WO2015130854A1 - Compounds for treatment of complement mediated disorders - Google Patents

Compounds for treatment of complement mediated disorders Download PDF

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Publication number
WO2015130854A1
WO2015130854A1 PCT/US2015/017609 US2015017609W WO2015130854A1 WO 2015130854 A1 WO2015130854 A1 WO 2015130854A1 US 2015017609 W US2015017609 W US 2015017609W WO 2015130854 A1 WO2015130854 A1 WO 2015130854A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
independently chosen
cycloalkyl
halogen
hydroxyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/017609
Other languages
English (en)
French (fr)
Inventor
Avinash S. Phadke
Xiangzhu Wang
Dawei Chen
Akihiro Hashimoto
Venkat Rao GADHACHANDA
Godwin Pais
Qiuping Wang
Atul Agarwal
Milind Deshpande
Jason Allan Wiles
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Achillion Pharmaceuticals Inc
Original Assignee
Achillion Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020167026303A priority Critical patent/KR102366025B1/ko
Priority to CA2940777A priority patent/CA2940777A1/en
Priority to MX2016011038A priority patent/MX2016011038A/es
Priority to EA201691725A priority patent/EA035501B1/ru
Priority to RU2016137832A priority patent/RU2703995C2/ru
Priority to JP2016570944A priority patent/JP6537532B2/ja
Priority to CN201580010598.5A priority patent/CN106458981B/zh
Priority to AU2015223084A priority patent/AU2015223084B2/en
Priority to AP2016009437A priority patent/AP2016009437A0/en
Application filed by Achillion Pharmaceuticals Inc filed Critical Achillion Pharmaceuticals Inc
Priority to EP15755573.1A priority patent/EP3110805B1/en
Publication of WO2015130854A1 publication Critical patent/WO2015130854A1/en
Priority to ZA2016/05832A priority patent/ZA201605832B/en
Priority to US15/246,049 priority patent/US20160361329A1/en
Priority to IL247452A priority patent/IL247452B/en
Priority to SA516371744A priority patent/SA516371744B1/ar
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • 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 phaogytosis 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 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 (PNH), multiple sclerosis, and rheumatoid arthritis.
  • 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.
  • factor D inhibitors While initial attempts have been made to develop inhibitors of factor D, there are currently no small molecule factor D inhibitors in clinical trials. Examples of factor D inhibitors or prolyl compounds are described in the following disclosures.
  • Novartis PCT patent publications WO2014/002057 titled “Pyrrolidine derivatives and their use as complement pathway modulators” and WO2014/009833 titled “Complement pathway modulators and uses thereof describe additional factor D inhibitors with heterocyclic substituents. Additional factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002058, WO2014/002059, and WO2014/005150.
  • 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.
  • 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.
  • R and R' are independently chosen from H, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl 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 mixtrues 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.
  • Z is F, CI, NH 2 , CH 3 , CH 2 D, CHD 2 , or CD 3 .
  • R , R , R , R , and R are independently chosen at each occurence from (c) and (d):
  • any one of the following rings (e), (f), (g), (h), (i), or j) may be present: (e) 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 chosen from N, O, or S;
  • R 2 and R 2 may be taken together to form a 3- to 6-membered carbocyclic spiro ring
  • R 2 and R 2 may be taken together to form a 3- to 6-membered heterocyclic spiro ring, each of which spiro rings (e), (f), and (g) is unsubstituted or substituted with 1 or more substituents independently chosen 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, C 2 - C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C 3 - C 7 cycloalkyl), -0-Co-C 4 alkyl(C 3 -C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy
  • 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 ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S.
  • R 2 and R 3 if bound to adjacent carbon atoms, may be taken together to form a 3- to 6- membered carbocyclic ring or a 3- to 6-membered heterocyclic ring; each of which ring (h), (i), and (j) may be unsubstituted or substituted with 1 or more substituents independently chosen 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, C 2 -C 4 alkanoyl, hydroxyCi-C 4 alkyl, (mono- and di-Ci-C 4 alkylamino)Co-C 4 alkyl, -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -0-Co-C 4 alkyl(C 3 - C 7 cycloalkyl), Ci
  • R and R , R and R , or R and R can be taken together to form a carbonyl group.
  • R 1 and R 2 or R 2 and R 3 can be taken together to form a carbon-carbon double bond.
  • A is a group chosen from (k) and (1) where (k) is
  • X 4 is B(OH) and Y is CHR 9 ; or X 4 is CHR 9 and Y is B(OH).
  • R 101 is hydrogen, alkyl, carboxy.
  • R 4 is (m) or (n):
  • each of which R 4 other than hydrogen, -CHO, and -CONH 2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 2 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or optionally substituted.
  • R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C(0)alkyl, C(0)cycloalkyl, C(0)aryl, C(0)heterocycle, and C(0)heteroaryl.
  • R 6 is hydrogen, halogen, hydroxyl, Ci-C 4 alkyl, or Ci-C 4 alkoxy; or R 6 and R 6 may be taken together to form an oxo, vinyl, or imino group.
  • R 7 is hydrogen, Ci-C 6 alkyl, or -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl).
  • two A groups can be bonded together to form a dimer through a suitable linking group that achieves the desired purpose.
  • linking groups include but are not limited to, urea, amide, -C(0)-C(0)-, carbamate and ketone.
  • two heteroaryl rings for example, two indole rings, are linked through a urea to form the dimer.
  • R 16 is 0 or 1 or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, -Co-C 4 alkyl(mono- and di- Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -Cycycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 19 is hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, -S0 2 Ci-C 6 alkyl, (mono- and di-Ci-C 6 alkylamino)Ci-C 4 alkyl, -Co-C 4 alkyl(C 3 -Cycycloalkyl), -Co-C 4 alkyl(C 3 - Cyheterocycloalkyl), -C 0 -C 4 alkyl(aryl), C 0 -C 4 alkyl(heteroaryl), and -C(0)(CH 2 )i- 2 C(0)OR 9 each of which R 19 other than hydrogen is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-C 4 alkyl.
  • X 11 is N or CR 11 .
  • X 12 is N or CR 12 .
  • X 13 is N or CR 13 .
  • X 14 is N or CR 14 .
  • R 17 , R 17 0 , or OH where R 17 is hydrogen or Ci-C 6 alkyl and R 18 and R 18 are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3;
  • B is a monocyclic, bicyclic carbocyclic or carbocyclic-oxy group or 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, or B is a C 2 - C 6 alkenyl or C 2 -C 6 alkynyl group, or B is -(Co-C 4 alkyl)(aryl), -(Co-C 4 alkyl)(heteroaryl), or -(C 0 - C 4 alkyl)(biphenyl) .
  • J is independently chosen at each occurrence from a covalent bond, Ci- C 4 alkylene, -OCi-C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene.
  • R 21 and R 22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, (C 3 -Cvcycloalkyl)Co-C 4 alkyl, (phenyl)C 0 -C 4 alkyl, -Ci-C 4 alkylOC(0)OCi-C 6 alkyl, -C C 4 alkylOC(0)Ci-C 6 alkyl, -C C 4 alkylC(0)OCi-C 6 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1 , 2, or 3 heteroatoms independently chosen 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 chosen from N, O, and S.
  • R 23 is independently chosen at each occurrence from (C -C 7 cycloalkyl)C 0 - C 4 alkyl, (phenyl)Co-C 4 alkyl, (4- to 7-membered heterocycloalkyl)Co-C 4 alkyl having 1 , 2, or 3 heteroatoms independently chosen 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 chosen from N, O, and S.
  • Either X 2 is nitrogen or at least one of (d), (e), (g), (i), (1), (n), (p), (s), (v), (x), and (y) is present.
  • Pharmaceutical compositions comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier are also disclosed.
  • ASD age-related macular degeneration
  • retinal degeneration other ophthalmic diseases (e.g., geographic atrophy), paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), arthritis including rheumatoid arthritis (RA), a respiratory disease or a cardiovascular disease)
  • PNH paroxysymal nocturnal hemoglobinuria
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • a respiratory disease or a cardiovascular disease comprising administering a therapeutically effective amount of a compound or salt of Formula I to a host, including a human, in need of such treatment are also disclosed.
  • an effective amount of an active factor D inhibiting compound is provided to treat an inflammatory or immune disorder, including an autoimmune disorder, that is meadited or affected by factor D.
  • an inflammatory or immune disorder including an autoimmune disorder, that is meadited or affected by factor D.
  • the compound of Formula I can be used to treat a disorder mediated by the complement pathway, regardless whether it is acting through Factor D.
  • the present invention includes at least the following features:
  • cascade factor D including age-related macular degeneration (AMD), retinal degeneration, paroxysymal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS), and rheumatoid arthritis (RA) and other disorders described further herein;
  • 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.
  • "Formula I” includes all subgeneric groups of Formula I, such as Formula IA and Formula IB and also includes pharmaceutically acceptable salts of a compound of Formula I, unless clearly contraindicated by the context in which this phrase is used.
  • Forma I also includes all subgeneric groups of Formula I, such as Formulas IC - ID, and Formulas II - XXX, and also includes pharmaceutically acceptable salts of all subgeneric groups of Formula I, such as Formulas IA - ID, and Formulas II - XXX, unless contraindicated by the context in which this phrase is used.
  • the present invention includes compounds of Formula I and the use of compounds 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 that can be incorporated into compounds of the invention 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.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
  • 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.
  • 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 occurs within an R group substituent on the L-B moiety region. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R 18 , R 18' , R 33 , R 34 , R 35 , and/or R 36. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group substituent within the A-carbonyl moiety region.
  • the substitution of a hydrogen atom for a deuterium atom occurs within an R group when at least one of the variables within the R group is hydrogen (e.g., 2 H or D) or alkyl (e.g., CD 3 ).
  • the alkyl residue is typically deuterated, e.g., CD 3i CH 2 CD 3 or CD 2 CD 3 .
  • the hydrogen may be isotopically enriched as deuterium (i.e., 2 H).
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • a stable compound or stable structure refers to a compound leading to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
  • "optionally substituted” includes one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH 2 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -Ci- C 6 alkoxy, C 2 -C 6 arkanoyl, Ci-Cealkylester, (mono- and di-Ci-C 6 alkylamino)Co-C 2 alkyl, Ci- C 2 haloalkyl, hydoxyCi-C 6 alkyl, ester, carbamate, urea, sulfonamide,-Ci-C 6 alkyl(heterocyclo), Ci-C 6 alkyl(heteroaryl), -Ci-C 6 alkyl(C 3 -C 7 cycloalkyl),
  • 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 Ci-C 2 , Ci-C 3 , 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- C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 0 -C n alkyl When C 0 -C n alkyl is used herein in conjunction with another group, for example, (C 3 _ C 7 cycloalkyl)Co-C 4 alkyl, or -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), 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-C 4 alkyl(C 3 -C 7 cycloalkyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted as described above.
  • 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 C 2 -Csalkenyl, C 2 -C 6 alkenyl and C 2 -C 4 alkenyl.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl include, but are not limited to, ethenyl and propenyl. 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, C 2 -Cgalkynyl 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-C 4 alkylene, Ci-C 3 alkylene, or Ci-C 2 alkylene.
  • 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 C 2 -C 4 alkynylene.
  • alkenyloxy is an alkenyl group as defined covalently bound to the group it substitutes by an oxygen bridge (-0-).
  • Haloalkyl indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • 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.
  • Halo or "halogen” indicates independently any of fluoro, chloro, bromo, and iodo.
  • Aryl indicates aromatic groups 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.
  • substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4- methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl.
  • 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 radical 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 and sulfur, 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, and S) or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), 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.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A.
  • Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently chosen from N, S, and O, with remaining ring atoms being carbon. In a typical embodiment, nitrogen is the heteroatm. 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.
  • “Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt of Formula I, 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.
  • “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, 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.
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a "patient” or “host” or “subject” is a human or non-human animal in need of modulation of the complement factor D pathway. Typically the host is a human.
  • a "patient” or “host” or “subject” also refers to for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • 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 of Formula I with at least one additional active agent means the compound of Formula I 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 separated by some amount of time that is within the time in which both the compound of Formula I and the at least one additional active agent are within the blood stream of a patient.
  • the compound of Formula I 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.
  • Non- limiting examples of compounds falling within Formula I with variations in the variables e.g., A, B, R ⁇ -R 3 , and L, are illustrated below. The disclosure includes all combinations of these definitions so long as a stable compound results.
  • n 0 or 1.
  • the disclosure includes compounds and salts of Formula I and pharmaceutically acceptable compositions thereof, and any of its subformulae (II-XXX) in which at least one of the following conditions is met in the embodiments described below.
  • R 12 and R 13 are independently chosen at each occurrence from (q), (r) and (s):
  • R 12 or R 13 are independently selected from:
  • the disclosure provides compounds of Formula I, wherein;
  • R 30 is as defined in the summary section above.
  • R 5 is hydrogen, halogen, or Ci-C 2 alkyl
  • R 11 , R 13 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, amino, Ci-C 4 alkyl, Ci-C 4 alkoxy, -Co-C 2 alkyl(mono- and di- Ci-C 2 alkylamino), trifluoromethyl, and trifluoromethoxy;
  • R 12 and R 13 are selected from hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R 12 and R 13 is chosen from (s):
  • the central core moiety is 4-fluoroproline.
  • R 1 , R 1 ' , R 2 ' , R 3 , and R 3 ' if present, are all hydrogen; and R 2 is fluoro.
  • 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:
  • a second heteroatom such as N, O, S, or Si
  • Another modification within the scope of the disclosure is joining a substituent on the central pyrrolidine ring to R 7 or R 8 to form a 5- to 6- membered heterocyclic ring, for example:
  • R 18 and R 18 are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0 or 1 ; and
  • the disclosure further includes compounds and salts of Formula I in which B is 2-fluoro-3-chlorophenyl.
  • B 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.
  • B is phenyl, pyridyl, or indanyl each of which is unsubstituted or substituted with one or more substituents independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci- C 6 thioalkyl, (mono- and di-Ci-C 6 alkylamino)Co-C 4 alkyl, (C 3 -Cvcycloalkyl)Co-C 4 alkyl, -C 0 - C 4 alkoxy(C 3 -C 7 cycloalkyl), (phenyl)Co-C 2 alkyl, (pyridyl)Co-C 2 alkyl; each of which substituents other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one
  • R 23 is independently chosen at each occurrence from (C 3 - Cycycloalkyl)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 chosen 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 chosen from N, O, and S.
  • R s y rogen met y, or tr uoromet y
  • R s y rogen or aogen an R s hydrogen, methyl, trifluoromethyl, or -Si(CH 3 )2C(CH 3 ) 3 .
  • A is a group chosen from (k) and (1) where (k) is
  • R 4 is (m) or (n):
  • each of which R 4 other than hydrogen, -CHO, and -CONH 2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 2 alkoxy, -Co-C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 5 and R 6 are independently chosen from (o) and (p):
  • R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH is unsubstituted or optionally substituted.
  • R 5 and R 6 other than hydrogen, hydroxyl, cyano, and -COOH may be substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C(0)alkyl, C(0)cycloalkyl, C(0)aryl, C(0)heterocycle, and C(0)heteroaryl.
  • R 7 is hydrogen, Ci-C 6 alkyl, or -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl).
  • R 8 and R 8 are independently chosen from hydrogen, halogen, hydroxyl, Ci- C 6 alkyl, Ci-C 6 alkoxy, and (Ci-C 4 alkylamino)Co-C 2 alkyl, or R 8 and R 8 are taken together to form an oxo group, or can be taken together with the carbon that they are bonded to form a 3- membered carbocyclic ring.
  • R 19 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, -S0 2 Ci-C 6 alkyl, (mono- and di-Ci-C 6 alkylamino)Ci-C 4 alkyl, -Co-C 4 alkyl(C3-C 7 cycloalkyl), -C 0 -C 4 alkyl(C 3 - C 7 heterocycloalkyl), -Co-C 4 alkyl(aryl), Co-C 4 alkyl(heteroaryl), each of which R 19 other than hydrogen is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, -COOH, and -C(0)OCi-C 4 alkyl.
  • X 12 is N or CR 12 .
  • X 14 is N or CR 14 .
  • R 11 , R 14 , and R 15 are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, -NR 9 C(0)R 10 , C(0)NR 9 R 10 , -0(PO)(OR 9 ) 2 , -(PO)(OR 9 ) 2 , d- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkenyl(aryl), C 2 -C 6 alkenyl(cycloalkyl), C 2 -C 6 alkenyl(heterocycle), C 2 -C 6 alkenyl(heteroaryl), C 2 -C 6 alkynyl, C 2 -C 6 alkynyl(aryl), C 2 -C 6 alkynyl(cycloalkyl), C 2 - C 6 alkynyl(heterocycle), C 2 -Cealkynyl(heteroaryl), C 2 -C 6 alkyl
  • R 5 and R 6 are independently chosen from -CHO, -C(0)NH 2 , -C(0)NH(CH 3 ), C 2 -C 6 alkanoyl, 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 chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, Ci-C 2 alkyl, Ci-C 4 alkoxy, -Co- C 2 alkyl(mono- and di-Ci-C 4 alkylamino), Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy i C(0)alkyl, C(0)cycloalkyl, C(0)aryl, C(0)heterocycle, and C(0)heteroaryl.
  • R 8 and R 8 are independently hydrogen or methyl.
  • R 8 and R 8 are hydrogen.
  • R 7 is hydrogen or methyl.
  • R is hydrogen.
  • two A groups can be bonded together to form a dimer through a suitable linking group that achieves the desired purpose.
  • linking groups include but are not limited to, urea, amide, -C(0)-C(0)-, carbamate and ketone.
  • two heteroaryl rings for example, two indole rings, are linked through a urea to form indole-NHC(0)NH-indole.
  • this disclosure includes compounds and salts of Formula IA:
  • R 6 , R 13 , and B may carry any of the definitions set forth herein for this variable.
  • this disclosure includes compounds and salts of Formula IB, IC, and I
  • R 1 , R 2 , R 2 , and R 3 are independently chosen from hydrogen, halogen, Ci- C 4 alkyl, Ci-C 4 alkoxy, -C 0 -C 2 alkylNR 9 R 10 , -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -O-C 0 -C 4 alkyl(C 3 - C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy;
  • R 8 and R 8 are independently chosen from hydrogen, halogen, and methyl;
  • R 5 is hydrogen, hydroxyl, cyano, -COOH, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 2 - C 6 alkanoyl -C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), -C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl, Ci-C 2 haloalkyl, or C i -C 2 haloalkoxy ;
  • R 6 is -C(0)CH 3 , -C(0)NH 2 , -C(0)CF 3 , -C(0)(cyclopropyl), or
  • R 11 and R 14 are independently chosen from hydrogen, halogen, hydroxyl, amino, nitro, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, Ci-C 6 alkoxy, Ci-C 6 thioalkyl, -C 0 - C 4 alkyl(mono- and di-Ci-Cealkylamino), -Co-C 4 alkyl(C 3 -C 7 cycloalkyl), -OCo-C 4 alkyl(C 3 - C 7 cycloalkyl), Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • compositions comprising an effective amount of compound or pharmaceutically acceptable salt of Formula I, together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain a compound or salt of Formula I as the only active agent, or, in an alternative embodiment, Formula I and at least one additional active agent.
  • 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 a compound of Formula I and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
  • the pharmaceutical composition may also include a molar ratio of a compound of Formula I and an additional active agent.
  • 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 another antiinflammatory agent.
  • Compounds disclosed 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, intraveneous, intra-aortal, intracranial, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • 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.
  • Carriers include excipients and diluents and 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, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, 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.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • compositions/combinations can be formulated for oral administration.
  • These compositions can contain any amount of active compound for Formula I that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of a compound of Formula I and usually at least about 5 wt.% of a compound of Formula I.
  • Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound of Formula I.
  • the complement factor D inhibitors of the present invention can be administered, for example, either systemically or locally.
  • Systemic administration includes, for example, oral, transdermal, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal.
  • Local administration for ocular administration includes: topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, sub-tenon, or via an intraocular device.
  • the inhibitors may be delivered via a sustained delivery device implanted intravitreally or transsclerally, or by other known means of local ocular delivery.
  • the compounds and pharmaceutical compositions disclosed herein are useful for treating or preventing a disorder that is mediated by the complement pathway, and in particular, a pathway that is modulated by complement factor D.
  • the disorder is an inflammatory disorder, an immune disorder, an autoimmune disorder, or complement factor D related disorders in a host.
  • the disorder is an ocular disorder.
  • Complement mediated disorders that may be treated or prevented by the compounds and compositions of this disclosure include, but are not limited to, inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), ischemia/ reperfusion injury (I/R injury), psoriasis, myasthenia gravis, system lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burn injury, capillary leak syndrome, obesity, diabetes, Alzheimer's dementia, stroke, schizophrenia, epilepsy, age-related macular degeneration, glaucoma, diabetic retinopathy, asthma, allergy, acute respiratory distress syndrome (ARDS), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), cystic fibrosis, myocardial infarction, lupus nephritides, Crohn's disease, rheumatoid arthritis, at
  • lung disease and disorders such as dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex- associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome, arthritis,
  • COPD chronic ob
  • complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases.
  • ophthalmic diseases including early or neovascular age-related macular degeneration and geographic atrophy
  • autoimmune diseases including arthritis, rheumatoid arthritis
  • respiratory diseases including cardiovascular diseases.
  • the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
  • a method for the treatment of paroxysmal nocturnal hemoglobinuria includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of age- related macular degeneration is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of rheumatoid arthritis is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of multiple sclerosis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of myasthenia gravis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of atypical hemolytic uremic syndrome (aHUS) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of C3 glomerulonephritis includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of abdominal aortic aneurysm includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method for the treatment of neuromyelitis optica (NMO) is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • the present invention provides methods of treating or preventing an inflammatory disorder or a complement related disease, by administering to a host in need thereof an effective amount of a compound of Formula I of the invention.
  • the present invention provides methods of treating or preventing an inflammatory disorder more generally, an immune disorder, autoimmune disorder, or complement factor D related disease, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to patient with a factor D mediated inflammatory disorder.
  • a compound or salt of Formula I may be provided as the only active agent or may be provided together with one or more additional active agents.
  • a method for the treatment of a disorder associated with a dysfunction in the complement cascade includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method of inhibiting activation of the alternative complement pathway in a subject includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a method of modulating factor D activity in a subject is provided that includes the administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • prevention means decreasing the likelihood of the appearance of symptoms in a patient administered the compound prophylactically as compared to the likelihood of the appearance of symptoms in patients not administered the compound or decreasing the severity of symptoms in a patient administered the compound prophylactically as compared to the severity of symptoms experienced by patients with the disorder or condition who were not administered the compound.
  • an effective amount of a compound of Formula I is used to prevent or prophylaxis of a complement factor D related disorder.
  • An effective amount of a pharmaceutical composition/ combination of the invention may be 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 disease; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease; or (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement factor D related disease.
  • An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or theoretically, by calculating bioavailability.
  • a compound or salt of Formula I may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action.
  • a compound or salt of Formula I may be provided in combination with a complement C5 inhibitor or C5 convertase inhibitor.
  • a compound or salt of Formula I may be provided in combination with eculizumab.
  • a compound or salt of Formula I may be provided in combination with additional inhibitors of factor D.
  • a compound or salt of Formula I may be provided together with a compound that inhibits an enzyme that metabolizes protease inhibitors. In one embodiment, a compound or salt of Formula I may be provided together with ritonavir.
  • a compound or salt of Formula I may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitors, receptor agonists, or siRNAs.
  • Nonlimiting examples of active agents in these categories are: [0246] Protease inhibitors: plasma-derived Cl-INH concentrates, for example Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®; and recombinant human CI -inhibitors, for example Rhucin®;
  • Soluble complement regulators Soluble complement receptor 1 (TP 10) (Avant
  • Immunotherapeutics sCRl-sLe x /TP-20 (Avant Immunotherapeutics); MLN-2222 /CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals);
  • Therapeutic antibodies Eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX- 558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S);
  • Complement component inhibitors include Compstatin/POT-4 (Potentia Pharmaceuticals); ARC 1905 (Archemix);
  • Receptor agonists PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);
  • the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention.
  • AMD age-related macular degeneration
  • the compositions of the present invention are administered in combination with an anti-VEGF agent.
  • Nonlimiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech/Roche); anecortane acetate, squalamine lactate, and corticosteroids, including, but not limited to, triamcinolone acetonide.
  • a compound of Formula I can be combined with a second agent in order to treat a disorder of the eye.
  • Examples of types of therapeutic agents that can be used in combination for ocular applications include anti-inflammatory drugs, antimicrobial agents, anti-angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs and combinations thereof.
  • therapeutic agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itrac
  • eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-prolife
  • a compound of Formula I, or a combination of Formula I and another active agent can be administered into an eye compartment of via injection into the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera, the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial).
  • a compound of Formula I, or a combination of Formula I and another active agent can be administered into an eye compartment via binding to a mucosal penetrating particle to treat a condition located in the vitreous chamber, subretinal space, subchoroidal space, the episclera, the conjunctiva, the sclera or the anterior chamber, and the cornea and compartments therein (e.g., subepithelial, intrastromal, endothelial).
  • Mucosal penetrating particles are known in the art, and are described in, for example, PCT published application WO 2013166436 to Kala Pharmaceuticals, incorporated in its entirety herein.
  • a composition comprising compound of Formula I suitable for topical administration to an eye.
  • the pharmaceutical composition comprises a plurality of coated particles, comprising a core particle comprising a compound of Formula I, wherein Formula I constitutes at least about 80 wt% of the core particle, and a coating comprising one or more surface-altering agents, wherein the one or more surface-altering agents comprise at least one of a poloxamer, a poly(vinyl alcohol), or a polysorbate.
  • the one or more surface-altering agents is present on the outer surface of the core particle at a density of at least 0.01 molecules/nm.
  • the one or more surface-altering agents is present in the pharmaceutical composition in an amount of between about 0.001% to about 5% by weight.
  • the plurality of coated particles have an average smallest cross-sectional dimension of less than about 1 micron.
  • the pharmaceutical composition also includes one or more ophthalmically acceptable carriers, additives, and/or diluents.
  • particles suitable for use with the presently disclosed methods can exist in a variety of shapes, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings, nanorings, rod- shaped particles, arrow-shaped particles, teardrop-shaped particles, tetrapod- shaped particles, prism-shaped particles, and a plurality of other geometric and non-geometric shapes.
  • the presently disclosed particles have a spherical shape.
  • the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system or another active compound with a different biological mechanism of action.
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with eculizumab.
  • PNH paroxysmal nocturnal hemoglobinuria
  • a compound of Formula I is administered in combination or alternation with at least one anti-rhuematoid arthritis drug selected from: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine), indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors, including diclofenac
  • the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention. In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with additional inhibitors of the complement system. In another embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the current invention in combination or alternation with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.
  • a compound of Formula I is combined with at least one anti- multiple sclerosis drug selected from: Aubagio (teriflunomide), Avonex (interferon beta- la), Betaseron (interferon beta- lb), Copaxone (glatiramer acetate), Extavia (interferon beta- lb), Gilenya (fmgolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta- la), Rebif (interferon beta- la), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH), and combinations thereof.
  • Aubagio teriflunomide
  • Avonex interferon beta- la
  • Betaseron interferon beta- lb
  • Copaxone
  • a compound or salt of Formula I may be provided in combination or alternation with an immunosuppressive agent or an anti-inflammatory agent.
  • a compound described herein can be administered in combination or alternation with at least one immunosuppressive agent.
  • the immunosuppressive agent as nonlimiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natal
  • anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids,
  • a compound of Formula I is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • a heteroaryl compound, Structure 9-1 is coupled to an activated ester, Structure 9-2, to generate Structure 9-3.
  • the leaving group, LGi is a halide.
  • LG is a halide.
  • Structure 9-3 is treated with an inorganic cyanide and two organometallic catalyst to generate structure 9- 4.
  • the inorganic cyanide is zinc cyanide.
  • the two organometallic catalysts are Pd 2 (dba) 3 and Pd(dppf)Cl 2 .
  • Structure 9-4 is treated with an organic acid to generate Structure 9-5.
  • the organic acid is trifluoroacetic acid.
  • Structure 9-5 is coupled to Structure 3 from Route 1 to generate compounds of Formula I. This chemistry is illustrated in Route 9.
  • a central core that is directed linked to an aryl or heteroaryl group in place of the L-B region can be prepared according to known processes.
  • a central core is alkylated to generate a central core -A compound comprising a carboxylic acid is reduced to an alcohol and used to generate an alkyl halide.
  • the alkyl halide is treated with a heteroaryl compound to generate a compound of Formula I.
  • This chemistry can be carried out by those skilled in the art of organic chemistry. See for example: Advanced Organic Chemistry: Reactions, Mechanisms and Structure by J. March.
  • 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(l,l-dimethylethyl) ester, (4S)-, CAS 209269-08-9 can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144.
  • Step 2 the protected azaspiro[2.4]heptane is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety.
  • the amine is (3-chloro-2-fluorophenyl) methanamine.
  • the organic solvent is DMF.
  • Boc-L-proline is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to generate an amide bond; the L-B moiety.
  • the amine is (3-chloro-2-fluorophenyl) methanamine.
  • the organic solvent is DMF.
  • the base is diisopropylethylamine.
  • the coupling reagent is HATU.
  • the Boc protecting group is removed.
  • the starting material is reacted with an acid in the presence of an organic solvent.
  • the acid is 4N hydrochloric acid.
  • the organic solvent is dioxane.
  • the compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-l,2-dicarboxylic acid 1-tert- butyl ester can be prepared as a mixture according to WO 2012/093101 to Novartis and the regioisomers can be ultimately separated once coupled to generate the central core-L-B synthons.
  • the compound (S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the Aldrich Chemical Co.
  • Structure 1-5 from Example 4 Route 4a, is coupled to Structure 3 from Route 1 to generate compounds of Formula I. This chemistry is illustrated in Route 5 a.
  • Structure 3-5 from Example 4 Route 4c, is coupled to Structure 3 from Route 1 to generate compounds of Formula I. This chemistry is illustrated in Route 5c.
  • Step 3 (2S,4R)-N-(2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)-4-fluoropyrrolidine-2- carboxamide hydrochloride (Int-1)
  • SM8 was dissolved in DCM and equal volume of TFA was added. The mixture was stirred for 30 min at rt. The volatiles were removed under reduced pressure and the the residue Int-2 was used without further purification.
  • Step 4 tert-Butyl 2-(3-cyano-lH-thieno[3,2-c]pyrazol-l-yl)acetate(99e)
  • Step 6 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-thieno[3,2-c]pyrazole-3-carboxamide (99)
  • reaction mixture was stirred for 0.5 h at rt , then quenched by aq NaHC0 3 (5 mL).
  • the mixture was extracted with EtOAc (30 mL) and the organic layer was washed with water and brine.
  • the solvent was removed under reduced pressure and the remaining residue was purified by column chromatography (eluent: 5% MeOH in DCM) to give 109 (57 mg).
  • Step 7 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-5-methyl-lH-thieno[3,2-c]pyrazole-3-carboxamide (113)
  • Step 1 Ethyl l-(2-(tert-butoxy)-2-oxoethyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxylate (104b)
  • Step 2 2-(3-(Ethoxycarbonyl)-4,5,6,7-tetrahydro-lH-indazol-l-yl)acetic acid (104d)
  • Step 3 Ethyl l-(2-((2S,4R)-2-((2'-chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxylate (104e)
  • Step 4 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxylic acid (104f)
  • Step 5 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxamide (104)
  • Acid 104f (252 mg, 0.46 mmol) from Step 4 was mixed with NH 4 C1 (125 mg, 2.32 mmol) in DMF (3 mL). To this solution was added HATU (262 mg, 0.69 mmol) followed by dropwise addition of DIEA (1.38 mmol, 0.24 mL). The mixture was stirred for 3 h at rt and the volatiles were removed under reduced pressure. The remaining residue was diluted with 10%> aq sodium carbonate (15 mL) and water (15 mL), and then extracted with ethyl acetate (3 ⁇ 25 mL). The combined organic solution was washed with water and brine, and then dried over MgS0 4 .
  • Step 1 Methyl 2-(3-acetyl-8-(3-chlorophenyl)-lH-pyrazolo[4,3-g]indolizin-l-yl)acetate (105c)
  • Step 3 (2S,4R)-l-(2-(3-Acetyl-8-(3-chlorophenyl)-lH-imidazo[l,2-a]pyrazolo[3,4-c]pyridin- l-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (105)
  • Step 5 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-7-cyano-lH-indazole-3-carboxamid (111)
  • Step 1 l-(3'-Amino-6-chloro-2'-fluoro-[l,l'-biphenyl]-3-yl)ethanone (117c)
  • Step 3 (2S,4R)-N-(5 '- Acetyl-2 '-chloro-2-fluoro- [1 , 1 '-biphenyl] -3-yl)-4-fluoropyrrolidine-2- carboxamide TFA salt (117e)
  • Step 4 l-(2-((2S,4R)-2-((5'-Acetyl-2'-chloro-2-fluoro-[l,l , -biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (117)
  • Step 1 tert-Butyl 2-(4-bromo-3-carbamoyl-lH-pyrazol-l-yl)acetate (110b)
  • Step 2 tert-Butyl 2-(3-carbamoyl-4-(2-methoxypyrimidin-5-yl)-lH-pyrazol-l-yl)acetate (110c)
  • Step 4 l-(2-((2S,4R)-2-((2'-Chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-4-(2-methoxypyrimidin-5-yl)-lH-pyrazole-3- carboxamide (110)
  • Step 2 (1R,3 S,5R)-2-(2-(4-Bromo-3-carbamoyl- lH-pyrazol- l-yl)acetyl)-N-(2 '-chloro-2- fluor 0- [1,1 '-biphenyl] -3-yl)-2-azabicyclo [3.1.0] hexane-3-carboxamide (77)
  • the title compound 77 (50 mg) was prepared from 2-(4-bromo-3 -carbamoyl- 1H- pyrazol-l-yl)acetic acid 77a and (lR,3S,5R)-N-(2 , -chloro-2-fluoro-[l,l , -biphenyl]-3-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (131 mg) in a manner similar to that described in Scheme 5.
  • the reaction mixture was cooled to rt and the volatiles were removed under reduced pressure. The remaining residue was purified by column chromatography. The desired product fractions were collected and concentrated, and then the HC1 salt 80c was made by treatment with HCl/MeOH. 13.1 g of 80c was obtained.
  • Step 3 (2S,4R)-tert-Butyl l-iil'-chloro-l ⁇ S'-trifluoro-Il ⁇ '-biphen ll-S- carbamo l) ⁇ - fluoropyrrolidine-l-carboxylate (80d)
  • Step 4 (2S,4R)-N-(2'-Chloro-2,4',5 , -trifluoro-[l,l , -biphenyl]-3-yl)-4-fluoropyrrolidine-2- carboxamide hydrochloride (80e)
  • tert-Butyl 2-(3 -carbamoyl- lH-indazol-l-yl)acetate 80g (1.0 g) was taken in 4 N HC1 in dioxane (10 mL) and the resulting reaction mixture was stirred at rt for 2 h. The solvent was then removed under reduced pressure and the remaining residue 80h was used directly without further purification.
  • Step 7 l-il-iilS ⁇ Ri-l-iil'-Chloro-l ⁇ S'-trifluoro-Il ⁇ '-biphenyll-S-y carbamoyl) ⁇ - fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-indazole-3-carboxamide (80)
  • Table 1 shows illustrative compounds of Formula I with characaterizing data.
  • the assay of Example 8 was used to determine the ICso's of the compounds.
  • Other standard factor D inhibition assays are also available.
  • Three ***s are used to denote compounds with an IC 50 less than 1 micromolar; two **s indicate compound with an IC 50 between 1 micromolar and 10 micromolar, and one * denotes compounds with an IC 50 greater than 10 micromolar.
  • Human factor D (purified from human serum, Complement Technology, Inc.) at 80 nM final concentration is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl, pH 7.5.
  • a synthetic substrate Z-L-Lys- SBzl and DTNB (Ellman's reagent) are added to final concentrations of 100 ⁇ each.
  • the increase in color is recorded at OD405 nm in a microplate in kinetic mode over 30 minutes with 30 second time points in a spectra fluorimeter.
  • IC50 values are calculated by non- linear regression from the percentage of inhibition of complement factor D activity as a function of test compound concentration.
  • the hemolysis assay was previously described by G. Ruiz-Gomez, et al, J. Med. Chem. (2009) 52: 6042-6052.
  • red blood cells RBC
  • rabbit erythrocytes purchased from Complement Technologies
  • GVB Buffer 0.1 % gelatin, 5 mM Veronal, 145 mM NaCl, 0.025 % NaN 3 , pH 7.3
  • Cells are used at a concentration of 1 x 10 8 cells/mL.
  • the optimum concentration of Normal Human Serum (NHS) needed to achieve 100% lysis of rabbit erythrocytes is determined by titration.
  • NHS (Complement Technologies) is incubated with inhibitor for 15 min at 37 °C, rabbit erythrocytes in buffer were added and incubated for an additional 30 min at 37 °C.
  • Positive control (100% lysis) consists of serum and RBC and negative control (0% lysis) of Mg-EGTA buffer and RBC only. Samples are centrifuged at 2000g for 5 min, and supernatants collected. Optical density of the supernatant is monitored at 405 nm using a UV/visible spectrophotometer. Percentage lysis in each sample is calculated relative to positive control (100% lysis).

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