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Definitions

• the invention relates to the inhibition of the complement alternative pathway and particularly to inhibition of Factor D, in patients suffering from conditions and diseases associated with complement alternative pathway activation such as age-related macular degeneration, diabetic retinopathy and related ophthalmic diseases.
• the complement system is a crucial component of the innate immunity system and 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 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 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 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. Muller-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 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
• Complement factor H polymorphism in age-related macular degeneration Science. 2005 Apr 15;308(5720):385-9; Lau LI, et al. Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3242-6; Simonelli F, et al. 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.
• complement factor 3 Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007 Oct;39(10): 1200-1 and Park KH, et al Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3386-93. Epub 2009 Feb 21.). Taken together, the genetic variations in the alternative pathway components CFH, CFB, and C3 can predict clinical outcome in nearly 80% of cases.
• the present invention provides compounds that modulate, and preferably inhibit, activation the alternative complement pathway.
• the present invention provides compounds that modulate, and preferably inhibit, Factor D activity and/or Factor D mediated complement pathway activation.
• Factor D modulators are preferably high affinity Factor D inhibitors that inhibit the catalytic activity of complement Factor D, such as primate Factor D and particularly human Factor D.
• the compounds of the present invention inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation (including for example activation of the classical, lectin or ficolin pathways).
• Factor D modulators provided herein are compounds of Formula I and salts thereof:
• Factor D modulators provided herein are compounds of Formula VII and salts thereof:
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of formula (I) or subformulae thereof and one or more pharmaceutically acceptable carriers.
• the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to the definition of formula (I) or subformulae thereof and one or more
• the invention further provides methods of treating or preventing complement mediated diseases, the method comprising the steps of identifying a patient in need of complement modulation therapy and administering a compound of Formula (I) or a subformulae thereof.
• Complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), Respiratory diseases, cardiovascular diseases.
• the present invention provides compounds that modulate Factor D activation and/or Factor D-mediated signal transduction of the complement system.
• Such compounds may be used in vitro or in vivo to modulate (preferably inhibit) Factor D activity in a variety of contexts.
• the invention provides compounds of Formula I and
• Z is C and L is a divalent residue selected from the group consisting of -N(H)- and - C(H)(R 1 )-, or
• Z is N and L is CH 2 ;
• R is hydrogen, hydroxy, or amino
• Z 2 is C(R 2 ) or N;
• Z 3 is C or N
• Z 4 is C(R 4 ) or N;
• Z 5 is C(R 5 ) or N, or an N-oxide thereof;
• Z 6 is C(R 6 ) or N, or an N-oxide thereof;
• Z 7 is C(R 7 ) or N, or an N-oxide thereof;
• Z Z 3 , Z 8 and Z 9 wherein one of Z Z 3 , Z 8 and Z 9 is N and three of Z Z 3 , Z 8 and Z 9 are C;
• R 2 is hydrogen or d-C 6 alkyl
• R 3 is selected from the group consisting of hydrogen, C C 4 alkyl, hydroxyC C 4 alkyl, C C 4 alkoxyC C 4 alkyl, haloC C 4 alkyl, amino or methylamino;
• R 4 is selected from the group consisting of hydrogen, halogen, and CrC 6 alkyl
• R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR 8 R 9 , cyano, C0 2 H, CONR 0 R 11 S0 2 C C 6 alkyl, and S0 2 NH 2 , SO 2 NR 0 R 11 , C C 6 alkoxycarbonyl, -C(NR 0 )NR 8 R 9 , C C 6 alkyl, haloC C 6 alkyl, C 2 -C 6 alkenyl, C C 6 alkoxy, haloCrC 6 alkoxy, C 2 -C 6 alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, tetrazole, C C 4 alkoxy, C C 4 haloalkoxy, C0 2 H, C C 6 alkoxycarbonyl, C(O)NR 0 R 11
• R 5 and R 6 taken in combination with the atoms to which they are attached, form a cycle having 4 to 7 ring atoms and 0, 1 or 2 additional ring N, O or S atoms;
• R 7 is selected from the group consisting of hydrogen, halogen, C C 6 alkyl, C C 6 alkoxy, haloC-C 6 alkyl, haloC-C 6 alkoxy C C 6 alkoxycarbonyl, C0 2 H and C(O)NR 0 R 11 ;
• R 8 and R 9 are independently selected from the group consisting of hydrogen, and C C 6 alkyl, haloC C 6 alkyl, C C 6 alkoxyCi-C 6 alkyl, hydroxyC C 6 alkyl, or NR 8 R 9 , taken in combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, which heterocycle is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of C C 4 alkyl, halogen, hydroxy, C C 4 alkoxy;
• R 0 and R 11 are each independently selected from the group consisting of hydrogen and CrC 6 alkyl, haloCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, or hydroxyCrC 6 alkyl;
• X 1 is CR 4 R 15 or sulfur
• X 2 is CR 6 R 17 , oxygen sulfur, N(H) or N(C C 6 alkyl), wherein at least one of X 1 and X 2 is carbon; or
• X 3 is (CR 8 R 9 ) m or N(H) wherein m is 0, 1 or 2, wherein X 3 is CR 8 R 19 or (CR 8 R 9 ) 2 when either X 1 or X 2 is sulfur or X 2 is oxygen; or
• R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C
• R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, d-C 6 alkyl, haloC C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C C 6 alkoxy, haloC C 6 alkoxy, NR 8 R 9 , N(H)C(0)C C 6 alkyl, N(H)C(0)OC C 6 alkyl and OC(O)NR 0 R 11 each of alkyl, alkoxy, alkenyl, and alkynyl substituents may be substituted with 0, 1 , or 2 groups independently selected at each occurrence from the group consisting of halogen, hydroxy, CrC 6 alkyl, CrC 6 alkoxy, and NR 8 R 9 ;
• R 6 is hydrogen, halogen, hydroxy, azide, cyano, COOH, CrC 6 alkoxycarbonyl, C C 6 alkyl, C C 6 alkoxy, C C 6 haloalkyl, C C 6 haloalkoxy, NR 8 R 9 , N(H)C(0)C C 6 alkyl, hydroxyd- C 6 alkyl, Ci-CealkoxyCi-Cealkyl, or C C 6 alkyl substituted with NR 8 R 9 , N(H)C(0)H or
• R 7 is hydrogen, halogen, hydroxy, cyano, CrC 6 alkyl, CrC 6 alkoxy, hydroxyCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, haloCrC 6 alkyl, or CrC 6 haloalkoxy;
• R 8 is selected from the group consisting of hydrogen, phenyl and CrC 6 alkyl, which alkyl group is unsubstituted or substituted with hydroxy, amino, azide, and NHC(0)CrC 6 alkyl;
• R 9 and R 20 are each independently selected from hydrogen and CrC 6 alkyl; or
• CR 6 R 17 taken in combination forms a spirocyclic 3 to 6 membered carbocycle which is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halogen and methyl; or
• R 5 and R 6 taken in combination form an epoxide ring or a 3 to 6 membered carbocyclic ring system which carbocyclic ring is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC C 4 alkyl, Ci-C 6 alkoxyCrC 4 alkyl, C C 4 alkoxycarbonyl, C0 2 H, and C C 4 alkyl substituted with NR 8 R 9 ; or
• R 6 and R 8 or R 7 and R 9 taken in combination, form a fused 3 membered carbocyclic ring system which is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC C 4 alkyl, Ci-C 6 alkoxyCrC 4 alkyl, C C 4 alkoxycarbonyl, C0 2 H, and C C 4 alkyl substituted with NR 8 R 9 ; or
• R 4 and R 20 taken in combination form a fused 3 carbocyclic ring system
• R 4 and R 9 taken in combination form a form 1 to 3 carbon alkylene linker
• R 7 and R 20 taken in combination form 1 to 3 carbon alkylene linker
• G is a divalent residue selected from C(0)-N(H), CH 2 -N(H)-S(0) 2 - CH 2 -N(H)-C(0), CH 2 -N(H)-C(0)-0, CH 2 N(H), CH 2 -N(H)-C(0)-N(H), CH 2 -N(H)-C(0)-N(Me), CH 2 N(H)-S(0) 2 - N(H)-, and CH 2 N(H)-S(0) 2 -N(Me)-, wherein the right most residue is attached to -(CR 2 R 22 ) q ; q is 0, 1 , 2, 3 or 4; R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, halogen, C C 6 alkyl, haloC C 6 alkyl, phenyl, C0 2 H, C C 6 alkoxy carbonyl, C(0)NH 2 , hydroxyC C 6 alkyl, d-Cealkoxyd-Ce
• R 22 is independently selected at each occurrence from hydrogen or CrC 6 alkyl; or when q is 1 , 2, 3 or 4, R 2 and a R 22 substituent, taken in combination with the carbon atoms to which they are attached, form a 3 to 6 membered carbocycle or 4 to 6 membered heterocyle having a ring oxygen or nitrogen; or
• Z is CrC 6 alkyl, CrC 6 haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C 3 - Cycycloalkyl, indanyl, a 5, 6, 9 or 10 membered saturated or partially unsaturated, monocyclic or bicyclic heterocycle having 1 , 2, or 3 ring heteroatoms selected from N, O, or S, or a 5 or 6 membered heteroaryl or heteroaryloxy, which heteroaryl has 1 or 2 ring heteroatoms selected from N, O or S provided that the ring does not have 2 O or S atoms, each residue is unsubstituted or substituted with 1 , 2, 3, or 4 substituents which are independently selected from the group consisting of substituted or unsubstituted C C 6 alkyl, C C 6 haloalkyl, halogen, CN, hydroxy, C0 2 H, tetrazolyl, C(0)R 25 , S(0) 2 R 26 , substitute
• unsubstituted or substituted phenyl which substituted phenyl has 1 or 2 substituents independently selected from the group consisting of cyano, halo, CrC 6 alkyl or CrC 6 haloalkyl, OH, COOH, COR 25 , S(0) 2 R 26 , amino, and CH 2 NH 2 , and which substituted alkyl or alkoxy has a substituent selected from hydroxy, C C 4 alkoxy, cyano, C0 2 H, tetrazole or NR 23 R 24 ;
• R 23 is hydrogen or CrC 6 alkyl
• R 24 is hydrogen, CrC 6 alkyl, hydroxyCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, aminoCr C 6 alkyl, mono- and di-CrC 6 alkylaminoCrC 6 alkyl; or
• NR 23 R 24 taken in combination form a 4, 5 or 6 membered heterocycle having 0 or 1 additional ring heteroatoms selected from the group consisting of N, O or S, and which is substituted with 0, 1 or 2 substituents independently selected from fluoro, hydroxy, C C 4 alkyl or C C 4 alkoxy;
• R 25 is independently selected at each occurrence from the group consisting of C C 6 alkoxy and NR 23 R 24 ; and R is selected from the group consisting of amino, hydroxy, CrC 6 alkyl, and, mono- and di-CrC 6 alkylamino.
• the compounds of formula (I) preferably have the stereochemistry of compounds represented by formula (la):
• compounds of formula (I) include those compounds represented by formula (II):
• Z 2 is CH or N
• X 1 isCHR 5 orS
• X 2 is CR 6 R 17 or S, wherein at least one of X 1 and X 2 is not sulfur;
• X 3 is CR 8 R 19 or N(H);
• R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, d-C 6 alkyl, haloC Cealkyl, CrC 6 alkoxy, haloC C 6 alkoxy, NR 8 R 9 , N(H)C(0)C C 4 alkyl, N(H)C(0)OC C 4 alkyl and OC(O)NR 0 R 11 , each alkyl and alkoxy may be substituted with 0, 1, or 2 groups independently selected at each occurrence from the group consisting of hydroxy, CrC 6 alkyl, C C 6 alkoxy, and NR 8 R 9 ;
• R 6 is hydrogen, halogen, hydroxy, amino, cyano, C C 4 alkyl, C C 4 alkoxy, C C 4 haloalkyl, C C 4 haloalkoxy, heterocycleC 0 -C 4 alkyl, NR 8 R 9 , N(H)C(0)C C 4 alkyl, hydroxyC C 4 alkyl, C C 4 alkoxyC C 4 alkyl or C C 4 alkyl substituted with NR 8 R 9 ;
• R 7 is hydrogen, halogen, hydroxy, C C 4 alkyl, hydroxyC C 4 alkyl or CrC 2 alkoxyC C 4 alkyl;
• R 8 is selected from the group consisting of hydrogen, phenyl and CrC 6 alkyl, which alkyl group is unsubstituted or substituted with hydroxy, amino, NHC(0)CrC 6 alkyl, amide or mono- or di- CrC 4 alkyl-amide;
• R 9 is hydrogen
• CR 6 R 17 taken in combination, forms a spirocyclic 3 to 6 membered carbocycle;
• R 5 and R 6 taken in combination, form a cyclopropyl ring which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxy methyl, hydroxyethyl, methoxymethyl, ; or
• the invention provides compounds of Formula (VII):
• L is a divalent residue selected from the group consisting of -N(H)- and -C(H)(R 1 )-,
• R 1 is hydrogen, hydroxy, or amino
• Z 1 is C or N
• Z 2 is C(H) or N
• Z 3 is C or N
• Z 5 is C(R 5 ), N or an N oxide thereof;
• Z 6 is C(R 6 ), N or an N oxide thereof;
• z 7 is C(R 7 ), N or an N oxide thereof;
• z 8 is C or N
• R 3 is selected from the group consisting of hydrogen, C C 4 alkyl, hydroxyC C 4 alkyl, C C 4 alkoxyC C 4 alkyl, haloC C 4 alkyl, amino or methylamino;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR 8 R 9 , cyano, C0 2 H, CONR 0 R 11 S0 2 C C 6 alkyl, and SO 2 NR 0 R 11 , Ci- Cealkoxycarbonyl, C(NR 8 )NR 8 R 9 , C C 6 alkyl, haloC C 6 alkyl, C 2 -C 6 alkenyl, C C 6 alkoxy, haloCrC 6 alkoxy, C 2 -C 6 alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, tetrazole, C C 4 alkoxy, C C 4 haloalkoxy, C0 2 H, C C 6 alkoxycarbonyl, C(O)NR 0 R 11 , NR 8 R 9 optionally substituted
• R 5 and R 6 taken in combination with the atoms to which they are attached, form a cycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms;
• R 7 is selected from the group consisting of hydrogen, halogen, C C 6 alkyl, d-C 6 alkoxy, haloC-C 6 alkyl, haloC-C 6 alkoxy C C 6 alkoxycarbonyl, C0 2 H and C(O)NR 0 R ;
• R 8 and R 9 are independently selected from the group consisting of hydrogen, and CrC 6 alkyl, haloCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, hydroxyCrC 6 alkyl, or NR 8 R 9 , taken in combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, which heterocycle is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of C C 4 alkyl, halogen, hydroxy, C C 4 alkoxy;
• R 8 and R 9 are independently selected from the group consisting of hydrogen, and C C 6 alkyl, haloC C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, hydroxyC C 6 alkyl, or NR 8 R 9 , taken in combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, which heterocycle is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of C C 4 alkyl, halogen, hydroxy, C C 4 alkoxy;
• R 0 and R 11 are each independently selected from the group consisting of hydrogen and CrC 6 alkyl, haloCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, or hydroxyCrC 6 alkyl;
• R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C
• R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, d-C 6 alkyl, haloC C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C C 6 alkoxy, haloC C 6 alkoxy, NR 8 R 9 , N(H)C(0)C C 6 alkyl, N(H)C(0)OC C 6 alkyl and OC(O)NR 0 R 11 each of alkyl, alkoxy, alkenyl, and alkynyl substituents may be substituted with 0, 1 , or 2)groups independently selected at each occurrence from the group consisting of halogen, hydroxy, CrC 6 alkyl, CrC 6 alkoxy, and NR 0 R 11 ;
• R 6 is hydrogen, halogen, hydroxy, azide, cyano, COOH, CrC 6 alkoxycarbonyl, C C 6 alkyl, C C 6 alkoxy, C C 6 haloalkyl, C C 6 haloalkoxy, NR 8 R 9 , N(H)C(0)C C 6 alkyl, hydroxyd- C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, or C C 6 alkyl substituted with NR 8 R 9 , N(H)C(0)H or
• R 7 is hydrogen, halogen, hydroxy, CrC 6 alkyl, C C 4 alkoxy, hydroxyCrC 6 alkyl, Ci- CealkoxyCi-Cealkyl, or CrC 6 haloalkoxy;
• R 8 is selected from the group consisting of hydrogen, phenyl and CrC 6 alkyl, which alkyl group is unsubstituted or substituted with hydroxy, amino, azide, and NHC(0)CrC 6 alkyl;
• R 9 and R 20 are each independently selected from hydrogen and CrC 6 alkyl; or CR 6 R 17 , taken in combination, form a spirocyclic 3 to 6 membered carbocycle which is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halogen and methyl; or
• R 7 and R 9 or R 6 and R 8 taken in combination, form a fused 3 membered carbocyclic ring system which is substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC C 4 alkyl, C C 4 alkoxycarbonyl, C0 2 H, and C C 4 alkyl substituted with NH 8 R 9 ; or
• R 4 and R 20 taken in combination form a fused 3 carbocyclic ring system
• R 4 and R 9 taken in combination, form a 1 to 3 carbon alkylene linker
• R 7 and R 20 taken in combination, form a 1 to 3 carbon alkylene linker
• G is a divalent residue selected from C(0)-N(H), CH 2 -N(H)-S(0) 2 - CH 2 -N(H)-C(0), CH 2 -N(H)-C(0)-0, CH 2 N(H), CH 2 -N(H)-C(0)-N(H), CH 2 -N(H)-C(0)-N(Me), CH 2 N(H)-S(0) 2 - N(H)-, and CH 2 N(H)-S(0) 2 -N(Me)-, wherein the right most residue is attached to -(CR 2 R 22 ) q ; q is 0, 1 , 2, 3 or 4;
• R 2 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, halogen, C C 6 alkyl, haloC C 6 alkyl, phenyl, C0 2 H, C C 6 alkoxy carbonyl, C(0)NH 2 , hydroxyC C 6 alkyl, d-Cealkoxyd-Cealkyl, C C 6 alkyl substituted with NR 8 R 9 , imidazoylC C 6 alkyl heterocycleC C 6 alkyl, where the heterocycle is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1-oxa-6-aza-spiro[3.3]heptane, 2-oxa-6-aza- spiro[3.3]heptane, piperazinyl, 1 ,6-diaza-spiro[3.3]heptane, and 2,6-diaza-spiro[3.3]heptane each of which is optionally sus
• R 22 is independently selected at each occurrence from hydrogen or CrC 6 alkyl; or when q is 1 , 2, 3 or 4, R 2 and a R 22 substituent, taken in combination with the carbon atoms to which they are attached, form a 3 to 6 membered carbocycle or 4 to 6 membered heterocyle having a ring oxygen or nitrogen; or
• Z is CrC 6 alkyl, CrC 6 haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C 3 - Cycycloalkyl, indanyl, a 5, 6, 9 or 10 membered saturated or partially unsaturated, monocyclic or bicyclic heterocycle having 1 , 2, or 3 ring heteroatoms selected from N, O, or S, or a 5 or 6 membered heteroaryl or heteroaryloxy, which heteroaryl has 1 or 2 ring heteroatoms selected from N, O or S provided that the ring does not have 2 O or S atoms, each residue is unsubstituted or substituted with 1 , 2, 3, or 4 substituents which are independently selected from the group consisting of substituted or unsubstituted C C 6 alkyl, C C 6 haloalkyl, halogen, CN, hydroxy, C0 2 H, tetrazolyl, C(0)R 25 , S(0) 2 R 26 , substitute
• unsubstituted or substituted phenyl which substituted phenyl has 1 or 2 substituents independently selected from the group consisting of cyano, halo, CrC 6 alkyl or CrC 6 haloalkyl, OH, COOH, COR 25 , S(0) 2 R 26 , amino, and CH 2 NH 2 , and which substituted alkyl or alkoxy has a substituent selected from hydroxy, C C 4 alkoxy, cyano, C0 2 H, tetrazole or NR 23 R 24 ;
• R 23 is hydrogen or CrC 6 alkyl
• R 24 is hydrogen, CrC 6 alkyl, hydroxyCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, aminod- C 6 alkyl, mono- and di-CrC 6 alkylaminoCrC 6 alkyl; or
• NR 23 R 24 taken in combination form a 4, 5 or 6 membered heterocycle having 0 or 1 additional ring heteroatoms selected from the group consisting of N, O or S, and which is substituted with 0, 1 or 2 substituents independently selected from fluoro, hydroxy, C C 4 alkyl or C C 4 alkoxy;
• R 25 is independently selected at each occurrence from the group consisting of C C 6 alkoxy and NR 23 R 24 ;
• R 26 is selected from the group consisting of amino, hydroxy, C C 6 alkyl, and, mono- and di-CrC 6 alkylamino.
• X 1 is CHR 5 ; and R 5 is hydrogen, fluoro, hydroxy, amino, C C 4 alkyl, C C 6 alkoxy, OCH 2 CH 2 OMe, or C 2 - C 4 alkoxy substituted with NR 8 R 9 ;
• X 2 is CR 6 R 17 ;
• R 6 is hydrogen, halogen, hydroxy, C C 4 alkyl, C C 4 alkoxy, C C 4 haloalkyl, C
• R 7 is hydrogen, halogen, hydroxy or C C 4 alkyl
• R 5 and R 6 taken in combination form a cyclopropyl ring
• compounds of formula (I) or (II) are provided in which X 1 is S; and X 2 and X 3 are CH 2 ; or X 1 is CHR 5 , wherein R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy, methoxyethoxy or amino; X 3 is CH 2 ; and X 2 is CR 6 R 17 , wherein R 6 is fluoro, amino, hydroxy methyl, methoxymethyl, aminomethyl or methyl and R 7 is hydrogen or fluoro; or
• X 1 is CHR 15
• X 2 is CR 6 R 17
• X 3 is CHR 19
• R 7 and R 9 taken in combination form a cyclopropyl ring
• R 6 is hydrogen, hydroxymethyl, or methoxymethyl
• R 5 is hydrogen
• X 1 is CHR 15
• X 2 is CR 6 R 17
• X 3 is CHR 19
• R 5 and R 6 taken in combination form a cyclopropyl ring, R 7 and R 9 are hydrogen
• X 1 and X 2 are CH 2 , and X 3 is N(H).
• compounds of formula (I) or (II) include compounds in which the heteroclick ring of the formula:
• compounds of formula (VII) include compounds in which the heterocyclic ring of the formula:
• Certain preferred compounds of formula (I), (la), (II), (VII) or any subformula thereof provided herein include those compounds in which L is -N(H)- or -CH 2 - Certain other preferred compounds of formula (I), (la), (II), (VII) or any subformula thereof provided herein include those compounds in which G is -C(0)-N(H)-.
• Still other preferred compounds of formula (I), (la), (II) or (VII) or any subformula thereof provided herein include those compounds in which q is 0 or 1 ;
• R 2 is selected from the group consisting of hydrogen, CrC 6 alkyl, hydroxyCrC 6 alkyl, Ci-C e alkoxyCi-C e alkyl and C C 6 alkyl substituted with NR 8 R 9 ;
• R 22 is hydrogen
• Z is phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, thienyl, each of which is unsubstituted or substituted with 1 , 2 or 3 substituents, each of which is independently selected from the group consisting of:
• halogen hydroxy, C C 4 alkyl, C C 4 alkoxy, haloC C 4 alkyl, haloC C 4 alkoxy, NR 23 R 24 , C0 2 H, C(0)NR 23 R 24 , C0 2 (C C 4 alkyl), tetrazole, piperidinyl, piperazinyl, morpholino, and alkyl substituted with C C 4 alkoxy or NR 23 R 24 .
• R 2 is selected, at each occurrence, from the group consisting of hydrogen, d-C 6 alkyl, hydroxyC C 6 alkyl, Ci-CealkoxyCi-Cealkyl and C C 6 alkyl substituted with NR 8 R 9 ;
• R 22 is hydrogen; or CR R CR R taken in combination, forms a cis or trans cyclopropane ring;
• Z is phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, thienyl, each of which is unsubstituted or substituted with 1 , 2 or 3 substituents, each of which is independently selected from the group consisting of:
• halogen hydroxy, C C 4 alkyl, C C 4 alkoxy, haloC C 4 alkyl, haloC C 4 alkoxy, NR 23 R 24 , C0 2 H, C(0)NR 23 R 24 , C0 2 (C C 4 alkyl), tetrazole, piperidinyl, piperazinyl, morpholino, and alkyl substituted with C C 4 alkoxy or NR 23 R 24 .
• Still other preferred compounds of formula (I), (la), (II) or (VII) or any subformula thereof provided herein include those compounds in which q is 0 or 1 ;
• R 2 is selected from the group consisting of hydrogen, CrC 6 alkyl, hydroxyCrC 6 alkyl, Ci-C 6 alkoxyCrC 6 alkyl, aminoC C 6 alkyl, and mono- and di-CrC 4 alkylaminoCrC 6 alkyl;
• R 22 is hydrogen
• Z is phenyl which is unsubstituted or substituted with 1 , 2, or 3 substituents, each of which is independently selected from the group consisting of halogen, hydroxy, C C 4 alkyl, C C 4 alkoxy, haloC C 4 alkyl, haloC C 4 alkoxy, C0 2 H, C(0)NH 2 , C0 2 (C C 4 alkyl), amino, and mono- and di-C C 4 alkylamino, wherein each N-alkyl residue is substituted with 0 or 1 residues selected from the group consisting of hydroxy, C C 4 alkoxy, amino, or mono- or di-C
• Still other preferred compounds of formula (I), (la), (II) or (VII) or any subformula thereof provided herein include those compounds in which q is 0, 1 or 2;
• R 2 is hydrogen
• R 22 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, amino, or mono- or di-methyl amino; or
• Z is phenyl which is unsubstituted or substituted with 1 , 2, or 3 residues selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, mono- and di-C C 2 alkylamino, tetrazole or C0 2 H; or
• Z is pyridyl or thienyl, each of which is unsubstituted or substituted with 1 or 2 substitutents selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
• the invention provides compounds of formula (I) or formula (II) in which the compounds are represented by formulae (III), (IV) or (V):
• Z 2 is CH or N
• Z 5 is CR 5 or N
• Z 6 is CR 6 or N
• Z 7 is CH or N, wherein 0, 1 or 2 of Z 5 , Z 6 and Z 7 is N;
• R 3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe;
• R 5 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, tetrazole , C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, tetrazole, C C 4 alkoxy, C0 2 H, C
• R 6 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, NR 0 R 11 , tetrazole, cyano, imidazolyl, C C 4 alkoxy, C0 2 H, C C 4 alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy, mono- and dimethyl amino, and
• L is CH 2 or NH ;
• R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH 2 CH 2 OMe,
• R 6 is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl, or aminomethyl
• R 7 is hydrogen, fluoro or methyl
• R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R 5 and R 6 , taken in combination, form a cyclopropyl ring;
• G is -C(0)N(H)-
• q is O, 1 , or 2;
• R 2 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, amino, mono- or di-methyl amino, morpholinomethyl, optionally substituted azetidinomethyl, which azetidino ring is substituted with 0 or 1 fluoro or methoxy; or
• R 22 is hydrogen
• Z is phenyl, pyridyl, or thienyl , each of which is unsubstituted or substituted with 1 , 2, or 3 residues independently selected at each occurrence from the group consisting of halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, C0 2 H, tetrazole, and NR 23 R 24 .
• Certain compounds of Formula (III) provided by the invention include compounds represented by formula (Ilia):
• R 3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe;
• R 5 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, tetrazole , C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, tetrazole, C C 4 alkoxy, C0 2 H, C
• R 6 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is
• C 4 alkoxy, C0 2 H, C C 4 alkoxycarbonyl optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy, mono- and dimethyl amino, and C0 2 H;
• R 7 is hydrogen or methyl
• R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH 2 CH 2 OMe,
• R 6 is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl, or aminomethyl
• R 7 is hydrogen, fluoro or methyl
• R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R 5 and R 6 , taken in combination, form a cyclopropyl ring;
• G is -C(0)N(H)-
• q is 0 or 1 ;
• Z is pyridyl, pyrazinyl, or thienyl , each of which is unsubstituted or substituted with 1 , 2, or 3 residues independently selected at each occurrence from the group consisting of halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, C0 2 H, tetrazole, and NR 23 R 24 .
• compounds of the first embodiment include those compounds represented by one of the formulae (1Mb) or (IVb):
• Z 2 is CH or N
• Z 5 is CR 5 or N
• Z 6 is CR 6 or N
• Z 7 is CH, C(CH 3 ) or N, wherein 0 or 1 or 2 of Z 5 , Z 6 and Z 7 is N;
• R 3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe;
• R 5 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, tetrazole , C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, cyano, tetrazole, C C 4 alkoxy, C0 2 H, C
• R 6 is hydrogen, halogen, C C 4 alkyl, C C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkenyloxy, hydroxy, C0 2 H, C C 4 alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is
• C 4 alkoxy, C0 2 H, C C 4 alkoxycarbonyl optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy, mono- and dimethyl amino, and C0 2 H;
• L is CH 2 or NH ;
• R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH 2 CH 2 OMe,
• R 6 is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl, or aminomethyl
• R 7 is hydrogen, fluoro or methyl
• R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R 5 and R 6 , taken in combination, form a cyclopropyl ring;
• G is -C(0)N(H)-
• q is 0 or 1 ;
• R 2 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, cyano, amino, mono- or di-methyl amino,
• morpholinomethyl optionally substituted azetidinomethyl, which azetidino ring is subsituted with 0 or 1 fluoro or methoxy; or
• R 22 is hydrogen
• Z is phenyl, pyridyl, pyrazinyl or thienyl , each of which is unsubstituted or substituted with 1 , 2, or 3 residues independently selected at each occurrence from the group consisting of halogen, methyl, cyclopropyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, SF 5, C0 2 H, tetrazole, and NR 23 R 24 , unsubstituted or substituted phenyl and unsubstituted or substituted pyridinyl, which substituted phenyl and pyridinyl has 1 or 2 substituents
• q 0, 1 or 2;
• R 2 is hydrogen
• R 22 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, amino, or mono- or di-methyl amino; or
• Z is phenyl which is unsubstituted or substituted with 1 , 2, or 3 residues selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy,
• Z is pyridyl or thienyl, each of which is unsubstituted or substituted with 1 or 2 substitutents selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
• the compound of formula (I) is represented by the structure of formula (VI):
• individual compounds according to the invention are those listed in the Examples section below.
• the compound is selected from the group consisting of:
• compositions which comprise one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
• combinations in particular pharmaceutical combinations, are provided which comprise a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
• methods of modulating complement alternative pathway activity in a subject comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
• methods of treating a disorder or a disease in a subject mediated by complement activation in particular mediated by activation of the complement alternative pathway, are provided, which methods comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV),
• methods of treating age related macular degeneration in a subject comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
• the invention provides for the use of compounds of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof for use in the preparation of a medicament and more particularly for use in the manufacture of a medicament for the treatment of a disorder or disease in a subject mediated by complement activation or activation of the complement alternative pathway.
• the invention provides for the use of a compound according to any one of formulae (I), (la), (II), (III), (IV), (V),
• the invention provides a combination, in particular a
• compositions comprising a therapeutically effective amount of the compound according to the definition of formula (I), (la), (II), (VII) or subformulae thereof or any one of the specifically disclosed compounds of the invention and one or more therapeutically active agents (preferably selected from those listed infra).
• alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, / ' so-butyl, te/f-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl and the like.
• alkylene refers to divalent alkyl group as defined herein above having 1 to 20 carbon atoms. It comprises 1 to 20 carbon atoms, Unless otherwise provided, alkylene refers to moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
• alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, / ' so-propylene, n-butylene, sec-butylene, iso- butylene, te/f-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3- methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n- nonylene, n-decylene and the like.
• haloalkyl refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein.
• the haloalkyl can be
• a monohaloalkyi can have one iodo, bromo, chloro or fluoro within the alkyl group.
• Dihaloalky and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
• the polyhaloalkyi contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
• Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl,
• a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
• aryl refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms.
• aryl refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
• Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl- S-, nitro, cyano, carboxy, alkyl-O-C(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.
• substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino,
• alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
• Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/f-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
• alkoxy groups typically have about 1-7, more preferably about 1-4 carbons.
• heterocyclyl refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 1 1-, 12-, 13-, 14- or 15- membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
• the heterocyclic group can be attached at a heteroatom or a carbon atom.
• the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
• heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 , 4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, and the like.
• heterocyclyl further refers to heterocyclic groups as defined herein substituted with 1 to 5 substituents independently selected from the groups consisting of the following:
• heterocyclooxy wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge
• cycloalkyi refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyi refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms, each of which can be optionally substituted by one, or two, or three, or more substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, alkyl-C(O)-, acylamino, carbamoyl, alkyl-NH-, (alkyl) 2 N-, thiol, alkyl-
• exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
• Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6- dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
• Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
• aryloxy refers to both an --O-aryl and an 0-O-heteroaryl group, wherein aryl and heteroaryl are defined herein.
• heteroaryl refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S.
• the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 memberred bicycle) or a 5-7 membered ring system.
• Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5- isoxazolyl, 3- or 5-1 ,2,4-triazolyl, 4- or 5-1 ,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4- pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.
• heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6- , 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3- , 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or
• 6- or 7-2H- furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5- 1 H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino[2,3- d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2, 1-b] thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1 ,2- b][1 ,2,4]triazinyl, 2-
• Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
• a heteroaryl group may be substituted with 1 to 5 substituents independently selected from the groups consisting of the following:
• heterocyclooxy wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge
• (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.
• halogen refers to fluoro, chloro, bromo, and iodo.
• optionally substituted refers to a group that is unsubstituted or is substituted by one or more, typically 1 , 2, 3 or 4, suitable non- hydrogen substituents, each of which is independently selected from the group consisting of:
• heterocyclooxy wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge
• (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.
• the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
• an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
• “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.
• the asterisk (*) indicated in the name of a compound designate a racemic mixture.
• Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
• Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
• the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
• the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g. , acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydr
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
• such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
• a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, C, 3 C, 4 C, 5 N, 8 F 3 P, 32 P, 35 S, 36Q
• the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 3 C, and 4 C , are present.
• isotopically labelled compounds are useful in metabolic studies (with 4 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 8 F or labeled compound may be particularly desirable for PET or SPECT studies.
• Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
• selective deuteration of compounds of Formula (I) include deuteration of R 3 , when R 3 is alkanoyl, e.g., C(0)CD 3 .
• certain substitutents on the pyrrole ring are selectively deuterated.
• the alkyl residue is preferably deuterated, e.g., OCD 3 or OC 2 D 5 .
• the unsubstituted methylene carbon is selectively deuterated.
• Certain preferred deuterated compounds are provided in Examples 619 and 620 infra.
• Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
• solvates refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules.
• solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to a recipient, e.g., water, ethanol, dimethylsulfoxide, acetone and other common organic solvents.
• hydrate refers to a molecular complex comprising a compound of the invention and water.
• Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
• Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers.
• These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
• Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfit
• antibacterial agents antifungal agents
• isotonic agents absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
• a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
• a therapeutically effective amount refers to the amount of the compound of the present invention that, when
• administered to a subject is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) mediated by Factor D, or (ii) associated with Factor D activity, or (iii) characterized by activity (normal or abnormal) of the complement alternative pathway; or (2) reducing or inhibiting the activity of Factor D; or (3) reducing or inhibiting the expression of Factor D; or (4) reducing or inhibiting activation of the complement system and particularly reducing or inhibiting generation of C3a, iC3b, C5a or the membrane attack complex generated by activation of the complement alternative pathway.
• a disease or biological process e.g., tissue regeneration and reproduction
• a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non- cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Factor D and/or the complement alternative pathway; or at least partially reducing or inhibiting the expression of Factor D and/or the complement alternative pathway.
• a therapeutically effective amount as illustrated in the above embodiment for Factor D and/or the complement alternative pathway.

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