WO2014005150A1 - Formes cristallines du l-(2-((1r,3s,5r)-3-((2-fluoro-3-(trifluorométhoxy)phényl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-5-méthyl-1h-pyrazolo[3,4-c]pyridine-3-carboxamide et sels de celui-ci - Google Patents

Formes cristallines du l-(2-((1r,3s,5r)-3-((2-fluoro-3-(trifluorométhoxy)phényl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-5-méthyl-1h-pyrazolo[3,4-c]pyridine-3-carboxamide et sels de celui-ci Download PDF

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WO2014005150A1
WO2014005150A1 PCT/US2013/048960 US2013048960W WO2014005150A1 WO 2014005150 A1 WO2014005150 A1 WO 2014005150A1 US 2013048960 W US2013048960 W US 2013048960W WO 2014005150 A1 WO2014005150 A1 WO 2014005150A1
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WIPO (PCT)
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pharmaceutically acceptable
hexan
oxoethyl
pyrazolo
trifluoromethoxy
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PCT/US2013/048960
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English (en)
Inventor
Christopher Towler
Eva Altmann
Ulrich Hommel
Edwige Liliane Jeanne Lorthiois
Juergen Klaus Maibaum
Nils Ostermann
Jean Quancard
Stefan Andreas Randl
Oliver Simic
Anna Vulpetti
Olivier Rogel
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Novartis Ag
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Publication of WO2014005150A1 publication Critical patent/WO2014005150A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present disclosure generally relates to polymorphic forms of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of 10 methods of using the form(s) in the treatment of Age-related Macular Degeneration
  • the complement system is a crucial component of the innate immunity system
  • the 15 comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391 ). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease 0 complexes known as the C3-convertase and the C5-convertase.
  • the classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes.
  • the alternative pathway is a 5 magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
  • Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (about 0 1.8 ⁇ g/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Mijller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J. E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401 ).
  • Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with 5 abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the macula lutea In the center of the retina is the macula lutea, which is about 1/3 to 1 ⁇ 2 cm in diameter.
  • the macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganlion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones.
  • the choroid Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid
  • Age-related macular degeneration is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity.
  • Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form.
  • the dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces.
  • About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).
  • Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years.
  • Neovascular AMD cases originate from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
  • CNV choroidal neovascularizaton
  • AMD AMD
  • CNF complement factor H
  • Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population. Br J Ophthalmol. 2006
  • Embodiments of these crystalline forms include those characterized herein as 110 Forms A, B, C and D.
  • the present disclosure provides salts of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • Embodiments of these salts include those characterized herein as hydrochloride, fumarate, malonate, benzoate and glutamate.
  • the names used herein to characterize a specific form e.g. "Form A”, “Form 115 B", “Form C", “Form D", “Hydrochloride”, “Fumarate”, “Malonate", “Benzoate” and
  • Glutamate should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
  • FIG. 1 illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
  • FIG. 2. illustrates the differential scanning calorimetry (DSC)
  • thermogravimetric analysis of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
  • FIG. 3. illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3-((2- 130 fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
  • FIG. 4. illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- 135 methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 5 illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
  • FIG. 6. illustrates the differential scanning calorimetry (DSC) and 140 thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • FIG. 7 illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 145 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
  • FIG. 8. illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 9. illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Hydrochloride.
  • FIG. 10 illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- 155 (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Hydrochloride.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 1 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Fumarate.
  • FIG. 12. illustrates the differential scanning calorimetry (DSC)
  • thermogravimetric analysis of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Fumarate.
  • FIG. 13 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-((2- 165 fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Malonate.
  • FIG. 14 illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- 170 methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Malonate.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 15. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Benzoate.
  • FIG. 16. illustrates the differential scanning calorimetry (DSC) and
  • thermogravimetric analysis TGA of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • FIG. 17 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 180 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Glutamate.
  • FIG. 18 illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of crystalline 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Glutamate.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the disclosure relates to crystalline forms and salts of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, which are described and
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions
  • solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Solvates may occur as dimers or oligomers comprising more than one molecule or 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-
  • amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
  • substantially pure when used in reference to a form, means a
  • a crystalline form of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time
  • the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1 % by weight of any other physical forms of the compound.
  • compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.
  • the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.
  • composition consisting essentially of the crystalline form A of the 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form A of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 255 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide in the composition.
  • the invention is a crystalline form of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide .
  • the invention is a crystalline form according to the first embodiment, comprising 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • the invention is a crystalline form according to fist and
  • the invention is a crystalline form according to the first, second and third embodiments is Form A in a substantially pure form.
  • the invention is a crystalline form according to the first, second, third or fourth embodiments is characterized by a x-ray powder diffraction
  • the invention is a crystalline form according to the fifth embodiment is further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 7.56 ⁇ 0.2°, 8.05 ⁇ 0.2°, 9.54 ⁇ 0.2°, 10.25 ⁇ 0.2°, 10.97 ⁇ 0.2°, 10.97 ⁇ 0.2°, 1 1.92 ⁇ 0.2°, 12.69 ⁇ 0.2°, 14.68 ⁇ 0.2°, 16.88 ⁇ 0.2°, 17.55 ⁇ 0.2°, 18.10 ⁇ 0.2°, 18.91 ⁇ 0.2°, 19.43 ⁇ 0.2°, 19.95 ⁇ 0.2°, 20.69 ⁇ 0.2°, 22.57 ⁇ 0.2°,
  • the invention is a crystalline form of 1-(2-((1 R,3S,5R)- 3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 285 1.
  • the invention is a crystalline form of 1-(2-((1 R,3S,5R)-3- ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown 290 in FIG. 2.
  • DSC differential scanning calorimetry
  • the invention is a crystalline form 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 2.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical composition comprising the crystalline form according to the first through ninth embodiments and a
  • the invention is a pharmaceutical composition according to the tenth embodiment wherein said crystalline form is Form A.
  • the invention is a pharmaceutical composition according to the eleventh embodiment wherein said Form A is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first through ninth embodiments and a 305 second therapeutically active agent.
  • the invention is a pharmaceutical composition according to the thirteenth embodiment wherein said crystalline form is Form A.
  • the invention is a pharmaceutical composition according to the fourteenth embodiment wherein said Form A is in substantially pure 310 form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1-(2-((1 R,3S,5R)-3-
  • the invention is a method according to the sixteenth embodiment wherein said crystalline form is Form A.
  • the invention is a method according to the seventeenth embodiment wherein said Form A is in substantially pure form.
  • the invention is a method according to the sixteenth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 325 weight % of the crystalline form according to second through ninth embodiments, based the weight of the composition.
  • the invention is a process of making Form A of 1-(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 330 carboxamide comprising the steps of Example 1.
  • composition consisting essentially of the crystalline form B of the 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • 335 may comprise at least 90 weight % of the crystalline form B of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-
  • the invention is the crystalline form according to the first embodiment comprising 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
  • the invention is the crystalline form according to the first or twenty second embodiments consisting essentially of Form B.
  • the invention is the crystalline form according to the first or twenty second through twenty third embodiments wherein said Form B is in substantially pure form.
  • the invention is the crystalline form according to the first and twenty second through twenty fourth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 5.53 ⁇ 0.2°, 6.21 ⁇ 0.2°, 7.73 ⁇ 0.2°, 9.68 ⁇ 0.2°, 10.81 ⁇ 0.2°, 1 1.16 ⁇ 0.2°, 12.03 ⁇ 0.2°, 13.42 ⁇ 0.2°, 14.29 ⁇ 0.2°, 15.1 1 ⁇ 0.2°, 15.88 ⁇ 0.2°, 16.40 ⁇ 0.2°, 16.82 ⁇ 0.2°,
  • the invention is the crystalline form according to the twenty fifth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 5.53 ⁇ 0.2°, 360 6.21 ⁇ 0.2°, 7.73 ⁇ 0.2°, 9.68 ⁇ 0.2°, 10.81 ⁇ 0.2°, 1 1 .16 ⁇ 0.2°, 12.03 ⁇ 0.2°, 13.42 ⁇ 0.2°,
  • the invention is a crystalline form of 1-(2- 365 ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
  • the invention is a crystalline form of 1-(2- 370 ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 4.
  • DSC differential scanning calorimetry
  • the invention is a crystalline form 1-(2- 375 ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 4.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical composition
  • the invention is the pharmaceutical composition according to the thirtieth embodiment wherein said crystalline form is Form B.
  • the invention is the pharmaceutical composition 385 according to the thirty first embodiment wherein said Form B is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and twenty second through twenty ninth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the thirty third embodiment wherein said crystalline form is Form B.
  • the invention is the pharmaceutical composition according to the thirty fourth embodiment wherein said Form B is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1-(2-((1 R,3S,5R)-3- ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- 400 oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and twenty second through twenty ninth embodiments.
  • the invention is the method according to the thirty sixth embodiment wherein said crystalline form is Form B.
  • the invention is the method according to the thirty 405 seventh embodiment wherein said Form B is in substantially pure form.
  • the invention is the method according to the thrity sixth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the twenty second through the twenty ninth 410 embodiments based the weight of the composition.
  • the invention is a process of making Form B of 1-(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide comprising the steps of Example 2.
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form C of 1 -(2-((1 R,3S,5R)-3-((2-
  • the invention is the crystalline form according to the first embodiment comprising 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
  • the invention is the crystalline form according to the
  • first and forty second embodiments 42 consisting essentially of Form C.
  • the invention is the crystalline form according to the first and forty second through forty third embodiments wherein said Form C is in substantially pure form.
  • the invention is the crystalline form according to the
  • first and forty second through forty fourth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 7.53 ⁇ 0.2°, 9.22 ⁇ 0.2°, 10.50 ⁇ 0.2°, 1 1.72 ⁇ 0.2°, 12.33 ⁇ 0.2°, 14.62 ⁇ 0.2°, 16.18 ⁇ 0.2°, 17.33 ⁇ 0.2°, 17.87 ⁇ 0.2°, 19.43 ⁇ 0.2°, 23.04 ⁇ 0.2°, 24.89 ⁇ 0.2° and 26.44 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to the forty fifth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 7.53 ⁇ 0.2°, 9.22 ⁇ 0.2°, 10.50 ⁇ 0.2°, 1 1.72 ⁇ 0.2°, 12.33 ⁇ 0.2°, 14.62 ⁇ 0.2°, 16.18 ⁇ 0.2°, 17.33 ⁇ 0.2°, 17.87 ⁇ 0.2°, 19.43 ⁇ 0.2°, 23.04 ⁇ 0.2°, 24.89 ⁇ 0.2° and 26.44 ⁇ 0.2°, at a temperature of
  • the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray
  • the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a differential scanning calorimetry (DSC) thermogram substantially
  • the invention is a crystalline form 1-(2-((1 R,3S,5R)-3- ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in shown in
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form according to the first and forty second through forty ninth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition
  • the invention is the pharmaceutical composition according to the fifty first embodiment wherein said Form C is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the 470 crystalline from according to any one of the first and forty second through forty ninth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the fifty third embodiment wherein said crystalline form is Form C.
  • the invention is the pharmaceutical composition 475 according to the fifty fourth embodiment wherein said Form C is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the 480 mammal a therapeutically-effective amount of a crystalline form of 1-(2-((1 R,3S,5R)-3- ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and forty second through forty ninth embodiments.
  • the invention is the method according to the fifty 485 sixth embodiment wherein said crystalline form is Form C.
  • the invention is the method according to the fifty seventh embodiment wherein said Form C is in substantially pure form.
  • the invention is the method according to the fifty sixth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the forty second through forty ninth embodiments based the weight of the composition.
  • the invention is a process of making Form C of 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 495 azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide comprising the steps of Example 3.
  • composition consisting essentially of the crystalline form D of the 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form D of 1 -(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 505 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide in the composition.
  • the invention is the crystalline form according to claim 1 comprising 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 510 carboxamide Form D.
  • the invention is the crystalline form according to the first of sixty second embodiments consisting essentially of Form D.
  • the invention is the crystalline form according to the first and sixty second through sixty third embodiments wherein said Form D is in 515 substantially pure form.
  • the invention is the crystalline form according to the first and sixty second through sixty fourth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 6.91 ⁇ 0.2°, 7.55 ⁇ 0.2°, 8.32 ⁇ 0.2°, 1 1 .12 ⁇ 0.2°, 13.00 ⁇ 0.2°, 13.83 ⁇ 0.2°, 14.61 ⁇ 0.2°, 520 16.71 ⁇ 0.2°, 17.99 ⁇ 0.2°, 19.10 ⁇ 0.2°, 20.01 ⁇ 0.2°, 20.72 ⁇ 0.2°, 21 .18 ⁇ 0.2°, 22.19 ⁇ 0.2°, 22.99 ⁇ 0.2°, 23.48 ⁇ 0.2°, 24.15 ⁇ 0.2°, 24.95 ⁇ 0.2° and 28.03 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to the sixty fifth embodiment further characterized by a x-ray powder diffraction pattern
  • 525 comprising five or more 2 ⁇ values selected from the group consisting of 6.91 ⁇ 0.2°, 7.55 ⁇ 0.2°, 8.32 ⁇ 0.2°, 1 1 .12 ⁇ 0.2°, 13.00 ⁇ 0.2°, 13.83 ⁇ 0.2°, 14.61 ⁇ 0.2°, 16.71 ⁇ 0.2°, 17.99 ⁇ 0.2°, 19.10 ⁇ 0.2°, 20.01 ⁇ 0.2°, 20.72 ⁇ 0.2°, 21.18 ⁇ 0.2°, 22.19 ⁇ 0.2°, 22.99 ⁇ 0.2°, 23.48 ⁇ 0.2°, 24.15 ⁇ 0.2°, 24.95 ⁇ 0.2° and 28.03 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is a crystalline form of 1 -(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-(2-aminoethyl)-2-(2-aminoethyl)-2-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the invention is a crystalline form of 1 -(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-(2-aminoethyl)-2-(2-aminoethyl)-2-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the invention is a crystalline form 1-(2-((1 R,3S,5R)-
  • thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 8.
  • the invention is a pharmaceutical composition 545 comprising the crystalline form according to the first and sixty second through sixty ninth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the seventieth embodiment wherein said crystalline form is Form D.
  • the invention is the pharmaceutical
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and sixty second through sixty ninth 555 embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the seventy third embodiment wherein said crystalline form is Form D.
  • the invention is the pharmaceutical composition according to the seventy fourth embodiment wherein said Form D is in substantially pure 560 form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1-(2-((1 R,3S,5R)-3- 565 ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and sixty second through sixty ninth embodiments.
  • the invention is the method according to the seventy sixth embodiment wherein said crystalline form is Form D.
  • the invention is the method according to the sevety seventh embodiment wherein said Form D is in substantially pure form.
  • the invention is the method according to seventy sixth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 575 weight % of the crystalline form according to the sixty second through sixty ninth
  • the invention is a process of making Form D of 1- (2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 580 carboxamide comprising the steps of Example 4.
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide.
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide hydrochloride.
  • the composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • the invention is the pharmaceutically acceptable salt according to the eighty second embodiment comprising 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Hydrochloride.
  • the invention is the pharmaceutically acceptable
  • the invention is the pharmaceutically acceptable salt according to eighty second through eighty fourth embodiments wherein said hydrochloride salt is in substantially pure form.
  • the invention is the pharmaceutically acceptable salt according to the eighty second through eighty fifth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 5.74 ⁇ 0.2°, 8.25 ⁇ 0.2°, 9.70 ⁇ 0.2°, 10.47 ⁇ 0.2°, 10.95 ⁇ 0.2°, 1 1 .93 ⁇ 0.2°, 12.39 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.48 ⁇ 0.2°, 14.84 ⁇ 0.2°, 15.69 ⁇ 0.2°, 16.36 ⁇ 0.2°, 17.87 ⁇ 0.2°,
  • the invention is the pharmaceutically acceptable salt according to the eighty sixth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group
  • the invention is a pharmaceutically acceptable 620 salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 9.
  • the invention is a pharmaceutically acceptable 625 salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 10.
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutically acceptable salt of 630 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 10.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical composition 635 comprising the pharmaceutically acceptable salt according to the eighty second through ninetieth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to ninety first embodiment wherein said pharmaceutically acceptable salt is the hydrochloride.
  • the invention is the pharmaceutical composition according to the ninety second embodiment wherein said hydrochloride salt is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the 645 pharmaceutically acceptable salt according to any one of the eighty second through
  • ninetieth embodiments and a second therapeutically active agent are provided.
  • the invention is the pharmaceutical composition according to the ninety fourth embodiment wherein said pharmaceutically acceptable salt is the hydrochloride.
  • the invention is the pharmaceutical composition according to the ninety fifth embodiment wherein said hydrochloride salt is in
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by
  • the invention is the method according to the
  • the invention is the method according to the ninety eighth embodiment wherein said hydrochloride salt is in substantially pure form.
  • the invention is the method according to ninety
  • the invention is a composition comprising at least 90 weight % of the pharmaceutically acceptable salt according to eighty second through ninetieth embodiments based the weight of the composition.
  • the invention is a process of making the
  • composition consisting essentially of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide fumarate, based on the weight of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide fumarate, based on the weight of 1-(2-((1 R,3S,5R)-3-((2-flu
  • the invention is the pharmaceutically acceptable salt according to the eighty second embodiment comprising 1-(2-((1 R,3S,5R)-3-((2-
  • the invention is the pharmaceutically acceptable salt according to eighty second and hundred third embodiments consisting essentially of the fumarate salt.
  • the invention is the pharmaceutically acceptable salt according to the eighty second and hundred third through hundred fourth embodiments wherein said fumarate salt is in substantially pure form.
  • the invention is the pharmaceutically acceptable salt according to the eighty second and hundred third through the hundred fifth
  • 695 embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 3.75 ⁇ 0.2°, 4.55 ⁇ 0.2°, 5.94 ⁇ 0.2°, 6.66 ⁇ 0.2°, 7.40 ⁇ 0.2°, 8.20 ⁇ 0.2°, 9.29 ⁇ 0.2°, 10.65 ⁇ 0.2°, 12.13 ⁇ 0.2°, 14.09 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.74 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.96 ⁇ 0.2°, 20.83 ⁇ 0.2°, 22.80 ⁇ 0.2°, 25.49 ⁇ 0.2° and 28.74 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the pharmaceutically
  • acceptable salt according to the hundred sixth embodiment further characterized by a x- ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 3.75 ⁇ 0.2°, 4.55 ⁇ 0.2°, 5.94 ⁇ 0.2°, 6.66 ⁇ 0.2°, 7.40 ⁇ 0.2°, 8.20 ⁇ 0.2°,
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 710 carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 1.
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 715 carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 12.
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 720 carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 12.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical composition comprising the pharmaceutically acceptable salt according to the eighty second and hundred second through the hundred tenth embodiments and a
  • the invention is the pharmaceutical composition according to the hundred eleventh embodiment wherein said pharmaceutically acceptable salt is the fumarate.
  • the invention is the pharmaceutical 730 composition according to the hundred and twelfth embodiment wherein said fumarate salt is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the pharmaceutically acceptable salt according to any one of the eighty second and hundred 735 second through the hundred tenth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the hundred fourteenth embodiment wherein said
  • pharmaceutically acceptable salt is the fumarate.
  • the invention is the pharmaceutical
  • composition according to the hundred fifteenth embodiment wherein said fumarate salt is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular
  • the invention is the method according to the hundred seventeenth embodiment wherein said pharmaceutically acceptable salt is the fumarate.
  • the invention is the method according 755 to the one hundred eighteenth embodiment wherein said fumarate salt is in substantially pure form.
  • the invention is the method according to the hundred seventeenth embodiment wherein the subject is a human.
  • the invention is a composition comprising 760 at least 90 weight % of the pharmaceutically acceptable salt according to the eighty second and hundred second through the hundred tenth embodiments based the weight of the composition.
  • the invention is a process of making the fumarate salt of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)- 765 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide comprising the steps of Example 6.
  • a composition consisting essentially of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide malonate, based on the weight of 1-(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • the invention is the pharmaceutically acceptable salt according to the eighty second embodiment comprising 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • the invention is the pharmaceutically acceptable salt according to the eighty second and hundred twenty third embodiments consisting essentially of the malonate salt.
  • the invention is the pharmaceutically
  • the invention is the pharmaceutically 790 acceptable salt according to the eighty second and hundred twenty third through the hundred twenty fifth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 5.45 ⁇ 0.2°, 6.19 ⁇ 0.2°, 8.59 ⁇ 0.2°, 10.45 ⁇ 0.2°, 12.01 ⁇ 0.2°, 12.36 ⁇ 0.2°, 12.72 ⁇ 0.2°, 13.07 ⁇ 0.2°, 14.05 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.54 ⁇ 0.2°, 16.94 ⁇ 0.2°, 17.43 ⁇ 0.2°, 17.96 ⁇ 0.2°, 18.50 ⁇ 0.2°, 795 19.17 ⁇ 0.2°, 19.61 ⁇ 0.2°, 20.41 ⁇ 0.2°, 20.76 ⁇ 0.2°, 21.07 ⁇ 0.2°, 21 .69 ⁇ 0.2°, 22.06 ⁇ 0.2°, 22.85 ⁇ 0.2°, 23.23 ⁇ 0.2°, 23.65 ⁇ 0.2°, 24.49 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.21 ⁇ 0.2°, 25.65 ⁇
  • the invention is the 800 pharmaceutically acceptable salt according to the hundred and twenty sixth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 5.45 ⁇ 0.2°, 6.19 ⁇ 0.2°, 8.59 ⁇ 0.2°, 10.45 ⁇ 0.2°,
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 810 azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 13.
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 815 azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 14.
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- 820 azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 14.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical
  • composition comprising the pharmaceutically acceptable salt according to the eighty 825 second and one hundred twenty third through the one hundred thirtieth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the hundred thirty first embodiment wherein said
  • pharmaceutically acceptable salt is the malonate.
  • the invention is the pharmaceutical
  • composition according to the hundred thirty second amendment wherein said malonate salt is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the 835 pharmaceutically acceptable salt according to any one of the eighty second and one hundred twenty third through the one hundred thirtieth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the hundred thirty fourth embodiment wherein said 840 pharmaceutically acceptable salt is the malonate.
  • the invention is the pharmaceutical composition according to the hundred thirty fifth embodiment wherein said malonate salt is in substantially pure form.
  • the invention is a method of treating a 845 disorder or a disease in a subject mediated by complement activation, in particular
  • the invention is the method according to the hundred thirty seventh embodiment wherein said pharmaceutically acceptable salt is the malonate.
  • the invention is the method according to the hundred thirty eighth embodiment wherein said malonate salt is in substantially pure form.
  • the invention is the method according to the hundred thirty seventh embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the pharmaceutically acceptable salt according to the eighty second and one hundred twenty third through the one hundred thirtieth embodiments based the weight of the composition.
  • the invention is a process of making the
  • composition consisting essentially of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide benzoate, based on the weight of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide benzoate, based on the weight of 1 -(2-((1 R,3S,5R)-3-
  • the invention is the pharmaceutically acceptable salt according to the eighty second embodiment comprising 1 -(2- 880 ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide benzoate.
  • the invention is the pharmaceutically acceptable salt according to the eighty second and hundred forty third embodiments 885 consisting essentially of the benzoate salt.
  • the invention is the pharmaceutically acceptable salt according to the eighty second and hundred forty third through the hundred forty fourth embodiments wherein said benzoate salt is in substantially pure form.
  • the invention is the pharmaceutically
  • acceptable salt according to eighty second and hundred forty third through the hundred forty fifth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 6.14 ⁇ 0.2°, 9.59 ⁇ 0.2°, 10.59 ⁇ 0.2°, 1 1 .00 ⁇ 0.2°, 1 1 .88 ⁇ 0.2°, 13.24 ⁇ 0.2°, 14.92 ⁇ 0.2°, 15.71 ⁇ 0.2°, 16.15 ⁇ 0.2°,
  • the pharmaceutically acceptable salt according to the hundred forty sixth embodiment further characterized by a x-ray powder
  • 900 diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 6.14 ⁇ 0.2°, 9.59 ⁇ 0.2°, 10.59 ⁇ 0.2°, 1 1.00 ⁇ 0.2°, 1 1.88 ⁇ 0.2°, 13.24 ⁇ 0.2°, 14.92 ⁇ 0.2°, 15.71 ⁇ 0.2°, 16.15 ⁇ 0.2°, 16.84 ⁇ 0.2°, 17.19 ⁇ 0.2°, 19.02 ⁇ 0.2°, 19.80 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.27 ⁇ 0.2°, 21 .89 ⁇ 0.2°, 22.56 ⁇ 0.2°, 22.91 ⁇ 0.2°, 23.35 ⁇ 0.2°, 23.75 ⁇ 0.2°, 24.88 ⁇ 0.2°, 26.37 ⁇ 0.2°, 27.22 ⁇ 0.2°, 28.57 ⁇ 0.2° and 29.73 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is a pharmaceutically
  • the invention is a pharmaceutically
  • the invention is a pharmaceutically acceptable salt of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 16.
  • TGA thermo gravimetric analysis
  • the invention is a pharmaceutical composition
  • the pharmaceutically acceptable salt according to the eighty second and hundred forty third through the hundred fiftieth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical 925 composition according to the hundred fifty first embodiment wherein said
  • pharmaceutically acceptable salt is the benzoate.
  • the invention is the pharmaceutical composition according to the hundred fifty second embodiment wherein said benzoate salt is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the pharmaceutically acceptable salt according to any one of the eighty second and hundred forty third through the hundred fiftieth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the hundred fifty fourth embodiment wherein said
  • pharmaceutically acceptable salt is the benzoate.
  • the invention is the pharmaceutical
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering 945 to the mammal a therapeutically-effective amount of a pharmaceutically acceptable salt of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide according to the eighty second and hundred forty third through the hundred fiftieth embodiments.
  • the invention is the method according to the hundred fifty seventh embodiment wherein said pharmaceutically acceptable salt is the benzoate.
  • the invention is the method according to the hundred fifty eighth embodiment wherein said benzoate salt is in substantially pure form.
  • the invention is the method according to the hundred fifty seventh embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the pharmaceutically acceptable salt according to the eighty second and hundred forty third through the hundred fiftieth embodiments, based the weight of
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide glutamate.
  • the composition of this embodiment may comprise at least 90 weight % of the crystalline form of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • the invention is the pharmaceutically
  • the invention is the pharmaceutically
  • 980 acceptable salt according to the eighty second and the hundred sixty third embodiments consisting essentially of the glutamate salt.
  • the invention is the pharmaceutically acceptable salt according to the eighty second and the hundred sixty third through the hundred sixty fourth embodiments wherein said glutamate salt is in substantially pure
  • the invention is the pharmaceutically acceptable salt according to the eighty second and the hundred sixty third through the hundred sixty fifth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 5.51 ⁇ 0.2°, 990 6.16 ⁇ 0.2°, 7.63 ⁇ 0.2°, 10.40 ⁇ 0.2°, 10.77 ⁇ 0.2°, 1 1.09 ⁇ 0.2°, 1 1 .96 ⁇ 0.2°, 13.32 ⁇ 0.2°,
  • the invention is the pharmaceutically acceptable salt according to the hundred sixty sixth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting of 5.51 ⁇ 0.2°, 6.16 ⁇ 0.2°, 7.63 ⁇ 0.2°, 10.40 ⁇ 0.2°, 10.77 ⁇ 0.2°, 1 1.09 ⁇ 0.2°,
  • the invention is a pharmaceutically
  • the invention is a pharmaceutically
  • the invention is a pharmaceutically
  • thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 18.
  • the invention is a pharmaceutical
  • composition comprising the pharmaceutically acceptable salt according to the eighty second and the hundred sixty third through the hundred seventieth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical 1025 composition according to the hundred seventy first embodiment wherein said
  • pharmaceutically acceptable salt is the glutamate.
  • the invention is the pharmaceutical composition according to the hundred seventy second embodiment wherein said glutatame salt is in substantially pure form.
  • the invention is a combination, in
  • a pharmaceutical combination comprising a therapeutically effective amount of the pharmaceutically acceptable salt according to any one of the eighty second and the hundred sixty third through the hundred seventieth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical
  • composition according to the hundred seventy fourth embodiment wherein said pharmaceutically acceptable salt is the glutamate.
  • the invention is the pharmaceutical composition according to the hundred seventy fifth embodiment wherein said glutamate 1040 salt is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a pharmaceutically acceptable salt 1045 of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide according to the eighty second and the hundred sixty third through the hundred seventieth embodiments.
  • the invention is the method according 1050 to the hundred seventy seventh embodiment wherein said pharmaceutically acceptable salt is the glutamate.
  • the invention is the method according to the hundred seventy eighth embodiment wherein said glutamate salt is in substantially pure form.
  • the invention is the method according to the hundred seventy seventh embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the pharmaceutically acceptable salt according to the eighty second and the hundred sixty third through the hundred seventieth embodiments based the
  • the invention is a process of making the glutamate salt of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide comprising the steps of Example 9.
  • reaction impurities and/or processing impurities may be any reaction impurities and/or processing impurities.
  • the present invention provides a crystalline form of 1-(2-((1 R,3S,5R)-3-((2-fluoro-
  • peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2°.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative
  • Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a
  • Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
  • Crystals of drugs including polymorphs, methods of preparation, and
  • solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the
  • antisolvent is a solvent in which the compound has low solubility.
  • a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • slurry means a saturated solution of the compound, which may also contain an
  • Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount
  • 1110 of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in “Programmed Cooling of Batch Crystallizers,” J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971 ,26, 369- 377.
  • seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or
  • a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and
  • the isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product.
  • the resulting crystalline form is typically produced in an amount of greater than about 70
  • 1125 weight % isolated yield preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
  • the product may be comilled or passed through a mesh screen to delump the product, if necessary.
  • Crystalline forms may be prepared directly from the reaction medium of the final process for preparing 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • a solvent or a mixture of solvents from which 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- 1135 carboxamide may be crystallized.
  • crystalline forms may be obtained by distillation or solvent addition techniques.
  • Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
  • the presence of more than one polymorph in a sample may be determined by
  • the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample.
  • the simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray
  • an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon
  • the DSC instrument used to test the crystalline forms was a TA Instrument® Differential Scanning Calorimetry Model 2910, TA Instruments® Modulated Differential Scanning Calorimetry Model 2920, or TA Instruments® Modulated Differential Scanning 1170 Calorimetry Model Q1000.
  • the DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas.
  • the instrument was calibrated with high purity indium.
  • the accuracy of the measured sample temperature with this method is within about ⁇ 1 °C, and the heat of fusion can be measured within a relative error of about ⁇ 5%.
  • the sample was placed into an open aluminum DSC pan and measured against an empty reference
  • 1175 pan About 2-6 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10°C. per minute in the temperature range between 25 and 300°C.
  • the plot was made with the endothermic peaks pointing down.
  • the endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.
  • the TGA instruments used to test the crystalline forms was a TA
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic
  • compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions, emulsions, each of which may be suitable for ophthalmic administration).
  • a solid form including without limitation capsules, tablets, pills, granules, powders or suppositories
  • liquid form including without limitation solutions, suspensions, emulsions, each of which may be suitable for ophthalmic administration.
  • the pharmaceutical compositions can be subjected to conventional
  • 1200 pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, 1210 tragacanth, methylcellulose, sodium carboxymethylcellulose and/or
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
  • Tablets may contain the active
  • excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for
  • magnesium stearate, stearic acid or talc examples include magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active
  • ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • compositions may be sterilized and/or contain adjuvants, such as preserving,
  • compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a
  • bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application e.g., to the skin and eyes, include
  • aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for ophthalmic application, e.g., for the treatment of eye diseases e.g., for therapeutic or prophylactic use in treating age related macular degeneration and other complement mediated ophthalmic disorders.
  • Such may contain solubilizers, stabilizers,
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones,
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted
  • hydrocarbons such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • the present invention further provides anhydrous pharmaceutical compositions
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared
  • compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the present invention provides methods of treating a disease or disorder associated with increased complement activity by administering to a subject in need
  • methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway.
  • methods 1320 of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
  • the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the
  • the methods of treating or preventing AMD include, but are not limited to, methods of treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration,
  • RPE degeneration RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
  • carboxamide can be used, inter alia, to prevent the onset of AMD, to prevent the
  • the present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention,
  • said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein
  • the present invention provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention.
  • a complement related disease or disorder examples include: neurological disorders, multiple sclerosis, stroke,
  • lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal
  • vasculitis immune complex-associated inflammation
  • uveitis including Behcet's disease and other sub-types of uveitis
  • antiphospholipid syndrome antiphospholipid syndrome
  • the present invention provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention, wherein said disease or disorder is
  • asthma e.g., rheumatoid arthritis
  • autoimmune heart disease multiple myelomasis
  • sclerosis inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome
  • glomerulonephritis including membrane proliferative glomerulonephritis
  • blistering cutaneous diseases including bullous pemphigoid, pemphigus, and
  • the present invention provides methods of treating glomerulonephritis by administering to a subject in need thereof an effective amount of a
  • composition comprising a compound of the present invention.
  • glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen-BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts;
  • the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present invention provides methods of reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention.
  • a composition comprising an compound of the present invention.
  • 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion.
  • transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
  • 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.
  • the compounds of the invention may be used in blood ampules, diagnostic kits and other equipment used in the collection and sampling of
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either
  • aqueous solution aqueous solution.
  • the dosage in vitro may range between about 10 "3 molar and 10 "9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or 1450 different route of administration, or together in the same pharmaceutical composition as the other agents.
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is
  • Products provided as a combined preparation include a composition comprising 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide and the other therapeutic agent(s) together in the same pharmaceutical
  • the invention provides a pharmaceutical composition comprising 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains 1 -(2-((1 R,3S,5R)-3-((2-
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-
  • the invention also provides 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- 1500 methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for use in a method of treating a
  • the invention 1505 also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is prepared for administration with 1 -(2-((1 R,3S,5R)-3-((2-fluoro- 3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the invention also provides 1 -(2-((1 R,3S,5R)-3-((2-fluoro- 3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is administered with 1 -(2- ((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-
  • the invention also provides the use of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating a disease or condition
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the complement alternative pathway and/or Factor D wherein the patient has previously (e.g. within 24 hours) been treated with 1 -(2-((1 R,3S,5R)-3-((2-
  • compositions can be administered alone or in combination with other molecules known to have a beneficial effect on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and/or
  • anti-VEGF agents such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin
  • VEGF agents such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin
  • basic fibroblast growth factor (bFGF) basic fibroblast growth factor (bFGF)
  • ciliary neurotrophic factor (CNTF) ciliary neurotrophic factor (CNTF), axokine (a mutein of CNTF), leukemia inhibitory factor (LIF), neutrotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor I I, prostaglandin E2, 30 kD survival factor, taurine, and
  • agents for combination treatment with the compounds of the invention include agents known in the art that are able to modulate the activities of complement components.
  • a combination therapy regimen may be additive, or it may produce synergistic results (e.g., reductions in complement pathway activity more than expected for the combined use of the two agents).
  • the present invention provide a combination therapy for preventing and/or treating AMD or another complement related ocular disease as described above with a compound of the invention and an anti-
  • angiogenic such as anti-VEGF agent (including Lucentis and Avastin) or photodynamic therapy (such as verteporfin).
  • anti-VEGF agent including Lucentis and Avastin
  • photodynamic therapy such as verteporfin
  • the present invention provide a combination therapy for preventing and/or treating autoimmune disease as described above with a compound of the invention and a B-Cell or T-Cell modulating agent (for example cyclosporine or
  • a compound of the invention may include the combination of a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex and the like.
  • the invention provides a method of modulating activity of the
  • the invention further provides methods of modulating the activity of the complement alternative pathway in a subject by
  • the method comprises administering to the subject a therapeutically effective amount of 1-(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5- methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the invention provides 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-
  • the invention provides the use of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, for the treatment of a disorder or
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide, for the treatment of a disorder or disease mediated by activation of the complement alternative pathway.
  • the invention provides the use of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, in the manufacture of a medicament for the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly in the manufacture of a medicament for the
  • the invention provides the use of 1-(2-((1 R,3S,5R)-3-((2- fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)- 5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for the treatment of a disorder or
  • the invention provides uses of the compounds provided herein in the treatment of a disease or disorder characterized by over activiation of the complement alternative pathway or the C3 amplification loop of the alternative pathway.
  • the use is in the treatment of a disease or disorder is selected from retinal
  • the present invention provides use of the compounds of the invention for treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-3- (trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-
  • uses are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway.
  • uses of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or
  • the present invention provides use of the compounds of the invention for treating or preventing age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for
  • AMD 1610 administration with a compound of the invention.
  • the use in treating or preventing AMD include, but are not limited to, uses in treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor
  • RPE degeneration Regeneration 1615 degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
  • 1620 carboxamide can be used, inter alia, to prevent the onset of AMD, to prevent the
  • the present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention,
  • said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein
  • the present invention provides uses for treating a complement related disease or disorder.
  • complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate
  • pulmonary fibrosis diseases and disorders such as dyspnea, hemoptysis, ARDS, asthma, 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
  • irritant gases and chemicals e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid
  • smoke injury e.g., burn, freeze
  • thermal injury e.g., burn, freeze
  • hypersensitivity pneumonitis parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease
  • the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e.g.,
  • rheumatoid arthritis 1665 rheumatoid arthritis
  • autoimmune heart disease multiple sclerosis
  • inflammatory bowel disease ischemia-reperfusion injuries
  • Barraquer-Simons Syndrome hemodialysis
  • systemic lupus lupus erythematosus
  • psoriasis multiple sclerosis
  • transplantation diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS),
  • cutaneous diseases including bullous pemphigoid, pemphigus, and epidermolysis bullosa
  • ocular cicatrical pemphigoid or MPGN I I.
  • the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
  • glomerulonephritis Symptoms of glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen— BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary
  • the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PN H) by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase
  • PN H paroxysmal nocturnal hemoglobinuria
  • 1685 inhibitor such as Soliris.
  • the present invention provides use 1 -(2-((1 R,3S,5R)-3- ((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for reducing the
  • 1-(2-((1 R,3S,5R)-3-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-5-methyl-1 H-pyrazolo[3,4-c]pyridine-3- carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at
  • Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart
  • the various crystalline forms of the disclosure may be used alone or in combination, or formulated with one or more excipients or other active pharmaceutical ingredients to provide formulations suitable for the treatment of the indications identified above.
  • the new crystalline forms have improved solubility compared to the free form and different moisture sorption profiles
  • X-ray powder diffraction (PXRD) data were obtained using a Bruker GADDS (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was
  • the TGA instruments used to test the crystalline forms was a TA
  • 1850 range between 25°C. and about 300°C.

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Abstract

L'invention concerne des formes cristallines et des sels pharmaceutiquement acceptables du l-(2-((1R,3S,5R)-3-((2-fluoro-3-(trifluorométhoxy)phényl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-5-méthyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Le l-(2-((1R,3S,5R)-3-((2-fluoro-3-(trifluorométhoxy)phényl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-5-méthyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide est utile dans le traitement de la dégénérescence maculaire liée à l'âge (AMD).
PCT/US2013/048960 2012-06-29 2013-07-01 Formes cristallines du l-(2-((1r,3s,5r)-3-((2-fluoro-3-(trifluorométhoxy)phényl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-5-méthyl-1h-pyrazolo[3,4-c]pyridine-3-carboxamide et sels de celui-ci WO2014005150A1 (fr)

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