WO2022066774A1 - Pharmaceutical compounds for the treatment of complement mediated disorders - Google Patents

Pharmaceutical compounds for the treatment of complement mediated disorders Download PDF

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Publication number
WO2022066774A1
WO2022066774A1 PCT/US2021/051559 US2021051559W WO2022066774A1 WO 2022066774 A1 WO2022066774 A1 WO 2022066774A1 US 2021051559 W US2021051559 W US 2021051559W WO 2022066774 A1 WO2022066774 A1 WO 2022066774A1
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alkyl
haloalkyl
compound
hydrogen
halogen
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French (fr)
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Jason Allan Wiles
Venkat Rao GADHACHANDA
Evans O. Onyango
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Achillion Pharmaceuticals Inc
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Achillion Pharmaceuticals Inc
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Priority to JP2023518377A priority Critical patent/JP7787164B2/ja
Priority to US18/027,506 priority patent/US20250171423A1/en
Priority to CN202180078240.1A priority patent/CN116437913A/zh
Priority to EP21873357.4A priority patent/EP4216946A4/en
Priority to CA3193488A priority patent/CA3193488A1/en
Publication of WO2022066774A1 publication Critical patent/WO2022066774A1/en
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
    • C07D487/08—Bridged systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • complement-mediated disorders including complement C1-mediated disorders.
  • the complement system is a part of the innate immune system which does not adapt to changes over the course of the host’s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system.
  • the complement system has three pathways: classical, alternative, and lectin.
  • the classical pathway is triggered by antibody-antigen complexes with the antibody isotypes IgG and IgM.
  • the antibody-antigen complex binds to C1 and this initiates the cleavage of C4 and C2 to generate C3 convertase that then splits C3 into C3a and C3b.
  • C3a interacts with its C3a receptor to recruit leukocytes
  • C3b binds to C3 convertase to form C5 convertase.
  • C5 convertase cleaves C5 into C5a and C5b.
  • C5a interacts with its C5a receptor to recruit leukocytes
  • C5b interacts with C6, C7, C8, and C8 and together these proteins form the cylindrical membrane attack complex (MAC) that causes the cell to swell and burst.
  • MAC cylindrical membrane attack complex
  • the present disclosure provides compounds and their uses and compositions to treat disorders arising from or amplified by a disfunction of the complement system.
  • the present disclosure also provides compounds, uses, compositions, combinations, and processes of manufacture that inhibit C1s (complement 1 esterase) and thus can treat disorders mediated by C1s.
  • This disclosure includes a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • the compound or its salt or composition, as described herein is used to treat a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity including for example, the classical complement pathway, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration.
  • a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity including for example, the classical complement pathway, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other all
  • a method for the treatment of a disorder mediated by complement activity includes the administration of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, as described in more detail below.
  • the disorder is associated with the complement classical pathway and the compound inhibits the classical pathway.
  • the disorder is associated with the alternative complement cascade pathway.
  • the disorder is associated with the complement lectin pathway.
  • the active compound or its salt or prodrug may act through a different mechanism of action than the complement cascade to treat a disorder described herein.
  • the active compound, and/or its salt or prodrug inhibits a combination of these pathways.
  • a method for treating a host, typically a human, with a disorder mediated by the complement system, that includes administration of a prophylactic antibiotic or vaccine to reduce the possibility of a bacterial infection during the treatment using one of the compounds described herein.
  • the host typically a human
  • the host is given a prophylactic vaccine prior to, during or after treatment with one of the compounds described herein.
  • the host typically a human
  • the infection is a meningococcal infection (e.g., septicemia and/or meningitis), an Aspergillus infection, or an infection due to an encapsulated organism, for example, Streptococcus pneumoniae or Haemophilus influenza type b (Hib), especially in children.
  • the vaccine or antibiotic is administered to the patient after contracting an infection due to, or concomitant with, inhibition of the complement system.
  • R 14 , R 15 , and R 16 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 - C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , carbocycle, heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18
  • R 5 and/or R 6 may also be C 1 -C 6 hydroxyalkyl or C(O)R 31 .
  • R 30 may also be optionally substituted with carbocycle (e.g., cycloalkyl).
  • carbocycle e.g., cycloalkyl
  • for compounds of Formula I and Formula II at least one of the following is satisfied: a. X 3 is C(R 17 ) and X 4 is C(R 18 ); b. R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; c. X 5 is Si; d.
  • X 5 is S, at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen; e. Z is C(CH 2 ); f. Z is CH 2 ; g. R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or a carbonyl; h.
  • R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; i. R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or a carbonyl; j.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 or R 12 is not hydrogen; k.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 8 or R 10 is not hydrogen; l.
  • R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m.
  • X 6 is selected from n.
  • R 3 and R 4 is CN, -SR 30 or C(O)R 31 ; or o.
  • R 3 and R 4 are combined to form a dihydroxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; an imidazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; or a dihydroimidazole optionally substituted 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and o
  • the compound of the present disclosure is of Formula X, XI, or XII:
  • R 22 is selected from -C 1 -C 6 alkyl-R 23 , -C 2 -C 6 alkenyl-R 23 , -C 2 -C 6 alkynyl-R 23 , -heteroaryl-R 23 , - carbocycle-R 23 , and bicyclic cycloalkyl-R 23 , each of which R 22 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 - C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl,
  • X 3 is C(R 17 ) and X 4 is C(R 18 );
  • R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ;
  • X 5 is Si;
  • X 5 is S, at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen;
  • Z is C(CH 2 ); f. Z is CH 2 ; g.
  • R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or a carbonyl; h.
  • R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; i.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; j. R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or a carbonyl; k.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; l.
  • R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m.
  • R 22 is substituted with at least three OR 30 groups; n.
  • R 23 is a sugar; o. at least one of R 3 and R 4 is CN, -SR 30 , or C(O)R 31 ; or p.
  • R 3 and R 4 are combined to form an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo.
  • R 23 is selected from hydrogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 .
  • the compound of Formula X is selected from:
  • R 23 is selected from -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and - S(O) 2 R 31 .
  • the compound of Formula X, XI, or XII is selected from ; ora pharmaceutically acceptable salt, prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier.
  • the compound of Formula XII is or a pharmaceutically acceptable salt thereof.
  • the compound of the present disclosure is of Formula XIII: or a pharmaceutically acceptable salt prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier; wherein: X 7 is selected from O, S, N(R 30 ), and CR 5 R 6 ; o is 0, 1, or 2; each R 25 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; each of which R 25 groups other than hydrogen, halogen, cyano, and nitro are optional
  • the compound of the present disclosure is of Formula XIV: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier; wherein the variables are as defined herein and for compounds of Formula XIV at least one of the following is satisfied: a. X 1 is O or N(R 30 ); b. R 14 is not hydrogen; c. R 1 is not hydrogen; d. R 2 is not hydrogen; e. R 3 is not hydrogen; or f. R 4 is not hydrogen.
  • the compound of Formula XIII or XIV is selected from or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier.
  • the compound of the present disclosure is of Formula XV:
  • each X 8 and X 9 is independently selected from O, S, NR 30 , CR 9 R 10 , CR 5 R 6 . and CH 2 ; wherein X 8 and X 9 cannot both be the same group; and all other variables are as defined herein.
  • the compound of formula in an alternative embodiment is replaced with , for example in this embodiment the compound of formula can be replaced with
  • the compound of the present disclosure is of Formula XVI, XVII, or XVIII: , or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier; wherein: X 10 is selected from R 35 is selected from C 3 -C 10 alkyl or C 3 -C 10 haloalkyl; and all other variables are as defined herein.
  • the compound of the present disclosure is of Formula XIX or Formula XX: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof optionally in pharmaceutically acceptable carrier; wherein: R 29 is selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , - SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, and heteroaryl, each of which R 29 groups other than hydrogen and halogen are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,
  • R 29 is hydrogen.
  • Pharmaceutical compositions comprising a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, together with a pharmaceutically acceptable carrier are also disclosed.
  • the present disclosure thus includes at least the following features: a. a compound of the present disclosure or a pharmaceutically acceptable salt, prodrug, N- oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition; b.
  • a disorder including but not limited to the development of fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure; dermatomyositis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics (e.g., CAR T- cell therapy); hereditary angioedema (HAE), chronic immune thrombocytopenia (ITP), cold agglutinin disease, cold agglutinin syndrome, warm autoimmune hemolytic anemia, cryoglobulinemia, bullous pemphigoid, common variable immunodeficiency, endotoxemia, sepsis, multiple organ dysfunction syndrome, hemolytic ure
  • a process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder, or generally for treating or preventing disorders mediated by the classical complement pathway characterized in that a compound of the present disclosure or an embodiment of the active compound is used in the manufacture; g. a compound of the present disclosure ora salt thereof as described herein in substantially pure form (e.g., at least 90 or 95%); h.
  • a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure
  • the compounds in any of the Formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context.
  • the compound of the present disclosure may form a solvate with solvents (including water). Therefore, in one embodiment, the disclosure includes a solvated form of the active compound.
  • solvate refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the disclosure and water.
  • solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
  • a solvate can be in a liquid or solid form.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • substituted as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded and the resulting compound is stable.
  • a stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
  • a stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use.
  • a stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use.
  • Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.
  • Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C 2 -C 6 alkanoyl group); carboxamide; alkyl, carbocycle (e.g., cycloalkyl or cycloalkenyl), alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those having one or more sulfony
  • Such groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino.
  • “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH 2 , alkyl including C 1 -C 6 alkyl, alkenyl including C 2 - C 6 alkenyl, alkynyl including C 2 -C 6 alkynyl, -C 1 -C 6 alkoxy, alkanoyl including C 2 -C 6 alkanoyl, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 2 alkyl, haloalkyl including C 1 -C 6 haloalkyl, hydoxyC 1 -C 6 alkyl, ester, carbamate, urea, sulfonamide,-C 1 -C 6 alkyl(heter
  • Alkyl is a branched or straight chain saturated hydrocarbon group. In one embodiment, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C 1 -C 6 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C0-Cn alkyl is used herein in conjunction with another group, for example, (C 3 -C 7 cycloalkyl)C0-C 4 alkyl, or –C0-C 4 alkyl(C 3 -C 7 cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C 0 alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms.
  • Alkyl groups can also be attached via other groups such as heteroatoms as in –O-C0-C 4 alkyl(C 3 -C 7 cycloalkyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert- pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl.
  • Alkyl groups can be optionally substituted independently with one or more substituents described herein.
  • alk When a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context.
  • alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.
  • Alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain.
  • Non-limiting examples are C 2 -C 8 alkenyl, C 2 -C 7 alkenyl, C 2 -C 6 alkenyl, C 2 -C 5 alkenyl and C 2 -C 4 alkenyl.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl include, but are not limited to, ethenyl and propenyl.
  • Alkenyl groups can be optionally substituted independently with one or more substituents described herein.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C 2 -C 8 alkynyl or C 2 -C 6 alkynyl.
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • Alkynyl groups can be optionally substituted independently with one or more substituents described herein.
  • Haloalkyl indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta- fluoroethyl.
  • Haloalkyl groups can be optionally substituted independently with one or more substituents described herein.
  • Halo or halogen indicates independently, any of fluoro, chloro, bromo, or iodo.
  • Aryl indicates an aromatic group containing only carbon in the aromatic ring or rings.
  • the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members.
  • such aryl groups may be further substituted with carbon or non-carbon atoms or groups.
  • substitution may include fusion to a 4 to 7 or a 5 to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4- methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1- naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant.
  • Heterocycle refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O.
  • the term “heterocycle” includes monocyclic 3-12 membered rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro, bicyclic ring systems), and excludes rings containing -O-O-. -O-S-, or -S-S- portions.
  • saturated heterocycle groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • nitrogen atoms e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl
  • partially saturated heterocycle radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,
  • “Bicyclic heterocycle” includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. “Bicyclic heterocycle” also includes heterocyclic radicals that are fused with a carbocycle radical. For example, partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms are all encompassed.
  • Heterocycle groups can be optionally substituted independently with one or more substituents described herein.
  • bicyclic heterocycles include: Unless otherwise drawn or clear from the context, the term “bicyclic heterocycle” includes cis and trans diastereomers.
  • Non-limiting examples of chiral bicyclic heterocycles include: “Carbocycle” refers to a non-aromatic monocyclic or polycyclic (e.g., bicyclic or tricyclic) in which all ring atoms are carbon atoms.
  • Carbocycle groups include saturated groups (i.e., cycloalkyl) and unsaturated groups (e.g., cycloalkenyl, which includes one or more double bonds and no triple bonds and cycloalkynyl, which includes at least one triple bond).
  • “carbocycle” is cycloalkyl.
  • “carbocycle” is cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl).
  • “carbocycle” includes 3 to 13 carbon atoms.
  • “carbocycle” is a tricyclic cycloalkenyl group (e.g., fluorenyl). In some embodiments, “carbocycle” (e.g., cycloalkyl or cycloalkenyl) is optionally substituted with one or more substituents described herein.
  • Heteroaryl refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1 , 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms.
  • bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8 or 10 ring atoms in which one 5, 6, or 7 member aromatic ring is fused to a second aromatic or non-aromatic ring wherein the point of attachment is the aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1 , these heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number ofS and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazoly
  • a “dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • a “dosage form” can also include an implant, for example an optical implant.
  • “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a pharmaceutically acceptable carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Pharmaceutically acceptable salts include salts which are acceptable for human consumption, and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic acids.
  • salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) 1-4 -COOH, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic
  • carrier applied to pharmaceutical compositions/combinations according to the disclosure refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” may be used interchangeably and mean an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, acceptable for human consumption, and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.
  • an excipient is used that is acceptable for mammalian, particularly human, use.
  • a “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, including but not limited to by modulation of the classical complement pathway or with a condition that is treatable with one of the compounds described herein.
  • the host is a human.
  • a “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, bird, and the like.
  • a “prodrug” refers to a compound which when administered to a host in vivo is converted into a parent drug.
  • the term "parent drug” means any of the presently described chemical compounds herein.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo.
  • Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug.
  • Non-limiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, ph os ph ora mid ate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
  • “Providing a compound with at least one additional active agent,” for example, in one embodiment can mean that the compound and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration.
  • the compound administrations are separated by some amount of time that is within the time in which both the compound and the at least one additional active agent are within the blood stream of a patient.
  • the compound and the additional active agent need not be prescribed for a patient by the same medical care worker.
  • the additional active agent or agents need not require a prescription.
  • Administration of the compound or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intraaortal, transdermal, polymeric controlled delivery, non-polymeric controlled delivery, nano or microparticles, liposomes, and/or topical contact.
  • the instructions for administration in a form of combination therapy is provided in the drug labeling.
  • a “therapeutically effective amount” of a pharmaceutical composition/combination of this disclosure means an amount effective, when administered to a host, to provide a therapeutic benefit, such as an amelioration of symptoms or reduction ordimunition ofthe disease itself.
  • a therapeutically effective amount is an amount sufficient to prevent a significant increase, or will significantly reduce, the detectable level of hemolysis in the patient’s blood, serum, or tissues.
  • any ofthe active compounds can be provided in its N-oxide form to a patient in need thereof.
  • an N-oxide of an active compound or a precursor of the active compound is used in a manufacturing scheme.
  • the N-oxide is a metabolite of administration of one ofthe active compounds herein, and may have independent activity.
  • the N-oxide can be formed by treating the compound of interest with an oxidizing agent, for example, a suitable peroxyacid or peroxide, to generate an N-oxide compound.
  • a heteroaryl group for example a pyridyl group
  • an oxidizing agent such as sodium percarbonate
  • a rhenium-based catalyst under mild reaction conditions to generate an N-oxide compound.
  • oxidizing agent such as sodium percarbonate
  • protecting groups may be necessary to carry out the chemistry. See Jain, S.L. et al., “Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006.
  • any of the active compounds with a sulfur can be provided in its sulfoxide or sulfone form to a patient in need thereof.
  • a sulfoxide or sulfone of one of the active compounds or a precursor of the active compound is used in a manufacturing scheme.
  • a sulfur atom in a selected compound as described herein can be oxidized to form a sulfoxide or a sulfone using known methods.
  • the compound 1,3,5- triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is an efficient promoter for the oxidation of sulfides to sulfoxides. See, Bahrami, M.
  • Sulfides can be oxidized to sulfones using, for example, niobium carbide as the catalyst, see Kirihara, A., et al., “Tantalum Cardide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones”, Synlett, 1557- 1561 (2010).
  • Urea-hydrogen peroxide adduct is a stable inexpensive and easily handled reagent for the oxidation of sulfides to sulfones, see Varma, R.S.
  • alkyl is a C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, or C 1 -C2alkyl.
  • “alkyl” has one carbon. In certain embodiments, “alkyl” has two carbons. In certain embodiments, “alkyl” has three carbons. In certain embodiments, “alkyl” has four carbons. In certain embodiments, “alkyl” has five carbons.
  • alkyl has six carbons.
  • Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl.
  • haloalkyl is a C 1 -C 1 0haloalkyl, C 1 -C9haloalkyl, C 1 -C 8 haloalkyl, C 1 - C 7 haloalkyl, C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkyl, and C 1 -C 2 haloalkyl.
  • haloalkyl has one carbon. In certain embodiments, “haloalkyl” has one carbon and one halogen. In certain embodiments, “haloalkyl” has one carbon and two halogens. In certain embodiments, “haloalkyl” has one carbon and three halogens. In certain embodiments, “haloalkyl” has two carbons. In certain embodiments, “haloalkyl” has three carbons. In certain embodiments, “haloalkyl” has four carbons. In certain embodiments, “haloalkyl” has five carbons. In certain embodiments, “haloalkyl” has six carbons.
  • Non-limiting examples of “haloalkyl” include: , , Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: Embodiments of “aryl” In certain embodiments, “aryl” is a 6 carbon aromatic group (phenyl) In certain embodiments, “aryl” is a 10 carbon aromatic group (napthyl) In certain embodiments, “aryl” is “substituted aryl”. Embodiments of “heteroaryl” In certain embodiments, “heteroaryl” is a 5 membered aromatic group containing 1, 2, or 3, nitrogen atoms.
  • Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include:
  • heteroaryl is a 6 membered aromatic group containing 1 , 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
  • Non-limiting examples of 6-membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: In certain embodiments, “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or
  • heteroaryl groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include:
  • heteroaryl groups that are bicyclic include: In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: In an alternative embodiment, heteroaryl is tetrazole.
  • “carbocycle” is a saturated or an unsaturated, non-aromatic cyclic group containing only carbon atoms as the ring atoms, e.g., C 3 -C 8 carbocycle, C 3 -C 7 carbocycle, C 3 -C 6 carbocycle, C 3 -C 5 carbocycle, C 3 -C 4 carbocycle, C 4 -C 8 carbocycle, C 5 -C 8 carbocycle, or C 6 -C 8 carbocycle.
  • “carbocycle” has three carbons.
  • “carbocycle” has four carbons.
  • “carbocycle” has five carbons.
  • “carbocycle” has six carbons. In certain embodiments, “carbocycle” has seven carbons. In certain embodiments, “carbocycle” has eight carbons. In certain embodiments, “carbocycle” has nine carbons. In certain embodiments, “carbocycle” has ten carbons. In certain embodiments, “carbocycle” has eleven carbons. In certain embodiments, “carbocycle” has twelve carbons. In certain embodiments, “carbocycle” has thirteen carbons. In certain embodiments, “carbocycle” is a saturated cyclic group, i.e., a “cycloalkyl” group.
  • “carbocycle” is an unsaturated, non-aromatic cyclic group, i.e., a “cycloalkenyl” group.
  • “cycloalkyl” is a C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl, C 3 - C 5 cycloalkyl, C 3 -C 4 cycloalkyl, C 4 -C 8 cycloalkyl, C 5 -C 8 cycloalkyl, or C 6 -C 8 cycloalkyl.
  • cycloalkyl ha s three carbons. In certain embodiments, “cycloalkyl” has four carbons. In certain embodiments, “cycloalkyl” has five carbons. In certain embodiments, “cycloalkyl” has six carbons. In certain embodiments, “cycloalkyl” has seven carbons. In certain embodiments, “cycloalkyl” has eight carbons. In certain embodiments, “cycloalkyl” has nine carbons. In certain embodiments, “cycloalkyl” has ten carbons.
  • cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.
  • cycloalkyl is a C 4 -C 8 cycloalkenyl, C 4 -C 7 cycloalkenyl, C 4 - C 6 cycloalkenyl, C 4 -C 5 cycloalkenyl, C 4 -C9cycloalkenyl, C 4 -C 10 cycloalkenyl, C 4 -C 11 cycloalkenyl, C 4 - C 12 cycloalkenyl, C 4 -C 13 cycloalkenyl,C 5 -C 8 cycloalkenyl, or C 6 -C 8 cycloalkenyl.
  • cycloalkenyl has four carbons. In certain embodiments, “cycloalkenyl” has five carbons. In certain embodiments, “cycloalkenyl” has six carbons. In certain embodiments, “cycloalkenyl” has seven carbons. In certain embodiments, “cycloalkenyl” has eight carbons. In certain embodiments, “cycloalkenyl” has nine carbons. In certain embodiments, “cycloalkenyl” has ten carbons. In certain embodiments, “cycloalkenyl” has eleven carbons. In certain embodiments, “cycloalkenyl” has twelve carbons. In certain embodiments, “cycloalkenyl” has thirteen carbons.
  • cycloalkenyl includes one double bond. In certain embodiments, “cycloalkenyl” includes two or more double bonds. In certain embodiments, “cycloalkenyl” is a bicyclic group. In certain embodiments, “cycloalkenyl” is a tricyclic group. Non-limiting examples of “cycloalkenyl” include: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecenyl. A non-limiting example of tricyclic “alkenyl” is fluorenyl.
  • heterocycle refers to a saturated or unsaturated, non-aromatic cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment, “heterocycle” refers to a saturated or unsaturated, non-aromatic cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment, “heterocycle” refers to a saturated or unsaturated, non-aromatic cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a saturated or unsaturated, non-aromatic cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In one embodiment, “heterocycle” refers to a saturated or unsaturated, non-aromatic cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane.
  • heterocycle examples include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.
  • heterocycle include dihydrooxadiazole and dihydropyrimidine.
  • Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include: Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: , , , , , Additional non-limiting examples of “heterocycle” include: Embodiments of “sugar” In some embodiments, “sugar” refers to a compound of formula C 3 H 5 O 3, C 4 H 7 O 4, C 5 H 9 O 5 , C 6 H 11 O 6 , C 7 H 13 O 7 , or C 8 H 15 O 8.
  • Non-limiting examples of sugar include , , , Additional embodiments of the present disclosure: In some embodiments, selected from:
  • R 22 is selected from In some embodiments, R 22 is selected from In some embodiments, is selected from In some embodiments, is selected from In some embodiments, is selected from , , , , , In some embodiments, In some embodiments, In some embodiments, In some embodiments, In some embodiments, In some embodiments, R 26 is selected from In some embodiments, R 27 is selected from , , , In some embodiments, is selected from In some embodiments, R 21 is selected from: F,
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • the compound of the present disclosure is selected from:
  • the compound of the present disclosure is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula I is selected from:
  • a compound of Formula IV is selected from:
  • a compound of Formula V is selected from:
  • the compound of Formula I is selected from: ora pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein all variables are as defined herein.
  • the compound of Formula I is selected from: ora pharmaceutically acceptable salt, prodrug, or isolated isomerthereof, optionally in pharmaceutically acceptable carrier; wherein all variables are as defined herein.
  • the compound of Formula I is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier; wherein: R 200 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ); and all other variables are as defined herein.
  • R 200 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ); and all other variables are as defined herein.
  • the compound of Formula I is selected from:
  • the compound of Formula I is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; for example, in one embodiment, wherein in this aspect at least one of R 8 and R 10 is not hydrogen; and all other variables are as defined herein.
  • the compound of Formula I is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; for example, in one embodiment; wherein in this aspect at least one of R 10 and R 12 is not hydrogen; and all other variables are as defined herein.
  • the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S, wherein is substituted with 1, 2, 3, or 4 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; and all other variables are as defined herein.
  • the compound of Formula X is selected from:
  • the compound of Formula X is selected from: ora pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein all variables are as defined herein.
  • the compound of Formula X is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: R 200 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) and all other variables are as defined herein.
  • the compound of Formula X is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: is selected from a 3- to 6-membered carbocyclic ring and a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; in an alternative embodiment, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; all other variables are as defined herein.
  • the compound of Formula X is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; wherein in this aspect at least one of R 8 and R 10 is not hydrogen; and all other variables are as defined herein.
  • the compound of Formula X is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; for example, in one embodiment wherein in this aspect at least one of R 10 and R 12 is not hydrogen; and all other variables are as defined herein.
  • the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein: is a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S, wherein is substituted with 1, 2, 3, or 4 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; and all other variables are as defined herein.
  • a 3- to 8-membered carbocycle is a 4- to 8-membered carbocycle.
  • a 3- to 8-membered carbocycle is a 4- to 8-membered carbocycle.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S;
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S;
  • the compound of Formula XIV is selected from: ora pharmaceutically acceptable salt, prodrug, or isolated isomer thereof, optionally in pharmaceutically acceptable carrier; wherein all variables are as defined herein.
  • the compound of Formula XIV is selected from:
  • R 201 is selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , - SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, and heteroaryl, each of which R 201 groups other than halogen are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, CC 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , - C
  • the compound of the present disclosure is selected from:
  • the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt thereof.
  • the compound of the present disclosure is selected from:
  • each R 40 is independently selected from: SF 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.
  • the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt thereof.
  • the compound of the present disclosure is:
  • the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; each of which R 1 and R 2 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
  • R 14 , R 15 , and R 16 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from SF 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, - OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18 are independently selected
  • each R 30 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, carbocycle, aryl, heteroaryl, heterocycle, and C(O)R 31 , each R 30 other than C(O)R 31 is optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, halogen, SF 5 , -C(O)R 31 , -N(R 30 ) 2 , aryl, heteroaryl, -OR 32 , - S(O)(NR 31 )R 31 , and carbocycle; or R 30 and R 4 in , together with the N and O atoms to which each is attached and the carbon atom to which the N and O atoms are attached, combine to form oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and - OR 30 ; each R 31
  • X 3 is C(R 17 ) and X 4 is C(R 18 );
  • R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ;
  • X 5 is Si;
  • X 5 is S and at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen;
  • Z is C(CH 2 ); f.
  • Z is CH 2 ; g. R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; h. R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; i.
  • R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; j.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 8 or R 10 is not hydrogen; k.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 or R 12 is not hydrogen; l. R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m.
  • X 6 is selected from n. at least one of R 3 and R 4 is CN, nitro, -S(O) 2 R 31 , -SR 30 , or C(O)R 31 ; o.
  • R 3 and R 4 are combined to form a dihydroxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; an imidazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; or a dihydroimidazole optionally substituted 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; or p.
  • R 27 is 30 4 , and R and R in , together with the N and O atoms to which each is attached and the carbon atom to which the N and O atoms are attached, combine to form oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; wherein for compounds of Formula X and Formula XI at least one of the following is satisfied: a. X 3 is C(R 17 ) and X 4 is C(R 18 ); b.
  • R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; c. X 5 is Si; d. X 5 is S and at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen; e. Z is C(CH 2 ); f. Z is CH 2 ; g.
  • R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; h.
  • R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; i.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; j.
  • R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; k.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 3- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; l. R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m. R 22 is substituted with at least three OR 30 groups; n. R 23 is a sugar; o. at least one of R 3 and R 4 is CN, nitro, -S(O) 2 R 31 , -SR 30 , or C(O)R 31 ; p.
  • R 3 and R 4 are combined to form a dihydroxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; an imidazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; or a dihydroimidazole optionally substituted 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; or q.
  • R 27 is , 30 4 and R and R in , together with the N and O atoms to which each is attached and the carbon atom to which the N and O atoms are attached, combine to form oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; wherein for compounds of Formula XIV at least one of the following is satisfied: a. X 1 is O or N(R 30 ); b. R 14 is not hydrogen; c. R 1 is not hydrogen; d. R 2 is not hydrogen; e. R 3 is not hydrogen; or f. R 4 is not hydrogen. 3. The compound of embodiment 1 or 2, wherein the compound is selected from: or a pharmaceutically acceptable salt, prodrug, or isolated isomer thereof.
  • R 21 is selected from C 1 -C 6 alkyl and -O-C 1 -C 6 alkyl; each R 25 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; each of which R 1 and R 2 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl,
  • R 1 and R 2 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; each of which R 1 and R 2 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 14 , R 15 , and R 16 groups other than hydrogen, halogen, cyano, and nitro are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , - SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro; R 17 and R 18 are independently selected from hydrogen,
  • X 3 is C(R 17 ) and X 4 is C(R 18 );
  • R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ;
  • X 5 is Si;
  • X 5 is S and at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen;
  • Z is C(CH 2 ); f.
  • Z is CH 2 ; g. R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; h. R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; i.
  • R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; j.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 or R 12 is not hydrogen; k.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 8 or R 10 is not hydrogen; l.
  • R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m.
  • X 6 is selected from n. at least one of R 3 and R 4 is CN, -SR 30 nitro, -S(O) 2 R 31 , or C(O)R 31 ; o.
  • R 3 and R 4 are combined to form a dihydroxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; an imidazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; or a dihydroimidazole optionally substituted 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; p.
  • R 27 is , and R 30 and R 4 in , together with the N and O atoms to which each is attached and the carbon atom to which the N and O atoms are attached, combine to form oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; wherein for compounds of Formula X and Formula XI at least one of the following is satisfied: a. X 3 is C(R 17 ) and X 4 is C(R 18 ); b.
  • R 17 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and -N(R 30 ) 2 ; c. X 5 is Si; d. X 5 is S and at least two of R 7 , R 8 , R 11 , and R 12 are not hydrogen, no more than one of R 7 and R 8 is halogen, and no more than one of R 11 and R 12 is halogen; e. Z is C(CH 2 ); f. Z is CH 2 ; g.
  • R 7 and R 8 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; h.
  • R 9 and R 10 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; or a carbonyl; i.
  • R 9 and R 11 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; j.
  • R 11 and R 12 are taken together with the carbon to which they are attached to form a 3- to 6-membered carbocyclic spiro ring; a 4- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; ; or a carbonyl; k.
  • R 7 and R 9 are taken together with the atoms to which they are attached to form a 4- to 8-membered carbocycle or a 4- to 8-membered heterocycle containing 1 or 2 heteroatoms independently chosen from N, O, and S; and R 10 is not hydrogen; l. R 7 and R 11 are taken together with the atoms to which they are attached to form a 1 or 2 carbon bridge; m. R 22 is substituted with at least three OR 30 groups; n. R 23 is a sugar; o. at least one of R 3 and R 4 is -SR 30 or C(O)R 31 ; p.
  • R 3 and R 4 are combined to form a dihydroxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; an oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; an imidazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; or a dihydroimidazole optionally substituted 1, 2, or 3 substituents independently selected from C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, -OR 30 , and oxo; or q.
  • R 27 is and R 30 and R 4 in , together with the N and O atoms to which each is attached and the carbon atom to which the N and O atoms are attached, combine to form oxadiazole optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and -OR 30 ; wherein for compounds of Formula XIV at least one of the following is satisfied: a. X 1 is O or N(R 30 ); b. R 14 is not hydrogen; c. R 1 is not hydrogen; d. R 2 is not hydrogen; e. R 3 is not hydrogen; or f. R 4 is not hydrogen. 9.
  • R 10 is selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , and -S(O) 2 R 31 , each R 10 other than hydrogen and halogen are optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 - C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , hetero
  • R 10 is selected from carbocycle, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , - SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, nitro, and azido. 58.
  • R 19 is selected from C 1 - C 6 alkyl, C 5 -C 10 bicyclic carbocycle, C 4 -C 6 heterocycle, halogen, C 1 -C 6 haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 ) n - R 33 , and 108.
  • R 20 is hydrogen.
  • R 20 is selected from C 1 - C 6 alkyl, C 5 -C10 bicyclic carbocycle, C 4 -C 6 heterocycle, halogen, C 1 -C 6 haloalkyl, -OR 30 , -N(R 30 ) 2 , -(CH 2 )n- R 33 , and 110.
  • R 20 is -(CH 2 ) n -R 33 .
  • 111 The compound of any one of embodiments 1-110, wherein R 21 is C 1 -C 6 haloalkyl. 112.
  • R 21 is -O-C 1 -C 6 haloalkyl.
  • R 21 is phenyl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from SF 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.
  • R 22 is -C 1 -C 6 alkyl-R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro. 122.
  • R 22 is –C 3 -C 6 alkyl-R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.
  • R 22 is –C 3 -C 6 alkyl-R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 ,
  • R 22 is bicyclic cycloalkyl- R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.
  • substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31
  • R 22 is -heteroaryl-R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C6alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro.
  • R 22 is 126.
  • R 22 is 127.
  • R 22 is -carbocycle-R 23 optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , heterocycle, aryl, heteroaryl, cyano, and nitro. 128.
  • R 25 is S-methylsulfonimidoyl. 142.
  • the compound of any one of embodiments 1-133, wherein R 25 is methylphosphinyl. 143.
  • R 26 is 144.
  • the compound of any one of embodiments 1-142, wherein R 26 is selected from: 145.
  • the compound of any one of embodiments 1-142, wherein R 26 is 146.
  • the compound of any one of embodiments 1-142, wherein R 26 is 147.
  • R 26 is 148.
  • R 26 is selected from: 149.
  • R 33 is independently selected from heteroaryl, aryl, -C 6 H 5 -OR 30 ; -OR 30 , -SR 30 , -SeR 30 , -N(R 30 ) 2 , and -C(O)R 31 .
  • R 33 is guanidine.
  • the compound is of formula: or a pharmaceutically acceptable salt thereof.
  • any one of embodiments 214-216, wherein the disorder is dense deposit disease. 223. The method of any one of embodiments 214-216, wherein the disorder is angioedema. 224. The method of any one of embodiments 214-216, wherein the disorder is hereditary angioedema.
  • any one of embodiments 214-216, wherein the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE- induced angioedema, kidney transplantation, and acute kidney injury.
  • the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute
  • ATD age-related macular degeneration
  • any one of embodiments 229-231 wherein the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE-induced angioedema, kidney transplantation, and acute kidney injury.
  • the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE
  • any one of embodiments 244-246, wherein the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute ACE- induced angioedema, kidney transplantation, and acute kidney injury.
  • the disorder is selected from hereditary angioedema type 1 , hereditary angioedema type 2, trauma, inflammation, sepsis, multiple organ dysfunction syndrome, endotoxemia, end stage renal disease, kidney failure, delayed graft function, ischemic reperfusion injury, neuromyelitis optica, common variable immunodeficiency, antibody-mediated rejection, graft rejection, asthma, allergic asthma, angioneurotic edema, acute
  • Active compounds described herein can be administered to a host in need thereof as the neat chemical, but are more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of such treatment of an active compound as described herein or its pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof.
  • the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof together with at least one pharmaceutically acceptable carrier for any of the uses described herein.
  • the pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent.
  • an effective amount of an active compound as described herein, or the active compound described herein in combination or alternation with, or preceded by, concomitant with or followed by another active agent can be used in an amount sufficient to (a) inhibit the progression of a disorder mediated by the complement pathway, including an inflammatory, immune, including an autoimmune, disorder or complement related disorder; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement related disorder; (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement related disorder; or inhibit or prevent the development of an inflammatory, immune, including an autoimmune, disorder or complement related disorder. Accordingly, an effective amount of an active compound or its salt or composition described herein will provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit.
  • the exact amount of the active compound or pharmaceutical composition described herein to be delivered to the host, typically a human, in need thereof, will be determined by the health care provider to achieve the desired clinical benefit.
  • the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least about 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, or 1600 mg of active compound, or its salt, N-oxide, or prodrug.
  • the dosage form has at least about 1mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000mg, 1200 mg, or 1600 mg of active compound, N-oxide, prodrug, or its salt.
  • the amount of active compound in the dosage form is calculated without reference to the salt.
  • the dosage form can be administered, for example, once a day (q.d.), twice a day (b.i.d .) , three times a day (t.i.d .) , four times a day (q.i.d.), once every other day (Q2d), once every third day (Q3d), as needed, or any dosage schedule that provides treatment of a disorder described herein.
  • Compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intravenous, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, transnasal, sublingual, intrathecal, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the compound can be administered, as desired, for example, as a solution, suspension, or other formulation via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, subchorodial, chorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, ortearduct injections, orthrough a mucus, mucin, ora mucosal barrier, in an immediate or controlled release fashion or via an ocular device, injection, or topically administered formulation, for example, a solution or suspension provided as an eye drop.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, a microparticle, a nanoparticle, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution or suspension.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • compositions, and methods of manufacturing such compositions, suitable for administration as contemplated herein are known in the art.
  • known techniques include, for example, US Patent Nos. 4,983,593; 5,013,557; 5,456,923; 5,576,025; 5,723,269; 5,858,411; 6,254,889; 6,303,148; 6,395,302; 6,497,903; 7,060,296; 7,078,057; 7,404,828; 8,202,912; 8,257,741; 8,263,128; 8,337,899; 8,431,159; 9,028,870; 9,060,938; 9,211,261; 9,265,731; 9,358,478; and 9,387,252; incorporated by reference herein.
  • compositions contemplated here can optionally include a carrier.
  • Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, fillers, flavorants, glidents, lubricants, pH modifiers, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
  • Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
  • Examples of surface active agents include sodium lauryl sulfate and polysorbate 80.
  • drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins.
  • disintegrants examples include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium.
  • binders examples include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
  • lubricants examples include magnesium stearate and calcium stearate.
  • pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids.
  • bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids.
  • buffers generally comprising mixtures of acids and the salts of said acids.
  • optionalal other active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present disclosure.
  • the pharmaceutical composition for administration further includes a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, and optionally comprises one or more of a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether;
  • the pharmaceutical preparation may include polymers for controlled delivery of the described compounds, including, but not limited to pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1 ,3-dioxan- 2one)); polyan hydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates.
  • pluronic polymers e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1 ,3-dioxan- 2one)
  • polyan hydrides e.g., poly(sebacic anhydride)
  • polyethers e.g., polyethylene glycol
  • polyurethanes e.g., polymethacrylates
  • polymers may be modified with polyethylene glycol (PEG), with a carbohydrate, and/or with acyclic polyacetals derived from polysaccharides.
  • PEG polyethylene glycol
  • carbohydrate e.g., a carbohydrate
  • acyclic polyacetals derived from polysaccharides See, e.g., Papisov, 2001 , ACS Symposium Series, 786:301 , incorporated by reference herein.
  • the compounds of the present disclosure can be formulated as particles.
  • the particles are, or include, microparticles.
  • the particles are or include nanoparticles.
  • common techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable methods of particle formulation are briefly described herein. Pharmaceutically acceptable excipients, including pH modifying agents, disintegrants, preservatives, and antioxidants, can optionally be incorporated into the particles during particle formation.
  • the particles are derived through a solvent evaporation method.
  • a compound described herein or polymer matrix and one or more compounds described herein
  • a volatile organic solvent such as methylene chloride.
  • the organic solution containing a compound described herein is then suspended in an aqueous solution that contains a surface active agent such as poly(vinyl alcohol).
  • the resulting emulsion is stirred until most of the organic solvent evaporated, leaving solid nanoparticles or microparticles.
  • the resulting nanoparticles or microparticles are washed with water and dried overnight in a lyophilizer (under vacuum, with or without heat). Nanoparticles with different sizes and morphologies can be obtained by this method.
  • compositions which contain labile polymers may degrade during the fabrication process due to the presence of water.
  • labile polymers such as certain polyanhydrides
  • methods which are performed in completely or substantially anhydrous organic solvents can be used to make the particles.
  • Solvent removal can also be used to prepare particles from a compound that is hydrolytically unstable.
  • the compound or polymer matrix and one or more compounds
  • a volatile organic solvent such as methylene chloride.
  • This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion.
  • Solid particles form from the emulsion, which can subsequently be isolated from the supernatant.
  • the external morphology of spheres produced with this technique is highly dependent on the identity of the drug.
  • an active compound as described herein is administered to a patient in need thereof as particles formed by solvent removal.
  • the present disclosure provides particles formed by solvent removal comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by solvent removal comprise a compound of the present disclosure and an additional therapeutic agent.
  • the particles formed by solvent removal comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by solvent removal can be formulated into a tablet, and then coated to form a coated tablet.
  • the particles formed by solvent removal are formulated into a tablet but the tablet is uncoated.
  • the particles are derived by spray drying.
  • a compound or polymer matrix and one or more compounds
  • an organic solvent such as methylene chloride.
  • the solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the micro droplets, forming particles.
  • Microparticles and nanoparticles can be obtained using this method.
  • an active compound as described herein is administered to a patient in need thereof as a spray dried dispersion (SDD).
  • the present disclosure provides a spray dried dispersion (SDD) comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients as defined herein.
  • the SDD comprises a compound of the present disclosure and an additional therapeutic agent.
  • the SDD comprises a compound of the present disclosure, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described spray dried dispersions can be coated to form a coated tablet.
  • the spray dried dispersion is formulated into a tablet but the tablet is uncoated.
  • Particles can be formed from the active compound as described herein using a phase inversion method.
  • the compound or polymer matrix and one or more active compounds
  • the solution is poured into a strong non-solvent for the compound to spontaneously produce, under favorable conditions, microparticles or nanoparticles.
  • the method can be used to produce nanoparticles in a wide range of sizes, including, for example, from nanoparticles to microparticles, typically possessing a narrow particle size distribution.
  • an active compound as described herein is administered to a patient in need thereof as particles formed by phase inversion.
  • the present disclosure provides particles formed by phase inversion comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by phase inversion comprise a compound of the present disclosure and an additional therapeutic agent.
  • the particles formed by phase inversion comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by phase inversion can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by phase inversion are formulated into a tablet, but the tablet is uncoated.
  • Coacervation involves the separation of a compound (or polymer matrix and one or more compounds) solution into two immiscible liquid phases.
  • One phase is a dense coacervate phase, which contains a high concentration of the compound, while the second phase contains a low concentration of the compound.
  • the compound forms nanoscale or microscale droplets, which harden into particles.
  • Coacervation may be induced by a temperature change, addition of a nonsolvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer thereby forming an interpolymer complex (complex coacervation).
  • an active compound as described herein is administered to a patient in need thereof as particles formed by coacervation.
  • the present disclosure provides particles formed by coacervation comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by coacervation comprise a compound of the present disclosure and an additional therapeutic agent.
  • the particles formed by coacervation comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by coacervation can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by coacervation are formulated into a tablet, but the tablet is uncoated.
  • a compound of the present disclosure is administered to a patient in need thereof as particles formed by low temperature casting.
  • the present disclosure provides particles formed by low temperature casting comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by low temperature casting comprise a compound of the present disclosure and an additional therapeutic agent.
  • the particles formed by low temperature casting comprise a compound of the present disclosure, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
  • any of the described particles formed by low temperature casting can be formulated into a tablet and then coated to form a coated tablet.
  • the particles formed by low temperature casting are formulated into a tablet, but the tablet is uncoated.
  • an effective amount of an active compound as described herein is incorporated into a nanoparticle, e.g., for convenience of delivery and/or extended release delivery.
  • a nanoparticle e.g., for convenience of delivery and/or extended release delivery.
  • the use of materials in nanoscale provides one the ability to modify fundamental physical properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and/or immunogenicity.
  • a number of nanoparticle-based therapeutic and diagnostic agents have been developed forthe treatment of cancer, diabetes, pain, asthma, allergy, and infections. These nanoscale agents may provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce health-care costs.
  • nanoparticles can allow targeted delivery and controlled release.
  • nanoparticle-based compound delivery can be used to release compounds at a sustained rate and thus lower the frequency of administration, deliver drugs in a targeted manner to minimize systemic side effects, or deliver two or more drugs simultaneously for combination therapy to generate a synergistic effect and suppress drug resistance.
  • a number of nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drugs and polymer-based conjugates account for a large proportion of the products. See Zhang, L., et al., Nanoparticles in Medicine: Therapeutic Applications and Developments, Clin. Pharm. and Ther., 83(5):761-769, 2008.
  • polyesters examples include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J.
  • the polymeric particle is between about 0.1 nm to about 10000 nm, between about 1 nm to about 1000 nm, between about 10 nm and 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm, between about 1 and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm.
  • the micro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm.
  • a compound described herein may be covalently coupled to a polymer used in the nanoparticle, for example a polystyrene particle, PLGA particle, PLA particle, or other nanoparticle.
  • compositions according to the disclosure can be formulated for oral administration.
  • These compositions can contain any amount of active compound that achieves the desired result, for example, between 0.1 and 99 weight % (wt.%) of the compound, and usually at least about 5 wt.% of the compound.
  • Some embodiments contain at least about 10%, 15%, 20%, 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound.
  • compositions suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • conventional solid carriers for example, cocoa butter
  • compositions suitable fortopical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient fora prolonged period of time.
  • Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6) :318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
  • microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
  • compositions suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven singleZ-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
  • nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.
  • Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
  • inhalation drug delivery devices and methods include, for example, US 7,383,837 titled “Inhalation Device” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powder Inhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled “Inhalable Pharmaceutical Formulations Employing Desiccating Agents and Methods of Administering the Same” (Glaxo Group Ltd and SmithKline Beecham Corporation); US9,095,670 titled “Inhalation Device and Method of Dispensing Medicament”, US 8,205,611 titled “Dry Powder Inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler” (Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled “Inhalation Device with Feedback System”, US 8,910,625 and US/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy” (Vectura), WO/2006
  • WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-Release Formulation in the Eye”, (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions and Methods for Intracellular Delivery and Release of Cargo”, WO/2007/133808 titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled “Medical device, materials, and methods”, WO/2010/065748 titled “Method for producing patterned materials”, and WO/2007/081876 titled “Nanostructured surfaces for biomedical/biomaterial applications and processes thereof” (Liquidia Technologies, Inc.).
  • Additional non-limiting examples of methods and devices for drug delivery to the eye include, for example, WO2011/106702 and US 8,889,193 titled “Sustained delivery of therapeutic agents to an eye compartment”, WO2013/138343 and US 8,962,577 titled “Controlled release formulations for the delivery of HIF-1 inhibitors”, WO/2013/138346 and US2013/0272994 titled “Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents”, WO2005/072710 and US 8,957,034 titled “Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers”, WO2008/030557, US2010/0215580, US2013/0164343 titled “Compositions and Methods for Enhancing Transport Through Mucous”, WO2012/061703, US2012/0121718, and US2013/0236556 titled “Compositions and Methods Relating to Reduced Mucoadhesion”, WO2012/03
  • Additional non-limiting examples of drug delivery devices and methods include, for example, US 2009/0203709 titled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories); US 2005/0009910 titled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug”, US 20130071349 titled “Biodegradable polymers for lowering intraocular pressure”, US 8,481,069 titled “Tyrosine kinase microspheres”, US 8,465,778 titled “Method of making tyrosine kinase microspheres”, US 8,409,607 titled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”, US 8,512,738 and US 2014/0031408 titled “Biodegradable intravitreal tyrosine kinase implants”, US 2014/029
  • an effective amount of an active compound or its salt or composition as described herein is used to treat a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade) including a complement- related disorder or alternative complement pathway-related disorder, a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration.
  • a medical disorder which is an inflammatory or immune condition
  • a disorder mediated by the complement cascade including a dysfunctional cascade
  • a complement- related disorder or alternative complement pathway-related disorder a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or
  • a complement-mediated disease or disorder is a disease or disorder in which the amount or activity of complement is such as to cause disease or disorder in an individual.
  • the complement-mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement-mediated disease or disorder is an autoimmune disease. In some embodiments, the complement-mediated disease or disorder is cancer.
  • the complement-mediated disease or disorder is an infectious disease.
  • the complement-mediated disease or disorder is an inflammatory disease.
  • the complement-mediated disease or disorder is a hematological disease.
  • the complement-mediated disease or disorder is an ischemiareperfusion injury.
  • the complement-mediated disease or disorder is ocular disease. In some embodiments, the complement-mediated disease or disorder is a renal disease.
  • the complement-mediated disease or disorder is transplant rejection.
  • the complement-mediated disease or disorder is antibody-mediated transplant rejection.
  • the complement-mediated disease or disorder is a vascular disease.
  • the complement-mediated disease or disorder is a vasculitis disorder. In some embodiments, the complement-mediated disease or disorder is a neurodegenerative disease or disorder.
  • the complement-mediated disease is a neurodegenerative disease.
  • the complement-mediated disorder is a neurodegenerative disorder. In some embodiments, the complement-mediated disease or disorder is a tauopathy.
  • an effective amount of an active compound described herein, or it pharmaceutically acceptable salt is used to treat a medical disorder of the central nervous system (CNS) or peripheral nervous system disorders involving complement activation.
  • the CNS disorder is an acquired brain or spinal cord injury, including, but not limited to ischaemic- reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI).
  • the disorder is a neurodegeneration disorder. In embodiments, the disorder is a neuroinflammation disorder.
  • an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Alzheimer's disease (AD).
  • AD is characterized by two hallmark pathologies; amyloid-p (Ap) plaques and neurofibrillary tangles comprising hyperphosphorylated tau.
  • SNPs single nucleotide polymorphisms
  • CLU complement proteins Clusterin
  • CR1 CR1
  • an effective amount of active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat certain forms of frontotemporal dementia including, but not limited to, Pick's disease, sporadic Frontotemporal dementia and Frontotemporal dementia with Parkinsonism linked to chromosome 17, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), and Subacute sclerosing panencephalitis.
  • frontotemporal dementia including, but not limited to, Pick's disease, sporadic Frontotemporal dementia and Frontotemporal dementia with Parkinsonism linked to chromosome 17, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), and Subacute sclerosing panencephalitis.
  • an effective amount of active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat multiple sclerosis (MS).
  • MS multiple sclerosis
  • C3 has been shown to be deposited in the brains of MS patients.
  • T-cell clone (TCC) has been shown to be in association with capillary endothelial cells, predominantly within plaques and adjacent white matter. Localization of C activation to areas of active myelin destruction has also been shown, with TCC deposited exclusively in such areas.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat neuromyelitis optica (NMO).
  • NMO neuromyelitis optica
  • NMO is an inflammatory demyelinating disease affecting predominantly the optic nerves and spinal cord.
  • NMO-immunoglobulin G (reported sensitivity of 58-76% and specificity of 85-99% for NMO).
  • NMO patients have higher levels of C3a and anti-C1q antibodies than healthy controls.
  • C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG. Nytrova et al., Complement activation in patients with neuromyelitis optica. J Neuroimmunol. 2014 Sep 15;274(1 -2):185-91.
  • an effective amount of an active compound as described herein, or a pharmaceutically acceptable salt thereof is used to treat amyotrophic lateral sclerosis (ALS).
  • ALS is caused by progressive loss of upper and lower (a) motor neurons resulting in denervation of neuromuscular junctions in the peripheral nervous system, progressive muscle weakness, atrophy, spasticity, respiratory failure, and ultimately paralysis and death.
  • Recent studies have shown increased C1q protein in motor cortex and spinal cord of ALS post-mortem tissue; C3 activation fragments and TCC in areas of pathology; C4d and TCC staining of degenerating neurons and glia in ALS motor cortex and spinal cord, and C5aR1 upregulation in areas of pathology.
  • C3d and C4d have been found on oligodendroglia and degenerating neurites, surrounded by CR4-positive microglia, in spinal cord and motor cortex, and C1q, C3, and TCC have been shown to be present on motor end-plates in intercostal muscles in ALS donors even early in the disease process. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Parkinson's disease (PD).
  • PD is characterized by loss of dopaminergic neurons in the substantia nigra and deposits of the protein a-synuclein that form the pathological hallmarks of the disease, Lewy bodies. Patients present with resting tremor, bradykinesia, and rigidity. Complement activation has been associated with a-synuclein and Lewy bodies in Parkinson's disease; in vitro studies have demonstrated that the disease-associated splice variant a-synuclein 112, but not the full-length protein, cause activation of complement.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Huntington's disease (HD).
  • HD is an autosomal dominant, inherited neurodegenerative disease characterized by progressive motor symptoms, psychiatric disturbances, and dementia. It is caused by expansion of a three-base-pair (CAG) repeat (39-121 repeats vs. normal range 8-39 repeats) in exon 1 of the HTT gene that translates into a polyglutamine tract at the N-terminus of the protein. This results in a polyglutamine lengthdependent misfolding and accumulation of huntingtin protein in the striatum and cortex (layers 3, 5, and 6) followed by neuronal loss in these areas which spreads to the hippocampus.
  • CAG three-base-pair
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal lobar degeneration, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, Tangle only dementia, multi-infarct dementia,
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat a hereditary motor and sensory neuropathy (HMSN).
  • HMSN hereditary motor and sensory neuropathy
  • the hereditary and sensory neuropathy is Charcot-Marie-Tooth (CMT) disease.
  • CMT Charcot-Marie-Tooth
  • the HSMN is Charcot-Marie-Tooth disease type 1A or type 1B.
  • the HSMN is Charcot-Marie-Tooth disease type 2.
  • the HSMN is Dejerine-Sottas disease (Charcot-Marie-Tooth type 3). In some embodiments, the HSMN is Refsum disease.
  • the HSMN is Charcot-Marie-Tooth with pyramidal features. In some embodiments, the HSMN is Charcot-Marie-Tooth type 6. In some embodiments, the HSMN is HMSN+retinitis pigmentosa.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Churg-Strauss syndrome. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat a peripheral artery disease (PAD).
  • PAD peripheral artery disease
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat myasthenia gravis with CNS involvement.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat dementia with Lewy bodies.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat an individual suffering from prion disease.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat Behcet's Disease.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat congenital myasthenia.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat subacute sclerosing panencephalitis (SSPE).
  • SSPE subacute sclerosing panencephalitis
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Guillain-Barre syndrome.
  • the CNS disorder to be treated is a demyelinating disease, including, but not limited to, demyelinating myelinoclastic diseases and demyelinating leukostrophic disease.
  • the disorder to be treated is a demyelinating myelonoclastic disease including, but not limited to, multiple sclerosis, neuromyelitis optica, neuromyelitis optica spectrum of disorders (NMOSD), idiopathic inflammatory demyelinating diseases (HDD), anti-NMDA receptor encephalitis, acute disseminated encephalomyelitis, anti-MOG autoimmune encephalomyelitis, chronic relapsing inflammatory optic neuritis (CRION), acute disseminated encephalomyelitis (ADEM), immune-mediated encephalomyelitis, progressive multifocal leukoencephalopathy (PML); McDonaldspositive multiple sclerosis, acute hemorrhagic leukoencephalitis, Rasmussen's Encephalitis, Marburg multiple sclerosis, pseudotumefactive and tumefactive multiple sclerosis, Balo concentric sclerosis, diffuse myelinoclastic sclerosis, solitary s
  • the disorder to be treated is a demyelinating leukostrophic disease including, but not limited to, myelitis, central pontine myelinolysis (CPM), extrapontine myelinolysis, tabes dorsalis, progressive multifocal leukoencephalopathy, leukoencephalopathy with vanishing white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, megalencephalic leukoencephalopathy with subcortical cysts, megalencephalic leukoencephalopathy with subcortical cysts 1 , hypertensive leukoencephalopathy, Metachromatic leukodystrophy, Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, cerebrotendineous xanthomatosis, Pelizaeus-Merzbacher disease, and Refsum disease.
  • myelitis central pontine myelinolysis (
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Buerger's disease, also known as thromboangiitis obliterans.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat giant cell arteritis.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat Raynaud's disease.
  • the disorder to be treated is a demyelinating disease of the peripheral nervous system, including, but not limited to, Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie- Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy, Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy), and progressive inflammatory neuropathy.
  • demyelinating disease of the peripheral nervous system including, but not limited to, Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie- Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy, Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy), and progressive inflammatory neuropathy.
  • the disorder to be treated is a neurological inflammatory disorder.
  • the disorder to be treated includes, but is not limited to, cranial arteritis; giant cell arteritis; Holmes-Adie syndrome; inclusion body myositis (IBM); meningitis; neurologic paraneoplastic syndrome including, but not limited to, Lambert-Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis, cerebellar degeneration, limbic and/or brainstem encephalitis, neuromyotonia, and opsoclonus (involving eye movement) and sensory neuropathy; polymyositis; transverse myelitis; vasculitis including temporal arteritis; arachnoiditis; Kinsbourne syndrome or opsoclonus myoclonus syndrome (OMS); or Saint Vitus Dance or sydenham chorea (SD) disease.
  • cranial arteritis giant cell arteritis
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat transverse myelitis.
  • the disorder to be treated is a peripheral neuropathy.
  • the peripheral neuropathy is a mononeuropathy.
  • the neuropathy is a polyneuropathy.
  • the polyneuropathy is distal axonopathy, diabetic neuropathy, a demyelinating polyneuropathy, small fiber peripheral neuropathy, mononeuritis multiplex, polyneuritis multiplex, autonomic neuropathy, or neuritis.
  • an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof is used to treat an autoimmune vascular disease.
  • the autoimmune vascular disease is vasculitis.
  • the vasculitis includes, but is not limited to, autoimmune inflammatory vasculitis, Cutaneous small-vessel vasculitis, Granulomatosis with polyangiitis , Eosinophilic granulomatosis with polyangiitis, Behçet's disease, Kawasaki disease, Buerger's disease, and "Limited" granulomatosis with polyangiitis vasculitis.
  • an active compound or its salt or composition as described herein is used to treat an arteritis.
  • the arteritis includes, but is not limited to, giant cell arteritis, Takayasu arteritis, temporal arteritis, and polyarteritis nodosa.
  • a method for the treatment of a glomerulonephritis is provided.
  • the glomerulonephritis is membranoproliferative glomerulonephritis (MPGN).
  • the MPGN is MPGN Type I.
  • the MPGN is MPGN Type II.
  • the MPGN is MPGN Type III.
  • the MPGN is C3 glomerulonephritis (C3G). In some embodiments, the MPGN is dense deposit disease (DDD). In some embodiments, the MPGN is a C4 deposition disorder. In some embodiments, the glomerulonephritis is IC-MPGN. In some embodiments, the glomerulonephritis is a membraneous glomerulonephritis. In some embodiments, the glomerulonephritis is IgA nephropathy. In some embodiments, the glomerulonephritis is Post-infectious glomerulonephritis.
  • the glomerulonephritis is a rapidly progressive glomerulonephritis, for example Type I (Goodpasture syndrome), Type II, or Type III rapidly progressive glomerulonephritis.
  • a method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) includes the administration of an effective amount of a compound to a host of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • a method for the treatment of hereditary angioedema includes the administration of an effective amount of a compound to a host of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. Mutations in the SERPING1 gene cause hereditary angioedema type I and type II.
  • Hereditary angioedema is a disorder characterized by recurrent episodes of severe swelling (angioedema). The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway.
  • the SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation.
  • C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues.
  • a protein fragment peptide
  • a method for the treatment of cold agglutinin disease includes the administration of an effective amount of a compound to a host of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • CAD is a rare autoimmune hemolytic condition with potentially serious acute and chronic consequences that are driven by C1 activation of the classical complement pathway.
  • a method for the treatment of atypical hemolytic uremic syndrome includes the administration of an effective amount of a compound to a host of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • Atypical hemolytic-uremic syndrome is a disease that primarily affects kidney function.
  • Atypical hemolytic uremic syndrome which can occur at any age, causes abnormal blood clots (thrombi) to form in small blood vessels in the kidneys. These clots can cause serious medical problems if they restrict or block blood flow.
  • Atypical hemolytic-uremic syndrome is characterized by three major features related to abnormal clotting: hemolytic anemia, thrombocytopenia, and kidney failure.
  • a method for the treatment of wet or dry age-related macular degeneration (AMD) in a host includes the administration of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, orXX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • ALD age-related macular degeneration
  • a method for the treatment of rheumatoid arthritis in a host includes the administration of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, orXX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • a method for the treatment of multiple sclerosis in a host includes the administration of an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition.
  • the active compounds, or pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, as disclosed herein, are also useful for administration in combination (in the same or a different dosage form) or alternation with a second pharmaceutical agent for use in ameliorating or reducing a side effect of the second pharmaceutical agent.
  • the active compound may be used in combination with an adoptive cell-transfer therapy to reduce an inflammatory response associated with such therapy, for example, a cytokine mediated response such as cytokine response syndrome.
  • the adoptive cell-transfer therapy is a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell used to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer.
  • CAR T chimeric antigen receptor T-Cell
  • dendritic cell used to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer.
  • the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancerthat expresses CD19.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • pancreatic cancer glioblastoma
  • glioblastoma or a cancerthat expresses CD19.
  • the adoptive cell-transfer therapy is a non-engineered T-cell therapy, wherein the T-cells have been activated and/or expanded to one or more viral or tumor antigens.
  • the associated inflammatory response is a cytokine mediated response.
  • the second pharmaceutical agent is a cell that has been transformed to express a protein, wherein the protein in the host is mutated or otherwise has impaired function.
  • the transformed cell includes a CRISPR gene.
  • Another embodiment includes the administration of an effective amount of an active compound, or a pharmaceutically acceptable salt, prodrug, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition to a host to treat an ocular, pulmonary, gastrointestinal, or other disorder.
  • any of the compounds described herein can be administered to the eye in any desired form of administration, including via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, scleral, circumcorneal, and tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion.
  • the active compound includes a lipophilic group, such as a lipophilic acyl group, which is delivered to the eye in a polymeric drug delivery system such as poly lactic acid, polylactide-co-glycolide, polyglycolide or other erodible polymer, ora combination thereof, or in another type of lipophilic material for ocular delivery.
  • a lipophilic active molecule is more soluble in the polymeric or other form of delivery system than in ocular fluid.
  • an active compound provided herein can be used to treat or prevent a disorder in a host mediated by complement.
  • the disclosure includes methods to treat or prevent complement associated disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder or by ischemic injury.
  • the disclosure also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by the classical complement pathway.
  • the disorder is selected from fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis and liver failure.
  • NASH nonalcoholic steatohepatitis
  • a method is provided for treating fatty liver disease in a host by administering an effective amount of an active compound or its salt or composition as described herein.
  • an active compound or its salt or composition as described herein is used to modulate an immune response prior to or during surgery or other medical procedure.
  • One nonlimiting example is use in connection with acute or chronic graft versus host disease, which is a common complication as a result of organ transplantation, allogeneic tissue transplant, and can also occur as a result of a blood transfusion.
  • the present disclosure provides a method of treating or preventing dermatomyositis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • the present disclosure provides a method of treating or preventing amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • the present disclosure provides a method of treating or preventing abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceutical or biotherapeutic (e.g., CAR T-cell therapy or monoclonal antibody therapy) in a host by administering an effective amount of an active compound or its salt or composition as described herein.
  • pharmaceutical or biotherapeutic e.g., CAR T-cell therapy or monoclonal antibody therapy
  • cytokine or inflammatory reactions may occur in response to a number of factors, such as the administrations of biotherapeutics.
  • the cytokine or inflammatory reaction is cytokine release syndrome.
  • the cytokine or inflammatory reaction is tumor lysis syndrome (which also leads to cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and skin rashes to bronchospasm, hypotension and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm, and can be fatal.
  • Fatal cytokine storms have been observed in response to infusion with several monoclonal antibody therapeutics. See, Abramowicz D, et al. “Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients” Transplantation (1989) 47(4):606-8; Chatenoud L, et al. “In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids” Transplantation (1990) 49(4):697-702; and Lim LC, Koh LP, and Tan P.
  • BITE bi-specific T-cell engagers
  • a bi-specific T-cell engager directs T-cells to target and bind with a specific antigen on the surface of a cancer cell.
  • Blinatumomab Amgen
  • BITE has recently been approved as a second line therapy in Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.
  • Blinatumomab is given by continuous intravenous infusion in 4-week cycles.
  • the use of BITE agents has been associated with adverse immune responses, including cytokine release syndrome.
  • cytokines in the CRS associated with ACT include IL-10, IL-6, and IFN-y (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BITE antibody blinatumomab. Blood (2012) 119:6226-6233).
  • the disorder is episcleritis, idiopathic episcleritis, anterior episcleritis, or posterior episcleritis.
  • the disorder is idiopathic anterior uveitis, HLA-B27 related uveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch’s heterochromic iridocyclitis, or cytomegalovirus anterior uveitis.
  • the present disclosure provides a method of treating or preventing a IC- MPGN by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • the present disclosure provides a method of treating or preventing a paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present disclosure provides a method of treating or preventing a hereditary angioedema (HAE) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • HAE hereditary angioedema
  • the present disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • CAD cold agglutinin disease
  • the present disclosure provides a method of treating or preventing atypical hemolytic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • aHUS atypical hemolytic syndrome
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • AMD age-related macular degeneration
  • the present disclosure provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • the present disclosure provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • the present disclosure provides a method of treating or preventing myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating or preventing atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein.
  • aHUS atypical hemolytic uremic syndrome
  • the present disclosure provides a method of treating or preventing a disorder as described below by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein, including: vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Eales disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis, or acute retinal necrosis; varicella zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or Dengue-associated disease (e.g., hemorraghic Dengue Fever); Masquerade syndrome, contact dermatitis, trauma induced inflammation, UVB induced inflammation, eczema, granuloma annulare, or acne.
  • an active compound or its salt or composition as described herein, including: vitritis, sarcoidos
  • the disorder is selected from: acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass operations, coronary artery disease, restenosis following stent placement, or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated transplant rejection, anaphylactic shock, anaphylaxis, allogenic transplant, humoral and vascular transplant rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reactions, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation- induced lung injury, eosinophilic pneumonia, radiographic contrast media allergy, bronchiolitis obliterans, or interstitial pneumonia; parkinsonism-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, tangle only dementia, cerebral
  • the disorder is selected from: atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, Discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulinemic vasculitis, mesenteric/enteric vascular disorder, peripheral vascular disorder, antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), IL-2 induced vascular leakage syndrome, or immune complex vasculitis;angioedema, low platelets (HELLP) syndrome, sickle cell disease, platelet refractoriness, red cell casts, or typical or infectious hemolytic uremic syndrome (tHUS); hematuri
  • the disorder is selected from: wet (exudative) AMD, dry (nonexudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, loss of vision (including loss of visual acuity or visual field), loss of vision from AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macular degeneration related disorder, optic nerve degeneration, photoreceptor degeneration, cone degeneration, loss of photoreceptor cells, pars planitis, scleritis, proliferative vitreoretinopathy, or formation of ocular drusen; chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), corticobas
  • the disorder is selected from: hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, ulceris, juvenile chronic arthritis, Kawasaki's disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renovascular disorder; multiple organ failure, multiple system atrophy
  • an active compound or its salt or composition as described herein is useful for treating or preventing a disorder selected from autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord’s thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto’s encephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum’s disease), adult onset Still’s disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shulman’s syndrome), Felty syndrome, lgG4-related disease, mixed connective tissue disease (MCTD), palindromic rheumatism (Hench-
  • eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-proliferative diabetic retin
  • the disorder is selected from glaucoma, diabetic retinopathy, blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid, uveitis, adult macular degeneration, diabetic retinopa retinitis pigmentosa, macular edema, diabetic macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, and central retinal vein occulusion (CVRO).
  • glaucoma including bullous pemphigo
  • complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, and cardiovascular diseases.
  • ophthalmic diseases including early or neovascular age-related macular degeneration and geographic atrophy
  • autoimmune diseases including arthritis, rheumatoid arthritis
  • respiratory diseases and cardiovascular diseases.
  • the compounds of the disclosure are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
  • disorders that may be treated or prevented by an active compound or its salt or composition as described herein also include, but are not limited to: hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain Barre Syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membrane proliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neural regeneration, or Barraquer-Simons Syndrome; inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or undesirable complement activation, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, systemic lupus erythematosus (SLE), lupus nephritides, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus
  • a method for the treatment of sickle cell in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of ANCA-vasculitis in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of IgA nephropathy in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of rapidly progressing glomerulonephritis (RPGN), in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of lupus nephritis, in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • a method for the treatment of hemorraghic dengue fever, in a host includes the administration of an effective amount of an active compound or its salt or composition as described herein.
  • an active compound or its salt or composition as described herein is used in the treatment of an autoimmune disorder.
  • the complement pathway enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body. It is part of the innate immune system and in healthy individuals is an essential process. Inhibiting the complement pathway will decrease the body’s immune system response. Therefore, it is an object of the present disclosure to treat autoimmune disorders by administering an effective does of an active compound or its salt or composition as described herein to a subject in need thereof.
  • the autoimmune disorder is caused by activity of the complement system. In some embodiments the autoimmune disorder is caused by activity of the alternative complement pathway. In some embodiments the autoimmune disorder is caused by activity of the classical complement pathway. In another embodiment the autoimmune disorder is caused by a mechanism of action that is not directly related to the complement system, such as the over-proliferation of T-lymphocytes or the over-production of cytokines.
  • Non-limiting examples of autoimmune disorders include: lupus, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.
  • autoimmune thyroid diseases such as Graves' disease and Hashimoto's thyroiditis
  • autoimmune uveoretinitis giant cell arteritis
  • inflammatory bowel diseases including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis
  • diabetes
  • an active compound or its salt or composition as described herein is used in the treatment of lupus.
  • lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, and lupus erythematosus-lichen planus overlap syndrome.
  • Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders.
  • the systemic form of the disease can have cutaneous as well as systemic manifestations.
  • SLE is an inflammatory disorder of unknown etiology that occurs predominantly in women, and is characterized by articular symptoms, butterfly erythema, recurrent pleurisy, pericarditis, generalized adenopathy, splenomegaly, as well as CNS involvement and progressive renal failure.
  • the sera of most patients (over 98%) contain antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. Conventional treatment for this disease has been the administration of corticosteroids or immunosuppressants.
  • DLE chronic cutaneous lupus
  • subacute cutaneous lupus subacute cutaneous lupus
  • acute cutaneous lupus a disfiguring chronic disorder primarily affecting the skin with sharply circumscribed macules and plaques that display erythema, follicular plugging, scales, telangiectasia and atrophy. The condition is often precipitated by sun exposure, and the early lesions are erythematous, round scaling papules that are 5 to 10 mm in diameter and display follicular plugging.
  • DLE lesions appear most commonly on the cheeks, nose, scalp, and ears, but they may also be generalized over the upper portion of the trunk, extensor surfaces of the extremities, and on the mucous membranes of the mouth. If left untreated, the central lesion atrophies and leaves a scar. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA-binding test) are almost invariably absent in DLE.
  • Diabetes can refer to either type 1 or type 2 diabetes.
  • an active compound or its salt or composition as described herein is provided at an effective dose to treat a patient with type 1 diabetes.
  • an active compound or its salt or composition as described herein is provided at an effective dose to treat a patient with type 2 diabetes.
  • Type 1 diabetes is an autoimmune disease.
  • An autoimmune disease results when the body's system for fighting infection (the immune system) attacks a part of the body. In the case of diabetes type 1, the pancreas then produces little or no insulin.
  • the complement-mediated disease or disorder comprises transplant rejection. In some embodiments, the complement-mediated disease or disorder is antibody-mediated transplant rejection.
  • an active compound or its salt or composition as described herein is used to treat a proliferative disorder, including, but not limited to, cancer.
  • Targeted cancers suitable for administration of an active compound or its salt described herein include, but are not limited to, estrogen-receptor positive cancer, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers, adenocarcinoma of the colon, adenocarcinoma of the rectum, central nervous system germ cell tumors, teratomas, estrogen receptornegative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumors, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, ova
  • the targeted cancers included estrogen-receptor positive, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers, metastatic colorectal cancer, metastatic melanoma with CDK4 mutation or amplification, or cisplatin-refractory, unresectable germ cell tumors, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,
  • the methods described herein can be used to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality.
  • a host for example a human
  • the methods as described herein can be administered to a host with a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma.
  • the host can have a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non- Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-
  • the patient has an acute myelogenous leukemia, for example an undifferentiated AML (MO); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7), small cell lung cancer, retinoblastoma, HPV positive malignancies like cervical cancer and certain head and neck cancers, MYC amplified tumors such as Burkitts’ Lymphoma, and triple negative breast cancer; certain classes of sarcoma, certain classes of non-small cell lung carcinoma, certain classes of melanoma, certain classes of pancreatic cancer, certain classes of
  • an active compound or its salt as described herein can be used to preserve or prevent damage to an organ or blood product.
  • an active compound or its salt described herein can be used to prevent damage to an organ, tissue, cell product, or blood product, that has been harvested for transplantation.
  • the organ is the heart, kidney, pancreas, lung, liver, or intestine.
  • the tissue is derived from the cornea, bone, tendon, muscle, heart valve, nerve, artery or vein, or the skin.
  • the blood product is whole blood, plasma, red blood cells or reticulocytes.
  • an active compound or its salt or composition as described herein prevents or delays the onset of at least one symptom of a complement-mediated disease or disorder in an individual.
  • an active compound or its salt or composition as described herein reduces or eliminates at least one symptom of a complement-mediated disease or disorder in an individual.
  • symptoms include, but are not limited to, symptoms associated with autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, renal disease, transplant rejection, ocular disease, vascular disease, or a vasculitis disorder.
  • the symptom can be a neurological symptom, for example, impaired cognitive function, memory impairment, loss of motor function, etc.
  • the symptom can also be the activity of C1s protein in a cell, tissue, or fluid of an individual.
  • the symptom can also be the extent of complement activation in a cell, tissue, or fluid of an individual.
  • administering an active compound or its salt or composition as described herein to an individual modulates complement activation in a cell, tissue, or fluid of an individual. In some embodiments, administration of an active compound or its salt or composition as described herein to an individual inhibits complement activation in a cell, tissue, or fluid of an individual.
  • an active compound or its salt or composition as described herein when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, inhibits complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to complement activation in the individual before treatment with the compounds described herein.
  • an active compound or its salt or composition as described herein reduces C3 deposition onto red blood cells; for example, in some embodiments, an an active compound or its salt or composition as described herein reduces deposition of C3b, IC3b, etc., onto RBCs. In some embodiments, an active compound or its salt or composition as described herein inhibits complement-mediated red blood cell lysis. In some embodiments, an active compound or its salt or composition as described herein reduces C3 deposition onto platelets; for example, in some embodiments, an active compound or its salt or composition as described herein reduces deposition of C3b, IC3b, etc., onto platelets.
  • administering an active compound or its salt or composition as described herein results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho-Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition,
  • an active compound or its salt or composition as described herein when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, is effect to achieve a reduction of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, of one or more of the following outcomes: (a) complement activation; (b) decline in cognitive function; (c) neuron loss; (d) phospho-Tau levels in neurons; (e) glial cell activation; (f) lymphocyte infiltration; (g) macrophage infiltration; (h) antibody deposition, (i) glial cell loss; (j) oligodendrocyte loss; (k) dendritic cell infiltration; (l) neutrophil infiltration; (m) red blood cell lysis; (n) red blood cell phagocytosis; (
  • an active compound or its salt or composition as described herein when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, is effect to achieve an improvement of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, of one or more of the following outcomes: a) cognitive function; b) transplant graft survival; c) vision; d) motor control; e) thrombus formation; f) clotting; g) kidney function; and h) hematocrit (red blood cell count), compared to the level or degree of the outcome in the individual before treatment with the active compound.
  • administering an active compound or its salt or composition as described herein to an individual reduces complement activation in the individual.
  • an active compound or its salt or composition as described herein when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement- mediated disease or disorder, reduces complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to complement activation in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein improves cognitive function in the individual.
  • an active compound described herein when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, improves cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the cognitive function in the individual before treatment with the active compound.
  • administering an active compound or its salt or composition as described herein reduces the rate of decline in cognitive function in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces the rate of decline of cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the rate of decline in cognitive function in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein to an individual reduces neuron loss in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces neuron loss in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to neuron loss in the individual before treatment with the active compound.
  • administering an active compound or its salt or composition as described herein to an individual reduces phospho-Tau levels in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces phospho-Tau in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the phospho-Tau level in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein to an individual reduces glial cell activation in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces glial activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to glial cell activation in the individual before treatment with the active compound or its salt.
  • the glial cells are astrocytes or microglia.
  • administering an active compound or its salt or composition as described herein to an individual reduces lymphocyte infiltration in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces lymphocyte infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to lymphocyte infiltration in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein to an individual reduces macrophage infiltration in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces macrophage infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to macrophage infiltration in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein to an individual reduces antibody deposition in the individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, reduces antibody deposition in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to antibody deposition in the individual before treatment with the active compound or its salt.
  • administering an active compound or its salt or composition as described herein to an individual reduces anaphylatoxin (e.g., C3a, C4a, C5a) production in an individual.
  • an active compound or its salt when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement- mediated disease or disorder, reduces anaphylatoxin production in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the level of anaphylatoxin production in the individual before treatment with the active compound or its salt.
  • the present disclosure provides for use of an active compound or its salt of the present disclosure or a pharmaceutical composition comprising an active compound or its salt of the present disclosure and a pharmaceutically acceptable excipient to treat an individual having a complement- mediated disease or disorder. In some embodiments, the present disclosure provides for use of an active compound or its salt of the present disclosure to treat an individual having a complement- mediated disease or disorder. In some embodiments, the present disclosure provides for use of a pharmaceutical composition comprising an active compound or its salt of the present disclosure and a pharmaceutically acceptable excipient to treat an individual having a complement-mediated disease or disorder.
  • an active compound or its salt or composition as described herein may be provided in combination or alternation with or preceded by, concomitant with or followed by, an effective amount of at least one additional therapeutic agent, for example, for treatment of a disorder listed herein.
  • additional therapeutic agent for example, for treatment of a disorder listed herein.
  • second active agents for such combination therapy are provided as follows.
  • an active compound or its salt or composition as described herein may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action.
  • an active compound or its salt or composition as described herein may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitor, receptor agonist, chemotherapeutic agent, or siRNA.
  • an active compound described herein is administered in combination or alternation with an antibody against tumor necrosis factor (TNF), including but not limited to infliximab (REMICADE ® ), adalimumab (HUMIRA ® ), certolizumab (CIMZIA ® ), golimumab (SIMPONI ® ), or a receptor fusion protein such as etanercept (ENBREL ® ).
  • TNF tumor necrosis factor
  • the agent for combination therapy is a biosimilar of any agent named above, including, but not limited to, REMISMA ® (infliximab biosimilar), FLIXABI ® (infliximab biosimilar), AMGEVITA ® (adalimumab biosimilar), IMRALDI ® (adalimumab biosimilar), CYTELZO ® (adalimumab biosimilar), BENEPALI ® (etanercept biosimilar), and ERELZI ® (etanercept biosimilar).
  • REMISMA ® infliximab biosimilar
  • FLIXABI ® infliximab biosimilar
  • AMGEVITA ® adalimumab biosimilar
  • IMRALDI ® adalimumab biosimilar
  • CYTELZO ® adalimumab biosimilar
  • BENEPALI ® etanercept biosimilar
  • an active compound as described herein can be administered in combination or alternation with an anti-CD20 antibody, including but not limited to rituximab (RITUXAN ® ), ofatumumab (ARZERRA ® ), tositumomab (BEXXAR ® ), obinutuzumab (GAZYVA ® ), ibritumomab (ZEVALIN ® ), ocrelizumab (OCREVUS ® ), or veltuzumab.
  • the agent for combination therapy is a biosimilar of any agent named above, including, but not limited to, TRUXIMA ® (rituximab biosimilar).
  • an active compound as described herein can be administered in combination or alternation with an anti-IL6 antibody, including but not limited to tocilizumab (ACTEMRA ® ), siltuximab (SYLVANT ® ), sarilumab (KEVZARA ® ), sirukumab, clazakizumab, vobarilizumab, olokizumab, and WBP216 (MEDI5117).
  • the agent for combination therapy is a biosimilar of any agent named above, including, but not limited to, BAT1806 (tocilizumab biosimilar).
  • an active compound as described herein can be administered in combination or alternation with an IL17 inhibitor, including but not limited to secukinumab (Cosentyx), ixekizumab (TALTZ ® ), brodalumab (SILIQ ® ), bimekizumab, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, and MSB0010841.
  • an IL17 inhibitor including but not limited to secukinumab (Cosentyx), ixekizumab (TALTZ ® ), brodalumab (SILIQ ® ), bimekizumab, ALX-0761, CJM112, CNTO6785, LY3074828, SCH-900117, and MSB0010841.
  • the agent for combination therapy is a biosimilar of any agent named above.
  • an active compound as described herein can be administered in combination or alternation with a p40 (IL12/IL23) inhibitor, including but not limited to ustekinumab (STELARA ® ) and briakinumab (ABT874).
  • a p40 (IL12/IL23) inhibitor including but not limited to ustekinumab (STELARA ® ) and briakinumab (ABT874).
  • the agent for combination therapy is a biosimilar of any agent named above, including, but not limited to, FYB202 (ustekinumab biosimilar) and Neulara ® (ustekinumab biosimilar).
  • an active compound as described herein can be administered in combination or alteration with an IL23 inhibitor, including but not limited to risankizumab (SKYRIZI ® ), tildrakizumab (ILUMYA ® ), guselkumab (TREMFYA ® ), mirakizumab and brazikumab.
  • the agent for combination therapy is a biosimilar of any agent named above.
  • an active compound as described herein can be administered in combination or alteration with an anti-interferon ⁇ antibody, for example but not limited to sifalimumab, anifrolumab, and rontalizumab.
  • the agent for combination therapy is a biosimilar of any agent named above.
  • an active compound as described herein can be administered in combination or alteration with a kinase inhibitor, for example but not limited to a JAK1/JAK3 inhibitor, for example but not limited to tofacitinib (XELJANZ ® ).
  • a JAK1/JAK2 inhibitor for example but not limited to baracitinib (OLUMIANT ® ) and ruxolitinib (JAKAFI ® ).
  • an active compound as described herein can be administered in combination or alteration with an anti-VEGF agent, for example but not limited to: aflibercept (EYLEA ® ; Regeneron Pharmaceuticals); ranibizumab (LUCENTIS ® : Genentech and Novartis); pegaptanib (MACUGEN ® ; OSI Pharmaceuticals and Pfizer); bevacizumab (AVASTIN ® ; Genentech/Roche) and ziv- aflibercept (ZALTRAP ® ).
  • an anti-VEGF agent for example but not limited to: aflibercept (EYLEA ® ; Regeneron Pharmaceuticals); ranibizumab (LUCENTIS ® : Genentech and Novartis); pegaptanib (MACUGEN ® ; OSI Pharmaceuticals and Pfizer); bevacizumab (AVASTIN ® ; Genentech/Roche) and ziv- aflibercept (ZALTRAP ® ).
  • an active compound as described herein can be administered in combination or alternation with a tyrosine kinase inhibitor, for example but not limited to: lapatinib (TYKERB ® ); sunitinib (SUTENT ® ); axitinib (INLYTA ® ); pazopanib; sorafenib (NEXAVAR ® ); ponatinib (INCLUSIG ® ); regorafenib (STIVARGA ® ); cabozantinib (ABOMETYX ® ; COMETRIQ ® ); vendetanib (CAPRELSA ® ); ramucirumab (CYRAMZA ® ); lenvatinib (LENVIMA ® ); cediranib (RECENTIN ® ); anecortane acetate, squalamine lactate, and corticosteroids.
  • a tyrosine kinase inhibitor for example but not
  • an active compound as described herein can be administered in combination or alternation with an immune checkpoint inhibitor.
  • checkpoint inhibitors include anti-PD-1 or anti-PDL1 antibodies, for example, nivolumab (OPDIVO ® ), pembrolizumab (KEYTRUDA ® ), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.), atezolizumab (TECENTRIQ ® ), durvalumab (IMFINZI ® ), and KN035, or anti-CTLA4 antibodies, for example Ipilimum
  • Non-limiting examples of active agents that can be used in combination with active compounds described herein include, but are not limited to: Protease inhibitors: plasma-derived C1-INH concentrates, for example CETOR ® (Sanquin), BERINERT-P ® (CSL Behring, Lev Pharma), HAEGARDA ® (CSL Bering), CINRYZE ® ; recombinant human C1-inhibitors, for example RHUCIN ® ; ritonavir (NORVIR ® , Abbvie, Inc.); Soluble complement regulators: Soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLe x /TP-20 (Avant Immunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals); Therapeutic antibodies: Eculizumab/SOLIRIS ® (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ravul
  • Receptor agonists PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini); Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals); Imides and glutarimide derivatives such as thalidomide, lenalidomide, pomalidomide; Additional non-limiting examples that can be used in combination or alternation with an active compound or its salt or composition as described herein include the following.
  • the agent for combination therapy is a biosimilar of any agent named above.
  • an active compound or its salt or composition as described herein may be provided together with a compound that inhibits an enzyme that metabolizes an administered protease inhibitor.
  • a compound or salt may be provided together with ritonavir.
  • an active compound or its salt or composition as described herein may be provided in combination with a terminal complement inhibitor, for example a complement C5 inhibitor or C5 convertase inhibitor.
  • an active compound or its salt or composition as described herein may be provided in combination with eculizumab, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the tradename SOLIRIS ® . Eculizumab has been approved by the U.S.
  • an active compound or its salt or composition as described herein may be provided in combination with revulizumab, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the tradename ULTOMIRIS ® .
  • Revulizumab has been approved by the U.S. FDA for the treatment of PNH.
  • C5 and C5 convertase inhibitors include, but are not limited to, cemdisiran (Alnylam); prozelimab (Regeneron); BCD-148 (Biocad); ABP-959 (Amgen); SB-12 (Samsung Bioepis Co., Ltd.); LFG316 (Novartis); coversin (nomacopan; Akari)); zilucoplan (Ra Pharma); crovalimab (SKY59; Roche/Chugai); and mubodina (Adienne Pharma).
  • an active compound or its salt or composition as described herein is administered in combination with an anti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent, immunosuppressant, antibody, steroid, ocular antihypertensive drug or combinations thereof.
  • agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, n
  • an active compound or its salt or composition as described herein can be administered in combination or alternation with at least one immunosuppressive agent.
  • the immunosuppressive agent as non-limiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL ® ), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMUNE ® ), Everolimus (Certican ® ), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analog thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT ® ), OKT3 (ORTHOCLONE OKT3 ® ), Prednisone, ATGAM ® , THYMOGLOBULIN ® , Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA ® , CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT ® ), Daclizumab (ZENAPAX ® ), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ELIDEl ® ), CTLA4lg (Abatacept), belatacept, LFA3lg, etanercept (sold as ENBREL ® by Immunex), adalimumab (HUMIRA ® ), in
  • anti-inflammatory agents examples include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofe
  • an active compound or its salt or composition as described herein is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • an active compound or its salt or composition as described herein is administered in combination or alteration with an omega-3 fatty acid or a peroxisome proliferator- activated receptor (PPARs) agonist.
  • Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting DGAT and by stimulating peroxisomal and mitochondrial beta oxidation.
  • Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been found to have high affinity for both PPAR-alpha and PPAR-gamma.
  • Marine oils e.g., fish oils, are a good source of EPA and DHA, which have been found to regulate lipid metabolism.
  • Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
  • Omega-3 fatty acids lower serum triglycerides, increase serum HDL- cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor VII-phospholipid complex.
  • omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
  • One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark OMACOR ® .
  • PPARs Peroxisome proliferator-activated receptors
  • PPAR-alpha PPAR-beta/delta (or merely, delta)
  • PPAR-gamma PPAR-gamma
  • PPAR agonists e.g., PPAR-alpha agonists, PPAR-gamma agonists and PPAR-delta agonists.
  • Some pharmacological agents are combinations of PPAR agonists, such as alpha/gamma agonists, etc., and some other pharmacological agents have dual agonist/antagonist activity.
  • Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, are PPAR-alpha agonists and are used in patients to decrease lipoproteins rich in triglycerides, to increase HDL and to decrease atherogenic-dense LDL.
  • Fibrates are typically orally administered to such patients.
  • Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester has been known for many years as a medicinally active principle because of its efficacy in lowering blood triglyceride and cholesterol levels.
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti-VEGF agent.
  • AMD age- related macular degeneration
  • Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (EYLEA ® ; Regeneron Pharmaceuticals); ranibizumab (LUCENTIS ® : Genentech and Novartis); pegaptanib (MACUGEN ® ; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche); lapatinib (TYKERB ® ); sunitinib (SUTENT ® ); axitinib (INLYTA ® ); pazopanib; sorafenib (NEXAVAR ® ); ponatinib (INCLUSIG ® ); regorafenib (STIVARGA ® ); Cabozantinib (Abometyx; COMETRIQ ® ); vendetanib (CAPRELSA ® ); ramucirumab (CYRAMZA ® ); lenvatinib (LENVIMA
  • the disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with a complement C5 inhibitor, for example, a complement C5 inhibitor described herein and in the table above titled Non- limiting examples of potential therapeutics for combination therapy, including, but not limited to, eculizumab (Alexion Pharmaceuticals); ravulizumab (Alexion Pharmaceuticals); LFG316 (Novartis/Morphosys); cemdisiran, cemdisiran/ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); Coversin (Akari Therapeutics); Mubodine (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmers (SomaLogic); Erdigna (Adienne Pharma); ARC1905 (Ophtho
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with anti-properidin agent, for example, an anti-properidin agent as described above, including but not limited to NM9401 (Novelmed).
  • AMD age- related macular degeneration
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with a complement C3 inhibitor for example, a complement C3 inhibitor described above, including, but not limited to, a compstatin or compstatin analog, for example Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Apellis); CP40/AMY-101,PEG-Cp40 (Amyndas) Complement C3 or CAP C3 Convertase targeting molecules: TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) AL
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti-factor H or anti-factor B agent selected from Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas).
  • an anti-factor H or anti-factor B agent selected from Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas).
  • the present disclosure provides a method of treating or preventing age- related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti-MASP2, anti-C1s or anti-CR3 molecules, for example, but not limited to: Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).
  • AMD age- related macular degeneration
  • the disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with a multiple kinase inhibitor, for example as described herein including but not limited to Sorafenib Tosylate (NEXAVAR ® ); Imatinib Mesylate (GLEEVEC ® ); Sunitinib Malate (SUTENT ® ); Ponatinib (ICLUSIG ® ); Axitinib (INLYTA ® );; Nintedanib (OFEV ® ); Pazopanib HCl (VOTRIENT ® ); Dovitinib (TKI-258, Oncology Ventures); gilteritnib (XOSPATA ® ); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with a complement C5 inhibitor, for example, a complement C5 inhibitor described herein and in the table above titled
  • a complement C5 inhibitor for example, a complement C5 inhibitor described herein and in the table above titled
  • Non-limiting examples of potential therapeutics for combination therapy including, but not limited to, eculizumab (Alexion Pharmaceuticals); ravulizumab (Alexion Pharmaceuticals); LFG316 (Novartis/Morphosys); cemdisiran, cemdisiran/ALN-CC5 (Alnylam); ARC1005 (Novo Nordisk); Coversin (Akari Therapeutics); Mubodine (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmers (So
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with anti-properdin agent, for example, an anti-properdin agent as described above, including but not limited to NM9401 (Novelmed).
  • CAD cold agglutinin disease
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with a complement C3 inhibitor for example, a complement C3 inhibitor described above, including, but not limited to, a compstatin or compstatin analog, for example Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Apellis); CP40/AMY-101 ,PEG-Cp40 (Amyndas) Complement C3 or CAP C3 Convertase targeting molecules: TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) AL
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti-factor H or antifactor B agent selected from lONIS-FB-LRx (lonis Pharmaceuticals); Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas).
  • CAD cold agglutinin disease
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with an anti- MASP2, anti C1s, or anti-C1n molecule, for example but not limited to Cinryze ® (Takeda); Berinert ® (Bering CSL), Ruconest ® (Pharming), Haegarda ® (Bering CSL); TNT003 (Bioverativ/Sanofi); BIVV009 (Bioverativ/Sanofi); BIVV020 (Bioverativ/Sanofi); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera)
  • the disclosure provides a method of treating or preventing cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination with
  • the present disclosure provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein with an additional inhibitor of the complement system or another active compound with a different biological mechanism of action.
  • the present disclosure provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with eculizumab or ravulizumab.
  • the present disclosure provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with CP40.
  • the additional agent is PEGylated-CP40.
  • CP40 is a peptide inhibitor that shows a strong binding affinity for C3b and inhibits hemolysis of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes.
  • the additional agent is a complement component inhibitor, for example but not limited to Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Apellis); CP40/AMY-101,PEG-Cp40 (Amyndas); a PDGF inhibitor, for example, but not limited to Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG), CCNU
  • the present disclosure provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with methotrexate.
  • an active compound or its salt or composition as described herein is administered in combination or alternation with at least one additional therapeutic agent selected from: salicylates including aspirin (ANACIN ® , ASCRIPTIN ® , BAYER ASPIRIN ® , ECOTRIN ® ) and salsalate (MONO-GESIC ® , SALGESIC ® ); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (CATAFLAM ® , VOLTAREN ® ), ibuprofen (ADVIL ® , MOTRIN ® ), ketoprofen (ORUDIS
  • the present disclosure provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with an additional inhibitor of the complement system, or an active agent that functions through a different mechanism of action.
  • the present disclosure provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound or its salt or composition as described herein in combination or alternation with a corticosteroid.
  • corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.
  • an active compound or its salt or composition as described herein is combined with at least one anti-multiple sclerosis drug, for example, selected from: AUBAGIO ® (teriflunomide), AVONEX ® (interferon beta-1a), BETASERON ® (interferon beta-1b), COPAXONE ® (glatiramer acetate), EXTAVIA ® (interferon beta-1b), GILENYA ® (fingolimod), LEMTRADA ® (alemtuzumab), Novantrone (mitoxantrone), PLEGRIDY ® (peginterferon beta-1a), REBIF ® (interferon beta-1a), TECFIDERA ® (dimethyl fumarate), TYSABRI ® (natalizumab), SOLU- MEDROL ® (methylprednisolone), High-dose oral DELTASONE ® (prednisone), H.P.
  • AUBAGIO ® teriflunomide
  • an active compound or its salt or composition as described herein is useful in a combination with another pharmaceutical agent to ameliorate or reduce a side effect of the agent.
  • an active compound or its salt or composition as described herein may be used in combination with adoptive cell transfer therapies to reduce an associated inflammatory response associated with such therapies, for example, a cytokine mediated response such as cytokine release syndrome.
  • the adoptive cell transfer therapy includes the use of a chimeric antigen receptor T-Cell (CAR T).
  • the adoptive cell transfer therapy includes the use of a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer.
  • CAR T chimeric antigen receptor T-Cell
  • the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancer that expresses CD19.
  • an active compound or its salt or composition as described herein may be provided in combination with eculizumab or ravulizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis, neuromyelitis optica, or transplantation rejection.
  • an active compound or its salt or composition as described herein may be provided in combination with compstatin or a compstatin derivative for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis, neuromyelitis optica, neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 (AQP4) antibody positive, myasthenia gravis, generalized myasthenia gravis, or transplantation rejection.
  • compstatin or a compstatin derivative for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis, neuromyelitis optica, neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 (AQP4) antibody positive, myasthenia gravis, generalized myasthenia gravis, or
  • the additional agent is a complement component inhibitor, for example but not limited to Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1 ,APL-2 (Apellis); CP40/AMY-101 ,PEG-Cp40 (Amyndas); a PDGF inhibitor, for example, but not limited to Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCI (GW786034 HCI); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG), CCNU
  • an active compound or its salt or composition as described herein may be provided in combination with rituxan for the treatment of a complement mediated disorder.
  • the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), and Microscopic Polyangiitis (MPA).
  • the disorder is Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with cyclophosphamide for the treatment of a complement mediated disorder.
  • the disorder is an autoimmune disease.
  • the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), and Microscopic Polyangiitis (MPA).
  • the disorder is Lupus.
  • an active compound or its salt or composition as described herein is dosed in combination with a conventional DLE treatment for the treatment of lupus to a subject in need thereof.
  • Examples of conventional DLE treatments include topical corticosteroid ointments or creams, such as triamcinolone acetonide, fluocinolone, flurandrenolide, betamethasone valerate, or betamethasone dipropionate. Resistant plaques can be injected with an intradermal corticosteroid. Other potential DLE treatments include calcineurin inhibitors such as pimecrolimus cream or tacrolimus ointment. Particularly resistant cases can be treated with systemic antimalarial drugs, such as hydroxychloroquine (PLAQUENIL). In some embodiments, an active compound or its salt or composition as described herein may be provided in combination with methotrexate for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with azathioprine for the treatment of Lupus. In some embodiments, an active compound or its salt or composition as described herein may be provided in combination with a non-steroidal anti-inflammatory drug for the treatment of Lupus. In some embodiments, an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid for the treatment of Lupus. In some embodiments, an active compound or its salt or composition as described herein may be provided in combination with a belimumab (Benlysta) for the treatment of Lupus.
  • azathioprine for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with a non-steroidal anti-inflammatory drug for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided
  • an active compound or its salt or composition as described herein may be provided in combination with hydroxychloroquine (Plaquenil) for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with sifalimumab for the treatment of Lupus.
  • an active compound or its salt or composition as described herein may be provided in combination with OMS721 (Omeros) for the treatment of a complement mediated disorder.
  • an active compound or its salt or composition as described herein may be provided in combination with OMS906 (Omeros) for the treatment of a complement mediated disorder.
  • the complement mediated disorder is, for example, thrombotic thrombocytopenic purpura (TTP) or aHUS.
  • TTP thrombotic thrombocytopenic purpura
  • an active compound or its salt or composition as described herein may be provided in combination with an anti-inflammatory agent, immunosuppressive agent, or anti-cytokine agent for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics (e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, or monoclonal antibody therapy).
  • ACT adoptive T-cell therapy
  • CAR T-cell therapy such as CAR T-cell therapy, or monoclonal antibody therapy
  • an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid, for example prednisone, dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokine compounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGF ⁇ .
  • a corticosteroid for example prednisone, dexamethasone, solumedrol, and methylprednisolone
  • anti-cytokine compounds targeting e.g., IL-4, IL-10, IL-11, IL-13 and TGF ⁇ .
  • an active compound or its salt or composition as described herein may be provided in combination with an anti-cytokine inhibitor including, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof.
  • an anti-cytokine inhibitor including, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof.
  • Additional anti-inflammatory agents that can be used in combination with an active compound or its salt or composition as described herein include, but are not limited to, non-steroidal anti- inflammatory drug(s) (NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP- 571/BAY-10-3356 (humanized anti-TNF ⁇ antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNF ⁇ antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL- 2 fusion proteins; Seragen); Anti-T
  • an active compound or its salt or composition as described herein may be provided in combination with a corticosteroid for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with etarnercept for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with etarnercept and tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with infliximab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with golimumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
  • an active compound or its salt or composition as described herein may be provided in combination with methylprednisolone, azathioprine, mycophenolate, rituximab, methotrexate, an oral corticosteroid, mitoxantrone, tocilizumab, or a C5 inhibitor such as eculizumab or ravulizumab , or a combination thereof, for the treatment of NMO.
  • an active compound or its salt or composition as described herein may be provided in combination with Carbidopa-levodopa, a Dopamine agonists includinding, but not limited to pramipexole (Mirapex), ropinirole (Requip) and rotigotine (Neupro, given as a patch).
  • a Dopamine agonists includedinding, but not limited to pramipexole (Mirapex), ropinirole (Requip) and rotigotine (Neupro, given as a patch).
  • Apomorphine (Apokyn), an MAO B inhibitors, for example selegiline (Eldepryl, Zelapar), rasagiline (Azilect) and safinamide (Xadago), a Catechol O-methyltransferase (COMT) inhibitor, for example Entacapone (Comtan) and Tolcapone (Tasmar), an Anticholinergics., for example benztropine (Cogentin) or trihexyphenidyl, or Amantadine, or a combination thereof, for the treatment of Parkinson’s Disease.
  • MAO B inhibitors for example selegiline (Eldepryl, Zelapar), rasagiline (Azilect) and safinamide (Xadago)
  • a Catechol O-methyltransferase (COMT) inhibitor for example Entacapone (Comtan) and Tolcapone (Tasmar)
  • an Anticholinergics for example benztropine (Cogentin
  • an active compound or its salt or composition as described herein may be provided in combination with a cholinesterase inhibitor, Namenda, risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), vitamin E, sertraline (Zoloft), bupropion (Wellbutrin), citalopram (Celexa), paroxetine (Paxil), or venlafaxine (Effexor), or a combination thereof, for the treatment of Alzheimer’s Disease.
  • a cholinesterase inhibitor Namenda, risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel)
  • vitamin E sertraline
  • Zoloft bupropion
  • citalopram Celexa
  • paroxetine Paxil
  • venlafaxine venlafaxine
  • an active compound or its salt or composition as described herein may be provided in combination with Riluzole (Rilutek), Edaravone (Radicava), or a combination thereof, for the treatment of ALS.
  • an active compound or its salt or composition as described herein may be provided in combination with an immune modulator for the treatment of cancer, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor.
  • the immune modulator is an antibody, such as a monoclonal antibody.
  • Immune checkpoint inhibitors for use in the methods described herein include, but are not limited to PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM- 3 inhibitors, and V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, or combinations thereof.
  • the immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
  • the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from nivolumab (Opdivo ® ), pembrolizumab (Keytruda ® ), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), MGA012 (MacroGenics), BGB-A317 (BeiGene) SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.).
  • the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor nivolumab (Opdivo ® ) administered in an effective amount for the treatment of Hodgkin lymphoma, melanoma, non-small cell lung cancer, hepatocellular carcinoma, or ovarian cancer.
  • Nivolumab has been approved by the FDA for the use of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma.
  • the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda ® ) administered in an effective amount for the treatment of melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, or urothelial cancer.
  • the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pidilizumab (Medivation) administered in an effective amount for refractory diffuse large B-cell lymphoma (DLBCL) or metastatic melanoma.
  • the immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
  • PD-L1 inhibitors include, but are not limited to, atezolizumab, durvalumab, KN035CA-170 (Curis Inc.), and LY3300054 (Eli Lilly).
  • the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq ® ) administered in an effective amount for the treatment of metastatic bladder cancer, metastatic melanoma, metastatic non-small cell lung cancer, or metastatic renal cell carcinoma. In another aspect of this embodiment, the immune checkpoint inhibitor is durvalumab (AstraZeneca and MedImmune) administered in an effective amount for the treatment of non-small cell lung cancer or bladder cancer.
  • the immune checkpoint inhibitor is KN035 (Alphamab) administered in an effective amount for the treatment of PD-L1 positive solid tumors.
  • An additional example of a PD-L1 immune checkpoint inhibitor is BMS-936559 (Bristol-Myers Squibb), although clinical trials with this inhibitor have been suspended as of 2015.
  • the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immune suppression.
  • CTLA-4 inhibitors include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus).
  • the CTLA-4 immune checkpoint inhibitor is ipilimumab (Yervoy®) administered in an effective amount for the treatment of metastatic melanoma, adjuvant melanoma, or non-small cell lung cancer.
  • the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor.
  • LAG-3 immune checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).
  • the immune checkpoint inhibitor is a TIM-3 immune checkpoint inhibitor.
  • a specific TIM- 3 inhibitor includes, but is not limited to, TSR-022 (Tesaro).
  • B7-H3/CD276 immune checkpoint inhibitors such as MGA217
  • IDO indoleamine 2,3-dioxygenase
  • KIRs killer immunoglobulin-like receptors
  • CEACAM carcinoembryonic antigen cell adhesion molecule
  • anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1 , 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552.
  • the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9).
  • checkpoint inhibitors can be molecules directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87.
  • the active compounds described herein, or a pharmaceutically acceptable salt thereof is administered in an oral dosage form and can be in combination with any standard chemotherapeutic agent treatment modality for the treatment of cancer.
  • the chemotherapeutic agent inhibits cell growth.
  • the chemotherapeutic agent administered is a DNA damaging chemotherapeutic agent.
  • the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, DNA polymerase inhibitor, an anticancer enzyme, RAC1 inhibitor, thymidylate synthase inhibitor, oxazophosphorine compound, integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, antifolate or a folate antimetabolite.
  • the additional therapeutic agent is trastuzumab. In some embodiments, the additional therapeutic agent is lapatinib. In some embodiments, the additional therapeutic agent is osimertinib. In some embodiments, the additional therapeutic agent is alectinib.
  • the additional therapeutic agent is a MEK inhibitor.
  • the additional therapeutic agent is an Androgen Receptor ligand.
  • the additional therapeutic agent is a BTK inhibitor.
  • the additional therapeutic agents are a MEK inhibitor and a RAF inhibitor.
  • the additional therapeutic agent is a RAF inhibitor. In some embodiments, the additional therapeutic agent is regorafenib.
  • the MEK inhibitor is Binimetinib, Selumetinib, CI-040, PD-325901, PD035901, orTAK-733.
  • the MEK inhibitor is Tramatenib, U0126-EtOH, PD98059, Pimasertib, BIX 02188, AZD8330, PD318088, SL-327, Refametinib, Myricetin, BI-847325, Cobimetinib, APS-2-79 HCI, orGDC-0623.
  • the RAF inhibitor is PLX-4720, Dabrafenib, GDC-0879, Lifrafenib, CCT196969, RAF265, AZ 628, NVP-BHG712, SB590885, ZM 336372, Sorafenib, GW5074, TAK-632, CEP-32496, Encorafenib, PLX7904, LY3009120, RO5126766, orMLN2480.
  • the BTK inhibitor is CC-292, CNX-774, RN486, LFM-A13, ONO-4059, ibrutinib, Acalabrutinib, or CGI746.
  • the Androgen Receptor ligand is MK-2866, Apalutamide, Andarine, Boldenone, testosterone enanthate, dihydrotestosterone, Galertone, dehydroepiandrosterone, cyproterone acetate, megestrol acetate, epiandrosterone, AZD3514, spironolactone, chloromadinone acetate, ODM-201 , EPI-001.
  • the EGFR inhibitor is Lapatinib, Afatinib, Neratinib, Catertinib,
  • an active compound described herein is combined with a DNA- damaging chemotherapeutic agent for the treatment of cancer.
  • DNA- damaging chemotherapy or chemotherapeutic agent refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of undesirable cells, for example cancer cells, wherein the cytotoxic effect of the agent can be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, the inhibition of another nucleic acid-related activity (e.g., protein synthesis), or any other cytotoxic effect.
  • cytostatic or cytotoxic agent i.e., a compound
  • the cytotoxic effect of the agent can be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, the inhibition of another nucleic acid-related activity (e.g., protein synthesis), or any other cytotoxic effect.
  • DNA damaging chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalators, protein synthesis inhibitors, inhibitors of DNA or RNA synthesis, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomeric DNA binding compounds.
  • alkylating agents include alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as a benzodizepa, carboquone, meturedepa, and uredepa; ethylenimines and methylmelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitroso ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine.
  • aziridines such as
  • DNA-damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozocin.
  • Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine ⁇ -1-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, azaserine, 6-azauracil, 2′-azido- 2′-deoxynucleosides, 5-bromodeoxycytidine, cytosine ⁇ -1-D-arabinoside, diazooxynorleucine, dideoxynucleo
  • Chemotherapeutic protein synthesis inhibitors that may be combined with the active compounds described herein include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5- fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl imidodiphosphate, kanamycin, kasugamycin, kirromycin, and O-methyl threonine.
  • Additional protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycine, puromycin, ricin, shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.
  • Inhibitors of DNA synthesis that may be combined with the active compounds described herein include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents, such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide- intertwining; and other agents, such as distamycin and netropsin.
  • alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards
  • intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide- intertwining
  • other agents such as distamycin and netropsin.
  • Topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; inhibitors of cell division, including colcemide, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, ⁇ -amanitine and other fungal amatoxins, cordycepin (3′- deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydigin also can be used as the DNA damaging compound.
  • RNA synthesis inhibitors including actinomycin D, ⁇ -amanitine and other fungal amatoxins, cordycepin (3′- deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydigin also
  • the chemotherapeutic agent that may be combined with the active compounds described herein for the treatment of cancer is a DNA complex binder such as camptothecin, or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU, or fotesmustine; a guanine alkylating agent such as temozolomide, a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52, halichondrins, such as halichondrin B, dolastatins, such as dolastatin 10 and dolastatin 15, hemiasterlins, such as hemiasterlin A and hemiasterlin B, colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; a DNA polymerase inhibitor such as
  • the topoisomerase inhibitor is a type I inhibitor. In another embodiment the topoisomerase inhibitor is a type II inhibitor.
  • DNA-damaging chemotherapeutic agents that may be combined with the active compounds described herein for the treatment of cancer include, but are not limited to, cisplatin, hydrogen peroxide, carboplatin, procarbazine, ifosfamide, bleomycin, plicamycin, taxol, transplatinum, thiotepa, oxaliplatin, and the like, and similar acting-type agents.
  • the DNA damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, camptothecin, and etoposide.
  • chemotherapeutic agents that may be combined with the active compounds described herein include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • General anticancer pharmaceutical agents include: Vincristine (Oncovin®), liposomal vincristine (Marqibo®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Prednisone, and Dexamethasone (Decadron).
  • chemotherapeutic agents include but are not limited to 5-fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (formerly actinomycin), daunorubicin HCI, daunorubicin citrate, denileukin diftitox, dihydroxy anthracin dione, Docetaxel, doxorubicin HCI, E.
  • cytotoxic chemotherapeutic agents for use with the present disclosure include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vismodegib, azacytidine, doxifluridine, vindesine, and vinorelbine.
  • the chemotherapeutic agent that may be combined with the active compounds described herein for the treatment of cancer is a DNA complex binder.
  • the chemotherapeutic agent is a tubulin binder.
  • the chemotherapeutic agent is an alkylating agent.
  • the chemotherapeutic agent is a thiolate alkylating agent.
  • Additional chemotherapeutic agents that may be combined with the active compounds described herein for the treatment of cancer may include 2-methoxyestradiol or 2ME2, finasunate, etaracizumab (MEDI-522), HLL1, huN901-DM1, atiprimod, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, plitidepsin, P276-00, tipifarnib, lenalidomide, thalidomide, pomalidomide, simvastatin, and celecoxib.
  • 2-methoxyestradiol or 2ME2 finasunate
  • etaracizumab (MEDI-522)
  • HLL1 huN901-DM1
  • atiprimod saquinavir mesylate
  • ritonavir ritonavir
  • nelfinavir mesylate indin
  • Chemotherapeutic agents useful in the present disclosure include, but are not limited to, Trastuzumab (HERCEPTIN ® ), Pertuzumab (PERJETA TM ), Lapatinib (TYKERB ® ), Gefitinib (IRESSA ® ), Erlotinib (TARCEVA ® ), Cetuximab (ERBITUX ® ), Panitumumab (VECTIBIX ® ), Vandetanib (CAPRELSA ® ), Vemurafenib (ZELBORAF ® ), Vorinostat (ZOLINZA ® ), Romidepsin (ISTODAX ® ), Bexarotene (TARGRETIN ® ), Alitretinoin (Panretin ® ), Tretinoin (VESANOID ® ), Carfilzomib (KyprolisTM), Pralatrexate (FOLOTYN ® ), Bevacizumab (AV
  • a calcineurin inhibitor e.g. a cyclosporin or an ascomycin
  • Cyclosporin A Neoral ®
  • FK506 tacrolimus
  • pimecrolimus pimecrolimus
  • a mTOR inhibitor e.
  • a dual mTORC1 and mTORC2 inhibitor eg. Vistusertib (AZD2014)
  • fingolimod or an analogue thereof e.g. fingolimod or an analogue thereof
  • an anti IL-8 antibody mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CellCept ® ), OKT3 (Orthoclone OKT3 ® ), Prednisone, ATGAM ® , Thymoglobulin ® , Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide Arava ® , anti-CD25, anti-IL2R, Basiliximab (Simulect ® ), Daclizumab (Zenapax ® ), mizoribine, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel ® ), Abatacept, belatacept, LFA3lg, etanercept (sold as ENBREL ® by ImmuneXcite), adalimumab (HUMIRA ® ), infliximab (REMICADE ® ), an anti-LFA
  • the chemotherapeutic agent that may be combined with the active compounds described herein for the treatment of cancer is an estrogen receptor ligands such as tamoxifen, raloxifene, fulvestrant, anordrin, apeledoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, or toremifene; an androgen receptor ligand such as bicalutamide, enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, or cimetidine; an aromatase inhibitor such as letrozole, anastrozole, or exemestane; an anti-inflammatory such as prednisone; an oxidas
  • Additional chemotherapeutic agents that may be combined with the active compounds described herein for the treatment of cancer, particularly in the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer include an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.
  • Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921 , WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138.
  • anti-estrogen compounds include: SERMS such as anordrin, avalyctriol, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.
  • SERMS such as anordrin, adoxifen
  • Additional chemotherapeutic agents that may be combined with the active compounds described herein for the treatment of cancer, particularly in the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, include, but are not limited to, an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
  • the prostate or testicular cancer is androgen-resistant.
  • Non-limiting examples of anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112.
  • anti-androgen compounds include: chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
  • the chemotherapeutic agent that may be combined with the active compounds described herein for the treatment of cancer may include a kinase inhibitor, including but not limited to a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • PI3k inhibitors are well known.
  • PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, GDC-0032 (2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol- 3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) ⁇ [(2R)-l-phenoxy-2- butanyl]oxy ⁇ phosphonium)), BYL-719 ((2S)-N
  • BTK inhibitors are well known.
  • BTK inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL- 291/292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2- hydroxyethyl)piperazin
  • Syk inhibitors are well known, and include, for example, Cerdulatinib (4-(cyclopropylamino)-2- ((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5-Fluoro-2- [(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2- b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro
  • the chemotherapeutic agent that may be combined with the active compounds described herein for the treatment of cancer can also be a B-cell lymphoma 2 (Bcl-2) protein inhibitor.
  • BCL-2 inhibitors are known in the art, and include, for example, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4- dimethylcyclohex-1-en-1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2- (4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2- yl] amino]-3- nitrophenyl]sulfonylbenzamide), ABT-263 ((R)-4-(4-((4
  • Additional chemotherapeutic agents that may be combined with the active compounds described herein for the treatment of cancer for use in the methods contemplated herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof), RAF inhibitors, apoptotic compounds, topoisomerase inhibitors, AKT inhibitors, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, or FLT-3 inhibitors, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof
  • Examples of MEK inhibitors include but are not limited to trametinib /GSKl120212 (N-(3- ⁇ 3-Cyclopropyl- 5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H-yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3- methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-(
  • RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
  • ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378.
  • HSP inhibitors include but are not limited to Geldanamycin or 17- N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
  • Known ERK inhibitors include SCH772984 (Merck/Schering-Plough), VTX-11e (Vertex), DEL- 22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.
  • Raf inhibitors are well known, and include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2- carboxamide;4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4- oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6- (pyridin-3-yl)-1H-pyra
  • topoisomerase I inhibitors useful in the present disclosure include (S)-10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline- 3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-1H- pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), (1S,9S)-1-Amino-9- ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo(de)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-10,13-dione (exatecan), (7-(
  • C5 Inhibitor Combinations Provided herein are methods for a treating a complement mediated disorder in a subject comprising administering to the subject an effective amount of a C5 inhibitor in combination or alternation with an effective amount of an active compound as described herein.
  • C5 inhibitors are known in the art.
  • the C5 inhibitor is a monoclonal antibody targeting C5.
  • the C5 inhibitor is eculizumab (SOLIRIS ® Alexion Pharmaceuticals, Boston, MA, see, e.g., U.S. Patent No.9,352,035), or a biosimilar molecule thereof.
  • the C5 inhibitor is ravulizumab (ULTOMIRIS ® Alexion Pharmaceuticals, Boston, MA, see, e.g., U.S. Patent Nos.9,371,377; 9,079,949 and 9,633,574), or a biosimilar thereof.
  • the C5 inhibitor may be, but is not limited to: a recombinant human minibody, for example Mubodina ® (monoclonal antibody, Adienne Pharma and Biotech, Bergamo, Italy; see U.S. Patent No.7,999,081); coversin (nomacopan, Akari Therapeutics, London, England; see e.g., Penabad et al.
  • the C5 inhibitor is a recombinant human minibody, for example Mubodina ® .
  • Mubodina ® is a fully human recombinant antibody C5 developed by Adienne Pharma and Biotech. Mubodina ® is described in U.S. Patent No.7,999,081.
  • the C5 inhibitor is coversin. Coversin is a recombinant protein derived from a protein discovered in the saliva of the Ornithodoros moubata tick currently developed as a recombinant protein by Akari Therapeutics (also known as nomacopan). Coversin is described in Penabad et al. Lupus 2012, 23(12):1324-6.
  • the C5 inhibitor is Tesidolumab/LFG316.
  • Tesidolumab is a monoclonal antibody developed by Novartis and Morphosys. Tesidolumab is described in U.S. Patent Nos. 8,241,628 and 8,883,158.
  • the C5 inhibitor is ARC-1905. ARC-1905 is a pegylated RNA aptamer developed by Ophthotech. ARC-1905 is described in Keefe et al. Nature Reviews Drug Discovery, 9:537-550.
  • the C5 inhibitor is RA101348.
  • RA101348 is a macrocyclic peptide developed by Ra Pharmaceuticals.
  • the C5 inhibitor is RA101495.
  • RA101495 also known as zilucoplan, is a macrocyclic peptide developed by Ra Pharmaceuticals.
  • the C5 inhibitor is SOBI002.
  • SOBI002 is an affibody developed by the Swedish Orphan Biovitrum.
  • the C5 inhibitor is ARC1005.
  • ARC1005 is an aptamer developed by Novo Nordisk.
  • the C5 inhibitor is SOMAmers for C5.
  • SOMAmers are aptamers developed by SomaLogic.
  • the C5 inhibitor is SSL7.
  • SSL7 is a bacterial protein toxin described in Laursen et al. Proc. Natl. Acad. Sci. U.S.A., 107(8):3681-6.
  • the C5 inhibitor is MEDI7814.
  • MEDI7814 is a monoclonal antibody developed by MedImmune.
  • the C5 inhibitor is aurin tricarboxylic acid.
  • the C5 inhibitor is an aurin tricarboxylic acid derivative. These aurin derivatives were developed by Aurin Biotech and are further described in U.S. Patent Appl. Pub. No.2013/003592).
  • the C5 inhibitor is RG6107/SKY59.
  • RG6107/SKY59 is an anti-C5 recycling antibody developed by Roche Pharmaceuticals.
  • the C5 inhibtior is ravulizumab (ULTOMIRIS ® ).
  • the C5 inhibitor is ALXN5500.
  • Ravulizumab and ALXN5500 are monoclonal antibodies developed by Alexion Pharmaceuticals.
  • the C5 inhibitor is TT30. TT30 is a fusion protein licensed by Alexion Pharmaceuticals.
  • the C5 inhibitor is ABP959.
  • ABP959 is an eculizamab biosimilar monoclonal antibody developed by Amgen.
  • the C5 inhibtor is Anti-C5 siRNA cemdisiran. Anti-C5 siRNA was developed by Alnylam Pharmaceuticals.
  • the C5 inhibitor is Erdigna ® .
  • Erdigna ® is an antibody developed by Adienne Pharma.
  • the C5 inhibitor is avacincaptad pegol/Zimura ® .
  • Avacincaptad pegol is in aptamer developed by Ophthotech.
  • the C5 inhibitor is SOBI005.
  • SOBI005 is a protein in developed by the Swedish Orphan Biovitrum.
  • the C5 inhibitor is ISU305.
  • ISU305 is a monoclonal antibody developed by ISU ABXIS.
  • the C5 inhibitor is REGN3918.
  • REGN3918 is a monoclonal antibody developed by Regeneron.
  • the C5 inhibitor is BCD-148.
  • BCD is an eculizumab biosimilar being developed by Biocad.
  • the C5 inhibitor is SB-12.
  • SB-12 is an eculizumab biosimilar being developed by Samsung Bioepis Co., Ltd.
  • C3 Inhibitor Combinations Provided herein are methods for treating a complement-mediated disorder in a subject comprising administering to the subject an effective amount of a C3 inhibitor in combination or alternation with an effective amount of an active compound described herein.
  • C3 inhibitors are known in the art.
  • a compound of the present disclosure is administered in combination or alternation with compstatin and/or a compstatin analog.
  • Compstatin and compastin analogs are known and are found to be useful inhibitors of C3, see U.S. Patent Nos.
  • the compstatin analog having the amino acid sequence ICVVQDWGHHCRT (SEQ. ID. NO.1).
  • the C3 inhibitor is a compstatin analog.
  • the compstatin analog is 4(1MeW)/APL-1 of the sequence Ac-ICV(1-mW)QDWGAHRCT(SEQ. ID. NO.2), wherein Ac is acetyl and 1-mW is 1-methyltryptophan.
  • the compstatin analog is Cp40/AMY-101, which has an amino acid sequence yICV(1mW)QDW-Sar-AHRC-mI (SEQ. ID. NO. 3), wherein y is D-tyrosine, 1mW is 1- methyltryptophan, Sar is sarcosine, and mI is N-methylisoleucine.
  • the compstatin analog is PEG-Cp40, having the amino acid sequence PEG-yICV(1mW)QDW-Sar-AHRC-mI (SEQ. ID. NO.4), wherein PEG is polyethyleneglycol (40 kDa), y is D-tyrosine, 1mW is 1-methyltryptophan, Sar is sarcosine, and mI is N-methylisoleucine.
  • the compstatin analog is 4(1MeW)POT-4. 4(1MeW)POT-4 was developed by Potentia.
  • the compstatin analog is AMY-201.
  • AMY-201 was developed by Amyndas Pharmaceuticals.
  • a compound of the present disclosure can be combined with C3 inhibitors that include, but are not limited to: H17 (monoclonal antibody, EluSys Therapeutics, Pine Brook, NJ); mirococept (CR1-based protein); sCR1 (CR1-based protein, Celldex, Hampton, NJ); TT32 (CR-1 based protein, Alexion Pharmaceuticals, Boston, MA); HC-1496 (recombinant peptide); CB 2782 (enzyme, Catalyst Biosciences, South San Francisco, CA); APL-2 (pegylated synthetic cyclic peptide, Apellis Pharmaceuticals, Crestwood, KY); or combinations thereof.
  • C3 inhibitors include, but are not limited to: H17 (monoclonal antibody, EluSys Therapeutics, Pine Brook, NJ); mirococept (CR1-based protein); sCR1 (CR1-based protein, Celldex, Hampton, NJ); TT32 (CR-1 based protein, Alexion Pharmaceuticals, Boston, MA);
  • the C3 inhibitor is H17.
  • H17 is a humanized monoclonal antibody in development by EluSys Therapeutics. H17 is described in Paixao-Cavalcante et al. J. Immunol. 2014, 192(10):4844-4851.
  • the C3 inhibitor is mirococept.
  • Mirococept is a CR1 -based protein developed by Inflazyme Pharmaceuticals.
  • the C3 inhibitor is sCR1.
  • sCR1 is a soluble form of the CR1 protein developed by Celldex.
  • the C3 inhibitor is TT32.
  • TT32 is a CR-1 based protein licensed by Alexion Pharmaceuticals.
  • the C3 inhibitor is HC-1496.
  • HC-1496 is a recombinant peptide developed by InCode.
  • the C3 inhibitor is CB 2782.
  • CB 2782 is novel protease derived from human membrane type serine protease 1 (MTSP-1) that was developed by Catalyst Biosciences.
  • the C3 inhibitor is APL-2.
  • APL-2 is a pegylated version of APL-1 developed by Apellis Pharmaceuticals.
  • CFB inhibitors are known in the art.
  • a compound of the present disclosure can be combined with CFB inhibitors that include, but are not limited to: anti-FB SiRNA (Alnylam Pharmaceuticals, Cambridge, MA); TA106 (monoclonal antibody, Alexion Pharmaceuticals, Boston, MA); LNP023 (small molecule, Novartis, Basel, Switzerland); SOMAmers (aptamers, SomaLogic, Boulder, CO); bikaciomab (Novelmed Therapeutics, Cleveland, OH); complin (see, Kadam et al., J. Immunol.
  • anti-FB SiRNA Alnylam Pharmaceuticals, Cambridge, MA
  • TA106 monoclonal antibody, Alexion Pharmaceuticals, Boston, MA
  • LNP023 small molecule, Novartis, Basel, Switzerland
  • SOMAmers aptamers, SomaLogic, Boulder, CO
  • bikaciomab Novelmed Therapeutics, Cleveland, OH
  • complin see, Kadam et al., J. Immunol.
  • CFB inhibitors that can be combined with a compound of the present disclosure include those disclosed in PCT/US17/39587.
  • CFB inhibitors that can be combined with a compound of the present disclosure as described herein include those disclosed in PCT/US17/014458.
  • CFB inhibitors that can be combined with a compound of the present disclosure as described herein include those disclosed in U.S. Patent Appl. Pub. No. 2016/0024079; . PCT Int. Appl. WO 2013/192345; PCT Int. Appl. WO 2013/164802; PCT Int. Appl. WO 2015/066241; PCT Int. Appl. WO 2015/009616 (assigned to Novartis AG).
  • the CFB inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the CFB inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the CFB inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the CFB inhibitor is anti-FB siRNA.
  • Anti-FB siRNA was developed by Alnylam Pharmaceuticals.
  • the CFB inhibitor is TA106.
  • TA106 is a monoclonal antibody developed by Alexion Pharmaceuticals.
  • the CFB inhibitor is LNP023.
  • LNP023 is a small molecule inhibitor of CFB developed by Novartis.
  • the CFB inhibitor is complin.
  • Complin is a peptide inhibitor that is described in Kadam et al. J. Immunol.2010184(12):7116-24.
  • the CFB inhibitor is IONIS-FB-LRx. IONIS-FB-LRx was developed by Ionis Pharmaceuticals.
  • CFD Complement Factor D
  • a fD inhibitor may be used as described by BioCryst Pharmaceuticals in U.S. Patent No. 6,653,340 title “Compounds useful in the complement, coagulate and kallikrein pathways and methods for their preparation” which described fused bicyclic ring compounds that are potent inhibitors of Factor D.
  • a fD inhibitor may be used as described by Novartis in PCT Patent Publication No. WO 2012/093101 titled “Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration”.
  • a fD inhibitor may be used as described in Novartis PCT Patent Publication Nos.
  • a fD inhibitor may be used as described by Bristol-Myers Squibb in PCT Patent Publication No. WO2004/045518 titled “Open chain prolyl urea-related modulators of androgen receptor function”.
  • a fD inhibitor may be used as described by Japan Tobacco Inc. in PCT Patent Publication No. WO1999/048492 title “Amide derivatives and nociceptin antagonists”.
  • a fD inhibitor may be used as described by Ferring B.V. and Yamanouchi Pharmaceutical Co. LTD. in PCT Patent Publication No. WO 1993/020099 titled “CCK and/or gastrin receptor ligands”.
  • the fD inhibitor is the monoclonal antibody FCFD4515S as developed by Genentech/Roche.
  • the fD inhibitor is Nafamostat (FUT-175, Futhan) as developed by Torri Pharmaceuticals.
  • the fD inhibitor is aptamers (SOMAmers) to Factor D as developed by SomaLogic.
  • the fD inhibitor is the monoclonal antibody lampalizumab as developed by Roche.
  • the fD inhibitor is aptamers to Factor D as developed by Vitrisa Therapeutics.
  • the fD inhibitor is a fD inhibitor as developed by Ra Pharmaceuticals.
  • the fD inhibitor comprises a drug disclosed in PCT/US17/014458.
  • a fD inhibitor may be used as described by Alexion Pharmaceuticals in PCT Patent Publication No.
  • the fD inhibitor for use in combination with the compound of the disclosure is selected among those described by Achillion Pharmaceuticals in WO2015/130784; WO2015/130795; WO2015/130806; WO2015/130830; WO2015/130838; WO2015/130842; WO2015/130845; WO2015/130854; WO2016/044243; WO2017/035348; WO2017/035349; WO2017/035351; WO2017/035352; WO2017/035353; WO2017/035355; WO2017/035357; WO2017/035360; WO2017/035361; WO2017/035362; WO2017/035401; WO2017/035405; WO2017/035408; WO2017/035409; WO2017/03
  • the fD inhibitor is a compound of Formula: or a pharmaceutically acceptable salt thereof.
  • Q is CH or N.
  • X F is selected from N and CH; each R 1F is independently selected from hydrogen, C 1 -C 3 alkyl (e.g., methyl), and halogen (e.g., bromo, chloro, or fluoro);
  • R 2F is selected from hydrogen and C 1 -C 3 alkyl (e.g., methyl);
  • R 3F is selected from C 1 -C 3 alkyl (e.g., methyl), C 1 -C 3 haloalkyl, and halogen (e.g., bromo, chloro, or fluoro);
  • R 4F is selected from hydrogen, C 1 -C 3 alkyl (e.g., methyl), and halogen (e.g., bromo, chloro, or fluoro);
  • R 5F is selected from hydrogen, C 1 -C 3 alkyl (e.g.
  • the fD inhibitor is selected from: and or a pharmaceutically acceptable salt thereof.
  • pan-inhibitor of complement components are known in the art.
  • the inhibitor is FUT-175.
  • a method for treating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial vaccine prior to administration of an active compound or its salt or composition for any of the disorders described herein.
  • a method is provided fortreating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial drug, such as a pharmaceutical drug, prior to administration of an active compound or its salt or composition for any of the disorders described herein.
  • a method is provided fortreating a host in need thereof that comprises administering an effective amount of an anti-bacterial vaccine after administration of an active compound or its salt or composition for any ofthe disorders described herein.
  • a method fortreating a host in need thereof comprises administering an effective amount of an anti-bacterial drug, such as a pharmaceutical drug, after administration of an active compound or its salt or composition for any ofthe disorders described herein.
  • an anti-bacterial drug such as a pharmaceutical drug
  • the disorder is PNH, C3G, or aHUS.
  • the host has received an organ or other tissue or biological fluid transplant.
  • the host is also administered a C5 inhibitor, for example, eculizumab.
  • an active compound or its salt or composition as described herein is administered to a host concomitantly to a subject following the prophylactic administration of a vaccine against a bacterial infection.
  • the complement- mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement mediated disorder is PNH, C3G, or aHUS.
  • the subject has received an organ or other tissue or biological fluid transplant.
  • the subject is also administered eculizumab.
  • an active compound or its salt or composition as described herein is administered to a subject concomitantly with the prophylactic administration of a vaccine against a bacterial infection.
  • the complement-mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement mediated disorder is PNH, C3G, or aHUS.
  • the subject has received an organ or other tissue or biological fluid transplant.
  • the subject is also administered eculizumab.
  • an active compound or its salt or composition as described herein is administered to a subject and, during the administration period of the compound or salt, a vaccine against a bacterial infection is administered to the subject.
  • the complement-mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemiareperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement mediated disorder is PNH, C3G, or aHUS.
  • the subject has received an organ or other tissue or biological fluid transplant.
  • the subject is also administered eculizumab.
  • the subject is administered an active compound or its salt or composition as described herein in combination with an antibiotic compound for the duration of active compound administration.
  • the complement-mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement mediated disorder is PNH, C3G, or aHUS.
  • the subject has received an organ or other tissue or biological fluid transplant.
  • the subject is also administered eculizumab.
  • an active compound or its salt or composition as described herein is administered to a subject following the prophylactic administration of a vaccine against a bacterial infection, and in combination with an antibiotic compound for the duration of active compound administration.
  • the complement-mediated disease or disorder is selected from the group consisting of autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, ocular disease, renal disease, transplant rejection, vascular disease, and vasculitis disease.
  • the complement mediated disorder is PNH or aHUS.
  • the subject has received an organ or other tissue or biological fluid transplant.
  • the subject is also administered eculizumab.
  • the subject prior to receiving an active compound or its salt or composition as described herein, is vaccinated against a bacterial infection caused by the bacterium Neisseria meningitidis.
  • the subject is vaccinated against a bacterial infection caused by the bacterium Haemophilus influenzae.
  • the Haemophilus influenzae is Haemophilus influenzae serotype B (Hib).
  • the subject is vaccinated against a bacterial infection caused by Streptococcus pneumoniae.
  • the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae.
  • the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae.
  • the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-negative bacterium.
  • the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-positive bacterium.
  • the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneunemoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, and one or more of, but not limited to, Bacillus anthracis, Bordetella pertussis, Clostridium tetani, Coryne bacterium diphtheria, Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibrio cholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichia chaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacterium leprae, Borrelia burgdorferi, Borrelia mayonii, Borreli
  • the subject is vaccinated with one or more vaccines selected from, but not limited to, typhoid vaccine, live (Vivotif Berna Vaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi), pneumococcal 23-polyvalent vaccine, PCV13 (Pneumovax 23, Merck), pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal 13-valent vaccine, PCV13 (Prevnar 13, Pfizer), haemophilus b conjugate (prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK), haemophilus b conjugate (hboc) vaccine (HibTITER, Neuron Biotech), haemophilus b conjugate (prp- omp) vaccine (PedvaxHIB, Merck), haemophilus b conjugate (prp-t) vaccine/men
  • a subject receiving a compound of the present disclosure to treat a disorder is prophylactically administered an antibiotic compound in addition to a compound described herein.
  • the subject is administered an antibiotic compound for the duration of administration of the active compound to reduce the development of a bacterial infection.
  • Antibiotic compounds for concomitant administration with a compound described herein can be any antibiotic useful in preventing or reducing the effect of a bacterial infection.
  • Antibiotics are well known in the art and include, but are not limited to, amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin (Netromycin), tobramycin (Nebcin), paromomycin (Humatin), streptomycin, spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan), loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax), imipenem/cilastatin (Primaxin), meropenem (Merrem), cefadroxil (Duricef), cefazolin (Ancef), cefalotin/cefalothin (
  • the subject is administered a prophylactic antibiotic selected from cephalosporin, for example, ceftriaxone or cefotaxime, ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol, fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin, vancomycin, clindamycin, cefazolin, azithromycin, meropenem, ceftaroline, tigecycline, clarithromycin, moxifloxacin, trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin, rifampin, minocycline, spiramycin, and cefixime, or a combination of two or more thereof.
  • cephalosporin for example, ceftriaxone or cefotaxime, ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol, fluoro
  • Step 3 methyl (4-(4-(methylthio)phenoxy)benzoyl)glycinate (F).
  • DIPEA 1.5 mL, 9.15 mmol
  • EDCI 700 mg, 3.66 mmol
  • HOBT 370 mg, 2.75 mmol
  • Step 5 (4-(4-(S-methylsulfonimidoyl)phenoxy)benzoyl)glycine (H).
  • MeOH MeOH
  • water 1 mL
  • LiOH ⁇ H 2 O 61 mg, 1.41 mmol
  • Step 8 (1S,3S,5S)-N-((4-carbamimidoylthiophen-2-yl)methyl)-5-methyl-2-((4-(4-(S- methyl-sulfonimidoyl)phenoxy)benzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 3).
  • Step 2 (1S,3S,5S)-N-((4-((Z)-N'-hydroxycarbamimidoyl)thiophen-2-yl)methyl)-5-methyl- 2-((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (C).
  • DIPEA 82 mg, 0.63 mmol
  • EDCI 44 mg, 0.23 mmol
  • HOBt 26 mg, 0.19 mmol
  • Step 3 (S)-5-oxo-1-((4-phenoxybenzoyl)glycyl)pyrrolidine-2-carboxylic acid (E). To a solution of compound D (110 mg, 0.23 mmol) in MeOH was added 10% Pd/C (20 mg) at room temperature under N2 atmosphere and the reaction mixture was stirred at room temperature under H 2 atmosphere for 2 hours.
  • Step 2 methyl (1S,3S,5S)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride (C).
  • Step 3 methyl (1S,3S,5S)-5-methyl-2-((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]- hexane-3-carboxylate (E).
  • DIPEA 252 mg, 1.95 mmol
  • EDCI 134 mg, 0.70 mmol
  • HOBt 79 mg, 0.59 mmol
  • Step 6 (1S,3S,5S)-N-((4-cyanothiophen-2-yl)methyl)-5-methyl-2-((4-phenoxybenzoyl)- glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (I).
  • DIPEA 187 mg, 1.45 mmol
  • EDCI 100 mg, 0.52 mmol
  • HOBt 59 mg, 0.44 mmol
  • Step 8 (1S,3S,5S)-N-((4-carbamoylthiophen-2-yl)methyl)-5-methyl-2-((4- phenoxybenzoyl)-glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 8).
  • Step 5 2-(tert-butyl) 3-ethyl (1S,3S,5R)-5-(((4-nitrobenzoyl)oxy)methyl)-2-azabicyclo- [3.1.0]hexane-2,3-dicarboxylate (H).
  • compound F 4.07 g, 14.26 mmol
  • THF 100 mL
  • compound G 3.44 g, 18.54 mmol
  • DMAP 5.23 g, 42.79 mmol
  • Step 8 methyl (1S,3S,5R)-5-(hydroxymethyl)-2-((4-phenoxybenzoyl)glycyl)-2- azabicyclo-[3.1.0]hexane-3-carboxylate (9).
  • K 2 CO 3 80 mg, 0.58 mmol
  • Step 9 methyl (1S,3S,5R)-2-((4-phenoxybenzoyl)glycyl)-5-(((tetrahydro-2H-pyran-2- yl)oxy)-methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (M).
  • DCM dimethyl methoxycarbonate
  • DHP 0.03 mL, 0.33 mmol
  • PPTS (19 mg, 0.08 mmol
  • Step 11 (1S,3S,5R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-2-((4-phenoxybenzoyl)- glycyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (12).
  • Step 12 (1S,3S,5R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-5-(hydroxymethyl)-2-((4- phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 9).
  • Step 3 3-(hydroxymethyl)-4-phenoxybenzoic acid (D).
  • D 3-(hydroxymethyl)-4-phenoxybenzoic acid
  • Step 4 benzyl (3-(hydroxymethyl)-4-phenoxybenzoyl)glycinate (F).
  • DIPEA 333 mg, 2.58 mmol
  • HOBt 75 mg, 0.56mmol
  • EDCI 115 mg, 0.60 mmol
  • Step 6 benzyl (1S,3S,5S)-5-methyl-2-((3-(((methylsulfonyl)oxy)methyl)-4-phenoxy- benzoyl)-glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (I).
  • DIPEA 17.0 mg, 1.35 mmol
  • T 3 P 343 mg, 0.54 mmol, 50% in EtOAc
  • Step 7 benzyl (1S,3S,5S)-5-methyl-2-((3-(((methylsulfonyl)oxy)methyl)-4-phenoxy- benzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (J).
  • TEA 86.8 mg, 0.86 mmol
  • MsCl 48.3 mg, 0.42 mmol
  • Step 8 benzyl (1S,3S,5S)-2-((3-(azidomethyl)-4-phenoxybenzoyl)glycyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylate (K).
  • Step 9 benzyl (1S,3S,5S)-2-((3-(aminomethyl)-4-phenoxybenzoyl)glycyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylate (L).
  • PPh3 145.4 mg, 0.555 mmol
  • Step 11 (1S,3S,5S)-2-((3-(acetamidomethyl)-4-phenoxybenzoyl)glycyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylic acid (N).
  • Pd/C 20 mg, 10% wt
  • Step 12 (1S,3S,5S)-2-((3-(acetamidomethyl)-4-phenoxybenzoyl)glycyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylic acid (Compound 10).
  • Step 2 (1S,3S,5S)-5-methyl-N-((4-((Z)-N'-nitrocarbamimidoyl)thiophen-2-yl)methyl)-2- ((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 11).
  • DIPEA 81.9 mg, 0.635 mmol
  • T 3 P 162 mg, 0.254 mmol, 50 % in EtOAc
  • Step 2 hexyl (Z)-(amino(5-(aminomethyl)thiophen-3-yl)methylene)carbamate (3).
  • a mixture of compound B (32 mg, 0.066 mmol) and HCl/1,4-dioxane (2 mL) was stirred at room temperature for 2 hours and the mixture was concentrated to dryness under reduced pressure to give compound C (18 mg, yield 95%) as a yellow solid, which was used directly in the next step without further purification.
  • Step 3 hexyl ((Z)-amino(5-(((1S,3S,5S)-5-methyl-2-((4-phenoxybenzoyl)glycyl)-2- azabicyclo-[3.1.0]hexane-3-carboxamido)methyl)thiophen-3-yl)methylene)carbamate (Compound 12).
  • DIPEA 0.06 mL, 0.318 mmol
  • T 3 P 121 mg, 0.191 mmol, 50% wt. in EtOAc
  • Step 2 (Z)-5-(aminomethyl)-N'-(methylsulfonyl)thiophene-3-carboximidamide (3).
  • a mixture of compound B (47 mg, 0.108 mmol) and HCl/1,4-dioxane (2 mL) was stirred at room temperature for 3 hours.
  • the reaction was concentrated to dryness under reduced pressure to give compound C (25 mg, yield 98.8%) as yellow solid, which was used directly in the next step without further purification.
  • Step 3 (1S,3S,5S)-5-methyl-N-((4-((Z)-N'-(methylsulfonyl)carbamimidoyl)thiophen-2-yl)- methyl)-2-((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 13).
  • DIPEA 0.10 mL, 0.536 mmol
  • T 3 P 205 mg, 0.321 mmol
  • Step 1 tert-butyl ((4-(N-cyanocarbamimidoyl)thiophen-2-yl)methyl)carbamate (B).
  • EtOH ethyl alcohol
  • sodium hydrogencyanamide 189 mg, 2.96 mmol
  • Step 2 5-(aminomethyl)-N-cyanothiophene-3-carboximidamide (C).
  • TFA 1-(aminomethyl)-N-cyanothiophene-3-carboximidamide
  • Step 3 (1S,3S,5S)-N-((4-(N-carbamoylcarbamimidoyl)thiophen-2-yl)methyl)-5-methyl-2- ((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 19).
  • DIPEA 62 mg, 0.48 mmol
  • T 3 P 153 mg, 0.24 mmol
  • Step 2 2-(tert-butyl) 3-methyl (1S,3S,5R)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane- 2,3-dicarboxylate (3).
  • AgOTf 71 mg, 0.27 mmol
  • CH 3 I 78 mg, 0.54 mmol
  • 2,6-di-tert-butylpyridine 0.12 mL, 0.54 mmol
  • Step 6 (1S,3S,5R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-5-(methoxymethyl)-2-((4- phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 20).
  • DIPEA 0.06 mL, 0.36 mmol
  • T 3 P 0.12 mg, 0.18 mmol
  • Step 2 (3S,6S)-N-((4-carbamimidoylthiophen-2-yl)methyl)-1,1-difluoro-5-azaspiro[2.4]- heptane-6-carboxamide (2).
  • a mixture of compound 2 (70 mg, 0.17 mmol) in HCl/1,4-dioxane (5 mL) was stirred at 0 °C and the mixture was stirred at room temperature for 2 hours.
  • Step 2 (E)-2-methyl-N-((4-(methylthio)thiophen-2-yl)methylene)propane-2-sulfinamide (C).
  • Step 5 (5-(aminomethyl)thiophen-3-yl)(imino)(methyl)-l6-sulfanone (F).
  • a mixture of compound E ( 0.4 g, 1.36 mmol) and HCl/1,4-dioxane (6 mL) was stirred at room temperature for 1 hour and the mixture was concentrated to dryness under reduced pressure to give compound F (0.21 g, 84.0 % yield) as a white solid, which was used directly in the next step.
  • Step 6 (1S,3S,5S)-5-methyl-N-((4-(S-methylsulfonimidoyl)thiophen-2-yl)methyl)-2-((4- phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 23).
  • DIPEA 50.0 mg, 0.375 mmol
  • T 3 P 145 mg, 0.225 mmol
  • Step 2 tert-butyl (S)-2-(((4-carbamimidoylthiophen-2-yl)methyl)carbamoyl)-4-(difluoro- methylene)pyrrolidine-1-carboxylate (D).
  • DIPEA 0.37 mL, 2.14 mmol
  • T 3 P 682 mg, 1.07 mmol
  • Step 2 (2S,4R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-4-methoxypyrrolidine-2- carboxamide hydrochloride (D).
  • D (2S,4R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-4-methoxypyrrolidine-2- carboxamide hydrochloride
  • Step 2 1-benzyl 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (C).
  • compound B (294 mg, 2.06 mmol) and NaHCO 3 (344.4 mg, 4.12 mmol) in THF (5 mL) and H 2 O (5 mL) was added benzyl chloroformate (455 mg, 2.68 mmol) dropwise at 0 °C under N 2 atmosphere. The reaction was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc twice.
  • Step 5 methyl (4-phenoxybutanoyl)glycinate (G).
  • DIPEA 43.0 g, 333.2 mmol
  • methyl glycinate hydrochloride 15.7 g, 124.9 mmol
  • HOBt 15.7 g, 116.6 mmol
  • EDCI 20.7 g, 108.3 mmol
  • Step 9 (S)-N-((4-carbamimidoylthiophen-2-yl)methyl)-7-((4-phenoxybutanoyl)glycyl)- 1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide (Compound 28).
  • DIPEA 49.5 mg, 0.384 mmol
  • T 3 P 163 mg, 0.256 mmol, 50% in EtOAc
  • Step 2 methyl (2S,4R)-4-(difluoromethoxy)pyrrolidine-2-carboxylate (C).
  • a mixture of compound B (60 mg, 0.20 mmol) and HCl/1,4-dioxane (5 mL) was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated to dryness under reduced pressure to give compound C (35 mg, 87.5% yield) as a yellow oil, which was used directly in the next step.
  • Step 3 methyl (2S,4R)-4-(difluoromethoxy)-1-((4-phenoxybutanoyl)glycyl)pyrrolidine-2- carboxylate (E).
  • DIPEA 0.18 mL, 1.08 mmol
  • T 3 P 17.1 mg, 0.54 mmol
  • Step 5 (2S,4R)-N-((4-carbamimidoylthiophen-2-yl)methyl)-4-(difluoromethoxy)-1-((4- phenoxybutanoyl)glycyl)pyrrolidine-2-carboxamide (Compound 29).
  • DIPEA 0.07 mL, 0.45 mmol
  • T 3 P 143 mg, 0.23 mmol
  • Step 2 methyl (E)-5-(((tert-butoxycarbonyl)amino)methyl)-N-cyanothiophene-3- carbimidate (C).
  • t-BuONa 84 mg, 0.88 mmol
  • NBS 156 mg, 0.88 mmol
  • Step 4 methyl (E)-N-cyano-5-(((1S,3S,5S)-5-methyl-2-((4-phenoxybenzoyl)glycyl)-2- azabicyclo[3.1.0]hexane-3-carboxamido)methyl)thiophene-3-carbimidate (Compound 31).
  • DIPEA 0.09 mL, 0.49 mmol
  • T 3 P 156 mg, 0.25 mmol
  • Step 3 benzyl 7-((4-phenoxybenzoyl)glycyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (E).
  • DIPEA 0.64 mL, 3.9 mmol
  • T 3 P 1.2 g, 1.95 mmol
  • Step 3 (1S,3S,5S)-5-methyl-N-((4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)thiophen-2- yl)methyl)-2-((4-phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 34).
  • Step 2 methyl (2S,4S)-4-(difluoromethoxy)pyrrolidine-2-carboxylate (C).
  • a mixture of compound B (150 mg, 0.51 mmol) and HCl/1,4-dioxane (3 mL) was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated to dryness under reduced pressure to give compound C (95 mg, 96.0% yield) as a yellow oil, which was used directly in the next step.
  • Step 3 methyl (2S,4S)-4-(difluoromethoxy)-1-((4-phenoxybenzoyl)glycyl)pyrrolidine-2- carboxylate (E).
  • DIPEA 253 mg, 1.96 mmol
  • T 3 P 623 mg, 0.98 mmol, 50% in EtOAc
  • Step 5 (2S,4S)-N-((4-carbamimidoylthiophen-2-yl)methyl)-4-(difluoromethoxy)-1-((4- phenoxybenzoyl)glycyl)pyrrolidine-2-carboxamide (Compound 36).
  • DIPEA 59 mg, 0.46 mmol
  • T 3 P 146 mg, 0.23 mmol, 50% in EtOAc
  • Step 3 tert-butyl N-[(4-cyanothiophen-2-yl)methyl]-N-methylcarbamate (D).
  • TEA 1.4 g, 14.0 mmol
  • DMAP 171 mg, 1.4 mmol
  • Boc 2 O 1.5 g, 7.0 mmol
  • Step 5 tert-butyl N-[(4-carbamimidoylthiophen-2-yl)methyl]-N-methylcarbamate (F).
  • compound E 825 mg, 2.9 mmol
  • Raney Ni under H 2 atmosphere.
  • the mixture was heated to 30 oC and stirred for 3 hours.
  • the resulting mixture was filtered and concentrated under reduced pressure to give the crude product, which was further purified by column chromatography (silica gel: 10-25% methanol in dichloromethane) to afford the compound F (610 mg, 78 % yield) as a yellow solid.
  • Step 6 5-[(methylamino)methyl]thiophene-3-carboximidamide (G).
  • compound F 305 mg, 1.1 mmol
  • HCl/1,4-dioxane 5mL
  • the resulting mixture was concentrated under reduced pressure to afford the compound G (180 mg, 1.064 mmol, 94 % yield) as a white solid which was used in next step without further purification.
  • Step 7 (1S,3S,5S)-N-[(4-carbamimidoylthiophen-2-yl)methyl]-N,5-dimethyl-2- ⁇ 2-[(4- phenoxyphenyl)formamido]acetyl ⁇ -2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 35).
  • Step 5 tert-butyl N-(tert-butoxycarbonyl)-N-[(5-carbamimidoylthiophen-2-yl)methyl] carbamate (F).
  • methanol 3 mL
  • Raney-nickel 1 mL
  • acetic acid 0.5 mL
  • the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give compound 6 (160 mg, 83.6% yield) as white solid.
  • Step 3 (1S,3S,5S)-N-((4-(N-acetoxycarbamimidoyl)thiophen-2-yl)methyl)-5-methyl-2-((4- phenoxybenzoyl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Compound 39).
  • DIPEA 0.19 mL
  • T 3 P 358 mg, 0.56 mmol
  • Step 8 N- ⁇ 2-[(2S)-2- ⁇ [(4-carbamimidoylthiophen-2-yl)carbamoyl]methyl ⁇ pyrrolidin-1-yl]- 2-oxoethyl ⁇ -4-phenoxybenzamide (Compound 40).
  • DIPEA 107 mg, 0.832 mmol
  • T 3 P 264 mg, 0.416 mmol
  • Step 5 Synthesis of ethyl 1-(4-bromothiophen-2-yl)cyclopropane-1-carboxylate (F). To a solution of compound E (2.4 g, 10.52 mmol) in ethanol (25 mL) was added conc. H 2 SO 4 at 0°C under N2 atmosphere. The mixture was stirred at 90 °C for 16 hours.
  • Step 8 Synthesis of tert-butyl (1-(4-cyanothiophen-2-yl)cyclopropyl)carbamate (I). To a solution of compound G (200 mg, 1.04 mmol) and TEA (314 mg, 3.11 mmol) in t-BuOH (2 mL) was added DPPA (428 mg, 1.55 mmol) at room temperature under N2 atmosphere and the mixture was stirred at 90 oC overnight.

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