WO2017035418A1 - Composés disubstitués pour le traitement de troubles immunitaires et inflammatoires - Google Patents

Composés disubstitués pour le traitement de troubles immunitaires et inflammatoires Download PDF

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Publication number
WO2017035418A1
WO2017035418A1 PCT/US2016/048800 US2016048800W WO2017035418A1 WO 2017035418 A1 WO2017035418 A1 WO 2017035418A1 US 2016048800 W US2016048800 W US 2016048800W WO 2017035418 A1 WO2017035418 A1 WO 2017035418A1
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alkyl
disorder
compound
host
heteroaryl
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PCT/US2016/048800
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English (en)
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Jason Allan Wiles
Avinash S. Phadke
Milind Deshpande
Atul Agarwal
Dawei Chen
Venkat Rao GADHACHANDA
Akihiro Hashimoto
Godwin Pais
Qiuping Wang
Xiangzhu Wang
William Greenlee
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Achillion Pharmaceuticals, Inc.
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Publication of WO2017035418A1 publication Critical patent/WO2017035418A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • An immune disorder occurs when the immune system is not performing in a normal manner. Inflammation is a protective response that involves immune cells, the immune system generally, blood vessels, and molecular mediators. A wide variety of medical disorders are caused by detrimental immune or inflammatory responses, or the inability of a cell to respond to a normal immune or inflammatory process.
  • 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. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens together).
  • Complement Factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within C3 to produce C3(H 2 0), which associates with Factor B to form the C3(H 2 0)B complex. Complement Factor D acts to cleave Factor B within the C3(H 2 0)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H 2 0) to form the alternative pathway C3 convertase C3(H 2 0)Bb.
  • C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb.
  • This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b.
  • C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell.
  • complement pathway The dysfunction of or excessive activation of complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.
  • activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway.
  • disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (P H), multiple sclerosis, and rheumatoid arthritis.
  • AMD age-related macular degeneration
  • P H paroxysmal nocturnal hemoglobinuria
  • multiple sclerosis multiple sclerosis
  • rheumatoid arthritis Some examples include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (P H), multiple sclerosis, and
  • ASD Age-related macular degeneration
  • Paroxysmal nocturnal hemoglobinuria is a non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins. PNH erythrocytes are not capable of modulating their surface complement activation, which leads to the typical hallmark of PNH - the chronic activation of complement mediated intravascular anemia.
  • the anti- C5 monoclonal antibody eculizumab has been approved in the U.S. for treatment of PNH.
  • many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions.
  • treatment with eculizumab requires life-long intravenous injections. Thus, there is an unmet need to develop novel inhibitors of the complement pathway.
  • aHUS hemolytic uremic syndrome
  • HUS hemolytic uremic syndrome
  • MG myasthenia gravis
  • fatty liver nonalcoholic steatohepatitis
  • NASH nonalcoholic steatohepatitis
  • Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of Factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex.
  • Novartis PCT patent publication WO2012/093101 titled "Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration" describes certain Factor D inhibitors. Additional Factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150, and WO2014/009833.
  • Japan Tobacco Inc. PCT patent publication WO 1999/048492 titled “Amide derivatives and nociceptin antagonists” describes compounds with a proline-like core and aromatic substituents connected to the proline core through amide linkages useful for the treatment of pain.
  • Ferring B.V. and Yamanouchi Pharmaceutical Co. 1TD. PCT patent publication WO 1993/020099 titled “CCK and/or gastrin receptor ligands” describes compounds with a proline-like core and heterocyclic substituents connected to the proline core through amide linkages for the treatment of, for example, gastric disorders or pain.
  • Alexion Pharmaceuticals PCT patent publication WO 1995/029697 titled "Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases” discloses antibodies directed to C5 of the complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathologic activation of the complement system.
  • Alexion Pharmaceutical's anti-C5 antibody eculizumab Soliris® is currently the only complement-specific antibody on the market, and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).
  • new uses and compounds are needed for medical treatment.
  • new uses and compounds are needed to mediate the complement pathway, and for example, which act as Factor D inhibitors for treatment of disorders in a host, including a human, associated with misregulation of the complement cascade, or with undesired result of the complement cascade performing its normal function.
  • This invention includes an active compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R 12 and R 13 on the A group are each independently an R 69 moiety, wherein R 69 is R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , or R 87 ; and wherein R 12 and R 13 are not both from the same R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , or R 87 moiety, for use to treat any of the disorders described herein.
  • R 13 must be selected from R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , or R 87 .
  • R 69 can be optionally substituted.
  • R 69 can independently be an R 88 .
  • R 80 is an alkyne.
  • R 81 is an amide.
  • R 82 is an amine.
  • R 83 is a carbamate, ester or ketone.
  • R 84 is a direct linked aryl, heterocyclic or heteroaryl.
  • R 83 is an ether (typically bound through the oxygen).
  • R 86 is a phosphonate (typically bound through the phosphorus).
  • R 87 is an alkyl derivative.
  • R 88 is a sulfoximine. Any of these can be optionally substituted, and wherein the moieties are as described herein.
  • one of R 69 is R 80 and the other R 69 is R 81 .
  • one of R 69 is R 80 and the other R 69 is R 81 .
  • one of R 69 is R 80 and the other R 69 is R 82 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 83 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 84 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 87 .
  • one of R 69 is R 81 and the other R 69 is R 82 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 82 . In one
  • one of R 69 is R 81 and the other R 69 is R 83 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 84 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 87 .
  • one of R 69 is R 82 and the other R 69 is R 83 .
  • one of R 69 is R 82 and the other R 69 is R 83 .
  • one of R 69 is R 82 and the other R 69 is R 84 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 87 . [0006] In one embodiment, one of R is R and the other R is R In one embodiment, one of R 69 is R 83 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 83 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 83 and the other R 69 is R 87 .
  • one of R 69 is R 84 and the other R 69 is R 85 .
  • one of R 69 is R 84 and the other R 69 is R 85 .
  • one of R 69 is R 84 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 84 and the other R 69 is R 87 .
  • one of R 69 is R 85 and the other R 69 is R 86 .
  • one of R 69 is R 85 and the other R 69 is R 87 .
  • one of R 69 is R 86 and the other R 69 is R 87 .
  • 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), 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 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 host in need thereof typically a human.
  • the active compound may act as an inhibitor of the complement factor D cascade.
  • a method for the treatment of such a disorder includes the administration of an effective amount of a compound of Formula I, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.
  • the disorder is associated with the alternative complement cascade pathway.
  • the disorder is associated with the complement classical 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, or in particular as a complement factor D inhibitor, to treat the disorder described herein.
  • a method for the treatment of paroxysmal nocturnal hemoglobinuria includes the administration of an effective amount of a compound to a host of Formula I, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • 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, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • AMD wet or dry 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, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of multiple sclerosis in a host includes the administration of an effective amount of a compound of Formula I, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • an active compound or its salt or prodrug as described herein can be used to treat fatty liver and conditions stemming from fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, and liver failure, dermatomyocitis, or amyotrophic lateral sclerosis.
  • NASH nonalcoholic steatohepatitis
  • the active compound or its pharmaceutically acceptable salt, prodrug or a pharmaceutical composition thereof as disclosed herein is also useful for administration in combination 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.
  • 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 CD 19.
  • the associated inflammatory response is a cytokine mediated response.
  • Another embodiment includes the administration of an effective amount of an active compound or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier to a host to treat an ocular, pulmonary, gastrointestinal, or other disorder that can benefit from topical or local delivery.
  • 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, conjunctival, subconjunctival, episcleral, posterior juxtascleralscleral, circumcorneal, and tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion.
  • an active compound provided herein can be used to treat or prevent a disorder in a host mediated by complement factor D, or by an excessive or detrimental amount of the complement-C3 amplification loop of the complement pathway.
  • the invention 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 invention also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by factor D.
  • FIG. 1 provides non-limiting specific embodiments of the Central Core ring, wherein R, R', and R 3 are defined below.
  • FIGS. 2 A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 21, 2 J, 2K, 2L, and 2M provide non-limiting embodiments of CI '; wherein R 3 is as defined herein.
  • FIG. 3 provides non-limiting embodiments of C2.
  • FIGS. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 41, 4J, 4K, 4L, 4M, and 4N provide non- limiting embodiments of C3.
  • FIG. 5 provides non-limiting embodiments of central core small mimetics of a beta- turn, beta turn inducers, reverse turn mimetics and foldamer monomers
  • FIG. 6 provides non-limiting embodiments of ⁇ , wherein R 32 is defined below.
  • FIGS. 7A, 7B and 7C provide non-limiting embodiments of A2, wherein R 32 is defined below.
  • FIG. 8A, 8B, 8C, and 8D provide non-limiting embodiments of LI '.
  • FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H, 91, and 9J provide non-limiting embodiments of L2.
  • FIG. 10A, 10B, IOC, and 10D provide non-limiting specific embodiments of B l rings, wherein R 27 , R 28 , and R 29 are defined below.
  • FIG. 11A, 1 IB, 11C, 1 ID provide non-limiting specific embodiments of ⁇ rings, wherein halo is selected from F, CI, Br, or I.
  • FIG. 12 provides specific embodiments of B2 rings.
  • FIGS. 13 A, 13B, 13C, 13D, 13E, 13F, 13G, 13H, 131, 13 J, 13K, 13L, 13M, 13N, 130, 13P, 13Q, 13R, 13S, 13T, 13U, 13V, 13W, 13X, 13Y, and 13Z, provide specific embodiments of B3 moeities.
  • FIG. 14 provides non-limiting embodiments of L2-B3 wherein B3 is R 21 , and R 21 is defined below.
  • FIGS. 15A, 15B, and 15C provide non-limiting embodiments of R 80 .
  • FIGS. 16 provides non-limiting embodiments of R 81 .
  • FIGS. 17A and 17B provide non-limiting embodiments of R 82 .
  • FIGS. 18 provides non-limiting embodiments of R 72 .
  • FIGS. 19 provides non-limiting embodiments of R 83 .
  • FIGS. 20A and 20B provide non-limiting embodiments of R 84 .
  • FIGS. 21A and 21B provide non-limiting embodiments of R 85 .
  • FIGS. 22A and 22B provide non-limiting embodiments of R 86 .
  • FIGS. 23 A and 24B provide non-limiting embodiments of R 87 .
  • FIGS. 24A, 24B, 24C, 24D, 24E, 24F, 24G 24H, 241, 24J, 24K, 24L, 24M, 24N, 24N, 240, 24P, 24Q, 24R, 24S, 24T, 24U, 24V, 24W, 24X, 24Y, 24Z, and 24AA provide non- limiting examples of compounds of the present invention.
  • A is selected from Al, Al ' and A2.
  • B is selected from B l, B l ', B2, B3, and B4.
  • C is selected from CI, C I ', C2, C3, and C4.
  • L is selected from LI , LI ', L2, and L2' .
  • L3 is selected from L4 and L5.
  • At least one of A, B, C, L, or L3 is selected from A2, B3, C3, L2, L2', or L5.
  • At least one of A, B, C, L, or L3 is selected from A2, B3, C4, L2, L2', or L5 [0051] If C is CI, CI ' or C2, then Formula I includes at least one of A2, B3, L2, L2' or
  • Formula I can be any of A, B, L or L3.
  • Q 1 is NCR 1 ) or C ⁇ 'R 1' ).
  • Q 2 is C(R 2 R 2' ), C(R 2 R 2' )-C(R 2 R 2' ), S, O, N(R 2 ) or C(R 2 R 2' )0.
  • Q 3 is N(R 3 ), S, or C(R 3 R 3' ).
  • Q 1 , Q 2 , Q 3 , X 1 , and X 2 are selected such that a stable compound results.
  • Z is F, CI, NH 2 , CH 3 , CH 2 D, CHD 2 , or CD 3 .
  • R 1 , R 1 , R 2 , R 2 , R 3 , and R 3 are independently selected at each occurrence, as appropriate, and only where a stable compound results, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci-C6alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, C 2 -C 6 alkynyl, C 2 - Cealkanoyl, Ci-Cethioalkyl, hydroxyCi-Cealkyl, aminoCi-Cealkyl, -Co-C 4 alkylNR 9 R 10 , -C(0)OR 9 , -OC(0)R 9 , -NR 9 C(0)R 10 , -C(0)NR 9 R 10 , -OC(0)NR 9 R 10 , -NR 9 C(0)OR 10 , Ci- C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 9 and R 10 are independently selected at each occurrence from hydrogen, Ci- Cealkyl, (C 3 -C7cycloalkyl)Co-C4alkyl, -Co-C4alkyl(C 3 -C7cycloalkyl), and -0-Co-C 4 alkyl(C 3 - C7cycloalkyl).
  • R 1 and R 1 or R 3 and R 3 may be taken together to form a 3 - to 6-membered carbocyclic spiro ring or a 3 - to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;
  • R 2 and R 2 may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or
  • R 2 and R 2 may be taken together to form a 3- to 6-membered heterocyclic spiro ring; each of which spiro ring each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C4alkyl (including in particular methyl), C 2 - C 4 alkenyl, C2-C 4 alkynyl, Ci-C 4 alkoxy, C 2 -C 4 alkanoyl
  • R 1 and R 2 may be taken together to form a 3-membered carbocyclic ring;
  • R 1 and R 2 may be taken together to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or
  • R 2 and R 3 if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring; each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, - COOH, Ci-C 4 alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, C2- C
  • R 1 and R 1 , R 2 and R 2 , or R 3 and R 3 can be taken together to form a carbonyl group. In alternative embodiments, R 1 and R 2 or R 2 and R 3 can be taken together to form a carbon-carbon double bond.
  • Any of the structures illustrated herein, e.g., Al, Al ', A2, Bl, Bl ', B2, B3, B4, CI, CI ', C2, C3, C4, LI, LI ', L2, L2', L4 or L5 can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, of an R 48 substituent.
  • Non-limiting examples of CI include the structures of Figure 1.
  • R and R' are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl wherein each group can be optionally substituted or any other substituent group herein that provides the desired properties.
  • the ring includes one or more chiral carbon atoms.
  • the invention includes embodiments in which the chiral carbon can be provided as an enantiomer, or mixtures of enantiomers, including a racemic mixture. Where the ring includes more than one stereocenter, all of the enantiomers and diastereomers are included in the invention as individual species.
  • CI is CI ' .
  • Non-limiting examples of CI ' include the structures of Figure 2.
  • a methyl group in a structure illustrated above can be replaced with an alkyl.
  • the fluoro groups in the structures illustrated above can be replaced with any halogen.
  • any of the structures illustrated above or below can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, of an R 48 substituent.
  • C2 is selected from:
  • R 44 , R 44 , R 45 , R 45 are independently hydrogen, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; wherein each group can be optionally substituted.
  • R 44 and R 44 , R 45 and R 45 or two R 47 groups can be taken together to form a carbonyl group.
  • R 44 and R 44' or R 45 and R 45 or R 46 and R 46' can be taken together to form an optionally substituted 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S.
  • R 44 and R 45 or R 44 and R 45 can be taken together to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclic or heteroaryl ring; each of which ring may be unsubstituted or substituted with 1 or more substituents.
  • Non-limiting examples of C2 include the structures of Figure 3.
  • C3 is selected from:
  • X 3 is C ⁇ R 1' ).
  • X 4 is N or CH.
  • X 4a isN, CH orCZ.
  • X 5 and X 6 are C ⁇ R 1' )
  • X 8 is C ⁇ R 1' ) or N(R 43 ).
  • Q 4 is N or CH.
  • Q 5 is N(R 47 ) or C(R 46 R 46' ).
  • Q 5a is C(R 47 R 47 ), N(R 47 ), O, S, SO, or S0 2 .
  • Q 6 is N(R 47 ), C(R 46 R 46' ), S, or O.
  • Q 7 is C(R 46 R 46' ), S or N(R 47 ).
  • Q 8 , Q 9 , Q 10 , Q 11 and Q 12 are each independently C(R 2 R 2' ), S, SO, SO2, O, N(R 2 ), B(R 50 ), Si(R 49 ) 2 , however if X 1 is N and X 2 is CH then L and B taken together cannot be anisole substituted in the 4 position.
  • no more than one heteroatom is in a three or four membered C3 and no more than one, two or three heteroatoms can be in a five, six or seven membered C3. It is in general known by those of skill in the art which combinations of several heteroatoms will not form a stable ring system. For example, those of skill in the art would understand that the C3 ring system would not normally contain an -O-O-, -0-S-, -Si-Si-, -B-B-, -B-Si-, bond.
  • R 40 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted.
  • R 42 is halo, hydroxy, Ci-Cealkoxy, Ci-Cehaloalkoxy, -SH, or -S(Ci-C 6 alkyl).
  • R 43 is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl wherein each group can be optionally substituted.
  • R 46 and R 46 are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted and at least one of R 46 or R 46 is not hydrogen.
  • R 47 is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted.
  • R 49 is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl wherein each group can be optionally substituted or two R 49 groups can be taken together to form a double bond that can be optionally substituted.
  • R 50 is hydroxy or Ci-Cealkyoxy.
  • the bridged heterocyclic C3 compounds can be optionally substituted.
  • X 1 and Q 8 or Q 8 and Q 9 or Q 9 and Q 10 or Q 10 and Q 11 or Q 11 and Q 12 or Q 12 and X 2 can form a carbon-carbon double bond.
  • two Q 5a groups or a X 4a and a Q 5a group can form a carbon- carbon double bond.
  • All variables including but not limited to X 1 , X 2 , X 3 , X 4 , X 5 , X 5a , X 6 , X 7 , X 8 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , Q 8 , Q 9 , Q 10 , Q 11 , Q 12 , R 1 , R 40 , R 42 , R 43 , R 44 , R 44' , R 45 , and R 45 are independently selected at each occurrence, as appropriate, and only where a stable compound results.
  • C3 when C3 is a 7-membered ring and comprises silicon or boron, the ring will only comprise one Si(R 49 ) 2 or B(R 50 ) moiety.
  • 3, 4, 5, 6 and 7-membered rings will not comprise -O-O- or -O-S- bonds.
  • Non-limiting examples of C3 include the structures of Figure 4.
  • the methyl groups in the structures illustrated above can be replaced with an alkyl.
  • the fluoro groups in the structures illustrated above can be replaced with halo.
  • halo can be chloro.
  • any of the structures illustrated above or below can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, of an R 48 substituent.
  • the central core moiety, C3 can comprise a small mimetic of a beta-turn such as a benzodiazepine, a Friedinger lactam, a 2-oxo-l,3-oxazolidine-4- caroxylate or a ⁇ -D-glucose scaffold.
  • a beta-turn such as a benzodiazepine, a Friedinger lactam, a 2-oxo-l,3-oxazolidine-4- caroxylate or a ⁇ -D-glucose scaffold.
  • the central core moiety, C can comprise a reverse turn mimetic that can include, but is not limited to; a non-peptidic residue, a metal chelation based mimic, or a foldamer. See, Nair, R.V. et al., "Synthetic turn mimetics and hairpin nucleators: Quo Vadimus?”, Chem. Comm., 2014, 50, 13874-13884.
  • the central core moiety, C can comprise a conformationally constrained cyclic amino acid including but not limited to a (S)- or (R)-a-trifluoromethyl pyroglutamic acid derivative.
  • a conformationally constrained cyclic amino acid including but not limited to a (S)- or (R)-a-trifluoromethyl pyroglutamic acid derivative. See, Chaume, G. et al., "Concise access to enantiopure (S)- or (R)-a-trifluoromethyl pyroglutamic acids from ethyl trifluoropymvate-base chiral CF3-oxazolidines (Fox)", J. Fluor. Chem., 2008, 129, 1104-1109 and Andre, C.
  • the central core moiety, C can comprise a monomelic unit of a foldamer such as, but not limited to an oxazolidin-2-one. See, Tomasii, C, Angelicim G. and Castellucci, N., “Foldamers Based on Oxazolidin-2-ones", Eur. J. Org. Chem., 2011, 3648-3669.
  • Examples of central core small mimetics of a beta-turn, beta turn inducers, reverse turn mimetics and foldamer monomers include, but are not limited to the structures of Figure 5.
  • Al is selected from:
  • Al examples include:
  • Al is ⁇ .
  • Non-limiting examples of ⁇ include the stmctures of Fig [01 12] A2 is selected from:
  • Non-limiting examples of A2 include the structures of Figure 7.
  • R 4 , R 5 , and R 6 are selected from hydrogen, -JCHO, -JC(0)NH 2 , -JC 2 -Cealkanoyl, - JC(0)NH(CH 3 ), -J-COOH, -JP(0)(OR 9 ) 2 , -JOC(0)R 9 , -JC(0)OR 9 , -JC(0)N(CH 2 CH 2 R 9 )(R 10 ), -JNR 9 C(0)R 10 , -JS0 2 NH 2 , -JS(0)NH 2 , -JC(CH 2 ) 2 F, -JCH(CF 3 )NH 2 , -JC(0)Co-C 2 alkyl(C 3 - Cvcycloalkyl), -JNR 9 (C 2 -C 6 alkanoyl), -JNR 9 C(0)NR 9 R 10 , -JS0 2 (Ci-C 6 alkyl), -JS0 2 (Ci- Cehaloalkyl), -
  • R 4 , R 5 and R 6 other than hydrogen, nitro, halogen, cyano, cyanoimino, or -CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C2alkyl, Ci-C2alkoxy, -Co-C2alkyl(mono- and di-Ci-C4alkylamino), Ci- C2haloalkyl, and Ci-C2haloalkoxy.
  • R 4' is selected from -JCHO, -JCO H2, JC 2 -C 6 alkanoyl, -JSO2 H2, -JC(CH 2 ) 2 F, -JCH(CF 3 ) H 2 , Ci-Cealkyl, -Co-C4alkyl(C 3 -C7cycloalkyl), -JC(0)Co-C 2 alkyl(C 3 - C 7 cycloalkyl), JNR 9 (C2-C 6 alkanoyl), J R 9 C(0)NR 9 R 10 ,
  • each of which R 4 other than -CHO, is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C2alkyl, Ci-C2alkoxy, -Co-C2alkyl(mono- and di-Ci-C4alkylamino), Ci-C2haloalkyl, and Ci-C2haloalkoxy.
  • R 6 is hydrogen, halogen, hydroxyl, Ci-C4alkyl, -Co-C4alkyl(C 3 -C7cycloalkyl), or Ci-C4alkoxy; or R 6 and R 6 may be taken together to form an oxo, vinyl, or imino group.
  • R 7 is hydrogen, Ci-Cealkyl, or -Co-C 4 alkyl(C 3 -C7cycloalkyl).
  • R 8 and R 8 are independently selected from hydrogen, halogen, hydroxyl, Ci- C 6 alkyl, -Co-C4alkyl(C 3 -C7cycloalkyl), Ci-C 6 alkoxy, and (Ci-C4alkylamino)Co-C2alkyl; or R 8 and R 8 are taken together to form an oxo group; or R 8 and R 8 can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring.
  • R 16 is absent or may include one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, -Co- C4alkyl(mono- and di-Ci-C6alkylamino), -Co-C4alkyl(C 3 -C7cycloalkyl), Ci-C2haloalkyl, and Ci- C2haloalkoxy.
  • R is hydrogen, Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -Cealkanoyl, -SChCi-Cealkyl, (mono- and di-Ci-C6alkylamino)Ci-C4alkyl, -Co-C4alkyl(C3-C7cycloalkyl), -Co-C4alkyl(C3- C7heterocycloalkyl), -Co-C4alkyl(aryl), Co-C4alkyl(heteroaryl), and wherein R 19 other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-C4alkyl.
  • X u is N or CR u .
  • X 12 is N or CR 12 .
  • X 13 is N or CR 13 .
  • X 14 is N or CR 14 .
  • R 12 and R 13 on the A group are independently selected from an R 69 moiety, wherein R 69 is R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 ; and wherein R 12 and R 13 are not both from the same R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 or R 87 moiety.
  • R 12 moiety is R 80
  • R 82 , R 83 , R 84 , R 85 , R 86 or R 87 For clarity, for example, if an R 12 moiety is R 80 , then R 13 must be selected from R 81 , R 82 , R 83 , R 84 , R 85 , R 86 or R 87 .
  • R is -C 2 -C 6 alkynylR , and each R can be optionally substituted.
  • 8 0 include, for example, but are not limited to,
  • R 81 is C(0)NR 21 R 71 , -C(0)NR 24 R 25 , -C(0)NR 9 R 71 , -C(0)NR 21 S0 2 R 22 , - NR 9 C(0)OR 10 , -NR 9 C(0)OR 23 , -NR 9 C(0)R 21 , -NR 9 C(0)NR 9 R 10 , -NR 9 C(O)NR 10 R 23 , - NR 9 C(0)NR 24 R 25 .
  • R 82 is NR 72 R 73 , NR 9 S0 2 R 73 , N(S0 2 R 9 )CH 2 C(0)R 74 .
  • R 83 is -OC(0)(CH 2 )i -4 R 21 , -OC(0)NR 21 R 22 , -OC(0)NR 24 R 25 , -OC(0)(Ci- 6 alkyl or C3-6cycloalkyl)(aryl), -OC(0)(Ci- 6 alkyl or C3-6cycloalkyl)(heteroaryl), -OC(0)(Ci- 6 alkyl or C 3 - 6cycloalkyl)(heterocycle), -OC(0)(heteroaryl), -OC(0)(aryl), -OC(0)(Ci- 6 alkyl or C 3 - ecycloalkyl), -OC(0)NR 9 (CH 2 )i- 4 P(0)(OR 21 )(OR 22 ), -C(0)(Ci- 6 alkyl or C 3 -6cycloalkyl)(aryl), - C(0)(Ci- 6 alkyl or C 3 -6cycloalkyl)(heteroaryl),
  • R 84 is aryl; saturated or unsaturated heterocycle (for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S), in one embodiement the heterocycle is bonded through a carbon atom in the heterocyclic ring to a carbon atom of ring A in the R 12 or R 13 position; heteroaryl (for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S).
  • saturated or unsaturated heterocycle for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S
  • R 85 is -0(CH 2 )i -4 R 23a , -OC 2 -C 4 alkenylR 23a , -OC 2 -C 4 alkynylR 23 , -0(CH 2 )i- 4 paracyclophane, -0(CH 2 )i- 4 P(0)R 23b R 23b , -0(CH 2 )i- 4 S(0) R 21 R 22 , -0(CH 2 )i- 4 S(0) R 24 R 25 , - 0(CH 2 )i -4 S0 2 R 21 R 22 , -0(CH 2 )i -4 S0 2 R 24 R 25 , -0(C 3 -C 7 cycloalkyl), -O(aiyl), -O(heteroaiyl), - O(heterocycle).
  • R 86 is -P(0)R 75 R 75 .
  • R 87 is -C(CH 2 ) 6 R 76 or R 87 is (C 3 -C 7 cycloalkyl)R 76
  • R 69 can independently be an R 88 , which is
  • R 80 is an alkyne; R 81 is an amide; R 82 is an amine; R 83 is a carbamate, ester or ketone; R 84 is a direct linked aryl, heterocyclic or heteroaryl; R 85 is an ether (typically bound through the oxygen); R 86 is a phosphonate (typically bound through the phosphorus); each of which can be optionally substituted, and wherein the moieties are as defined herein.
  • one of R 69 is R 80 and the other R 69 is R 81 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 82 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 83 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 84 . In one embodiment, one of R is R and the other R 69 is R 85 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 80 and the other R 69 is R 87 .
  • one of R 69 is R 81 and the other R 69 is R 82 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 82 . In one
  • one of R 69 is R 81 and the other R 69 is R 83 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 84 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 81 and the other R 69 is R 87 .
  • one of R 69 is R 82 and the other R 69 is R 83 .
  • one of R 69 is R 82 and the other R 69 is R 84 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 82 and the other R 69 is R 87 .
  • one of R 69 is R 83 and the other R 69 is R 84 .
  • one of R 69 is R 83 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 83 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 83 and the other R 69 is R 87 .
  • one of R 69 is R 84 and the other R 69 is R 85 . In one embodiment, one of R 69 is R 84 and the other R 69 is R 85 . In one
  • one of R 69 is R 84 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 84 and the other R 69 is R 87 .
  • one of R 69 is R 83 and the other R 69 is R 86 . In one embodiment, one of R 69 is R 83 and the other R 69 is R 86 . In one
  • one of R 69 is R 83 and the other R 69 is R 87 .
  • one of R 69 is R 86 and the other R 69 is R 87 .
  • R 70 is independently selected at each occurrence from hydrogen, Ci-C6alkyl, Ci- Cehaloalkyl, (aryl)Co-C4alkyl, (C3-C7cycloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, (4- to 7- membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; COOH, Si(CH 3 )3, COOR 70a , C 2 -Cealkanoyl, -B(OH) 2 , -C(0)(CH 2 )i -4 S(0)R 21 , -P(0)(OR 21 )(OR 22 ), -P(0)(OR 21 )R 22 ,
  • R 70a is Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C3-C7cycloalkyl)Co-C4alkyl-, (aryl)Co-C4alkyl-, (3- to 7-membered heterocycloalkyl)Co-C4alkyl- having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which R 70a can be optionally substituted.
  • R 71 is selected at each occurrence from hydroxyl, Ci-C 6 alkoxy, (C 3 - C7c cloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C6alkyl, -Ci- C 4 alkylOC(0)Ci-C6alkyl, -Ci-C 4 alkylC(0)OCi-C6alkyl, (4- to 7-membered heterocycloalkyl)Co- C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each can be optionally substituted.
  • R 72 is selected at each occurrence from aryl, heteroaryl, hetercycle, alkynyl, hydroxyl, Ci-C 6 alkoxy, (C 3 -C7cycloalkyl)Co-C 4 alkyl, (aryl)Co-C 4 alkyl, (heterocycle)Co-C 4 alkyl, (heteroaiyl)Co-C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C6alkyl, -Ci-C 4 alkylOC(0)Ci-C6alkyl, -Ci- C 4 alkylOC(0)Ci-C6alkyl, -Ci- C 4 alkylC(0)OCi-C6alkyl, -S(0)(0)(alkyl), -S(0)(alkyl), -S(0)(0)(heteroalkyl), -S(0)(heteroalkyl), -S(0)(heteroalkyl), -S(0)(0)(aryl),
  • R 73 is selected at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci- C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, -Ci- C 4 alkylOC(0)OCi-C6alkyl, -Ci-C 4 alkylOC(0)Ci-C6alkyl, -Ci-C 4 alkylC(0)OCi-C6alkyl, (4- to 7- membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which groups can be optionally substituted.
  • R 74 is an optionally substituted proline amide.
  • R a is independently selected at each occurrence from (C3-C7cycloalkyl), and each R 23a can be optionally substituted.
  • R 23b is independently selected at each occurrence from hydroxyl, Ci-C6alkoxy,Ci- Cealkyl, (C3-C7cycloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, -0(CH2)2-40(CH 2 )8-i8, -OC(R 23c ) 2 OC(0)OR 23d , -OC(R 23c ) 2 OC(0)R 23d , an N-linked amino acid or an N-linked amino acid ester, and each R 23b can be optionally substituted.
  • R 23c is independently selected at each occurrence from hydrogen, Ci-Csalkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, (aryl)Co-C 4 alkyl, (aryl)C2-C 8 alkenyl- or (aryl)C2-C 8 alkynyl; or two R 23c groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 3-6 membered carbocyclic ring, and each R 23c can be optionally substituted.
  • R 23d is independently selected at each occurrence from Ci-C 8 alkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, (aryl)Co-C 4 alkyl, (aryl)C2-C 8 alkenyl or (aryl)C2-C 8 alkynyl, and each R 23d can be optionally substituted.
  • R 75 is independently selected at each occurrence from hydroxyl, Ci-C 6 alkoxy, Ci-Cehaloalkoxy, Ci-Cealkyl, (C3-C7cycloalkyl)Co-C 4 alkyl-, (aryl)Co-C 4 alkyl-, -O-Co- C 4 alkyl(aryl), -0-Co-C 4 alkyl(C3-C7cycloalkyl), (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl- O- having 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl-0- having 1, 2, or 3 heteroatoms independently selected from N, O, and S; -0(CH 2 )2- 4 0(CH2) 8 -i 8 , -OC(R 75a ) 2 OC(0)OR 75b , -OC(R 75a ) 2 OC(0)R 75
  • R 75a is independently selected at each occurrence from hydrogen, Ci-C 8 alkyl, C2- Csalkenyl, C2-C 8 alkynyl, (aryl)Co-C 4 alkyl-, (aryl)C2-C 8 alkenyl- or (aryl)C2-C 8 alkynyl-; or two R 75a groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 3-6 membered carbocyclic ring.
  • R 75b is independently selected at each occurrence from Ci-C 8 alkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, (aryl)Co-C 4 alkyl, (aryl)C2-C 8 alkenyl or (aryl)C2-C 8 alkynyl.
  • R 76 is -NR 9 C(0)R 77 or R 78 .
  • R and R are each independently selected from Ci-C6alkyl, Ci-C 6 haloalkyl, C 2 - C 6 alkenyl, C2-C 6 alkynyl, (C3-C7cycloalkyl)Co-C4alkyl, (aryl)Co-C4alkyl, (heterocycle)Co-C4alkyl and (heteroaryl)Co-C4alkyl wherein each group can be optionally substituted; or each of which (s) may be unsubstituted or substituted with one or more substituents independently selected from, but not limited to, halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 ) 3 , -COOH, - CONH2, -P(0)(OH)2, Ci-Cealkyl, Ci-Cealk
  • R 11 , R 14 , and R 15 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -0(PO)(OR 9 ) 2 , -(PO)(OR 9 ) 2 , Ci-Cealkyl, C 2 -C 6 alkenyl, C2- C 6 alkynyl, C 2 -C6alkenyl(aryl), C 2 -C6alkenyl(cycloalkyl), C 2 -C6alkenyl(heterocycle), C2- C6alkenyl(heteroaryl), C2-C 6 alkynyl, C 2 -C6alkynyl(aryl), C 2 -C6alkynyl(cycloalkyl), C2- C6alkynyl(heterocycle), C 2 -C6alkynyl(heteroaryl), C2-C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 alk
  • X 15 is H, O, or S.
  • X 16 is CR 12 .
  • X 17 is N or CR 13 .
  • X 18 is CR 12 .
  • X 19 is N or CR 13 .
  • X 20 is H or O.
  • X 21 is N or CR 14 .
  • X 22 is N or CR 13 .
  • X 23 is CR 12 .
  • X 24 and X 25 are each independently O or S.
  • X 26 is N or CR 41 .
  • X 27 is CR 12 , NH or O.
  • X 28 is N or CH.
  • X 30 is N or CR 5 .
  • X 31 is N, C(R 54 ) 2 or CR 54 .
  • X 32 is NH, C(R 54 ) 2 or CR 54 .
  • X 33 is -CO- or -SO- or -SO2-.
  • X 34 is CHR , H, O, or S.
  • R 41 is hydrogen, Ci-Cealkyl, or -(Co-C2alkyl)(C3-C 5 cycloalkyl).
  • R 48 is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 thioalkyl, Ci-C 6 alkoxy, - JC3-C 7 cycloalkyl, -B(OH) 2 , -JC(0)NR 9 R 23 ,-JOS0 2 OR 21 , -C(0)(CH 2 )i- 4 S(0)R 21 , -0(CH 2 )i- 4 S(0)NR 21 R 22 -JOP(0)(OR 21 )(OR 22 ), -JP(0)(OR 21 )(OR 22 ), -JOP(0)(OR 21 )R 22 , -JP(0)(OR 21 )R 22 , -JOP(0)R 21 R 22 , -JP(0)R 21 R 22 , -JP(0)R 21 R 22 , -J
  • R 54 is hydrogen, Ci-Cealkyl, C 2 -C 6 alkenyl, C2-C 6 alkynyl, Ci-Cealkoxy, C2- C 6 alkynyl, C2-C 6 alkanoyl, Ci-C 6 thioalkyl, hydroxyCi-Cealkyl, aminoCi-Cealkyl, -Co-C 4 alkyl(C3- C7cycloalkyl), (phenyl)Co-C 4 alkyl-, (heterocycloalkyl)Co-C 4 alkyl and (heteroaryl)Co-C 4 alkyl- wherein the groups can be optionally substituted.
  • s is 1 or 2.
  • L is selected from LI, LI ', L2 and L2' .
  • LI is a bond or is selected from the formulas [0185]
  • R 17 is hydrogen, Ci-Cealkyl, or -Co-C 4 alkyl(C3-C7cycloalkyl) and R 18 and R 18 are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.
  • LI is LI ' .
  • Non-limiting examples of LI ' include the structures of Figure 8.
  • methyl groups in the structures illustrated in Figure 8 can be replaced with an alkyl.
  • L2 is selected from:
  • R 51 is CH 3 , CH 2 F, CHF 2 or CF 3 .
  • R 53 is cyano, nitro, hydroxyl or Ci-C 6 alkoxy.
  • X 29 can be O or S.
  • L2 is a bond.
  • B can be hydrogen.
  • Non-limiting examples of L2 include the structures of Figure 9.
  • the methyl groups in the structures illustrated above can be replaced with an alkyl or acyl.
  • the carbocyclic, heterocyclic, aryl or heteroaryl rings can be optionally substituted.
  • any of the structures illustrated above or below can be optionally substituted with 0, 1 , 2, 3, or 4, as appropriate, and independently, of an R 48 substituent.
  • L3 is selected from L4 or L5.
  • L4 is -C(0)-.
  • L5 is -C(S)-, -P(0)OH-, -S(O)-, -S(0) 2 - or -C(R 52 ) 2 -;
  • each R 52 is independently selected from halo, hydrogen, or optionally substituted Cl-C 6 alkyl.
  • the two R 52 groups can be taken together to form a 3 - to 6-membered carbocyclic spiro ring or a 3 - to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S.
  • B l is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic- oxy group; a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring; C2-C 6 alkenyl; C 2 - C 6 alkynyl; -(Co-C4alkyl)(aryl); -(Co-C4alkyl)(heteroaryl); or -(Co-C4alkyl)(biphenyl), each of which B l is unsubstituted or substituted with one or more substituents independently selected from R 33 and R 34 , and 0 or 1 substituents selected from R 35 and R 36 .
  • R 33 is independently selected from halogen, hydroxyl, -COOH, cyano, Ci-C 6 alkyl, C 2 -C 6 alkanoyl, Ci-Cealkoxy, -Co-C 4 alkyl R 9 R 10 , -SO2R 9 , Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 34 is independently selected from nitro, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci- Cethioalkyl, -JC 3 -C 7 cycloalkyl, -B(OH) 2 , -JC(0) R 9 R 23 ,-JOS0 2 OR 21 , -C(0)(CH 2 )i-4S(0)R 21 , -0(CH 2 )i-4S(0) R 21 R 22 , -JOP(0)(OR 21 )(OR 22 ), -JP(0)(OR 21 )(OR 22 ), -JOP(0)(OR 21 )R 22 , -JP(0)(OR 21 )R 22 , -JOP(0)R 21 R 22 , -JP(0)R 21 R 22 , -JSP(0)(OR 21 )(OR 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(OR 21 )(R 22 ), -JSP(0)(R 21 )(R 22
  • R 35 is independently selected from naphthyl, naphthyloxy, indanyl, (4- to 7- membered heterocycloalkyl)Co-C4alkyl containing 1 or 2 heteroatoms selected from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and containing 4- to 7- ring atoms in each ring; each of which R 35 is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, Ci- C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, Ci-Cealkylester, -Co-C 4 alkyl(C 3 -C7cycloalkyl), -SO2R 9 , Ci-C 2 hal
  • R is independently selected from tetrazolyl, (phenyl)Co-C2alkyl, (phenyl)Ci- C 2 alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, B, and S, each of which R 36 is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, Ci- Cealkylester, -Co-C4alkyl(C3-C7cycloalkyl), -SO2R 9 , -OSi(CH 3 )2C(CH 3 )3, -Si(CH 3 ) 2 C(CH 3 )3, Ci- C 2
  • R 36 is selected from:
  • R 1 is selected from F, CI, Br, and Ci-C 6 alkyl.
  • R 1 is selected from hydroxyl and Ci-C 6 alkoxy.
  • R 1 is selected from C2-C 6 alkynyl, C2-C 6 alkanoyl, and Ci- C 6 thioalkyl.
  • R 1 is selected from aminoCi-Cealkyl and -Co-C4alkyl R 9 R 10 .
  • R 21 and R 22 are independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, -Ci-C4alkylOC(0)OCi-C 6 alkyl, -Ci-C 4 alkylOC(0)Ci-C6alkyl, -Ci- C4alkylC(0)OCi-C6alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R 21 and R 22 can be optionally substituted.
  • R 21 and R 22 can be optionally
  • R 23 is independently selected at each occurrence from Ci-C 6 alkyl, Ci-C 6 haloalkyl, (aryl)Co-C4alkyl, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R 23 can be optionally substituted.
  • R 24 and R 25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10- membered bicyclic heterocyclic group having fused, spiro, or bridged rings, and each R 24 and R 25 can be optionally substituted.
  • J is independently selected at each occurrence from a covalent bond, Ci-C4alkylene, -OCi-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene.
  • B l is selected from the structures of Figure 10.
  • R 27 is hydrogen, methyl, or trifluorom ethyl
  • R 28 is hydrogen or halogen
  • R 29 is hydrogen, methyl, trifluoromethyl, or -Si(CH3)2C(CH3)3.
  • B l is B l ' .
  • Non-limiting examples of ⁇ include the structures of Figures 1 1 A-D.
  • B moieties include, but are not limited to
  • B is B2 which is selected from the structures of Figure 12.
  • B3 is:
  • a monocyclic, bicyclic, or tricyclic heterocyclic group that has at least one boron or silicon atom in the ring or a a monocyclic, bicyclic, or tricyclic heteroaryl group that has at least one boron in the ring;
  • B3 can be further substituted one or more times with the substituents independently selected from R 35 , R 36 and R 48 .
  • B3 can be one of the following defined embodiments subject to the restriction that either A is A2, or C is C3, or L is L2 or L2', or L3 is L5; (I) a 4-membered carbocyclic fused to a 5- or 6- membered heteroaryl having
  • B3 can be further substituted 1, 2, 3 or 4 times or more with the substituents independently selected from R 33 , R 34 , R 35 R 36 and R 48 .
  • Non-limiting examples of B3 include the structures of Figure 13.
  • the methyl groups in the structures illustrated above can be replaced by alkyl.
  • the B3 groups illustrated above can be optionally substituted.
  • any of the structures illustrated above or below can be optionally substituted with 0, 1, 2, 3, or 4, as appropriate, and independently, with an R 48 substituent.
  • B3 can also be R 21 when L2 is either an optionally substituted monocyclic or bicyclic carbocyclic; an optionally substituted monocyclic or bicyclic carbocyclic-oxy group; an optionally substituted monocyclic or bicyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring, an optionally substituted -(Co-C4alkyl)(aryl); an optionally substituted -(Co-C4alkyl)(5- membered heteroaryl) selected from pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole and isothiazole or a substituted imidazole; an optionally substituted -(Co-C4alkyl)(6- membered heteroaryl); an optionally substituted -(Co-C4alkyl)(8-membered heteroary
  • Non-limiting examples of L2-B3 where B3 is R 21 include the structures of Figure
  • One of A, C, L, L3, or B is selected from A2, C3, L2 ⁇ L2, L5, and B3.
  • R 105 is hydrogen Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, C2-C 6 alkenyl(aryl), C 2 - C6alkenyl(cycloalkyl), C 2 -C6alkenyl(heterocycle), C 2 -C6alkenyl(heteroaryl), C2-C 6 alkynyl, C 2 - C6alkynyl(aryl), C 2 -C6alkynyl(cycloalkyl), C 2 -C6alkynyl(heterocycle), C 2 -C6alkynyl(heteroaryl), C2-C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -Co-C4alkyl(mono- and di-Ci-C6alkylamino), -Co- C4alkyl(C3-C7cycloalkyl), -
  • R 106 is selected from hydrogen, hydroxyl, amino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci- Cealkoxy, (C3-C7c cloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, -Ci-C4alkylOC(0)OCi-C 6 alkyl, - Ci-C4alkylOC(0)Ci-C 6 alkyl, -Ci-C4alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each of which can be optionally substituted.
  • R 107 is a bond, alkyl (including Ci-C 6 alkyl, which specifically includes cycloalkyl), aryl, heteroaryl or heterocyclic;
  • R 88 is independently R 12 or R 13 , i.e., R 69 .
  • R 88 is R 12 or R 13 and the other R 12 or R 13 is hydrogen;
  • R 88 is a substituent linked to any of A, L, B, X 1 , X 2 ,
  • R 88 is a substituent linked to any of A, L, B, X 1 , X 2 ,
  • Non-limiting examples of moieties with R 88 include:
  • Non-limiting examples of B with R include:
  • Non-limiting examples of L-B with R include:
  • Non-limiting examples of A with R 88 include:
  • one of the R 69 groups can be bonded to B via a linking group to form a compound of Formula ⁇ :
  • X y and X i(J are each independently CH 2 , NR , O or S; [0243] p is 2 to 10;
  • the disclosure provides a compound of Formula IM, wherein R 69 is monovalent or divalent, as indicated.
  • the disclosure provides a compound of Formula IN:
  • the disclosure provides a compound of Formula IO:
  • the disclosure provides a compound of Formula IP, whereinonovalent or divalent:
  • the disclosure provides a compound of Formula IQ: Formula IQ.
  • the disclosure provides a compound of Formula IR:
  • the X 9 -(CH 2 ) P -X 10 moiety can be saturated or partially unsaturated.
  • the X 9 -(CH2) P -X 10 moiety can comprise one or more heteroatoms.
  • the A group can be bonded to B via a linking group to form a compound of Formula ⁇ :
  • X 9 and X 10 are each independently CH 2 , R 9 , O or S;
  • t is 1, 2, or 3;
  • the disclosure provides a compound of Formula IS:
  • the disclosure provides a compound of Formula IT:
  • the X 9 -(CH2)t-X 10 moiety can be saturated or partially unsaturated. In another embodiment, the X 9 -(CH2)t-X 10 moiety can comprise one or more heteroatoms.
  • A is selected from Al, Al ' and A2.
  • B is selected from Bl, B l ', B2, B3 and B4.
  • L is selected from LI, LI ', L2 and L2' .
  • L3 is selected from L4 and L5.
  • R 37 is hydrogen, Ci-Cealkyl or -(Co-CialkylXCs-Cecylcoalkyl).
  • R 38 and R 39 are independently hydrogen, deuterium, Ci-C 6 alkyl (including C1-C3 alkyl), Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 alkoxy, (C3- C6cycloalkyl)Co-C4alkyl-, (aryl)Co-C2alkyl-, (heteroaryl)Co-C2alkyl-, or a side chain of an amino acid (i.e., a moiety which is found on the carbon linking the amino group and the carboxyl group in an amino acid) or its isomer; each of which is optionally substituted.
  • an amino acid i.e., a moiety which is found on the carbon linking the amino group and the carboxyl group in an amino acid
  • R 38 and R 39 substituents independently include but are not limited to any corresponding R 38 and R 39 positions found in natural amino acids (or their D-counterpart) and non-proteogenic amino acids, such as serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine (e.g., hydrogen), alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, ornithine, glutamine, arginine, histidine, proline, hydroxyproline, selenomethionine, lanthionine, 2-aminoisobutyric acid or dehydroalanine (i.e., R 38 or R 39 is an exo-double bond), with optional protection of functional groups such as hydroxyl, amino, thiol, etc.
  • non-proteogenic amino acids such as serine, threonine, asparagine, glutamine, cysteine
  • compositions comprising a compound or salt of Formula I, Formula ⁇ or Formula I" together with a pharmaceutically acceptable carrier are also disclosed.
  • the present invention thus includes at least the following features:
  • a compound of Formula I, Formula ⁇ or Formula I" or a pharmaceutically acceptable salt or prodrug thereof for use in treating or preventing a disorder listed in the Detailed Description, Part IV, including but not limited to the development of fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, or liver failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or inflammatory reactions in response to biotherapeutics (e.g.
  • CAR T-cell therapy paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), a respiratory disease or a cardiovascular disease;
  • CAR T-cell therapy paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), a respiratory disease or a cardiovascular disease; (e) a process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder listed in the Detailed Description, Part IV, or generally for treating or preventing disorders mediated by complement cascade Factor D, characterized in that a compound selected from Formula I, Formula ⁇ or Formula I" or an embodiment of the active compound is used in the manufacture;
  • 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.
  • the present invention includes compounds of Formula I, Formula ⁇ or Formula I" with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • the isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc.
  • the deuterium can be bound to carbon in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one embodiments deuterium is 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and enough to alter a detectable property of the drug in a human.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in any of the Al, Al ⁇ A2, B l, Bl ', B2, B3, B4, CI, CI ', C2, C3, C4, LI, LI ', L2, L2', L4 or L5.
  • the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R 1' , R 2 , R 2' , R 3 , R 3' , R 4 ' R 5 , R 6 , R 6' , R 7 , R 8 , R 8 , R 9 , 10 R l l R 12 R 13 R 14 ⁇ > 15 ⁇ > 16 ⁇ > 17 ⁇ > 18 R 18' ⁇ > 19 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 31 ⁇ 69 R 33 R 34 R 35 R 36 R 70 n il n 72 n 73 n 74 n 75 n 76 n 77 R 78 R 80 R 81 R 82 R 83 R 84 R 85
  • the alkyl residue may be deuterated (in nonlimiting embodiments, CD 3 , CH2CD3, CD2CD3, CDH2, CD2H, CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.).
  • an R group has a " ' " or an "a" designation, which in one embodiment can be deuterated.
  • the unsubstituted methylene carbon may be deuterated.
  • the compound of the present invention may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound.
  • solvate refers to a molecular complex of a compound of the present invention (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 invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d 6 -acetone, d 6 -DMSO.
  • a solvate can be in a liquid or solid form.
  • substituted 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 pyridyl group substituted by oxo is a pyridone.
  • 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.
  • Nonlimiting 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 invention and includes, but is not limited to, e.g., halogen (which can independently be F, CI, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio including those having one or more thioether linkages; alkyl sulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having one or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either
  • "optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, - CONH2, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Ci-Cealkoxy, C2-Cealkanoyl, Ci-Cealkylester, (mono- and di-Ci-C6alkylamino)Co-C2alkyl, Ci-C2haloalkyl, hydoxyCi-C 6 alkyl, ester, carbamate, urea, sulfonamide,-Ci-C6alkyl(heterocyclo), Ci-C6alkyl(heteroaryl), -Ci-C 6 alkyl(C3- C7cycloalkyl), 0-Ci-C6alkyl(C
  • Alkyl is a branched or straight chain saturated aliphatic 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 C1-C2, C1-C3, or Ci-C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • Ci-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.
  • Ci-C4alkyl 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.
  • Co-Cn alkyl is used herein in conjunction with another group, for example, (C3-C7cycloalkyl)Co-C4 alkyl, or -Co- C4alkyl(C3-C7cycloalkyl)
  • the indicated group in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms.
  • Alkyls can also be attached via other groups such as heteroatoms as in -0-Co-C4alkyl(C3- C7cycloalkyl).
  • 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.
  • the alkyl group is optionally substituted as described above.
  • trimethylsilyl can be used instead of t-butyl.
  • 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, aminoalkyl, alkylene, alkenylene, alkynylene, 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.
  • Nonlimiting examples are C2-C 8 alkenyl, C2-C 6 alkenyl and C2-C4alkenyl.
  • 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. In one embodiment, the alkenyl group is optionally substituted as described above.
  • 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, C2-C 8 alkynyl or C2-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.
  • the alkynyl group is optionally substituted as described above.
  • Alkylene is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example Ci-C4alkylene, Ci-C3alkylene, or Ci-C2alkylene.
  • Alkenylene is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene.
  • Alkynylene is a bivalent hydrocarbon having at least one carbon-carbon triple bond.
  • Alkynylenes for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene.
  • Alkoxy is an alkyl group as defined above covalently bound through an oxygen bridge (-0-).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • an "alkylthio” or a "thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.
  • alkenyloxy is an alkenyl group as defined covalently bound to the group it substitutes by an oxygen bridge (-0-).
  • the alkanoyl group is optionally substituted as described above.
  • Alkylester is an alkyl group as defined herein covalently bound through an ester linkage.
  • R a and R b are each independently selected from hydrogen, alkyl, for example, Ci-C 6 alkyl, alkenyl, for example, C 2 - C 6 alkenyl, alkynyl, for example, C 2 -C 6 alkynyl, -Co-C4alkyl(C3-C7cycloalkyl), -Co-C4alkyl(C3- C7heterocycloalkyl), -Co-C4alkyl(aryl), and -Co-C4alkyl(heteroaryl); or together with the nitrogen to which they are bonded, R a and R b can form a C3-C7heterocyclic ring.
  • the R a and R b groups are each independently optionally substituted as described above.
  • Carbocyclic group is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms.
  • a carbocyclic group typically contains 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.
  • Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents can have a cycloalkyl group, which is attached as a spiro group.
  • carbocyclic rings examples include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings.
  • the carbocyclic ring is optionally substituted as described above.
  • the cycloalkyl is a partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms.
  • the cycloalkyl is a saturated group containing all carbon ring atoms.
  • Carbocyclic-oxy group is a monocyclic carbocyclic ring or a mono- or bi-cyclic carbocyclic group as defined above attached to the group it substitutes via an oxygen, -0-, linker.
  • 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, trifluorom ethyl, monofluorom ethyl, difluorom ethyl, 2- fluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Hydroxyalkyl is an alkyl group as previously described, substituted with at least one hydroxyl subsitutuent.
  • aminoalkyl is an alkyl group as previously described, substituted with at least one amino subsitutuent.
  • 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 groups contain 1 to 3 separate or fused rings and is 6 to about 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. Such 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/or S, to form, for example, a 3,4-methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • heterocycle refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring without aromaticity) carbocyclic moiety of 3 to about 12, and more typically 3, 5, 6, 7 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus sulfur, silicon and boron, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described above.
  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, S, Si and B) or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, S, Si and B), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur, boron or silicon.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
  • Spiro moieties are also included within the scope of this definition.
  • the heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
  • Heterocyclicoxy group is a monocyclic heterocyclic ring or a bicyclic heterocyclic group as described previously linked to the group it substitutes via an oxygen, -0-, linker.
  • Heteroaryl indicates a stable monocyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1, 2 or 3 heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 4 to 7 or 5- to 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 to 7 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- to 7-member aromatic ring is fused to a second aromatic or non-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 of S 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, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, puriny
  • Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, S, O, Si and B with remaining ring atoms being carbon. In a typical embodiment, nitrogen is the heteroatom.
  • Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.
  • mono- and/ or di-alkylamino indicate a secondary or tertiary alkylamino group, wherein the alkyl groups are independently selected alkyl groups, as defined herein.
  • the point of attachment of the alkylamino group is on the nitrogen.
  • mono- and di- alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • 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 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, non-toxic, 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.
  • Examples of 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.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid 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-(CH2)n-COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • Lists of additional suitable salts may be found, e.g.
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic 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.
  • 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 complement Factor D pathway.
  • 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, fish, bird and the like.
  • a "prodrug” as used herein means 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 described 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.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate 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 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.
  • a "therapeutically effective amount" of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or dimunition of the disease itself.
  • a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of complement Factor D in the patient's blood, serum, or tissues.
  • Formula I can be considered to have a central core C, an L substituent, a B substituent, and a L3-A substituent.
  • Formula I comprises at least one of the A2, B3, C3, L2, L2', or L5 (and in certain embodiments, C4) moieties described herein.
  • the invention includes a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R 12 and R 13 on the A group are independently selected from R 69 .
  • the compound is an inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation.
  • the compound acts through a mechanism other than inhibition of complement D to treat a disorder described herein in a host, typically a human.
  • any of the active compounds can be provided in its N- oxide form to a patient in need thereof.
  • an N-oxide of one of the active compounds or a precursor of the active compound is used in a manufacturing scheme.
  • the N-oxide is a metabolite of administration of one of the 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
  • TAPC l,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride
  • Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide provides sulfoxides in high yields, see, Kirihara, A., et. al., "Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones", Synlett, 1557-1561 (2010).
  • 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.
  • the present invention also provides a compound of Formula ⁇ with an R 69 which is monovalent or divalent:
  • Formula ⁇ is comprised of a central core C moiety, an A substituent, a L3 substituent, a L substituent, a B substituent and a -X 9 -(CH2)p-X 10 linker; wherein R 12 or R 13 on the Al and A2 groups, are independently selected from R 69 .
  • Compounds of Formula I" are suitable inhibitors of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation. Alternatively, the compound may act through a different mechanism of action to treat the disorders described herein.
  • Compounds of Formula I or a pharmaceutically acceptable salt or composition thereof, wherein R 12 or R 13 on the Al and A2 groups, wherein Al and A2 are independently selected from R 69 in one embodiment, is an inhibitor of complement factor D, and therefore can be used as an effective amount to treat a host in need of complement factor D modulation.
  • the compound may act through a different mechanism of action to treat the disorders described herein.
  • Non-limiting examples of compounds falling within Formula I and Formula ⁇ with variations in the variables e.g., A, B, R ⁇ R 3 , and L, are illustrated below.
  • Non-limiting examples of compounds falling within Formula I" with variations in the variables e.g., R 37 , R 38 , R 39 , A, B, L and L3 are illustrated below.
  • the disclosure includes all combinations of these definitions so long as a stable compound results.
  • the disclosure includes compounds and salts of Formulas 2 - 651 for any use and in any composition described in this application.
  • n 0 or 1.
  • m 0 or 1.
  • n 0 or 1.
  • the disclosure includes compounds and salts of Formula I, Formula ⁇ and Formula I" pharmaceutically acceptable compositions thereof, and any of their subformulae (2-651) in which at least one of the following conditions is met in the embodiments described below.
  • the invention is the use of a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R 12 and R 13 on the A group are both substituted with certain R 69 moieties, for the treatment of a disorder in a host, typically a human, wherein the disorder is selected from the group disclosed in the Detailed Description, Part IV.
  • R 12 and R 13 are independently selected from R 69 , wherein R 69 is R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , or R 87 , wherein R 12 and R 13 must both be present and wherein R 12 and R 13 cannot be selected from the same R 69 group; and wherein each R 69 can be optionally substituted.
  • R 69 is R 88 .
  • R 80 is -Ci-CealkynylR 70 .
  • R 80 are:
  • R 81 is C(0) R 21 R 71 , -C(0) R 24 R 25 , -C(0)NR 9 R 71 , -C(0) R 21 S0 2 R 22 , - R 9 C(0)OR 10 , - R 9 C(0)OR 23 , - R 9 C(0)R 21 , - R 9 C(0) R 9 R 10 , - R 9 C(O) R 10 R 23 , - R 9 C(0) R 24 R 25 .
  • R 82 is R 72 R 73 , NR 9 S0 2 R 73 , N(S0 2 R 9 )CH 2 C(0)R 74 .
  • R 83 is -OC(0)(CH 2 )i- 4 R 21 , -OC(0) R 21 R 22 , -OC(0) R 24 R 25 , -OC(0)(Ci- 6 alkyl or C3-6cycloalkyl)(aryl), -OC(0)(Ci- 6 alkyl or C3-6cycloalkyl)(heteroaryl), -OC(0)(Ci- 6 alkyl or C 3 - 6cycloalkyl)(heterocycle), -OC(0)(heteroaryl), -OC(0)(aryl), -OC(0)(Ci- 6 alkyl or C 3 - ecycloalkyl), -OC(0)NR 9 (CH 2 )i- 4 P(0)(OR 21 )(OR 22 ), -C(0)(Ci- 6 alkyl or C 3 -6cycloalkyl)(aryl), - C(0)(Ci- 6 alkyl or C 3 -6cycloalkyl)(heteroaryl),
  • R 84 is aryl; saturated or unsaturated heterocycle (for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S), wherein the heterocycle is bonded through a carbon atom in the heterocyclic ring to a carbon atom of ring A in the R 12 or R 13 position; heteroaryl (for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S).
  • saturated or unsaturated heterocycle for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S
  • heterocycle for example a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S.
  • R 85 is -0(CH 2 )i- 4 R 23a , -OC2-C 4 alkenylR 23a , -OC 2 -C4alkynylR 23 , -0(CH 2 )i- 4 paracyclophane, -0(CH 2 )i- 4 P(0)R 23b R 23b , -0(CH 2 )i- 4 S(0) R 21 R 22 , -0(CH 2 )i- 4 S(0) R 24 R 25 , - 0(CH 2 )i-4S0 2 R 21 R 22 , -0(CH 2 )i-4S0 2 R 24 R 25 , -0(C 3 -C 7 cycloalkyl), -O(aiyl), -O(heteroaiyl), - O(heterocycle).
  • R 86 is -P(0)R 75 R 75 .
  • R 87 is -C(CH 2 ) 2 R 76 or R 87 is (Cj-C7cycloalkyl)R 76
  • R 69 can independently be an R 88 , which is
  • R is independently selected at each occurrence from hydrogen, Ci-C 6 alkyl, Ci- Cehaloalkyl, (aryl)Co-C4alkyl, (C3-C7cycloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, (4- to 7- membered heterocycloalkyl)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; COOH, Si(CH 3 ) 3 , COOR 70a , C 2 -Cealkanoyl, -B(OH) 2 , -C(0)(CH 2 )i -4 S(0)R 21 , -P(0)(OR 21 )(OR 22 ), -P(0)(OR 21 )R 22 ,
  • R 70a is Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C7cycloalkyl)Co-C 4 alkyl-, (aryl)Co-C 4 alkyl-, (3- to 7-membered heterocycloalkyl)Co-C 4 alkyl- having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which R 70a can be optionally substituted.
  • R 71 is selected at each occurrence from hydroxyl, Ci-C 6 alkoxy, (C 3 - C7cycloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C 6 alkyl, -Ci- C 4 alkylOC(0)Ci-C 6 alkyl, -Ci-C 4 alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)Co- C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each can be optionally substituted.
  • R is selected at each occurrence from aryl, heteroaryl, hetercycle, alkynyl, hydroxyl, Ci-C 6 alkoxy, (C3-C7cycloalkyl)Co-C4alkyl, (aryl)Co-C4alkyl, (heterocycle)Co-C4alkyl, (heteroaryl)Co-C4alkyl, -Ci-C 4 alkylOC(0)OCi-C6alkyl, -Ci-C 4 alkylOC(0)Ci-C6alkyl, -Ci- C 4 alkylOC(0)Ci-C6alkyl, -Ci- C4alkylC(0)OCi-C 6 alkyl, -S(0)(0)(alkyl), -S(0)(alkyl), -S(0)(0)(heteroalkyl), -S(0)(heteroalkyl), -S(0)(heteroalkyl), -S(0)(aryl), -S(0)(he
  • R 73 is selected at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci- C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, (C3-C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, -Ci- C4alkylOC(0)OCi-C 6 alkyl, -Ci-C4alkylOC(0)Ci-C 6 alkyl, -Ci-C4alkylC(0)OCi-C 6 alkyl, (4- to 7- membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which groups can be optionally substituted.
  • R 74 is an optionally substituted proline amide.
  • R 23a is independently selected at each occurrence from (C3-C7cycloalkyl), and each R 23a can be optionally substituted.
  • R 23b is independently selected at each occurrence from hydroxyl, Ci-C6alkoxy,Ci- Cealkyl, (C3-C7cycloalkyl)Co-C 4 alkyl, (phenyl)Co-C 4 alkyl, -0(CH2)2-40(CH 2 )8-i8, -OC(R 23c ) 2 OC(0)OR 23d , -OC(R 23c ) 2 OC(0)R 23d , an N-linked amino acid or an N-linked amino acid ester, and each R 23b can be optionally substituted.
  • R 23c is independently selected at each occurrence from hydrogen, Ci-Csalkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, (aryl)Co-C4alkyl, (aryl)C2-C 8 alkenyl- or (aryl)C2-C 8 alkynyl; or two R 23c groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 3-6 membered carbocyclic ring, and each R 23c can be optionally substituted.
  • R 23d is independently selected at each occurrence from Ci-C 8 alkyl, C2-C 8 alkenyl, C2-C 8 alkynyl, (aryl)Co-C4alkyl, (aryl)C2-C 8 alkenyl or (aryl)C2-C 8 alkynyl, and each R 23d can be optionally substituted.
  • R is independently selected at each occurrence from hydroxyl, Ci-C6alkoxy, Ci-Cehaloalkoxy, Ci-Cealkyl, (C3-C7cycloalkyl)Co-C4alkyl-, (aryl)Co-C4alkyl-, -O-Co- C4alkyl(aryl), -0-Co-C4alkyl(C3-C7cycloalkyl), (4- to 7-membered heterocycloalkyl)Co-C4alkyl- O- having 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl-0- having 1, 2, or 3 heteroatoms independently selected from N, O, and S; -0(CH2)2-40(CH2 -i8, -OC(R 75a ) 2 OC(0)OR 75b , -OC(R 75a ) 2 OC(0)R 75b , - R 9 R
  • R 75a is independently selected at each occurrence from hydrogen, Ci-Csalkyl, C 2 - Csalkenyl, C 2 -C 8 alkynyl, (aryl)Co-C4alkyl-, (aryl)C 2 -C 8 alkenyl- or (aryl)C 2 -C 8 alkynyl-; or
  • two R 75a groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 3-6 membered carbocyclic ring.
  • R 75b is independently selected at each occurrence from Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (aryl)Co-C4alkyl, (aryl)C 2 -C 8 alkenyl or (aryl)C 2 -C 8 alkynyl.
  • R 76 is - R 9 C(0)R 77 or R 78 .
  • R 77 and R 78 are each independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 - C 6 alkenyl, C2-C 6 alkynyl, (C3-C7cycloalkyl)Co-C4alkyl, (aryl)Co-C4alkyl, (heterocycle)Co-C4alkyl and (heteroaryl)Co-C4alkyl wherein each group can be optionally substituted; or each of which (s) may be unsubstituted or substituted with one or more substituents independently selected from, but not limited to, halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH) 2 , -Si(CH 3 )3, -COOH, - CONH2, -P(0)(OH) 2 , Ci-Cealkyl, Ci-Cealkoxy, -Co-C 2 alkyl(mono- and di-C
  • R 80 is selected from the structures of Figure 15.
  • R 81 is selected from the structures of Figure 16.
  • R 82 is selected from the structures of Figure 17.
  • R 72 is selected from the structures of Figure 18.
  • R 83 is selected from the structures of Figure 19.
  • R 84 is selected from the structures of Figure 20.
  • R 85 is selected from the structures of Figure 21.
  • R 86 is selected from the structures of Figure 22.
  • two R 75 groups in a P(0)R 75 R 75 phosphonate can come together to form a heterocyclic ring that can be optionally substituted with an R 100 group.
  • R 100 is aryl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl and cycloalkyl.
  • HepDirect Cyclic l-aryl-l,3-propanyl esters
  • Prodrugs Activation via CYP-mediated oxidation of the benzylic carbon. See Hecker, S. J. etal. J. Med. Chem.2007, 50, 3891-3896.
  • R 87 is selected from the structures of Figure 23.
  • R 12 isR 84 and R 13 isR 80
  • R 12 isR 84 and R 13 isR 81
  • R 12 isR 84 and R 13 isR 82
  • R 12 isR 84 and R 13 isR 83
  • R 12 isR 84 and R 13 is R 85
  • R 12 isR 84 and R 13 isR 86
  • R 12 isR 84 and R 13 isR 87
  • R 12 isR 86 and R 13 isR 80
  • R 12 isR 86 and R 13 isR 81
  • R 12 isR 86 and R 13 isR 82
  • R 12 isR 86 and R 13 isR 83
  • R 12 isR 86 and R 13 isR 84
  • R 12 isR 86 and R 13 isR 85
  • R 12 isR 86 and R 13 isR 87
  • R 13 isR 84 and R 12 isR 80
  • R 13 isR 84 and R 12 isR 81
  • R 13 isR 84 and R 12 isR 82
  • R 13 isR 84 and R 12 isR 83
  • R 13 isR 84 and R 12 isR 85
  • R 13 isR 84 and R 12 isR 86
  • R 13 isR 84 and R 12 isR 87
  • R 13 isR 86 and R 12 isR 80
  • R 13 isR 86 and R 12 isR 81 [0384] In one embodiment, R is R and R is R .
  • R 13 is R 86 and R 12 is R 83 .
  • R 13 is R 86 and R 12 is R 84 .
  • R 13 is R 86 and R 12 is R 85 .
  • R 13 is R 86 and R 12 is R 87 .
  • R 12 is aryl and R 13 is -P(0)R 75 R 75 .
  • R 12 is optionally substituted aryl and R 13 is -P(0)R 75 R 75 .
  • R 12 is an optionally substituted saturated or unsaturated heterocycle bonded through a carbon atom in the heterocyclic ring to a carbon atom of ring A in the R 12 position and R 13 is -P(0)R 75 R 75 .
  • R 12 is an optionally substituted heteroaryl and R 13 is - P(0)R 75 R 75 .
  • R 12 is -P(0)R 75 R 75 and R 13 is is aryl.
  • R 12 is -P(0)R 75 R 75 and R 13 is an optionally substituted aryl.
  • R 12 is -P(0)R 75 R 75 and R 13 is an optionally substituted saturated or unsaturated heterocycle bonded through a carbon atom in the heterocyclic ring to a carbon atom of ring A in the R 13 position.
  • R 12 is -P(0)R 75 R 75 and R 13 is optionally substituted heteroaryl.
  • C is CI, CI ', C2, C3 or C4.
  • C4 is selected from
  • R 101 is C1-C4 alkyl or C3-C7 cycloalkyl.
  • R is C1-C4 alkyl, fluorine, chlorine, or bromine.
  • R 1 and R 1 or R 3 and R 3 may be taken together to form a 3 - to 6-membered carbocyclic spiro ring or a 3 - to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;
  • R 2 and R 2 may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or
  • R 2 and R 2 may be taken together to form a 3- to 6-membered heterocyclic spiro ring; each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C4alkyl (including in particular methyl), C 2 -C4alkenyl, C 2 -C4alkynyl, Ci- C4alkoxy, C 2 -C4alkanoyl, hydroxyCi-C
  • R 1 and R 2 may be taken together to form a 3-membered carbocyclic ring;
  • R 1 and R 2 may be taken together to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O, and S; or
  • R 2 and R 3 if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring;
  • each of which ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C4alkyl (including in particular methyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C3-C7cycloalkyl), - 0-Co-C 4 alkyl(C3-C7cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, Ci-C4alkyl (including in particular methyl), C
  • the central core moiety is proline.
  • the central core moiety is 4-fluoroproline.
  • R 1 , R 1 , R 2 , R 3 , and R 3 are all hydrogen; and R 2 is fluoro.
  • R 1 , R 1 , R 2 , and R 3 are all hydrogen; and R 2 is fluoro and R 3 is -Co-C 4 alkyl(C3-C7cycloalkyl) or -0-Co-C 4 alkyl(C3-C7cycloalkyl).
  • R 1 and R 2 are taken together to form a 3- to 6-membered cycloalkyl group, and R 1 , R 2 , R 3 , and R 3 , where present, are all hydrogen.
  • R 1 , R 1 , R 3 , and R 3 are all hydrogen, and R 2 and R 2 are taken together to form a 5- or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.
  • R 1 is hydrogen and R 2 is fluoro.
  • R 1 and R 2 are joined to form a 3 membered ring.
  • the disclosure includes compounds of Formula I in which the central pyrrolidine is vinyl substituted, for example:
  • the compound of Formula I has the structure:
  • the central pyrrolidine is modified by addition of a second heteroatom to a pyrrolidine ring, such as N, O, S, or Si, for example:
  • Example compounds having the modifications disclosed above include:
  • L is selected from LI , LI ', L2 and L2' .
  • R 17 is hydrogen, Ci-C6alkyl, or -Co-C4alkyl(C3-C7cycloalkyl) and R 18 and R 18 are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.
  • B is selected from B 1, B 1 ', B2, B3 and B4.
  • R 26 and R 27 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, Ci- C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -Co-C4alkyl(mono- and di- Ci-C6alkylamino), -Co-C4alkyl(C3-C7cycloalkyl), -Co-C4alkoxy(C3-C7cycloalkyl), Ci- C2haloalkyl, Ci-C2haloalkoxy, and Ci-C2haloalkylthio.
  • R 18 and R 18 are independently selected from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0 or 1; and
  • R , R , and R are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, (C3-C7cycloalkyl)Co-C4alkyl, (aryl)Co-C4alkyl-, (heteroaiyl)Co- C4alkyl-, and -Co-C4alkoxy(C3-C7cycloalkyl); each of which R 26 , R 27 , and R 28 other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, Ci-C2alkoxy, Ci-C2halo
  • R 29 is hydrogen, Ci-C 2 alkyl, CiC 2 haloalkyl or -Si(CH 3 ) 2 C(CH 3 ) 3 .
  • m is 0.
  • the disclosure further includes compounds and salts of Formula I in which B l is 2-fluoro-3-chlorophenyl.
  • B l is 2-fluoro-3-chlorophenyl.
  • another carbocyclic, aryl, heterocyclic, or heteroaryl group such as 2-bromo-pyridin-6-yl, l-(2,2,2-trifluoroethyl)-lH- pyrazol-3-yl, 2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl is used.
  • Bl is phenyl, pyridyl, or indanyl each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, Ci-C 6 alkoxy, Ci- C 6 thioalkyl, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, (C3-C7cycloalkyl)Co-C4alkyl, -Co- C4alkoxy(C3-C7cycloalkyl), (phenyl)Co-C2alkyl, (pyridyl)Co-C2alkyl; each of which substituents other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from
  • B l is phenyl or pyridyl substituted with 1, 2, or 3 substituents selected from chloro, bromo, hydroxyl, -SCF3, Ci-C2alkyl, Ci-C2alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of which substituents other than chloro, bromo, hydroxyl, -SCF3, can be optionally substitued.
  • Bl is a 2-fluoro-3-chlorophenyl or a 2-fluoro-3- trifluoromethoxy phenyl group.
  • Bl is pyridyl, optionally substituted with halogen, Ci- C2alkoxy, and trifluoromethyl.
  • Bl is phenyl, substituted with 1, 2, or 3 substituents independently selected from halogen, Ci-C2alkyl, Ci-C2alkoxy, trifluoromethyl, and optionally substituted phenyl.
  • R 23 is independently selected at each occurrence from (C3- C7cycloalkyl)Co-C4alkyl, (phenyl)Co-C4alkyl, (4- to 7-membered heterocycloalkyl)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6- membered unsaturated or aromatic heterocycle)Co-C4alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S.
  • L1-B3 is:
  • R 27 , and R 28 are independently selected from hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, cyano, Ci-C6alkyl, C2-C 6 alkenyl, C2-C 6 alkanoyl, C2-C 6 alkoxy, C2-C 6 thioalkyl, (mono- and di-Ci-C6alkylamino)Co-C4alkyl, (C3-C7cycloalkyl)Co-C4alkyl, (aryl)Co-C4alkyl-, (heteroaryl)Co-C4alkyl-, and -Co-C4alkoxy(C3-C7cycloalkyl); each of which R 27 , and R 28 other than hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, and cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino,
  • L is selected from LI, LI ', L2 and L2' .
  • L3 is selected from L4 and L5;
  • L4 is -C(O)-.
  • L5 is described above in the summary section. [0445] A is selected from Al, Al ' and A2.
  • R 5 and R 6 are independently selected from -CHO, - C(0) H 2 , -C(0) H(CH 3 ), C 2 -Cealkanoyl, and hydrogen.
  • each R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C4alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C4alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 8 and R 8 are independently hydrogen or methyl.
  • R 8 and R 8 are hydrogen.
  • R 7 is hydrogen or methyl.
  • R 7 is hydrogen
  • this disclosure includes compounds and salts of Formula IA:
  • R 6 , R 12 , R 13 , and B3 may carry any of the definitions set forth herein for this variable.
  • this disclosure includes compounds and salts of Formula IB and
  • R 1 , R 2 , R 2 , and R 3 are independently selected from hydrogen, halogen, Ci-C4alkyl, Ci-C 4 alkoxy, -Co-C 2 alkyl R 9 R 10 , -Co-C4alkyl(C3-C7cycloalkyl), -0-Co-C 4 alkyl(C3- C7cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
  • R 8 and R 8 are independently selected from hydrogen, halogen, and methyl;
  • R 5 is hydrogen, hydroxyl, cyano, -COOH, Ci-Cealkyl, Ci-Cealkoxy, C 2 -Cealkanoyl -Co-C 4 alkyl(C3-C7cycloalkyl), -C(0)Co-C 4 alkyl(C3-C7cycloalkyl, Ci-C 2 haloalkyl, or Ci- C 2 haloalkoxy);
  • R 6 is -C(0)CH 3 , -C(0) H 2 , -C(0)CF 3 , -C(0)(cyclopropyl), or -ethyl(cyanoimino); and
  • R 11 and R 14 are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C6alkoxy, Ci-C 6 thioalkyl, -Co- C4alkyl(mono- and di-Ci-C6alkylamino), -Co-C4alkyl(C 3 -C7cycloalkyl), -OCo-C4alkyl(C 3 - C7cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • 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.
  • the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt 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 Factor D related disorder; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; or inhibit or prevent the development of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder.
  • 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.
  • dosage forms with at least about 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, or 1700 mg of active compound, or its salt.
  • the dosage form has at least about 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, lOOOmg, 1200 mg, or 1600 mg of active compound, 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.
  • the pharmaceutical composition may for example include a molar ratio of the active compound and an additional active agent that achieves the desired result.
  • the pharmaceutical composition may contain a molar ratio of about 0.5: 1, about 1 : 1, about 2: 1, about 3 : 1 or from about 1.5: 1 to about 4: 1 of an additional active agent in combination with the active compound (additional active agent: active compound), or its salt, described herein.
  • the additional active agent is an anti-inflammatory or immunosuppressing agent.
  • 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, or tear duct injections, or through a mucus, mucin, or a 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.
  • the pharmaceutical 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.
  • surface active agents include sodium lauryl sulfate and polysorbate 80.
  • Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins.
  • Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium.
  • Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
  • Examples of lubricants 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 invention.
  • the pharmaceutical composition for administration further includes a compound or salt of Formula I, ⁇ , or I" 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; a surface active fatty acid, such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (
  • 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(l,3-dioxan-2one)); polyanhydrides (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(l,3-dioxan-2one)
  • polyanhydrides e.g., poly(sebacic anhydride)
  • polyethers e.g., polyethylene glycol
  • polyurethanes polymethacrylates
  • polyacrylates polyacrylates
  • 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 invention 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 below. 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. 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 invention provides particles formed by solvent removal comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by solvent removal comprise a compound of the present invention and an additional therapeutic agent.
  • the particles formed by solvent removal comprise a compound of the present invention, 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 invention provides a spray dried dispersion (SDD) comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the SDD comprises a compound of the present invention and an additional therapeutic agent.
  • the SDD comprises a compound of the present invention, 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 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 invention provides particles formed by phase inversion comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by phase inversion comprise a compound of the present invention and an additional therapeutic agent.
  • the particles formed by phase inversion comprise a compound of the present invention, 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 non-solvent 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 invention provides particles formed by coacervation comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by coacervation comprise a compound of the present invention and an additional therapeutic agent.
  • the particles formed by coacervation comprise a compound of the present invention, 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 invention is administered to a patient in need thereof as particles formed by low temperature casting.
  • the present invention provides particles formed by low temperature casting comprising a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
  • the particles formed by low temperature casting comprise a compound of the present invention and an additional therapeutic agent.
  • the particles formed by low temperature casting comprise a compound of the present invention, 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 for the 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.
  • Methods for producing nanoparticles are known in the art.
  • 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 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.
  • compositions suitable for topical 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 for a 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 single/-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 GmbH
  • 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",
  • Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 titled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories); US20050009910 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 2014/0
  • 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 D-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 D-related disorder including a complement D-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 biopharmac
  • 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 non-limiting example is use in connection with acute or chronic graft versus host disease, which is a common complication as a result of allogeneic tissue transplant, and can also occur as a result of a blood transfusion.
  • the present invention 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 invention 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.
  • 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.
  • 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 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.
  • bi-specific T-cell engagers directs T-cells to target and bind with a specific antigen on the surface of a cancer cell.
  • Blinatumomab (Amgen)
  • Amgen a 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- ⁇ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD 19/CD3-bi specific 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 disorder is selected from:
  • vitritis sarcoidosis, syphilis, tuberculosis, or Lyme disease
  • retinal vasculitis Eales disease, tuberculosis, syphilis, or toxoplasmosis
  • varicella zoster virus herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or Dengue-associated disease (e.g., hemorraghic Dengue Fever);
  • the disorder is selected from:
  • amyotrophic lateral sclerosis parkinsonism-dementia complex
  • sporadic frontotemporal dementia frontotemporal dementia with Parkinsonism linked to chromosome 17
  • frontotemporal lobar degeneration tangle only dementia
  • cerebral amyloid angiopathy cerebrovascular disorder
  • certain forms of frontotemporal dementia CTE
  • CTE chronic traumatic encephalopathy
  • PPD PD with dementia
  • argyrophilic grain dementia dementia pugilistica
  • multi-infarct dementia multi-infarct dementia
  • v Creutzfeldt-Jakob disease, Huntington's disease, multifocal motor neuropathy (MMN), prion protein cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guamanian motor neuron disease with neurofibrillary tangles, neural regeneration, or diffuse neurofibrillary tangles with calcification.
  • MNN multifocal motor neuropathy
  • prion protein cerebral amyloid angiopathy polymyositis
  • postencephalitic parkinsonism postencephalitic parkinsonism
  • subacute sclerosing panencephalitis non-Guamanian motor neuron disease with neurofibrillary tangles
  • neural regeneration or diffuse neurofibrillary tangles with calcification.

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Abstract

L'invention concerne des composés, des méthodes d'utilisation, et des procédés de fabrication d'inhibiteurs du facteur D du complément de formule (I), (I") et (I'''), ou un sel pharmaceutiquement acceptable ou une composition de ceux-ci. Les inhibiteurs décrits dans la description ciblent le facteur D, et inhibent ou régulent la cascade du complément. Les inhibiteurs du facteur D décrits dans la description permettent de réduire l'activation excessive du complément.
PCT/US2016/048800 2015-08-26 2016-08-25 Composés disubstitués pour le traitement de troubles immunitaires et inflammatoires WO2017035418A1 (fr)

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US10550140B2 (en) 2014-02-25 2020-02-04 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10100072B2 (en) 2014-02-25 2018-10-16 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
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