation of Int-178.
  • Compound Int-247 was prepared by oxidation of Int-121 using the Jones’ reagent according to the procedure described for preparation of Int-178.
  • lnt-50 prepared according to: Subba Reddy, B. V. et al. Helv. Chim. Acta. 2013, 96,
  • lnt-51 known compound that may be prepared as disclosed in Takagi, Y. et al.
  • n-Butyllithium (n-BuLi, 2.0 M in cyclohexane, 18.1 mL, 36.3 mmol) was added slowly to a solution of TMS-acetylene (5.7 mL, 41.5 mmol) in THF (45 mL) at -78 °C and the mixture stirred at -78 °C for five minutes then warmed to room temperature and stirred for a further 15 minutes.
  • Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 9.7 mL, 9.70 mmol) was added dropwise to silylalkyne Int-52 (3.05 g, 9.62 mmol) in THF (40 mL) at 0 °C and the mixture stirred at room temperature for one hour. The reaction was diluted with water (25 mL) and the organic solvent removed under reduced pressure. The resulting solution was diluted with brine (100 mL) and the aqueous phase extracted with ethyl acetate (3 c 50 mL).
  • Int-17 was prepared as described above. [00500] A suspension of PdCl2(PPh3)2 (605 mg, 0.862 mmol) in DMF (40 mL) was degassed using N2 gas for five minutes, and then Cul (335 mg, 1.76 mmol), Et3N (2.40 mL, 17.2 mmol) and a degassed solution of alkyne Int-53 (2.11 g, 8.62 mmol) and enol triflate Int-17 (3.40 g, 13.00 mmol) in DMF (50 mL) were added. The mixture was degassed using a stream of N2 for a further five minutes and then heated at 70 °C for one hour.
  • Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 574 pL, 0.574 mmol) and acetic acid (32.8 pL, 0.574 mmol) were added to a solution of TBDPS ether Int-58 (395 mg, 0.383 mmol) in THF (15 mL) at 0 °C and the mixture stirred at room temperature for 17 hours.
  • the reaction was concentrated under reduced pressure and the residue diluted with ethyl acetate (30 mL), washed with water (2 c 20 mL) and brine (30 mL), dried (MgSCL) and concentrated under reduced pressure to give the crude product.
  • Int-25 was prepared as described above.
  • Int-211 was prepared from dec-9-yn-l-ol and TBDPSC1 using the procedure for preparation of Int-56, above.
  • 3 ⁇ 4 NMR 400 MHz, CDCh
  • 7.48 - 7.40 m, 6H
  • 1.63 (dq, J 6.4 Hz, 2H), 1.47 (m, 4H), 1.40 (m, 6H), 1.09 (s, 9H).
  • a suspension of PdCl2(PPh3)2 (6.44 g, 9.18 mmol) in CH 3 CN (180 mL) was degassed using N2 gas for five minutes, and then Cul (1.74 g, 9.18 mmol), Et 3 N (18.54 g, 183.7 mmol) and a degassed solution of alkyne Int-211 (36.0 g, 91.8 mmol) and Int-198 (29.75 g, 91.83 mmol) in CH 3 CN (180 mL) were added.
  • the mixture was degassed using a stream of N2 for a further five minutes and then heated at 60 °C for two hours.
  • Int-213 was prepared from Int-212 by analogy to the procedure for preparation of Int-
  • Int-214 was prepared from Int-213 by analogy to the procedure for preparation of Int-
  • Int-224 were prepared from Int-112 and /f/V-butyl di ethyl (tri dec- 12-yn- l -yl oxy)si 1 ane, which was prepared from dodecan-l,12-diol by mono-TBS protection (with TBSC1, imidazole, and DMAP in a mixture of DCM and DMF) followed by PCC oxidation and Ohira reagent homologation.
  • lnt-222: R f-Bu

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des promédicaments lipidiques destinés au système lymphatique, des compositions pharmaceutiques de ceux-ci, des procédés de production de tels promédicaments et compositions, et des procédés d'amélioration de la biodisponibilité ou d'autres propriétés d'un agent thérapeutique qui comprend une partie du promédicament lipidique. La présente invention concerne également des procédés de traitement d'une maladie, d'un trouble ou d'un état tel que ceux décrits ici, comprenant l'administration à un patient qui en a besoin d'un promédicament lipidique de l'invention ou d'une composition pharmaceutique de celui-ci.
PCT/US2020/020433 2019-02-28 2020-02-28 Promédicaments lipidiques d'inhibiteurs de btk et leurs utilisations WO2020176868A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962812071P 2019-02-28 2019-02-28
US62/812,071 2019-02-28

Publications (1)

Publication Number Publication Date
WO2020176868A1 true WO2020176868A1 (fr) 2020-09-03

Family

ID=72238673

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/020433 WO2020176868A1 (fr) 2019-02-28 2020-02-28 Promédicaments lipidiques d'inhibiteurs de btk et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2020176868A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021113365A1 (fr) * 2019-12-06 2021-06-10 Guide Therapeutics, Inc. Nanomatériaux
CN113440481A (zh) * 2021-08-13 2021-09-28 湖南慧泽生物医药科技有限公司 伊布替尼的自微乳组合物
CN114478391A (zh) * 2020-10-26 2022-05-13 南京锐志生物医药有限公司 奥硝唑酯类前药、药物组合物及其制备方法和应用
CN114940678A (zh) * 2021-09-26 2022-08-26 上海贵之言医药科技有限公司 一种吡唑并嘧啶酯类化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090297533A1 (en) * 2008-05-23 2009-12-03 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US20140328793A1 (en) * 2011-11-30 2014-11-06 Emory University Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections
US20180318318A1 (en) * 2015-11-12 2018-11-08 Board Of Regents Of The University Of Nebraska Polyethylene Glycol-Conjugated Glucocorticoid Prodrugs and Compositions and Methods Thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090297533A1 (en) * 2008-05-23 2009-12-03 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US20140328793A1 (en) * 2011-11-30 2014-11-06 Emory University Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections
US20180318318A1 (en) * 2015-11-12 2018-11-08 Board Of Regents Of The University Of Nebraska Polyethylene Glycol-Conjugated Glucocorticoid Prodrugs and Compositions and Methods Thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021113365A1 (fr) * 2019-12-06 2021-06-10 Guide Therapeutics, Inc. Nanomatériaux
CN114478391A (zh) * 2020-10-26 2022-05-13 南京锐志生物医药有限公司 奥硝唑酯类前药、药物组合物及其制备方法和应用
CN114478391B (zh) * 2020-10-26 2023-09-15 南京锐志生物医药有限公司 奥硝唑酯类前药、药物组合物及其制备方法和应用
CN113440481A (zh) * 2021-08-13 2021-09-28 湖南慧泽生物医药科技有限公司 伊布替尼的自微乳组合物
CN114940678A (zh) * 2021-09-26 2022-08-26 上海贵之言医药科技有限公司 一种吡唑并嘧啶酯类化合物
CN114940678B (zh) * 2021-09-26 2023-02-07 上海贵之言医药科技有限公司 一种吡唑并嘧啶酯类化合物
WO2023045411A1 (fr) * 2021-09-26 2023-03-30 上海贵之言医药科技有限公司 Composé d'ester de pyrazolopyrimidine

Similar Documents

Publication Publication Date Title
EP4306524A2 (fr) Promédicaments lipidiques dirigeant le système lymphatique
WO2020176859A1 (fr) Promédicaments lipidiques d'inhibiteurs de jak et leurs utilisations
WO2020176868A1 (fr) Promédicaments lipidiques d'inhibiteurs de btk et leurs utilisations
WO2020176856A1 (fr) Promédicaments lipidiques de glucocorticoïdes et leurs utilisations
JP6126131B2 (ja) Ｉｒａｋ阻害剤およびその使用
US11883497B2 (en) Lymphatic system-directing lipid prodrugs
US11938137B2 (en) Lipid prodrugs of mycophenolic acid and uses thereof
WO2021127278A1 (fr) Agents de dégradation d'irak et leurs utilisations
TW202136251A (zh) Irak降解劑及其用途
US20210300962A1 (en) Lipid prodrugs of pregnane neurosteroids and uses thereof
KR20160068832A (ko) 헤테로사이클릭 화합물 및 그의 용도
EP3727362A1 (fr) Promédicaments lipidiques d'acide mycophénolique et leurs utilisations
US11932624B2 (en) MDM2 degraders and uses thereof
TW202136242A (zh) Smarca降解劑及其用途
KR20220149534A (ko) 신경스테로이드의 지질 전구약물
WO2019126374A1 (fr) Promédicaments lipidiques de rapamycine et ses analogues et leurs utilisations
TW202237601A (zh) 介白素-1受體相關激酶(irak)降解物及其用途
US11608345B1 (en) Lipid prodrugs of rapamycin and its analogs and uses thereof
US20220339168A1 (en) Methods and compounds for treatment of metabolic disease
TWI840332B (zh) Tyk2抑制劑及其用途
TW202408538A (zh) Stat降解劑及其用途
KR20240017423A (ko) 이뮤노글로불린 및 다른 단백질의 분해를 위한 강력한 asgpr-결합 화합물
TW202415650A (zh) 芳基-***基及相關gpr84拮抗劑及其用途
WO2023220425A1 (fr) Agents de dégradation bcl-xl/bcl-2 et leurs utilisations
WO2023250058A1 (fr) Agents de dégradation de stat et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20762422

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20762422

Country of ref document: EP

Kind code of ref document: A1