WO2016088082A1

WO2016088082A1 - Amidomethyl-biaryl derivatives complement factor d inhibitors and uses thereof

Info

Publication number: WO2016088082A1
Application number: PCT/IB2015/059334
Authority: WO
Inventors: David Belanger; Stefanie Flohr; Christine Fang GELIN; Keith Jendza; Nan JI; Rajeshri Ganesh Karki; Donglei Liu; Edwige Liliane Jeanne Lorthiois; Nello Mainolfi; James J. Powers; Anna Vulpetti
Original assignee: Novartis Ag
Priority date: 2014-12-05
Filing date: 2015-12-03
Publication date: 2016-06-09

Abstract

The present invention provides a compound of formula (I): (I) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

Amidomethyl-Biaryl Derivatives Complement Factor D inhibitors and uses thereof

FIELD OF THE INVENTION

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, paroxysmal nocturnal hemoglobinuria, atypicaly hemolytic uremic syndrome, C3 nephropathy and related complement mediated diseases.

BACKGROUND OF THE INVENTION

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. It can also be activated in an antibody-independent manner by the binding of C-reactive protein complexed to ligand and by many pathogens including gram-negative bacteria. 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 μg/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Miiller-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. In the center of the retina is the macula lutea, which is about 1/3 to ½ 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 ganglion 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. 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. The choroidal blood vessels provide nutrition to the retina and its visual cells.

Age-related macular degeneration (AMD), the most prevalent form of 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.

The new blood vessels in neovascular AMD are usually derived from the choroid and are referred to as choroidal neovascularizaton (CNV). The pathogenesis of new choroidal vessels is poorly understood, but such factors as inflammation, ischemia, and local production of angiogenic factors are thought to be important. A published study suggests that CNV is caused by complement activation in a mouse laser model (Bora P.S., J. Immunol. 2005;174; 491 -497).

Human genetic evidence implicates the involvement of the complement system, particularly the alternative pathway, in the pathogenesis of Age-related Macular Degeneration (AMD). Significant associations have been found between AMD and polymorphisms in complement factor H (CFH) (Edwards AO, et al. Complement factor H polymorphism and age- related macular degeneration. Science. 2005 Apr 15;308(5720):421 -4; Hageman GS, et al Acommon haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005 May

17;102(20)7227-32; Haines JL, et al. Complement factor H variant increases the risk of age- related macular degeneration. Science. 2005 Apr 15;308(5720):419-21 ; Klein RJ, et al

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.; .Br J Ophthalmol. 2006

Sep;90(9):1 142-5; and Zareparsi S, et al Strong association of the Y402H variant in complement factor H at 1 q32 with susceptibility to age-related macular degeneration. Am J Hum Genet. 2005 Jul;77(1):149-53. ), complement factor B (CFB) and complement C2 (Gold B, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age- related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62 and Jakobsdottir J, et al. C2 and CFB genes inage-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One. 2008 May 21 ;3(5):e2199), and most recently in complement C3 (Despriet DD, et al Complement component C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar;1 16(3):474-480.e2; Mailer JB, et al 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.

Currently there is no proven medical therapy for dry AMD and many patients with neovascular AMD become legally blind despite current therapy with anti-VEGF agents such as Lucentis. Thus, it would be desirable to provide therapeutic agents for the treatment or prevention of complement mediated diseases and particularly for the treatment of AMD.

SUMMARY OF THE INVENTION

The present invention provides compounds that modulate, and preferably inhibit, activation of the alternative complement pathway. In certain embodiments, the present invention provides compounds that modulate, and preferably inhibit, Factor D activity and/or Factor D mediated complement pathway activation. Such Factor D modulators are preferably high affinity Factor D inhibitors that inhibit the catalytic activity of complement Factor Ds, 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 inital mechanism of activation (including for example activation of the classical, lectin or ficolin pathways).

Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.

Within certain aspects, Factor D modulators provided herein are compounds of Formula I and salts thereof:

In another embodiment, the invention provides 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.

In another embodiment, 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 therapeutically active.

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.

Other aspects of the invention are discussed infra.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, 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.

In a first embodiment, the invention provides compounds of Formula I and

pharmaceutically acceptable salts thereof, which modulate the alternative pathway of the complement system. Compounds of Formula I are represented by the structure:

or a salt thereof, wherein

X is N or CH;

A is O or NH;

B is C(O) when A is NH, or B is CHR¹ when A is O;

R¹ is hydrogen;

R² is hydrogen; or

R¹ and R², taken in combination form a -CH₂CH₂- group;

R³ is hydrogen, halogen, hydroxy, cyano, amino, NHR⁹, N(R⁹)₂, -C(0)NHR⁹, OR¹⁰, C C₄alkyl, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, phenyl, heterocycloalkyi having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, and heteroaryl having 5, 6, 9 or 10 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, wherein each heterocycloalkyi, heteroaryl, phenyl is optionally substituted with 0, 1 , 2, or 3 substituents independently selected from C₁-C₄alkyl, C C₄alkoxy, halogen, or C₃-C₆cycloalkyl, wherein each heterocycloalkyi or heteroaryl is optionally further substituted by 0 or 1 phenyl groups and wherein each alkyl, haloalkyl and cycloalkyl group is optionally substituted with 0, 1 , or 2 substituents independently selected from the group consisting of hydroxy, C₃-C₆cycloalkyl, amino, NHR⁹, N(R⁹)₂, OR¹⁰ and heterocycloalkyi having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and fluoro; and

R⁸ is hydrogen when A is NH and R⁸ is hydrogen or amino when A is O;

R⁹ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloCrC₄alkyl, C₃-C₆cycloalkyl, benzyl, CrC₄alkanoyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from CrC₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C dalkoxy, and wherein each heterocycloalkyi or heteroaryl is optionally fused to a benzo ring and further optionally substituted by 0, 1 , or 2 substituents independently selected from d-C₄alkyl, C0₂ d-C₄alkyl, C(0)NH C C₄alkyl, C₃-C₆cycloalkyl, or C C₄alkoxy; and R¹⁰ is independently selected at each occurrence from the group consisting of hydrogen, d- C₄alkyl, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, benzyl, benzoyl, phenyl, 4 to 6 member

heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from C₁-C₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or d-dalkoxy, and wherein each heterocycloalkyi or heteroaryl are optionally substituted by 0, 1 , or 2 substituents independently selected from d-C₄alkyl, C0₂ Ci-C₄alkyl, C(0)NH d-dalkyl, C₃-C₆cycloalkyl, or d-dalkoxy.

In a second embodiment of the invention, compounds of the first embodiment are provided in which X is CH.

In a third embodiment of the invention, compounds of the first or second embodiment are provided in which A is O and B is CH₂.

In a fourth embodiment of the invention, compounds of any one of the first to third embodiments are provided in which R², R⁴ and R⁵ are hydrogen.

In a fifth embodiment of the invention, compounds of any one of the first to fourth embodiments are provided in which R⁷ is hydrogen.

In a sixth embodiment of the invention, compounds of any one of the first to fifth

embodiments are provided in which R⁶ is fluorine.

In a seventh embodiment of the invention, compounds of any one of the first to sixth embodiments are provided in which R⁸ is hydrogen.

In an eighthh embodiment of the invention, compounds of any one of the first to seventh embodiments are provided in which X is CH, A is O, B is CH₂, R², R⁴, R⁵, R⁷, and R⁸ are hydrogen and R⁶ is fluorine.

In a ninth embodiment of the invention, compounds of any one of the first to eighth embodiments are provided in which R³ is NHR⁹, -C(0)NHR⁹, OR¹⁰, or five member heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, O and S and optionally substituted d-dalkyl or cyclopropyl;

R⁹ is d-dalkyl, d-dcycloalkyl, or 5 or 6 member heterocycloalkyi, wherein the alkyl group is optionally substituted with d-dalkoxy, d-dcycloalkyl, 5 or 6 member heterocycloalkyi and wherein each heterocycloalkyi is optionally fused to a benzo ring and further optionally substituted by d-dalkyl or cyclopropyl; and

R¹⁰ is d-dalkyl or C₃-dcycloalkyl wherein the alkyl group is optionally substituted with d-dalkoxy, d-dcycloalkyl, 5 or 6 member heterocycloalkyi and wherein each heterocycloalkyi is optionally fused to a benzo ring and further optionally substituted by d-dalkyl or cyclopropyl. In a tenth embodiment, compounds of the first embodiment are selected from the group consisting of

2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4-yl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(S)-2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1,r- biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-5-((cyclopropylmethyl)amino)-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-5-((cyclopropylmethyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-isopropoxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(methoxymethyl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(-)-2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 -hydroxyethyl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(+)-2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 -hydroxyethyl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4-((2- methoxyethyl)amino)picolinamido)phenyl)acetic acid;

(S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1 ,1 '-biphenyl]- 3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-5-cyclopropyl-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(f?)-2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(2-hydroxypropan-2-yl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(±)-2-(2-((6-(3-(2-Amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 -yl)oxy)phenyl)acetic acid; 2-(2-(3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid;

(S)-2-(2-(3'-(2-Amino-2-oxoethyl)-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '-bipheny^ ylcarboxamido)phenyl)acetic acid;

2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)picolinamido)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(1 ,2-Diamino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-4'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid;

2-(2-((3'-(2-Amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)-3-fluorophenyl)acetic acid;

2-(2-(3'-(2-amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-ylcarboxamido)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid; and

2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-[1 ,1 '-bipheny yl)methoxy)phenyl)acetic acid; and salts, especially pharmaceutically acceptable salts, thereof.

In an eleventh embodiment, pharmaceutical compositions are provided which comprise one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any one of embodiments one to ten.

In a twelfth embodiment, a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to any one of embodiment one to ten and a second therapeutically active agent.

Some of the compounds listed supra have been prepared in enantiopure form (i.e., greater than about 80%, greater than 90% or greater than 95% enantiomeric purity). Other compounds have been isolated as mixtures of stereoisomers, e.g., diastereoisomeric mixtures of two or more diastereoisomers. Each compound isolated as a mixture of stereoisomers has been marked as mixture in the foregoing list.

In one embodiment, 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), (II), (III), (IV) 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).

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

As used herein, the term "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. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, /^'so-butyl, fe/ -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.

As used herein, the term "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. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, /^'so-propylene, n-butylene, sec-butylene, iso- butylene, fe/ -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.

As used herein, the term "haloalkyi" refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. The haloalkyi can be monohaloalkyi, dihaloalkyi or polyhaloalkyi including perhaloalkyl. A monohaloalkyi can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyi and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.

Typically the polyhaloalkyi contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non- limiting examples of haloalkyi include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.

The term "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.

Furthermore, the term "aryl" as used herein, 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.

As used herein, the term "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, fe/f-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1 -7, more preferably about 1 -4 carbons.

As used herein, the term "heterocyclyl" or "heterocyclo" 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-, 1 1 -, 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. Examples of 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.

The term "heterocyclyl" further refers to heterocyclic groups as defined herein substituted with 1 to 5 substituents independently selected from the groups consisting of the following:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., =0;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge;

(j) alkyl-O-C(O)-;

(k) mercapto;

(I) nitro;

(m) cyano;

(n) sulfamoyl or sulfonamido;

(o) aryl;

(p) alkyl-C(0)-0-;

(q) aryl-C(0)-0-;

(r) aryl-S-;

(s) aryloxy;

(t) alkyl-S-; (u) formyl, i.e., HC(O)-;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.

As used herein, the term "cycloalkyl" refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyl 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)₂N-, thiol, alkyl-S-, nitro, cyano, carboxy, alkyl-O-C(O)-, sulfonyl, sulfonamido, sulfamoyl, and heterocyclyl.

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.

As used herein, the term "aryloxy" refers to both an -O-aryl and an -O-heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term "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. Typically, 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.

A heteroaryl group may be substituted with 1 to 5 substituents independently selected from the groups consisting of the following:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., =0; (e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(j) alkyl-O-C(O)-;

(k) mercapto;

(I) nitro;

(m) cyano;

(n) sulfamoyl or sulfonamido;

(o) aryl;

(P) alkyl-C(0)-0-;

(q) aryl-C(0)-0-;

(r) aryl-S-;

(s) aryloxy;

(t) alkyl-S-;

(u) formyl, i.e., HC(O)-;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH- alkylamino, dialkylamino or halogen.

As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.

As used herein, the term "optionally substituted" unless otherwise specified 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:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., =0;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge; (j) alkyl-O-C(O)-;

(k) mercapto;

(I) nitro;

(m) cyano;

(n) sulfamoyl or sulfonamido;

(o) aryl;

(P) alkyl-C(0)-0-;

(q) aryl-C(0)-0-;

(r) aryl-S-;

(s) aryloxy;

(t) alkyl-S-;

(u) formyl, i.e., HC(O)-;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH- alkylamino, dialkylamino or halogen .

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein , the term "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. "Diastereoisomers" or "diastereomers" 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 or as entantiomer 1 or 2 (or diastereomer 1 or 2) depending on elution time by chiral chromatography. 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.

As used herein, 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. In many cases, 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/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. 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. In certain embodiments, 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. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶CI, ¹²⁵l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as ³H, ¹³C, and ¹⁴C , are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), 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. In particular, an ¹⁸F 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.

Further, substitution with heavier isotopes, particularly deuterium (i.e., ²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If 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).

In certain embodiments, selective deuteration of compounds of Formula (I) or formula (II) include deuteration of R⁵, when R⁵ is alkanoyl, e.g., C(0)CD₃. In other embodiments, certain substitutents on the proline ring are selectively deuterated. For example, when any of R⁸ or R⁹ are methyl or methoxy, the alkyl residue is preferably deuterated, e.g., CD₃ or OCD₃. In certain other compounds, when two substituents of the proline ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is selectively deuterated. In certain other compounds of Formulae (I), (II), (III) or (IV), R¹⁰, R¹¹ and/or R¹² is deuterated alkyl, preferably CD₃.

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.

The compounds of the present invention may inherently or by design form solvates with solvents (including water). Therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules. Such 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. The term "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. D₂0, de-acetone, d₆-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).

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. , 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.

The term "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. In one non-limiting embodiment, the term "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. In another non-limiting embodiment, the term "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. The meaning of the term "a

therapeutically effective amount" as illustrated in the above embodiment for Factor D and/or the complement alternative pathway.

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g. , humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g. , stabilization of a discernible symptom), physiologically, (e.g. , stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used herein, a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the ( ?)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (£)- form.

Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g. , by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0, 0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31 -32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g. , esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein. Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyi esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)- lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower

alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.- D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen

Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of

Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage).

Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.

Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.

Mixtures of isomers obtainable according to the invention can be separated in a manner known to those skilled in the art into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallization and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallization, or by chromatography over optically active column materials.

Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned herein before and hereinafter. All the above-mentioned process steps can be carried out under reaction conditions that are known to those skilled in the art, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about - 100 °C to about 190 °C, including, for example, from approximately -80 °C to approximately 150 °C, for example at from -80 to -60 °C, at room temperature, at from -20 to 40 °C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps".

The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1 - or 2- propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or /V-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4^th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials. Typically, the compounds of formula (I) can be prepared according to the Schemes provided infra. Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

Compounds such as S-3, wherein R₄ is independently selected from the group consisting of hydrogen and fluoro, can be prepared by the general method outlined in Scheme 1.

Scheme 1

The acid group in S-1 can be protected as the corresponding tert-butyl ester with treatment of Boc-anhydride and DMAP in t-butanol at room temperature. The nitro group of S-2 can then be reduced under hydrogen atmosphere with platinum oxide as the catalyst in ethanol at room temperature to afford S-3.

Alternatively, compounds such as S-3, wherein R₄ is independently selected from the group consisting of hydrogen and fluoro, can be prepared by another general method outlined in Scheme 3.

Scheme 3

The bromo group of S-4 can be coupled with a zinc reagent ((2-(tert-butoxy)-2- oxoethyl)zinc(ll) chloride, CAS# 321745-86-2) under metal-catalyzed conditions (Pd(dba)₂ (CAS# 32005-36-0), Q-phos (CAS# 312959-24-3)) in THF to provide the corresponding t-butyl ester after purification. S-2 can then be transformed to provide S-3 by the same sequence shown in Scheme 1.

Compounds such as Q-2, wherein R₄ is independently selected from the group consisting of hydrogen and fluoro, can be prepared by the general method outlined in Scheme 3.

Scheme 3

Q-1 can react with Boc-anhydride in the presense of triethylamine with dichloromethane as the solvent at 40 °C for 4 days to provide the corresponding t-butyl ester Q-2.

Alternatively, compounds such as Q-5, wherein R₄ is independently selected from the group consisting of hydrogen and fluoro, can be prepared by another general method outlined in Scheme 4.

Scheme 4

The bromo group of Q-3 can be coupled with a zinc reagent ((2-(tert-butoxy)-2- oxoethyl)zinc(ll) chloride, CAS# 321745-86-2) under metal-catalyzed conditions (Pd(dba)₂ (CAS# 32005-36-0), Q-phos (CAS# 312959-24-3)) in THF to provide the corresponding t-butyl ester after purification. Both the methyl and t-butyl groups of Q-4 can then be removed with treatment of boron tribromide (CAS# 10294-33-4) in dichloromethane. The resulting mixture can then react with methanol to provide the correponding methyl ester Q-5.

Compounds such as T-2 wherein R⁶, R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and fluoro; and R⁸ is hydrogen or amino can be prepared as outlined in Scheme 5.

T-1 T-2 T-3

The carboxylate of T-1 can be reacted with 2-(1 -oxy-pyridin-2-yl)-1 ,1 ,3,3- tetramethylisothiouronium tetrafluoroborate (TOTT, CAS # 70340-04-4) and ammonium chloride in DMF at room temperature to provide the amide T-2. The bromide of T-2 can be converted to the boronate ester T-3 following standard palladium catalyzed borylation conditions.

Compounds such as P-3 wherein X is N or CH;

R¹ is hydrogen;

R² is hydrogen; or

R¹ and R², taken in combination form a -CH₂CH₂- group;

R³ is hydrogen, halogen, hydroxy, cyano, amino, NHR⁹, N(R⁹)₂, -C(0)NHR⁹, OR¹⁰, C C₄alkyl, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, phenyl, heterocycloalkyl having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, and heteroaryl having 5, 6, 9 or 10 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, wherein each heterocycloalkyl, heteroaryl, phenyl is optionally substituted with 0, 1 , 2, or 3 substituents independently selected from C₁-C₄alkyl, C C₄alkoxy, halogen, or C₃-C₆cycloalkyl, wherein each heterocycloalkyl or heteroaryl is optionally further substituted by 0 or 1 phenyl groups and wherein each alkyl, haloalkyl and cycloalkyl group is optionally substituted with 0, 1 , or 2 substituents independently selected from the group consisting of hydroxy, C₃-C₆cycloalkyl, amino, NHR⁹, N(R⁹)₂, OR¹⁰ and heterocycloalkyl having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S;

R⁸ is hydrogen when A is NH and R⁸ is hydrogen or amino when A is O;

R⁹ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloC dalkyl, C₃-C₆cycloalkyl, benzyl, C₁-C₄alkanoyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyl, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from C₁-C₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C₁-C₄alkoxy, and wherein each heterocycloalkyi or heteroaryl is optionally fused to a benzo ring and further optionally substituted by 0, 1 , or 2 substituents independently selected from C₁-C₄alkyl, C0₂ C₁-C₄alkyl, C(0)NH C C₄alkyl, C₃-C₆cycloalkyl, or C C₄alkoxy; and

R¹⁰ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloCrC₄alkyl, C₃-C₆cycloalkyl, benzyl, benzoyl, phenyl, 4 to 6 member

heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from d-C₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C^dalkoxy, and wherein each heterocycloalkyi or heteroaryl are optionally substituted by 0, 1 , or 2 substituents independently selected from C^dalkyl, C0₂ C^dalkyl, C(0)NH Ci-C₄alkyl, C₃-C₆cycloalkyl, or CrC₄alkoxy can be accessed by the general Scheme 6.

Scheme 6

T~2 or T~3

The alcohol of P-1 can be reacted with the phenol of Q-2 or Q-5 using standard "Mitsunobu" type conditions (PPh₃ inTHF with DIAD). P-2, where S is either Br or pinacol borane can react accordingly with either T-2 or T-3 to afford P-3.

Compounds such as P-6 wherein X is N or CH;

R¹ is hydrogen;

R² is hydrogen; or

R¹ and R², taken in combination form a -CH₂CH₂- group;

R³ is hydrogen, halogen, hydroxy, cyano, amino, NHR⁹, N(R⁹)₂, -C(0)NHR⁹, OR¹⁰, C C₄alkyl, haloC dalkyl, C₃-C₆cycloalkyl, phenyl, heterocycloalkyi having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, and heteroaryl having 5, 6, 9 or 10 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S, wherein each heterocycloalkyi, heteroaryl, phenyl is optionally substituted with 0, 1 , 2, or 3 substituents independently selected from C^dalkyl, C C₄alkoxy, halogen, or C₃-C₆cycloalkyl, wherein each heterocycloalkyi or heteroaryl is optionally further substituted by 0 or 1 phenyl groups and wherein each alkyl, haloalkyl and cycloalkyl group is optionally substituted with 0, 1 , or 2 substituents independently selected from the group consisting of hydroxy, C₃-C₆cycloalkyl, amino, NHR⁹, N(R⁹)₂, OR¹⁰ and heterocycloalkyi having 4 to 7 ring atoms and 1 , 2, or 3 ring heteroatoms independently selected from N, O and S;

R⁸ is hydrogen when A is NH and R⁸ is hydrogen or amino when A is O;

R⁹ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloC₁-C₄alkyl, C₃-C₆cycloalkyl, benzyl, C₁-C₄alkanoyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from C₁-C₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or CrC₄alkoxy, and wherein each heterocycloalkyi or heteroaryl is optionally fused to a benzo ring and further optionally substituted by 0, 1 , or 2 substituents independently selected from C₁-C₄alkyl, C0₂ C₁-C₄alkyl, C(0)NH C C₄alkyl, C₃-C₆cycloalkyl, or C C₄alkoxy; and

R¹⁰ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloC dalkyl, C₃-C₆cycloalkyl, benzyl, benzoyl, phenyl, 4 to 6 member

heterocycloalkyi, heteroaryl, wherein CrC₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from C dalkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C dalkoxy, and wherein each heterocycloalkyi or heteroaryl are optionally substituted by 0, 1 , or 2 substituents independently selected from Ci-C alkyl, C0₂ Ci-C alkyl, C(0)NH C ^alkyl, C₃-C₆cycloalkyl, or C dalkoxy can be accessed by the general Scheme 7.

Scheme 7

T-2 or Ϊ-3

The carboxylic acid of P-4 can be reacted with the aniline of S-3 using standard amide coupling conditions (HATU inDMF with Et₃N). P-5, where S is either Br or pinacol borane can react accordingly with either T-2 or T-3 to afford P-6.

In another aspect, the present invention provides 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 administration, etc. In addition, the pharmaceutical 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). The pharmaceutical compositions can be subjected to conventional 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.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g. , lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g. , starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable 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 pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic

pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

These 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 example 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. For example, 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.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

Suitable 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. For example, 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.

Suitable 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. Such 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, tonicity enhancing agents, buffers and preservatives.

As used herein 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 presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.

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 a

pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be desirable.

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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

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. Such 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 can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.

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 and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g. , vials), blister packs, and strip packs. The invention further provides pharmaceutical 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. Such 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.

Prophylactic and Therapeutic Uses

The compounds of formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. Factor D modulating properties, complement pathway modulating properties and modulation of the complement alternative pathway properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.

The present invention provides methods of treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of the compounds of Formula (I) of the invention. In certain aspects, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods of treating or preventing complement 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.

In a specific embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of the compound of Formula (I) of the invention. In certain embodiments, 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 invention. 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, 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.

The compound of Formula (I) of the invention can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be used in combination with anti-VEGF therapies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD. 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, wherein said disease or disorder is selected from uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.

In some embodiments, 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. Examples of known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and neural regeneration. In addition, other known complement related disease are 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 dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.

In a specific embodiment, 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, arthritis (e.g., 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), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.

In a specific embodiment, 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. 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 sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific embodiment, 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.

In a specific embodiment, 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. The compounds of the present invention 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. 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 transplant procedures and islet cell transplant procedures.

In other embodiments, 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. In another embodiment, the compounds of the invention may be used in blood ampules, diagnostic kits and other equipment used in the collection and sampling of blood. The use of the compounds of the invention in such diagnostic kits may inhibit the ex vivo activation of the complement pathway associated with blood sampling.

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 1 -50 mg of active ingredients. 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 prevent, treat or inhibit the progress of the disorder or disease.

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 enterally, parenterally,

advantageously intravenously, e.g., as a suspension or in 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 activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods.

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 different route of administration, or together in the same pharmaceutical composition as the other agents.

In one embodiment, 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. In one embodiment, the therapy is the treatment of a disease or condition mediated by alternative complement pathway. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as 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. To assist compliance, the kit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of the invention and 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 guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the

complement alternative pathway, wherein the medicament is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by the complement alternative pathway, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. 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 prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the compound of formula (I) is administered with another therapeutic agent. 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 a compound of formula (I).

The invention also provides the use of a compound of formula (I) 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 another therapeutic agent. 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 a compound of formula (I).

The pharmaceutical 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 inhibiting inflammation. Examples of useful, cofactors include anti-VEGF agents (such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin), basic fibroblast growth factor (bFGF), 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 II, prostaglandin E2, 30 kD survival factor, taurine, and vitamin A. Other useful cofactors include symptom-alleviating cofactors, including antiseptics, antibiotics, antiviral and antifungal agents and analgesics and anesthetics. Suitable 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). In some embodiments, 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).

In some embodiments, 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 analogs thereof, rapamycin, RAD001 or analogs thereof, and the like). In particular, for multiple sclerosis therapy 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.

In one embodiment, the invention provides a method of modulating activity of the complement alternative pathway in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to the definition of formula (I). The invention further provides methods of modulating the activity of the complement alternative pathway in a subject by modulating the activity of Factor D, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to the definition of Formula (I).

In one embodiment, the invention provides a compound according to the definition of formula (I), (la), (VII) or any subformulae thereof, for use as a medicament.

In one embodiment, the invention provides the use of a compound according to the definition of formula (I), (la), (VII) or any subformulae thereof, for the treatment of a disorder or disease in a subject mediated by complement activation. In particular, the invention provides the use of a compound according to the definition of formula (I), (la), (VII) or any subformulae thereof, for the treatment of a disorder or disease mediated by activation of the complement alternative pathway.

In one embodiment, the invention provides the use of a compound according to the definition of formula (I), (la), 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 treatment of a disease or disorder in a subject characterized by over activiation of the complement alternative pathway.

In one embodiment, the invention provides the use of a compound according to the definition of formula (I), (la), or subformulae thereof for the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly, 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. In certain embodiments, the use is in the treatment of a disease or disorder is selected from retinal diseases (such as age-related macular degeneration).

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 the compounds of Formula (I) of the invention. In certain aspects, uses are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, uses of treating or preventing complement 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.

In a specific embodiment, the present invention provides use of the compounds of the invention for treating or preventing age-related macular degeneration (AMD). In certain embodiments, 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 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 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.

In some embodiments, the present invention provides uses for treating a complement related disease or disorder. Examples of known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and neural regeneration. In addition, other known complement related disease are 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 dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.

In a specific embodiment, the present invention provides use of the compounds of the invention for treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e.g., 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), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.

In a specific embodiment, the present invention provides use of the compounds of the invention for treating 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 sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific embodiment, 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.

In a specific embodiment, the present invention provides use of the compounds of the invention for reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation. The compounds of the present invention 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. 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 transplant procedures and islet cell transplant procedures.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade (°C). If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

Abbreviations

Ac acetyl

AcCN acetonitrile

ACN acetonitrile

AcOH acetic acid

AIBN azobisisobutyronitrile

app apparent

aq. aqueous

atm atmosphere

Bis(pinacolato)diboron

4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane

Boc tertiary butyl carboxy

Boc-anhydride di-fe/ -butyl dicarbonate

(Boc)₂0 di-fe/ -butyl dicarbonate

br. broad

BrettPhos palladacycle chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1 ,1 '- biphenyl][2-(2-aminoethyl)phenyl]palladium(ll)

BSA bovine serum albumin

BuOH butanol

calcd. calculated

CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-1 -propanesulfonate

CH₃CN acetonitrile

Cs₂C0₃ cesium carbonate

CoCI₂.6H₂0 cobalt dichloride hexahydrate

CVF Cobra Venom Factor

Cy5 2-((1 E,3E,5E)-5-(1 -(5-carboxypentyl)-3,3-dimethyl-5-sulfoindolin-2- ylidene)penta-1 ,3-dien-1 -yl)-1 -ethyl-3,3-dimethyl-5-sulfo-3H-indol-1 -ium potassium salt

d doublet

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

dd doublet of doublets

DCC Λ/,Λ/'-Dicyclohexylcarbodiimide

DCM dichloromethane

DEA diethylamine

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DIEA N,N-diisopropylethylamine

DIBAL-H diisobutylaluminium hydride

DIPEA N,N-diisopropylethylamine

DMAP 4,4-dimethylaminopyridine

DME 1 ,4-dimethoxyethane

DMF Λ/,/V-dimethylformamide

Dess-Martin Periodinane

Dess-Martin reagent; 1 ,1 ,1 -Triacetoxy-1 ,1 -dihydro-1 ,2-benziodoxol-3(1 H)-one DMSO dimethylsulfoxide

ESI electrospray ionization

EtOAc, AcOEt ethyl acetate

Et ethyl

EtOH ethanol

FCC flash column chromatography

g grams

h hour(s) HATU 2-(1 /-/-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uranium hexafluorophosphate methanaminium

HBTU 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate

HC HPLC condition

HEPES 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid

HFIP 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol

HPLC high performance liquid chromatography

IPA 2-propanol

IR infrared spectroscopy

L liter(s)

LDA lithium diisopropyl amide

TMP 2,2',6,6'-tetramethylpiperidine, 2,2',6,6'-tetramethylpiperidyl

M molar

MHz mega Hertz

m multiplet

Me methyl

MeCN acetonitrile

Mel iodomethane

MeOH methanol

mg milligram(s)

mm millimeter(s)

min minutes

ml milliliter(s)

mL milliliter(s)

mmol millimoles

MP melting point

MS mass spectrometry

Ms₂0 methanesulfonyl anhydride

m/z mass to charge ratio

N normal

NaBH₄ sodium borohydride

Na(AcO)₃BH sodium triacetoxyborohydride

NBS N-Bromo succinamide

NH₄CI ammonium chloride

NMR nuclear magnetic resonance

PBS phosphate buffered saline

Pd/C palladium on carbon Pd(dppf)2CI₂ CH₂CI₂ adduct

1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex

Pd(dba)₂ bis(dibenzylideneacetone)palladium(0)

Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)

Ph phenyl

ppm parts per million

PyBOP benzotriazol-1 -yloxytripyrrolidinophosphonium hexafluorophosphate

Q-Phos 1 ,2,3,4,5-Pentaphenyl-1 '-(di-fe/?-butylphosphino)ferrocene

rac racemic

RockPhos 2-(di-t-butylphosphino)-3-methoxy-6-methyl-2',4',6'-tri-i-propyl-1 ,1 '-biphenyl RP- reverse phase

rt room temperature

RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

RuPhos palladacycle

chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1 ,1 '-biphenyl)[2-(

2-aminoethylphenyl)]palladium(ll)

s singlet

sat. saturated

Selectfluor 1 -chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate),

/V-chloromethyl-/V'-fluorotriethylenediammonium bis(tetrafluoroborate)

SEM 2-(trimethylsilyl)ethoxymethyl

SEMCI 2-(trimethylsilyl) ethoxymethyl chloride

SFC Supercritical Fluid Chromatography

Sphos palladacycle

Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 '-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll) - methyl-f-butyl ether adduct

t triplet

t_r retention time

TBAF tetra-n-butylammonium fluoride

TBAT tetrabutylammonium difluorotriphenylsilicate

TBSCI te/ -butyldimethylsilyl chloride

TEA, Et₃N triethylamine

tert- tertiary

tert-butyl Xphos 2-di-fe/ -butylphosphino-2',4',6'-triisopropylbiphenyl

TFA trifluoroacetic acid THF tetrahydrofuran

Ti(OiPr)₄ titanium isopropoxide

TLC Thin Layer Chromatography

TMSCF3 trifluoromethyltrimethylsilane

TOSMIC toluenesulfonylmethyl isocyanide

TMS trimethylsilyl

Ts p-toluenesulfonyl

TsOH p-toluenesulfonic acid

UPLC ultra performance liquid chromatography

v/v volume per volume

w/v weight per volume

w/w weight per weight

X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

X-Phos palladacycle

Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll)

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g. , spectroscopic characteristics, e.g. , MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. Ionic exchange cartridge PL-HCO₃ MP-SPE used to retain acidic salts are provided by Stratosphere (500mg, capacity of 0.9mmol, catalogue number PL3540-C603SPL)

Phase separating cartridge ISOLUTE SPEE are provided by Biotage.

Metal scavenger resin SiliaMetS®Thiol used to catch the residual palladium is provided by Silicycle, (Particle Size: 40-63 μηι, loading 1 .39 mmol/g, catalogue number R51030B). All reactions are carried out under nitrogen or argon unless otherwise stated. Optical rotations were measured in MeOH.

Proton NMR (¹H NMR) is conducted in deuterated solvent. In certain compounds disclosed herein, one or more ¹H shifts overlap with residual proteo solvent signals; these signals have not been reported in the experimental provided hereinafter.

Multiple parent ion masses are reported for mass spectroscopy data when the compound of the invention contains one or more bromine atoms. Bromine exists as an approximately 1 :1 molar ratio of ⁷⁹Br:⁸¹Br. Thus, a compound with a single bromine atom will exhibit two parent mass ions having a difference of 2 amu.

Following preparation methods were used for preparative HPLC.

Method A:

- Stationary phase: Gemini^® NX 5μηι C18 1 1 OA 100x30 mm

- Mobile phase: gradient, water with 0.1 % (28% ammonium hydroxide) / acetonitrile

Absolute stereochemistry and/or optical rotations are provided for the embodiments of the invention where applicable. The invention contemplates all stereochemical forms of the compounds provided herein. Where absolute stereochemistry is provided the assessment was made via X-ray diffraction, and/or chemical correlation, and/or at least one chiral center was from a purchased commercial enantiopure (> 15 : 1 er) starting material. In some instances compounds contain two or more chiral centers. The relative stereochemistry of these compounds was assessed via NMR studies and/or X-ray diffraction. In some instances the relative stereochemistry of a diastereomeric pair was not determined and thus the individual diasteromers are identified by the retention time under delineated HPLC conditions and the monikers "first diastereomer" or "second diastereomer", or "single diastereomer" when only one isomer is isolated and/or available.

In the case of a racemic samples, including intermediates, enantiomers are separated by chromatography using a chiral stationary phase and are identified/differentiated either by HPLC retention time employing a chiral stationary phase and the monikers "enantiomer-1 " or "enantiomer-2", and/or by a specific "+" or "-" sign referring to the rotation of polarized light when this data is available.

In some instances examples possess an acidic functional group as such during final purification procedures samples may contain an undetermined mixture of the free acid along with potassium and/or lithium salts of the titled compound. Small changes in the amount of salt present may change the observed chemical shift or intensity for some peaks in the ¹H NMR spectra.

Inter Alia the following in vitro tests may be used Biological Example 1 : Human complement factor D ELISA assay

Recombinant human factor D (expressed in E. coli and purified using standard methods) at 10 nM concentration is incubated with test compound at various concentrations for 1 hour at room temperature in 0.1 M PBS pH 7.4 containing 7.5 mM MgCI2 and 0.075% (w/v)

CHAPS. Cobra venom factor and human complement factor B substrate complex is added to a final concentration of 200 nM. After 1 hour incubation at room temperature, the enzyme reaction was stopped by addition of 0.1 M sodium carbonate buffer pH 9.0 containing 0.15 M NaCI and 40 mM EDTA . The product of the reaction, Ba, was quantified by means of an enzyme-linked- immunosorbent assay. IC₅₀ values are calculated from percentage of inhibition of factor D- activity as a function of test compound concentration.

Biological Example 2: Human complement factor D TR-FRET assay

Biological Example 2.1. 2-((1 E,3E,5E)-5-(1 -(6-((((3S,5S)-1 -(iert-Butoxycarbonyl)-5-((3- chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3- dimethyl-5-sulfoindolin-2-ylidene)penta-1 ,3-dien-1 -yl)-1 -ethyl-3,3-dimethyl-5-sulfo-3H- indol-1 -ium

To a solution of 2-((1 E,3E,5E)-5-(1 -(5-carboxypentyl)-3,3-dimethyl-5-sulfoindolin-2- ylidene)penta-1 ,3-dien-1 -yl)-1 -ethyl-3,3-dimethyl-5-sulfo-3H-indol-1 -ium potassium salt (Cy-5, CAS # 449175-58-0) (162 mg, 0.233 mmol) in DMF (1 mL) was added HBTU (1 12 mg, 0.295 mmol) at rt. After 10 min of stirring (2S,4S)-tert-butyl 4-(aminomethyl)-2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoro-pyrrolidine-1 -carboxylate (Intermediate B15 step C in WO2012093101) (129 mg, 0.32 mmol) and DIEA (86 μΙ_, 0.491) was added. The blue solution was stirred for 12 h and subsequently purified by preparative HPLC (Waters Sunfire C18 OBD, 5 μηι, 30*100mm, Eluent A: H₂O+0.1 % TFA, B: ACN+0.1 % TFA, Gradient: 5% to 100% B in 20 min hold 3 min, Flow 40 mL/min) to yield title compound as blue powder. MS (ESI+) m/z 1042.6 (M+).

Biological Example 2.2. 2-((1 E,3E,5E)-5-(1 -(6-((((3S,5S)-1 -((1 -carbamoyl-1 H-indol-3- yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3- yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1 ,3-dien-1 -yl)-1 - ethyl-3,3-dimethyl-5-sulfo-3H-indol-1 -ium ο

A solution of 2-((1 E,3E,5E)-5-(1 -(6-((((3S,5S)-1 -(tert-butylcarbamoyl)-5-((3-chloro-2- fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5- sulfoindolin-2-ylidene)penta-1 ,3-dien-1 -yl)-1 -ethyl-3,3-dimethyl-5-sulfo-3H-indol-1 -ium (210 mg, 0.2 mmol) in water (2 ml_) and TFA (93 μΙ_, 1 .2 mmol) was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. At this point TEA (24.8 μΙ_, 0.178 mmol) in THF (1 mL) was added 3-isocyanato-1 H-indole-1 -carboxamide (CAS # 1386456-25-2) (33.5 mg, 0.133 mmol) and 1 ml DMF. The reaction mixture was stirred at rt for 4 h and subsequently purified by preparative HPLC (Waters Sunfire C18 OBD, 5 μηι, 30*100mm, Eluent A: H₂O+0.1 % TFA, B: ACN+0.1 % TFA, Gradient:5% to 100% B in 20 min hold 3 min, Flow 40 mL/min), followed by Waters Sunfire C18, 5 μηι, 100*19mm, Eluent A: H₂O+0.1 % TFA, B: ACN+0.1 % TFA, Gradient:23% to 53% B, Flow 30 mL/min) to afford title compound. MS (ESI+) /z 1 143.5 (M+), HPLC (Waters Sunfire C18, 2.5 mm, 3*30 mm Eluent A: H2O+0.1 % TFA, B: ACN+0.1 % TFA, Gradient: 10% to 98% B in 2.5 min) t_R= 1 .752 min.

Biological Example 2.3. Human complement factor D TR-FRET assay.

Recombinant human factor D (expressed in E. coli and purified using standard methods) labeled with biotin (10 nM), europium-labeled streptavidin (2 nM) and 2-((1 E,3E,5E)-5-(1 -(6- ((((3S,5S)-1 -((1 -carbamoyl-1 H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3- fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-yli^ ,3- dien-1 -yl)-1 -ethyl-3,3-dimethyl-5-sulfo-3H-indol-1 -ium (Biological Example 2.2, 694 nM activity against factor D when tested using the assay of Biological Example 1) (10 nM) were incubated with test compound at various concentrations up to 2 hours at room temperature in 50 mM HEPES buffer, pH 7.4, containing 2.5 mM MgCI₂, 0.01 % (w/v) BSA and 0.05 % (w/v) CHAPS.

The time-gated decrease in fluorescence intensity related to the competition between labeled and unlabeled factor D ligands was recorded at both 620 nm and 665 nm, 70 με after excitation at 337 nm using a microplate spectrofluorimeter. IC₅₀ values were calculated from percentage of inhibition of complement factor D-2-((1 E,3E,5E)-5-(1 -(6-((((3S,5S)-1 -((1 - carbamoyl-1 H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3- yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1 ,3-dien-1 -yl)-1 -ethyl- 3,3-dimethyl-5-sulfo-3H-indol-1 -ium (Biological Example 2.2, 694 nM activity against factor D when tested using the assay of Biological Example 1) displacement as a function of test compound concentration.

The following Examples, while representing preferred embodiments of the invention, serve to illustrate the invention without limiting its scope.

Intermediate 1. 2-(3-Bromo-2-fluorophenyl)acetamide

Hiinig's base (0.749 ml_, 4.29 mmol) was added to a mixture of 2-(1 -oxy-pyridin-2-yl)- 1 ,1 ,3,3-tetramethylisothiouronium tetrafluoroborate (TOTT, CAS # 70340-04-4) (806 mg, 2.57 mmol), 2-(3-bromo-2-fluorophenyl)acetic acid (CAS# 786652-63-9) (500mg, 2.146 mmol) and NH₄CI (230 mg, 4.29 mmol) in DMF at 23 °C. The mixture was stirred at room temperature for 16 hours, then partitioned between 1 :1 EtOAc/heptane and water. The aqueous layer was extracted with 1 :1 EtOAc/heptane. The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated. The residue was purified by silica gel chromatography(0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 231 .9, 233.9 (M+H).

Intermediate 2. tert-Butyl 2-(2-hydroxyphenyl)acetate

To a suspension of (2-hydroxybenzyl)triphenylphosphonium bromide (CAS # 70340-04- 4) (50 g, 1 1 1 mmol) in DCM (500 mL) was added Et₃N (46.3 mL, 334 mmol) at room temperature. cf/^'-fe/ -Butyl dicarbonate (40.9 mL, 178 mmol) was added and the reaction mixture was stirred at 40 °C for 4 days. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The aqueous layer was extracted with DCM. The combined organics were dried and concentrated. The residue was absorbed onto silica gel and purified by silica gel chromatography (0-20% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 9.39 (s, 1 H) 6.98 - 7.1 1 (m, 2 H) 6.66 - 6.83 (m, 2 H) 3.43 (s, 2 H) 1 .39 (s, 9 H).

Intermediate 3.

Intermediate 3-A. tert-Butyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate

A solution of 3-bromo-5-chloro-benzyl alcohol (CAS # 917562-09-5) (2.24 g, 10.1 1 mmol) and fe/ -butyl 2-(2-hydroxyphenyl) acetate (Intermediate 2, 2.74 g, 13.15 mmol) and PPh₃ (3.45 g, 13.15 mmol) inTHF (50 mL) was cooled to 0 °C in an ice/water bath under nitrogen. DIAD (2.56 ml, 13.15 mmol) was added dropwise. The resulting yellow solution was allowed to warm to room temperature and then stirred for 16 hours. Excess base was quenched with water and the resulting mixture was extracted with EtOAc (2X), washed with brine, dried with MgS0₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, CHLOROFORM-cf₂) δ ppm 7.44 - 7.53 (m, 2 H) 7.38 (t, J=1 .64 Hz, 1 H) 7.17 - 7.24 (m, 2 H) 6.96 (d, J=1 .01 Hz, 1 H) 6.86 (d, J=8.21 Hz, 1 H) 5.02 (s, 2 H) 3.60 (s, 2 H) 1 .42 (s, 9 H).

Intermediate 3-B. Methyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate

The title compound was synthesized from 3-bromo-5-chloro-benzyl alcohol (CAS # 91 7562-09-5) and methyl 2-(2-hydroxyphenyl)acetate (CAS # 22446-37-3) in a similar manner as described in Intermediate 3-A. MS (ESI⁺) m/z 368.9, 370.9, 372.8 (M+H).

Intermediate 4. fert-Butyl 2-(2-((3-chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)acetate

A mixture of fe/ -butyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate (Intermediate 3-A, 2 g, 4.86 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (CAS # 731 83- 34-3) (1 .480 g, 5.83 mmol), potassium acetate (1 .430 g, 14.57 mmol), and PdCI₂(dppf) CH₂CI₂ adduct (CAS # 95464-05-4) (0.178 g , 0.243 mmol) in DMF (20 mL) was heated in a microwave reactor at 1 10 °C for 2 hours. The reaction mixture was cooled to room temperature and water was added . The resulting mixture was extracted with 1 :1 EtOAc/heptane (2X). The combined organics were concentrated and the residue was purified by silica gel chromatography (0-1 00% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, DICHLOROMETHANE-cf₂) δ ppm 7.57 - 7.61 (m, 2 H) 7.49 (s, 1 H) 7.08 - 7.1 8 (m, 2 H) 6.81 - 6.88 (m, 2 H) 4.97 (s, 2 H) 3.49 (s, 2 H) 1 .30 (s, 9 H) 1 .25 (s, 12 H).

Intermediate 5.

Intermediate 5-A. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-2^,-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetate

A mixture of fe/ -butyl 2-(2-((3-chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)acetate (Intermediate 4, 500 mg , 1 .090 mmol), 2-(3-bromo-2- fluorophenyl)acetamide (Intermediate 1 , 303 mg , 1 .308 mmol), K₃P0₄ (2.0 M solution, 2.72 ml, 5.45 mmol) and PdCI₂(dppf) CH₂CI₂ adduct (CAS # 95464-05-4) (39.9 mg, 0.054 mmol) in MeCN (4.0 ml) and DMF (5.0 ml) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to room temperature and the organic layer was filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 428.1 , 430.1 (M+H-fBu).

Intermediate 5-B. Methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate

A mixture of methyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate (Intermediate 3- B, 535 mg, 1 .447 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (416 mg, 1 .592 mmol), K₃P0₄ (2.0 M solution, 3.62 ml, 7.24 mmol) and PdCl₂(dppf) CH₂CI₂ adduct (CAS # 95464-05-4) (53.0 mg, 0.072 mmol) in MeCN (5.0 ml) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to rt, acidifed with 1 N HCI solution to pH around 5. The organic layer was filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 424.1 , 426.0 (M+H).

Intermediate 6. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4- yl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

A mixture of te/ -butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 5-A, 60 mg, 0.124 mmol), 1 -methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (51 .6 mg, 0.248 mmol), K₃P0₄ (2.0 M solution, 0.186 ml, 0.372 mmol) and and S-Phos palladacycle (CAS # 1375325-64-6) (4.17 mg, 6.20 μηιοΙ) in acetonitrile (2.0 ml) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to room temperature. The organic layer was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-100%

EtOAc/heptane) to provide the title compound. MS (ESI⁺) /z 530.3 (M+H). Intermediate 7. (S)-fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(((tetrahydrofuran- 2-yl)methyl)amino)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

A suspension of fe/ -butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 5-A, 60 mg, 0.124 mmol), (S)- (tetrahydrofuran-2-yl)methanamine (37.6 mg, 0.372 mmol), BrettPhos palladacycle (CAS # 1 148148-01 -9) (4.95 mg, 6.20 μηιοΓ) and Cs₂C0₃ (121 mg, 0.372 mmol) in MeCN (2 mL) was heated in a microwave reactor at 1 10 °C for 60 min. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 549.3 (M+H).

Intermediate 8. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-((cyclopropylmethyl)amino)-2'- fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 7 from te/ -butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 5-A) and cyclopropylmethanamine. MS (EST) m/z 519.3 (M+H).

Intermediate 9. (S)-Methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(((tetrahydrofuran-2- yl)methyl)amino)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 7 from methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 5-B) and (S)-(tetrahydrofuran-2-yl)methanamine. MS (ESI⁺) m/z 489.2 (M+H). Intermediate 10. tert-Butyl 2-(2-((3-chloro-5-((cyclopropylmethyl)amino)benzyl)oxy) phenyl)acetate

A suspension fe/ -butyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate (Intermediate 3-A, 320 mg, 0.777 mmol), cyclopropylmethanamine (58.0 mg, 0.816 mmol), BrettPhos palladacycle (CAS # 1 148148-01 -9) (31 .0 mg, 0.039 mmol) and Cs₂C0₃ (760 mg, 2.332 mmol) in MeCN (3.0 ml_) was heated in a microwave reactor at 1 10 °C for 60 min. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 402.1 , 404.1 (M+H).

Intermediate 11. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-((cyclopropylmethyl)amino)- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

A mixture of te/ -butyl 2-(2-((3-chloro-5- ((cyclopropylmethyl)amino)benzyl)oxy)phenyl)acetate (Intermediate 10, 75 mg, 0.187 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (73.1 mg, 0.280 mmol), K₃P0₄ (2.0 M solution, 0.467 ml, 0.933 mmol) and S-Phos palladacycle (CAS # 1375325-64-6) (6.28 mg, 9.33 μηιοΓ) in MeCN (2.0 mL) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to room temperature. The organic layer was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) m/z 501 .2 (M+H).

Intermediate 12. Methyl 2-(2-((3-chloro-5-((2-methoxyethyl)amino)benzyl)oxy)phenyl) acetate

The title compound was synthesized in a similar manner as described in Intermediate 10 from methyl 2-(2-((3-bromo-5-chlorobenzyl)oxy)phenyl)acetate (Intermediate 3-B) and 2- methoxyethanamine. MS (ESI⁺) m/z 364.1 , 366.1 (M+H).

Intermediate 13.

Intermediate 13-A. ferf-Butyl 2-(2-((3-bromo-5-(hydroxymethyl)benzyl)oxy)phenyl)acetate

A solution of (5-bromo-1 ,3-phenylene)dimethanol (CAS # 51760-22-6) (32.5 g, 150 mmol) and fe/f-butyl 2-(2-hydroxyphenyl)acetate (Intermediate 2) (15.6 g, 74.9 mmol) and PPh₃ (39.3 g, 150 mmol) in THF (250 mL) was cooled to 0 °C in an ice/water bath. DIAD (29.1 ml_, 150 mmol) was added dropwise and the resulting yellow solution was allowed to warm to room temperature and stirred overnight. Excess base was quenched with water, the resulting mixture was extracted with EtOAc, dried with MgS0₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/heptane) to provide the title compound. ¹H NMR (600 MHz, DMSO-c/₆) δ ppm 7.50 (s, 1 H) 7.46 (s, 1 H) 7.36 (s, 1 H) 7.16 - 7.27 (m, 2 H) 7.01 (d, J=8.07 Hz, 1 H) 6.91 (td, J=7.40, 0.87 Hz, 1 H) 5.34 (t, J=5.73 Hz, 1 H) 5.1 1 (s, 2 H) 4.50 (d, J=5.69 Hz, 2 H) 3.55 (s, 2 H) 1 .34 (s, 9 H).

Intermediate 13-B. Methyl 2-(2-((3-bromo-5-(hydroxymethyl)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 13-A from (5-bromo-1 ,3-phenylene)dimethanol (CAS # 51760-22-6) (32.5 g, 150 mmol) and methyl 2-(2-hydroxyphenyl)acetate (CAS # 22446-37-3). MS (ESI⁺) m/z 365.0, 367.0 (M+H). Intermediate 14. fert-Butyl 2-(2-((3-bromo-5-formylbenzyl)oxy)phenyl)acetate

To a solution of fe/ -butyl 2-(2-((3-bromo-5-(hydroxymethyl)benzyl)oxy)phenyl)acetate (Intermediate 13-A, 28.5 g, 70.0 mmol) in DCM (350 mL) under nitrogen at room temperature, Mn0₂ (122 g, 1399 mmol) was added and the resulting mixture was heated at 40 °C overnight. The reaction mixture was then filtered through Celite^®, the filtrate was concentrated and the residue was purified by silica gel chromatography (100% DCM) to provide the title compound. ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 9.99 (s, 1 H) 8.05 (s, 1 H) 7.97 (s, 2 H) 7.16 - 7.30 (m, 2 H) 7.03 (d, J=8.08 Hz, 1 H) 6.93 (t, J=7.33 Hz, 1 H) 5.23 (s, 2 H) 3.57 (s, 2 H) 1 .32 (s, 9 H). Intermediate 15. fert-Butyl 2-(2-((3-bromo-5-(methoxymethyl)benzyl)oxy)phenyl)acetate

To a solution of fe/ -butyl 2-(2-((3-bromo-5-(hydroxymethyl)benzyl)oxy)phenyl)acetate (Intermediate 13-A) (0.36 g, 0.88 mmol) in THF (8.84 mL) at 0 °C was added NaH (60% in mineral oil, 0.049 g, 1 .2 mmol), follwed by Mel (0.077 mL, 1 .2 mmol). The resulting mixture was stirred at room temperature. After 3 hours, additional NaH (0.049 g, 1 .2 mmol) and Mel (0.077 mL, 1 .2 mmol) were added. After another 90 minutes, additional NaH (0.049 g, 1 .2 mmol) and Mel (0.077 mL, 1 .2 mmol) were added and the reaction mixture was stirred at room temperature overnight. Excess base was quenched with saturated aqueous NH₄CI, the resulting mixture was extracted with EtOAc, dried with MgS0₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53 (s, 1 H) 7.45 (s, 1 H) 7.30 (s, 1 H) 7.16 - 7.25 (m, 2 H) 6.94 (td, J=7.45, 1 .01 Hz, 1 H) 6.87 (d, J=8.08 Hz, 1 H) 5.04 (s, 2 H) 4.43 (s, 2 H) 3.60 (s, 2 H) 3.40 (s, 3 H) 1 .41 (s, 9 H).

Intermediate 16. (±)-fert-Butyl 2-(2-((3-bromo-5-(1 -hydroxyethyl)benzyl)oxy)phenyl)acetate

To a solution of fe/ -butyl 2-(2-((3-bromo-5-formylbenzyl)oxy)phenyl)acetate

(Intermediate 14) (0.40 g, 0.99 mmol) in THF (9.9 mL) at 0 °C under nitrogen, MeMgBr (3.0 M in ether, 0.493 mL, 1 .48 mmol) was added and the reaction mixture was warmed to room temperature. After 10 minutes, excess based was quenched with saturated aqueous NH₄CI, the resulting mixture was extracted with EtOAc, washed with water, dried with MgS0₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 7.48 (s, 2 H) 7.38 (s, 1 H) 7.16 - 7.28 (m, 2 H) 7.01 (d, J=7.58 Hz, 1 H) 6.86 - 6.95 (m, 1 H) 5.31 (d, J=4.40 Hz, 1 H) 5.10 (s, 2 H) 4.65 - 4.78 (m, 1 H) 3.54 (s, 2 H) 1 .25 - 1 .38 (m, 12 H).

Intermediate 17. Methyl 3-bromo-5-((2-(2-(fert-butoxy)-2-oxoethyl)phenoxy)methyl) benzoate

To a suspension of fe/ -butyl 2-(2-((3-bromo-5-formylbenzyl)oxy)phenyl)acetate

(Intermediate 14) (0.30 g, 0.74 mmol) in MeOH (7.40 mL) under nitrogen, a solution of KOH (0.125 g, 2.22 mmol) in MeOH (3 mL) was added. The resulting mixture was cooled to 0 °C ,a solution of iodine (0.244 g, 0.962 mmol) in MeOH (3 mL) was added and the mixture was stirred at room temperature overnight. Saturated aqueous sodium thiosulfate was added, and the resulting mixture was extracted with EtOAc, washed with water, dried with MgS0₄, filtered and concentrated to provide the title compound. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 7.97 - 8.06 (m, 2 H) 7.94 (t, J=1 .71 Hz, 1 H) 7.15 - 7.31 (m, 2 H) 7.02 (d, J=7.58 Hz, 1 H) 6.92 (td, J=7.42, 0.95 Hz, 1 H) 5.21 (s, 2 H) 3.87 (s, 3 H) 3.55 (s, 2 H) 1 .32 (s, 9 H).

Intermediate 18. fert-Butyl 2-(2-((3-bromo-5-(2-hydroxypropan-2-yl)benzyl)oxy)phenyl) acetate

To a solution of methyl 3-bromo-5-((2-(2-(fe/?-butoxy)-2-oxoethyl)phenoxy)methyl) benzoate (Intermediate 17, 0.28 g, 0.643 mmol) in THF (6.43 mL) at 0 °C under nitrogen, MeMgBr (3.0 M in ether, 0.643 mL, 1 .93 mmol) was added and the reaction mixture was warmed to room temperature. After 30 minutes, additional MeMgBr (3.0 M in ether, 0.107 mL, 0.321 mmol) was added. After another 10 minutes, saturated aqueous NH₄CI was added, the resulting mixture was extracted EtOAc (2X), washed with water, dried with MgS0₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 7.60 (t, J=1 .71 Hz, 1 H) 7.50 (s, 1 H) 7.43 - 7.49 (m, 1 H) 7.15 - 7.29 (m, 2 H) 7.01 (d, J=7.70 Hz, 1 H) 6.85 - 6.94 (m, 1 H) 5.18 (s, 1 H) 5.10 (s, 2 H) 3.54 (s, 2 H) 1 .42 (s, 6 H) 1 .32 (s, 9 H).

Intermediate 19. Methyl 3-bromo-5-hydroxybenzoate

To 3-bromo-5-hydroxybenzoic acid (CAS # 140472-69-1) (5.25 g, 24.19 mmol) in MeOH (81 ml_) was added cone. HCI (10 ml_, 329 mmol). The resulting mixture was stirred at room temperature for 16 hours and then heated at 60 °C for 4 hours. After cooled to room temperature, the reaction mixture was concentrated. The residue was then partitioned between water and EtOAc. The organic layer was separated, dried (Na₂S0₄), concentrated. The residue was absorbed onto silica gel and purified by silica gel chromatography (0-30% EtOAc/heptane) to provide the title compound. MS (ESI ) /z 229.0, 230.6 (M-H).

Intermediate 20-A. (R)-Methyl 3-bromo-5-((tetrahydrofuran-2-yl)methoxy)benzoate

The title compound was synthesized in a similar manner as described in Intermediate 3-A starting with methyl 3-bromo-5-hydroxybenzoate (Intermediate 19) and (R)- (tetrahydrofuran-2-yl)methanol (CAS # 22415-59-4). MS (ESI⁺) m/z 314.8, 316.8 (M+H).

Intermediate 20-B. Methyl 3-bromo-5-(cyclopropylmethoxy)benzoate

The title compound was synthesized in a similar manner as described in Intermediate 3-A starting with methyl 3-bromo-5-hydroxybenzoate (Intermediate 19) and

cyclopropylmethanol. ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 7.61 (t, J=1 .52 Hz, 1 H) 7.42 - 7.45 (m, 1 H) 7.41 (dd, J=2.40, 1 .39 Hz, 1 H) 3.91 (d, J=7.07 Hz, 2 H) 3.86 (s, 3 H) 1 .15 - 1 .28 (m, 1 H) 0.55 - 0.61 (m, 2 H) 0.31 - 0.37 (m, 2 H).

Intermediate 20-C. Methyl 3-bromo-5-isopropoxybenzoate

The title compound was synthesized as described in Intermediate 3-A starting with methyl 3-bromo-5-hydroxybenzoate (Intermediate 19) and 2-propanol.

Intermediate 21 -A. (R)-(3-Bromo-5-((tetrahydrofuran-2-yl)methoxy)phenyl)methanol

To (R)-methyl 3-bromo-5-((tetrahydrofuran-2-yl)methoxy)benzoate (Intermediate 20-A, 0.127 g, 0.403 mmol) in THF (4 mL) at 0 °C was added 1 M LiAIH₄ in THF (0.806 mL, 0.806 mmol), and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aq. solution of ammonium chloride at 0 °C. The resulting mixture was partitioned between EtOAc and a saturated solution of sodium potassium tartrate. The layers were separated and the organic layer was separated, dried and concentrated. The residue was absorbed onto silica and purified by silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound. MS (ESI⁺) /z 286.7, 288.7 (M+H).

Intermediate 21 -B. (3-Bromo-5-(cyclopropylmethoxy)phenyl)methanol

The title compound was synthesized in a similar manner as Intermediate 21 -A starting from methyl 3-bromo-5-(cyclopropylmethoxy)benzoate (Intermediate 20-B) and

cyclopropylmethanol. MS (ESI⁺) m/z 256.8, 258.7 (M+H).

Intermediate 21 -C. (3-Bromo-5-isopropoxyphenyl)methanol

The title compound was synthesized in a similar manner as Intermediate 21 -A starting from methyl 3-bromo-5-(cyclopropylmethoxy)benzoate (Intermediate 20-C) and 2-propanol. Intermediate 22-A. (R)-fert-Butyl 2-(2-((3-bromo-5-((tetrahydrofuran-2- yl)methoxy)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 3-A from (R)-(3-bromo-5-((tetrahydrofuran-2-yl)methoxy)phenyl)methanol (Intermediate 21 -A) and tert- butyl-2-(2-hydroxyphenyl)acetate (Intermediate 2). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 7.17 - 7.26 (m, 3 H) 7.10 (t, J=2.02 Hz, 1 H) 7.04 (s, 1 H) 6.98 (d, J=7.70 Hz, 1 H) 6.91 (td, J=7.42, 0.95 Hz, 1 H) 5.09 (s, 2 H) 4.14 (qd, J=6.72, 3.98 Hz, 1 H) 3.89 - 4.03 (m, 2 H) 3.73 - 3.82 (m, 1 H) 3.67 (td, J=7.67, 6.25 Hz, 1 H) 3.55 (s, 2 H) 1 .93 - 2.04 (m, 1 H) 1 .78 - 1 .92 (m, 2 H) 1 .60 - 1 .71 (m, 1 H) 1 .32 - 1 .38 (m, 9 H)

Intermediate 22-B. ferf-Butyl 2-(2-((3-bromo-5- (cyclopropylmethoxy)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 22-A using (3-bromo-5-(cyclopropylmethoxy)phenyl)methanol (Intermediate 21 -B) and tert- butyl 2-(2-hydroxyphenyl)acetate (Intermediate 2). MS (ESI⁺) m/z 391 .0, 393.0 (M-fBu+H). Intermediate 22-C. ferf-Butyl 2-(2-((3-bromo-5-isopropoxybenzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 22-A using (3-bromo-5-isopropoxyphenyl)methanol (Intermediate 21 -C) and fe/ -butyl 2-(2- hydroxyphenyl)acetate (Intermediate 2). ¹H NMR (400 MHz, DMSO-d₆) δ 7.28 - 7.15 (m, 3H), 7.05 (t, J=2.1 Hz, 1 H), 7.02 - 6.96 (m, 2H), 6.90 (td, J=7A, 1 .1 Hz, 1 H), 5.07 (s, 2H), 4.66 (hept, J = 5.9 Hz, 1 H), 3.55 (s, 2H), 1 .34 (s, 9H), 1 .25 (d, J = 6.0 Hz, 6H).

Intermediate 23. Methyl 2-(2-((3-bromobenzyl)oxy)phenyl)acetate

The title compound was synthesized from 3-bromo-benzyl alcohol and methyl 2-(2- hydroxyphenyl)acetate (CAS # 22446-37-3) in a similar manner as described in Intermediate 3- A. ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (t, J = 1 .7 Hz, 1 H), 7.52 (dt, J = 7.9, 1 .6 Hz, 1 H), 7.44 - 7.33 (m, 2H), 7.29 - 7.21 (m, 2H), 7.03 (d, J = 8.1 Hz, 1 H), 6.92 (td, J = 7.3, 1 .0 Hz, 1 H), 5.12 (s, 2H), 3.66 (s, 2H), 3.58 (s, 3H).

Intermediate 24. Methyl 2-(2-((3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 4 starting with methyl 2-(2-((3-bromobenzyl)oxy)phenyl)acetate (Intermediate 23). MS (EST) m/z 383.1 (M+H).

Intermediate 25-A. ferf-Butyl 2-(2-((3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 4 starting with fe/ -butyl 2-(2-((3-bromo-5-(methoxymethyl)benzyl)oxy)phenyl)acetate (Intermediate 15). MS (ESI⁺) m/z 413.2 (M-fBu+H).

Intermediate 25-B. fert-Butyl 2-(2-((3-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 4 starting with fe/ -butyl 2-(2-((3-bromo-5-(cyclopropylmethoxy)benzyl)oxy)phenyl)acetate

(Intermediate 22-B). MS (ESI⁺) m/z 439.3 (M-iBu+H).

Intermediate 25-C. fert-Butyl 2-(2-((3-isopropoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate

(Intermediate 22-C).

Intermediate 25-D. (R)-fert-Butyl 2-(2-((3-((tetrahydrofuran-2-yl)methoxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate

(Intermediate 22-A). MS (ESI⁺) m/z 469.1 (M-iBu+H).

Intermediate 26-A. Methyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-[1 ,1 ^,-biphenyl]-3- yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A starting with methyl 2-(2-((3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)acetate (Intermediate 24) and 2-(3-bromo-2-fluorophenyl)acetamide (Intermediate 1). MS (ESf) m/z 408.1 (M+H).

Intermediate 26-B. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(methoxymethyl)- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A starting with fe/f-butyl 2-(2-((3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl) acetate (Intermediate 25-A) and 2-(3-bromo-2-fluorophenyl)acetamide (Intermediate 1). MS (ESf) m/z 438.2 (M-fBu+H).

Intermediate 26-C. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'- fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A starting with fe/f-butyl 2-(2-((3-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate (Intermediate 25-B) and 2-(3-bromo-2- fluorophenyl)acetamide (Intermediate 1). MS (ESf) m/z 464.3 (M-fBu+H).

Intermediate 26-D. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2^,-fluoro-5-isopropoxy-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A starting with fe/ -butyl 2-(2-((3-isopropoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)acetate (Intermediate 25-C) and 2-(3-bromo-2-fluorophenyl)acetamide (Intermediate 1). MS (ESI⁴) m/z 452.3 (M-fBu+H).

Intermediate 26-E. (R)-fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5- ((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A starting with (R)-tert-buty\ 2-(2-((3-((tetrahydrofuran-2-yl)methoxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate (Intermediate 25-D) and 2-(3-bromo-2- fluorophenyl)acetamide (Intermediate 1). MS (ESI⁺) m/z 494.3 (M-iBu+H).

Intermediate 27. 2-(2-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide

(Intermediate 1). MS (ESI⁴) m/z 280.1 (M+H).

Intermediate 28-A. (+) and (-)-ferf-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 - hydroxyethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A from f+)-fe/?-butyl 2-(2-((3-bromo-5-(1 -hydroxyethyl)benzyl)oxy)phenyl)acetate

(Intermediate 16) and 2-(2-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (Intermediate 27). MS (ESI⁺) m/z 516.3 (M+Na).

Resolution of the enantiomers of fe/ -butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 - hydroxyethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate(lntermediate 28-A) was achieved by chiral SFC using a CHIRALPAK^® OJ-H1 column with 30% MeOH and 5mM NH₄OH in C0₂ to give the first enantiomer (Intermediate 28-A1 , t_r = 1 .85 min) and the second enantiomer

(Intermediate 28-A2, t_r = 2.75 min).

Intermediate 28-B. fert-Butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(2-hydroxypropan- 2-yl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 5-A from fe/ -butyl 2-(2-((3-bromo-5-(2-hydroxypropan-2-yl)benzyl)oxy)phenyl) acetate (Intermediate 18) and 2-(2-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (Intermediate 27). MS (ESI⁺) m/z 434.2 (M-fBu-H₂0+H).

Intermediate 29-A. f erf-Butyl 2-(2-(4,6-dichloropicolinamido)phenyl)acetate

In a 100 ml_ round-bottomed flask, HATU (1 .834 g, 4.82 mmol) was added in one portion at room temperature to a solution of DIEA (1 .149 ml_, 6.58 mmol), 4,6-dichloropyridine-2- carboxylic acid (CAS # 88912-25-8) (1 g, 4.82 mmol), and ie f-butyl 2-(2-aminophenyl)acetate (CAS # 9891 1 -34-3) (0.842 g, 4.39 mmol)in DMF (20 ml_). After 1 .5 hr, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na₂S0₄), filtered and concentrated. The residue was purified by silica gel chromatography (10-90% EtOAc/heptane) to provide the title compound. MS (ESI ) m/z 379.3, 381 .3 (M-H).

Intermediate 29-B. f erf-Butyl 2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4- chloropicolinamido)phenyl)acetate

A 40 mL vial was charged with PdCI₂(PPh₃)₂ (0.046 g, 0.066 mmol), Cs₂C0₃ (1 .282 g, 3.93 mmol), and 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (0.479 g, 1 .836 mmol) and ie f-butyl 2-(2-(4,6- dichloropicolinamido)phenyl)acetate (Intermediate 29-A) (0.5 g, 1 .31 1 mmol). Dioxane (5 mL) and water (1 mL) were added, the vial head space was purged with nitrogen and the vial then sealed. After the suspension was stirred for 5 minutes at room temperature, the reaction mixture was heated at 55 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried (Na₂S0₄), filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/heptane) to provide the title compound. MS (ESI ) m/z 478.3, 480.2 (M-H).

Intermediate 29-C. ferf-Butyl 2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4-((2- methoxyethyl)amino)picolinamido)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 7 from fe/ -butyl 2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4-chloropicolinamido)phenyl)acetate (Intermediate 29-B) and 2-methoxyethanamine. MS (ESI⁺) m/z 519.2 (M+H).

Intermediate 30. 3-Bromo-5-((2-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzoic acid

To a solution of methyl 2-(2-((3-bromo-5-(hydroxymethyl)benzyl)oxy)phenyl)acetate (Intermediate 13-B) (2.22 g, 5.96 mmol) in CH₃CN (35 mL) were added TEMPO (65.2 mg, 0.417 mmol), tetrabutylammonium hydrogen sulfate (81 mg, 0.238 mmol) and 1 .4 M sodium- phosphate-buffer (pH = 6.5 at 22 °C) (22.2 mL). The mixture was heated to 35°C and a solution of NaCI0₂ (80 %, 1 .347 g, 1 1 .91 mmol) in H₂0 (6.0 mL) was added simultaneously with NaOCI (4%, 0.4 mL). The reaction mixture was stirred at 35°C for 5 hr. Then 1 mL of NaOCI was added and the mixture was stirred at 35 °C overnight. After cooling to room temperature, the mixture was diluted with water and Na₂S0₃ (1 .6 g) was added. Then the mixture was acidified with 4 N HCI (2 mL) to pH 1 -2. The mixture was extracted with EtOAc (2X). The combined organic layers were dried (Na₂S0₄), filtered and concentrated. The residue was triturated with Et₂0, filtered and dried to provide the title compound. MS (ESI⁺) m/z 378.9, 380.9 (M+H)

Intermediate 31. 3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-((2-(2-methoxy-2- oxoethyl)phenoxy)methyl)-[1 ,1 '-biphenyl]-3-carboxylic acid

A mixture of 3-bromo-5-((2-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzoic acid (Intermediate 30) (40 mg, 0.105 mmol), 2-(2-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (Intermediate 27) (38.3 mg, 0.137 mmol), K₃P0₄ H₂0 (72.9 mg, 0.316 mmol) and PdCI₂(PPh₃)₂ (3.7 mg, 0.053 mmol) in DME (0.4 mL) and H₂0 (0.13 mL) was stirred at 85 °C for 1 .75 hr. The reaction mixture was quenched with H₂0 / brine, acidified with 1 N HCI and extracted with EtOAc (2X). The combined organic layers were dried (Na₂S0₄), filtered and concentrated. The residue was dissolved in THF (10 mL) and SiliaMetS^® Thiol (loading 1 .4 mmol/g ; 80 mg, 0.1 12 mmol thiol) was added. The suspension was stirred at 40 °C for 1 h and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-90% EtOAc (+1 % AcOH)/c-hexane) to provide the title compound. MS (ESI⁺) m/z 452.2 [M+H].

Intermediate 32. (S)-Methyl 2-(2-((3^,-(2-amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'- fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

To a solution of 3'-(2-amino-2-oxoethyl)-2'-fluoro-5-((2-(2-methoxy-2- oxoethyl)phenoxy)methyl)-[1 ,1 '-biphenyl]-3-carboxylic acid (Intermediate 31) (25 mg, 0.047 mmol), (S)-chroman-4-amine (15.3 mg, 0.1 mmol) (CAS# 188198-38-1 ) and DIPEA (32.5 ul, 0.186 mmol) in DCM (0.5 mL) was added propylphosphonic anhydride (CAS# 68957-94-8) (50% in DMF, 47 ul, 0.079 mmol). The reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was quenched with H₂0 / brine and extracted with EtOAc (2X). The combined organic layers were dried (Na₂S0₄), filtered and concentrated. The residue was suspended in CH₃CN (1 .5 mL) and treated in an ultra sonic bath. The white precipitate formed was filtered and dried to provide the title compound. MS (ESI⁺) m/z 583.2 [M+H].

Intermediate 33. 2-(5-bromo-2-fluorophenyl)acetamide

The title compound was synthesized in a similar manner as described in Intermediate 1 from 2-(5-bromo-2-fluorophenyl)acetic acid. MS (ESI⁺) /z 231 .9, 233.9 (M+H).

Intermediate 34. Methyl 2-(3-fluoro-2-hydroxyphenyl)acetate

To a solution of 1 -bromo-3-fluoro-2-methoxybenzene (CAS # 845829-94-9) (2 g, 9.75 mmol) in THF (90 mL) under nitrogen was added Pd(dba)₂ (CAS # 32005-36-0) (0.280 g, 0.488 mmol) and Q-Phos (CAS # 312959-24-3) (0.347 g, 0.488 mmol), then lastly (2-(tert-butoxy)-2- oxoethyl)zinc(ll) chloride (CAS # 321745-86-2) (21 .46 mL, 10.73 mmol) (0.5M in ether). The reaction was stirred overnight, and then diluted with water and EtOAc, extracted with EtOAc, dried with MgS0₄, filtered and concentrated. The crude was passed through a silica pad eluting with 10% EtOAc in heptane. After evaporation, to a suspension of crude product (1 g, 4.16 mmol) in CH₂CI₂ (30 mL) at 0 °C was added 1 M BBr₃ in heptane (8.32 mL, 8.32 mmol). After stirring at 0 °C for 10 min, the suspension was allowed to stir at room temperature for another 10 minutes. Methanol (5 mL) was added and the resulting mixture was allowed to stir for 15 minutes. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and DCM. The organic layer was separated, dried, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc- heptane) to provide the title compound. MS (ESI⁴) m i 185.0 (M+H).

Intermediate 35. methyl 2-(2-((3-bromobenzyl)oxy)-3-fluorophenyl)acetate

1 -Bromo-3-(bromomethyl)benzene (890 mg, 3.56 mmol) was added to a suspension of K₂C0₃ (513 mg, 3.71 mmol) and methyl 2-(3-fluoro-2-hydroxyphenyl)acetate (Intermediate 34, 570 mg, 3.10 mmol) in DMF (5 mL) at 23 °C. The reaction was allowed to stir at rt overnight. The reaction mixture was then partitioned between EtOAc and sat. NH₄CI. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na₂S0₄), and concentrated. The residue was purified by flash column (EtOAc-heptane 0-20%) to provide the desired product as colorless oil. MS (ESI+) m/z 352.9, 354.9 (M+H).

Intermediate 36. Methyl 2-(2-(3-bromobenzamido)phenyl)acetate

TEA (0.276 ml_, 1 .984 mmol) was added to a mixture of 3-bromobenzoic acid (199 mg, 0.992 mmol) and HATU (415 mg, 1 .091 mmol) in DMF at 23 °C. In a separate vial, methyl 2-(2- aminophenyl)acetate hydrochloride (CAS # 49851 -36-7) (200 mg, 0.992 mmol) was stirred with TEA (0.276 ml_, 1 .980 mmol) in DMF (0.5 ml_). After 5 min, the solution of methyl 2-(2- aminophenyl)acetate hydrochloride (200 mg, 0.992 mmol) was added and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organics were washed with 5% aq LiCI, dried (Na₂S0₄) and concentrated. The resulting residue was purified by silica gel chromatography (EtOAc- heptanes 0-60%) to provide the title compound. MS (EST) m/z 348.0, 350.0 (M+H).

Intermediate 37. Methyl 2-(2-((3-bromo-4-fluorobenzyl)oxy)phenyl)acetate

To a solution of (3-bromo-4-fluorophenyl)methanol (205 mg, 1 .0 mmol) and methyl-2-(2- hydroxyphenyl)acetate (216 mg, 1 .3 mmol) in THF (10.0 ml_) at 0 °C was added

triphenylphosphine (341 mg, 1 .3 mmol) and diisopropylazodicarboxylate (0.253 ml_, 1 .3 mmol). The mixture was stirred at 0 °C, then gradually warmed to room termperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H₂0. The layers were separated and the organic phase was washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel

(heptanes/EtOAc = 100:0 to 50:50) to afford the title compound. ¹H NMR (400 MHz,

CHLOROFORM-d) δ ppm 7.63 (dd, J=6.57, 2.15 Hz, 1 H) 7.29 - 7.35 (m, 1 H) 7.20 - 7.28 (m, 2 H) 7.13 (t, J=8.40 Hz, 1 H) 6.96 (td, J=7.45, 1 .01 Hz, 1 H) 6.86 - 6.90 (m, 1 H) 5.02 (s, 2 H) 3.69 (s, 2 H), 3.67 (s, 3 H).

Intermediate 38. Methyl 2-(2-((3-bromo-2-fluorobenzyl)oxy)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 37 starting with (3-bromo-2-fluorophenyl)methanol. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51 (td, J=7.29, 1 .58 Hz, 1 H) 7.43 - 7.48 (m, 1 H) 7.20 - 7.29 (m, 2 H) 7.03 - 7.08 (m, 1 H) 6.91 - 6.99 (m, 2 H) 5.17 (s, 2 H) 3.68 (s, 2 H) 3.65 (s, 3 H). Intermediate 39-A. Methyl 2-(2-((3-bromo-5-cyanobenzyl)oxy)phenyl)acetate

To a solution of DIAD (2.60 mL, 13.38 mmol) and methyl 2-(2-hydroxyphenyl)acetate (CAS #: 22446-37-3) (2.123 g, 12.78 mmol) in anhydrous THF (20 mL), 3-bromo-5- (hydroxymethyl)benzonitrile (CAS #: 1205515-06-5) (2.58 g, 12.17 mmol) was added dropwise while stirring at 0°C under argon, followed by triphenylphosphine (3.51 g, 13.38 mmol). The reaction mixture was then warmed and stirred overnight at room temperature. The reaction mixture was diluted in DCM and washed with a sat. solution of sodium bicarbonate. The organic layer was dried (phase separator) and concentrated. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc: 10/0 to 5/5 in 24 min) to afford the title compound. MS (ESI⁺) m/z 359.9, 361 .9 (M+H). ¹H NMR (400 MHz, DMSO-c/₆) δ (ppm) : 8.13 (s, 1 H), 7.96 (s, 1 H), 7.87 (s, 1 H), 7.35 - 7.19 (m, 2H), 7.01 (m, 1 H), 6.94 (m, 1 H), 5.18 (s, 2H), 3.69 (s, 2H), 3.59 (s, 3H).

Intermediate 39-B. Methyl 2-(2-((3-(aminomethyl)-5-bromobenzyl)oxy)phenyl)acetate

To a solution of methyl 2-(2-((3-chloro-5-cyanobenzyl)oxy)phenyl)acetate (3.42g, 9.49 mmol) and CoCI₂.6H₂0 (3.39 g, 14.24 mmol) in THF (80 mL) / H₂0 (20 mL) at 0°C was added portionwise NaBH₄ (1 .078 g, 28.5 mmol). The reaction mixture was then stirred at 0 °C for 2.5 h, filtered, diluted in a large volume of DCM and washed with sat. Na₂C0₃. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried (phase separator), concentrated. The residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc: 10/0 to 0/10 in 20 min then DCM/MeOH: 10/0 for 8 min then to 97/3 in 22 min) to afford the title compound. MS (ESI⁺) m/z 364.0, 366.0 (M+H).

Intermediate 39-C. Methyl 2-(2-((3-bromo-5-(((2,2,2- trifluoroethyl)amino)methyl)benzyl)oxy)phenyl)acetate

To a solution of methyl 2-(2-((3-(aminomethyl)-5-bromobenzyl)oxy)phenyl)acetate (420 mg, 1 .153 mmol) in DMF (20 mL) were added DIPEA (0.604 ml_, 3.46 mmol) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (0.183 mL, 1 .268 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted in EtOAc and washed with water and a sat. solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc: 100/0 to 68/32 in 20 min) to afford the title compound. MS (ESI⁺) m/z 446.1 , 448.1 (M+H).

Intermediate 39-D. Methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(((2,2,2- trifluoroethyl)amino)methyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate

A mixture of methyl 2-(2-((3-bromo-5-(((2,2,2- trifluoroethyl)amino)methyl)benzyl)oxy)phenyl)acetate (50 mg, 0.038 mmol), 2-(3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (36.6 mg, 0.14 mmol), K3PO4.H2O (64.5 mg, 0.28 mmol) and PdCI₂(PPh₃)₂ (3.1 mg, 4.4 umol) in dioxane (840 uL) / H₂0 (280 uL) was vigorously stirred at 100°C for 1 .25 h. The reaction mixture was filtered on a chem elut extraction cartridge (Varian) with EtOAc, concentrated and purified by preparative HPLC (Waters Sunfire C18 OBD, 5 μηι, 30*100mm, Eluent A: H₂O+0.1 % TFA, B: ACN+0.1 % TFA, Gradient: 5 to 100% B in 20 min hold 3 min, Flow 40 mL/min). Pure fractions were filtered on a Stratosphere PL- HC03- MP SPE cartridge, 0.5 g (Varian polymer laboratories) with MeOH / ACN. To the filtrate was added mercaptomethyl-polymer-bound (100 mg, 2 mmol S/g, Aldrich 589985) and the mixture was stirred at room temperature for 3 h.The suspension was filtered and the filtrate was concentrated under vacuum to give the title compound. MS (EST) m/z 501 .3 Intermediate 40-A. ferf-Butyl 2-(2-(3-bromo-5-chlorobenzamido)phenyl)acetate

TEA (1 .184 ml_, 8.49 mmol) was added to a mixture of 3-bromo-5-chlorobenzoic acid (1 g, 4.25 mmol), ferf-butyl 2-(2-aminophenyl)acetate (CAS # 9891 1 -34-3) (0.880 g, 4.25 mmol) and HATU (1 .776 g, 4.67 mmol) in DMF at 23 °C. The mixture was stirred at room temperature overnight. The mixture was partitioned between 1 :1 EtOAc/heptane and water. The aqueous layer was extracted with 1 :1 EtOAc/heptane. The combined organic layers were washed with brine, dried (Na₂S0₄) and concentrated. The residue was purified by flash column (EtOAc- Heptane 0-100%) to give the title compound. MS (ESI ) m/z 422.2, 424.3, 426.3 (M-H).

Intermediate 40-B. ferf-Butyl 2-(2-(3-chloro-5-((2- methoxyethyl)amino)benzamido)phenyl)acetate

A suspension of fe/ -butyl 2-(2-(3-bromo-5-chlorobenzamido)phenyl)acetate

(Intermediate 40-A, 1 .1 g, 2.59 mmol), 2-methoxyethanamine (CAS # 109-85-3) (0.195 g, 2.59 mmol), BrettPhos palladacycle (CAS # 1 148148-01 -9) (0.103 g, 0.129 mmol) and Cs₂C0₃ (2.53 g, 7.77 mmol) in MeCN (2 ml_) was heated in a microwave at 1 10 °C for 60 min. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash column (EtOAc- Heptane 0-100%) to provide the title compound. MS (ESI-) m/z AM A (M-H).

Intermediate 41 -A. ((S)-tetrahydrofuran-2-yl)methyl 3-bromo-5-(((S)-tetrahydrofuran-2- yl)methoxy)benzoate

The title compound was synthesized in a similar manner as described in Intermediate 3-A starting with 3-bromo-5-hydroxybenzoic acid (CAS # 140472-69-1) and (R)- (tetrahydrofuran-2-yl)methanol (CAS # 22415-59-4). MS (ESI+) m/z 385.3, 387.3 (M+H).

Intermediate 41 -B. (S)-3-bromo-5-((tetrahydrofuran-2-yl)methoxy)benzoic acid

To a solution of ((S)-tetrahydrofuran-2-yl)methyl 3-bromo-5-(((S)-tetrahydrofuran-2- yl)methoxy)benzoate (Intermediate 41 -A) (1600 mg, 4.15 mmol) in THF (20 ml) at room temperature was added LiOH (1 M solution, 12.46 ml, 12.46 mmol). The mixture was stirred at room temperature for 16 h, and then diluted in EtOAc and washed with water. The organic layer was discarded. The water layer was acidified to pH around 1 with concentrated HCI, and then extracted with EtOAc twice. The organic layer was concentrated to provide the title product. MS (ESI ) m/z 299.2, 301 .2 (M-H).

Intermediate 41 -C. (S)-methyl 2-(2-(3-bromo-5-((tetrahydrofuran-2- yl)methoxy)benzamido)phenyl)acetate

The title compound was synthesized in a similar manner as described in Intermediate 29-A starting with (S)-3-bromo-5-((tetrahydrofuran-2-yl)methoxy)benzoic acid and methyl 2-(2- aminophenyl)acetate. MS (ESI⁺) m/z 448.3, 450.3 (M+H).

Intermediate 42-A. ferf-Butyl 2-(3-fluoro-5-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2- yl)phenyl)acetate

To a solution of 2-(3-bromo-5-fluorophenyl)-6-methyl-1 ,3,6,2-dioxazaborocane-4,8-dione (0.2 g, 0.606 mmol) in THF under nitrogen was added Pd(dba)₂ (0.017 g, 0.030 mmol), Q-Phos (0.022 g, 0.030 mmol), and (2-(fe/?-butoxy)-2-oxoethyl)zinc(ll) chloride (0.5M in ether, 1 .334 ml, 0.667 mmol) in that order. The mixture was stirred for 16 hours, then diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2X). The combined organics were dried with MgS0₄, filtered and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.25 - 7.17 (m, 1 H), 7.15 - 7.08 (m, 1 H), 7.07 - 7.00 (m, 1 H), 4.26 (d, J = 17.1 Hz, 2H), 4.05 (d, J = 17.1 Hz, 2H), 3.58 (s, 2H), 2.59 (s, 3H), 1 .44 (s, 9H).

Intermediate 42-B. ferf-Butyl 2-(5-fluoro-3'-(hydroxymethyl)-[1 ,1 ^,-biphenyl]-3-yl)acetate

fe/ -Butyl 2-(3-fluoro-5-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2-yl)phenyl)acetate (Intermediate 42-A) (150 mg, 0.41 1 mmol) was dissolved in NH₃ methanol solution (2M in MeOH, 1 .03 ml, 2.05 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated to provide (3-(2-(fe/?-butoxy)-2-oxoethyl)-5- fluorophenyl)boronic acid.

In a 2-5 ml microwave vial was placed (3-chlorophenyl)methanol (168 mg, 1 .181 mmol) and (3-(2-(tert-butoxy)-2-oxoethyl)-5-fluorophenyl)boronic acid (100 mg, 0.394 mmol) in MeCN (3 ml). Then K3PO4 (2 M solution, 0.98 ml, 1 .97 mmol) and S-Phos palladacycle (CAS # 1375325-64-6) (13.24 mg, 0.020 mmol) were added and the vial was sealed and heated in a microwave at 1 10°C for 60 min. The reaction mixture was cooled to room temperature. The organic layer was filtered and purified by flash column (0-100% EtOAc/heptane) to provide the title product. ¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (s, 1 H), 7.52 (ddd, J = 7.6, 1 .9, 1 .2 Hz, 1 H), 7.43 (td, J = 7.6, 0.6 Hz, 1 H), 7.38 - 7.34 (m, 2H), 7.26 - 7.24 (m, 1 H), 7.01 (ddd, J = 9.5, 2.4, 1 .4 Hz, 1 H), 4.67 (s, 2H), 3.63 (d, J = 0.6 Hz, 2H), 1 .45 (s, 9H).

Intermediate 42-C. 2-(5-Fluoro-3'-(hydroxymethyl)-[1 ,1 '-biphenyl]-3-yl)acetamide

A solution fe/ -butyl 2-(5-fluoro-3'-(hydroxymethyl)-[1 ,1 '-biphenyl]-3-yl)acetate

(Intermediate 42-B) (100 mg, 0.316 mmol) in DCM (0.5 ml) and TFA (0.5 ml) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to provide 80 mg of 2-(5-fluoro-3'-(hydroxymethyl)-[1 ,1 '-biphenyl]-3-yl)acetic acid. This was dissolved along with 2-(1 -oxy-pyridin-2-yl)-1 ,1 ,3,3-tetramethylisothiouronium tetrafluoroborate (TOTT, CAS # 70340-04-4) (144 mg, 0.461 mmol), and NH₄CI (32.9 mg, 0.615 mmol) in DMF Hunig's base (0.107 ml_, 0.615 mmol) was added and the brown mixture was stirred at room temperature for 16 hours. The mixture was partitioned between 1 :1 EtOAc/heptane and water and separated. The aqueous layer was extracted with 1 :1 EtOAc/heptane. The combined organic layers were washed with brine, dried (Na₂S0₄) and concentrated. The residue was purified by flash column (0-100% EtOAc/heptane) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (dq, J = 1 .8, 0.9 Hz, 1 H), 7.53 (dt, J = 7.6, 1 .7 Hz, 1 H), 7.45 - 7.39 (m, 2H), 7.38 - 7.34 (m, 1 H), 7.26 (ddd, J = 10.1 , 2.4, 1 .6 Hz, 1 H), 7.05 (ddd, J = 9.5, 2.5, 1 .5 Hz, 1 H), 4.67 (s, 2H), 3.59 (s, 2H).

Example 1. 2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4-yl)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid

A solution of fe/t-butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4- yl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 6, 30 mg, 0.057 mmol) in DCM (1 .0 ml) and TFA (0.436 ml, 5.66 mmol) was stirred at room temperature for 1 hour. LC-MS showed reaction completed. The reaction mixture was concentrated and the residue was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ

8.19 (d, J=0.8 Hz, 1 H), 7.92 (d, J=0.8 Hz, 1 H), 7.68 (t, J=1 .6 Hz, 1 H), 7.63 (d, J=1 .8 Hz, 1 H), 7.51 (s, 1 H), 7.44 (td, J=7.6, 1 .8 Hz, 1 H), 7.40 (d, J=1 .6 Hz, 1 H), 7.34 (td, J=7.3, 1 .8 Hz, 1 H), 7.24 (t, J=7.6 Hz, 3H), 7.10 - 7.04 (m, 1 H), 6.97 (d, J=3.0 Hz, 1 H), 6.91 (dt, J=7.4, 1 .0 Hz, 1 H),

5.20 (s, 2H), 3.87 (s, 3H), 3.61 (s, 2H), 3.53 (d, J=1 .3 Hz, 2H). HRMS calcd. for C27H24FN3O4 (M+H)⁺ 474.1829, found 474.1802.

Example 2. The compounds in the table below were synthesized as described in Example 1 from appropriate intermediates.

Structure/Chemical Name Inter ¹H NMR HRMS medi

ate

2-H 29-C (400 MHz, Methanol-d₄) δ calcd. for

8.29 (t, J = 1 .7 Hz, 1 H), C25H26N4O5

7.97-7.93 (m, J = 7.6, 2.9, (M+H)⁺

1 .5 Hz, 2H), 7.46 - 7.36 463.1981 ,

(m, 3H), 7.37-7.31 (m, found

2H), 7.22 (d, J = 2.2 Hz, 463.1964

1 H), 7.22 - 7.16 (m, 1 H),

3.75 (s, 2H), 3.68 - 3.61

2-(2-(6-(3-(2_^amino-2- (m, 4H), 3.48 (t, J = 5.4

oxoethyl)phenyl)-4-((2- Hz, 2H), 3.41 (s, 3H).

methoxyethyl)amino)pic

olinamido)phenyl)acetic

acid

Example 3. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid

LiOH (1 .0 M solution, 0.409 ml, 0.409 mmol) was added to a solution of (S)-methyl 2-(2- ((3'-(2-amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 9, 40 mg, 0.082 mmol) in MeCN (2.0 ml_). The resulting mixture was stirred at room temperature for 16 hours. Excess base was quenched with 1 .0 M HCI to pH around 7, the resulting mixture was filtered, and the filtrate was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (dd, J = 2.2, 1 .4 Hz, 1 H), 7.54 - 7.46 (m, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.29 - 7.19 (m, 2H), 7.12 (ddd, J = 8.1 , 7.4, 1 .8 Hz, 1 H), 7.02 (t, J = 1 .5 Hz, 1 H), 6.94 (dd, J = 8.3, 1 .1 Hz, 1 H), 6.89 - 6.78 (m, 3H), 5.08 (s, 2H), 4.12 (qd, J = 6.8, 4.7 Hz, 1 H), 3.89 (ddd, J = 8.3, 7.0, 6.3 Hz, 1 H), 3.80 - 3.72 (m, 1 H), 3.60 (s, 2H), 3.58 (s, 2H), 3.29 - 3.16 (m, 2H), 2.1 1 - 1 .84 (m, 3H), 1 .71 (ddt, J = 1 1 .8, 8.4, 6.9 Hz, 1 H). HRMS calcd. for C28H30N2O5 (M+H)⁺ 475.2233, found 475.2214.

Example 4. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-cyclopropyl-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid

A mixture of methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 5-B, 50 mg, 0.1 18 mmol), potassium

cyclopropyltrifluoroborate (CAS # 1065010-87-8) (34.9 mg, 0.236 mmol), K₃PO₄ (2.0 M solution, 0.295 ml, 0.590 mmol) and S-Phos palladacycle (CAS 1028206-58-7) (3.97 mg, 5.90 μηιοΙ) in MeCN (1 .0 ml) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to room temperature, acidifed with 1 N HCI solution to pH around 5. The organic layer was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (t, J = 1 .8 Hz, 1 H), 7.55 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 1 H), 7.28 (dq, J = 5.6, 1 .7 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 1 .6 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.90 (td, J = 7.4, 1 .1 Hz, 1 H), 5.13 (s, 2H), 3.66 (s, 2H), 3.58 (s, 2H), 1 .99 (tt, J = 8.4, 5.0 Hz, 1 H), 1 .02 - 0.95 (m, 2H), 0.82 - 0.73 (m, 2H). HRMS calcd. for C₂₆H₂₅N0₄(M+H)⁺ 416.1862, found 416.1852.

Example 5. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid

A mixture of methyl 2-(2-((3-chloro-5-((2-methoxyethyl)amino)benzyl)oxy)phenyl) acetate (Intermediate 12, 87 mg, 0.24 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (CAS # 843646-72-0) (94 mg, 0.360 mmol), Κ₃Ρ0₄ (2.0M solution, 0.60 mL, 1 .20 mmol) and S-Phos palladacycle (CAS 1028206-58-7) (8.07 mg, 0.012 mmol) in MeCN (2.0 mL) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to rt, acidifed with 1 N HCI solution to pH around 3. The organic layer was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J = 1 .9 Hz, 1 H), 7.50 (dt, J = 7.8, 1 .4 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.26 (dt, J = 7.6, 1 .4 Hz, 1 H), 7.22 (dd, J = 7.5, 1 .7 Hz, 1 H), 7.14 (ddd, J = 8.1 , 7.3, 1 .8 Hz, 1 H), 7.03 (t, J = 1 .5 Hz, 1 H), 6.95 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.90 - 6.78 (m, 3H), 5.08 (s, 2H), 3.63 - 3.59 (m, 4H), 3.58 (s, 2H), 3.38 (s, 3H), 3.36 - 3.32 (m, 2H). ). HRMS calcd. for C26H28N2O5 (M+H)⁺ 449.2076, found 449.2068.

Example 6. 2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid

The title compound was synthesized in a similar manner as described in Example 3 from methyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 26-A). ¹H NMR (400 MHz, Methanol-d₄) δ 7.66 - 7.61 (m, 1 H), 7.53 (dt, J = 6.9, 1 .9 Hz, 1 H), 7.49 - 7.38 (m, 3H), 7.35 - 7.28 (m, 1 H), 7.25 - 7.18 (m, 2H), 7.17 - 7.1 1 (m, 1 H), 6.96 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.87 (td, J = 7.4, 1 .1 Hz, 1 H), 5.16 (s, 2H), 3.65 (d, J = 1 .6 Hz, 2H), 3.58 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H)⁺ 394.1455, found 394.1448.

Example 7. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid

A solution of fe/f-butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 26-C, 1 12 mg, 0.215 mmol) in HCI (4M in dioxane) (2.150 mL, 8.60 mmol) was stirred at room temperature for 2 hours. 1 .0 mL water and sat. NH₄OH (1 .0 mL, 8.60 mmol) were added. The mixture was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol- d₄) δ 7.39 (td, J = 7.5, 1 .8 Hz, 1 H), 7.31 (td, J = 7.2, 1 .8 Hz, 1 H), 7.27 - 7.16 (m, 4H), 7.09 - 6.98 (m, 3H), 6.91 (td, J = 7.5, 1 .1 Hz, 1 H), 5.14 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 3.69 - 3.62 (m, 4H), 1 .33 - 1 .20 (m, 1 H), 0.67 - 0.57 (m, 2H), 0.42 - 0.33 (m, 2H). HRMS calcd. for C27H26FNO5 (M+H)⁺ 464.1873, found 464.1862.

Example 8. The compounds in the table below were synthesized as described in Example 7 from appropriate intermediates.

Structure/Chemical Name Interm ¹H NMR HRMS

ediate 8-A 26-E (400 MHz, Methanol-d₄) δ calcd. for

7.40 (td, J= 7.5, 1.8 Hz, C28H28FNO6

1H), 7.31 (td, J= 7.3, 1.8 (M+H)⁺

Hz, 1H), 7.27-7.17 (m, 494.1979,

4H), 7.10 (t, J= 1.8 Hz, found

1H), 7.07-6.99 (m, 2H), 494.1989 6.91 (td, J= 7.4, 1.1 Hz,

1H), 5.15 (s, 2H), 4.28 (qd,

(R)-2-(2-((3'-(2-amino-2- J = 6.8, 3.7 Hz, 1H),4.07

oxoethyl)-2'-fluoro-5- (dd, J= 10.1, 3.8 Hz, 1H),

((tetrahydrofuran-2- 4.00 (dd, J= 10.1, 6.2 Hz,

yl)methoxy)-[1,1'- 1H), 3.92 (dt, J= 8.2, 6.6

biphenyl]-3- Hz, 1H), 3.82 (td, J = 7.7,

yl)methoxy)phenyl)acetic

6.0 Hz, 1H), 3.67 (s, 2H),

acid

3.65 (s, 2H), 2.16-1.77

(m, 4H).

8-B 28-B (400 MHz, Methanol-d4) δ calcd. for

7.64 (q, J= 1.7 Hz, 1H), C26H26FNO5 7.59 (t, J= 1.7 Hz, 1H), (M+H-H₂0)⁺

7.50 (d, J= 1.8 Hz, 1H), 434.1768

7.41 (td, J= 7.6, 1.9 Hz, found

1H), 7.36-7.28 (m, 1H), 434.1755 7.27-7.17 (m, 3H), 7.07- 7.02 (m, 1H), 6.91 (td, J =

2-(2-((3'-(2-amino-2- 7.4, 1.1 Hz, 1H), 5.17 (s,

oxoethyl)-2'-fluoro-5-(2- 2H), 3.70-3.62 (m, 4H),

hydroxypropan-2-yl)-[1 ,1 '- 1.58 (s, 6H).

biphenyl]-3- yl)methoxy)phenyl)acetic

acid

Example 9. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid

A mixture of (S)-methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'- fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (21 mg, 0.036 mmol) and LiOH (6.7 mg, 0.281 mmol) in THF (0.18 mL), H₂0 (0.54 mL) and DMSO (0.4 mL) was stirred at 35 °C for 6 hr. The reaction mixture was acidified with 1 N HCI (320 uL). The white suspension was diluted with H₂0 (2 mL) and stored in the fridge for 2 days. The suspension was then treated in an ultra sonic bath for 1 min and then centrifuged. The solid was washed again with H₂0, centrifuged and lyophilized to provide the title compound. ¹ H NMR (400 MHz, DMSO-cf₆) δ (ppm) : 12.17 (br. s, 1 H), 9.07 (br. s, 1 H), 8.05 (m, 2H), 7.78 (s, 1 H), 7.55 -6.81 (m, 13H), 5.29 (m, 3H), 4.27 (m, 2H), 3.58 (s, 2H), 3.54 (s, 2H), 2.25 (m, 2H). LCMS (ESI⁺) m/z 569.3 (M+H).

Example 10.

Example 10-A. (±)-Methyl 2-(2-((6-bromo-2,3-dihydro-1 H-inden-1 -yl)oxy)phenyl)acetate

DIAD (1 .165 mL, 5.99 mmol) was added dropwise to a solution of PPh₃ (1 .571 g, 5.99 mmol), 6-bromo-2,3-dihydro-1 H-inden-1 -ol (CAS # 75476-86-7) (1 .1 1 g, 5.21 mmol) and methyl 2-(2-hydroxyphenyl)acetate (0.996 g, 5.99 mmol) in THF (1 5 mL) at 0 °C. The reaction mixture was allowed to stir for 15 minutes at 0 °C and then warmed to room temperature. The reaction mixture was stirred at room temperature overnight, partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc . The combined organics were washed with brine, dried (Na₂S0₄) and concentrated. The residue was purified by silica gel chromatography (30% EtOAc- heptane) tor provide the title compound. MS (ESI ) m/z 359.0, 361 .0 (M-H)^~.

Example 10-B. (±)-Methyl 2-(2-((6-(3-(2-amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 - yl)oxy)phenyl)acetate

A mixture of (±)-methyl 2-(2-((6-bromo-2,3-dihydro-1 /-/-inden-1 -yl)oxy)phenyl)acetate (200 mg, 0.443 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (139 mg, 0.532 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (36.2 mg, 0.044 mmol) and K₃P0₄ (0.664 ml_, 1 .329 mmol) in acetonitrile (6 ml_) was heated in a microwave reactor at 1 10 °C for 30 min. The reaction mixture was partitioned between EtOAc and sat. NH₄CI. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na₂S0₄) and concentrated. The residue was purified by silica gel chromatography (MeOH-DCM 2-10%) to provide the title compound as a brown oil. MS (ESI⁺) m/z 416.1 (M+H)⁺. Example 10-C. (±)-2-(2-((6-(3-(2-Amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 - yl)oxy)phenyl)acetic acid

1 N LiOH aqueous solution (1 .805 ml_, 1 .805 mmol) was added to a solution of (±)- methyl 2-(2-((6-(3-(2-amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 -yl)oxy)phenyl)acetate (100 mg, 0.181 mmol) in CH₃CN (2 ml_) at 23 °C. The resulting mixture was stirred at room temperature over night. The resulting mixture was filtered through a plug of Celite^® and the filtrate was purified by HPLC (Method A)to provide the title compound as white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.63 (s, 1 H), 7.58 (s, 1 H), 7.54 (dd, J=7.89, 1 .71 Hz, 1 H), 7.48 (dt, J=7.83, 1 .33 Hz, 1 H), 7.40 - 7.32 (m, 2 H), 7.30 - 7.23 (m, 2 H), 7.23 - 7.14 (m, 2 H), 6.92 (td, J=7.42, 1 .07 Hz, 1 H), 5.90 - 5.78 (m, 1 H), 3.57 (s, 2 H), 3.55 - 3.48 (m, 2 H), 3.20 - 3.10 (m, 1 H), 3.01 - 2.90 (m, 1 H), 2.67 (dddd, J=13.39, 8.34, 6.69, 5.05 Hz, 1 H), 2.19 (dddd, J=13.41 , 8.64, 6.13, 4.80 Hz, 1 H). HRMS calcd. for C₂₅H₂₃N0₄ (M) 401 .1627, found 401 .1627.

Example 11. 2-(2-(3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid

To a suspension of fe/ -butyl 2-(2-(3-chloro-5-((2-methoxyethyl)amino)benzamido) phenyl)acetate (Intermediate 40-B) (50 mg, 0.1 19 mmol) and 2-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (46.8 mg, 0.179 mmol) in MeCN (2 ml) was added K₃P0₄ (2.0 M solution, 0.30 ml, 0.60 mmol) and S-Phos palladacycle (CAS # 1375325-64-6) (4.01 mg, 5.97 μηιοΙ). The vial was sealed and heated in a microwave at 1 10 °C for 60 min. The reaction mixture was cooled to rt, acidified with 1 N HCI solution to pH around 5. The organic layer was filtered and purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 - 7.62 (m, 3H), 7.60 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 1 H), 7.25 (ddt, J = 6.2, 4.6, 1 .8 Hz, 3H), 7.18 (t, J = 1 .8 Hz, 1 H), 7.12 (td, J = 7.4, 1 .3 Hz, 1 H), 7.06 (t, J = 1 .8 Hz, 1 H), 6.85 (s, 1 H), 5.94 (t, J = 5.7 Hz, 1 H), 3.63 - 3.49 (m, 4H), 3.45 (s, 2H). HRMS calcd. for C26H27N3O5 (M+H) 462.2029, found 462.2012.

Example 12. (S)-2-(2-(3'-(2-Amino-2-oxoethyl)-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '- biphenyl]-3-ylcarboxamido)phenyl)acetic acid

In a 2-5 ml_ microwave vial was placed fSJ-methyl 2-(2-(3-bromo-5-((tetrahydrofuran-2- yl)methoxy)benzamido)phenyl)acetate (Intermediate 41 -C) (100 mg, 0.223 mmol) and 2-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (87 mg, 0.335 mmol) in MeCN (1 ml). Then K₃P0₄ (2 M solution, 0.56 ml, 1 .12 mmol) and X-phos palladacycle (8.24 mg, 0.01 1 mmol) were added and the vial was sealed and heated in a microwave at 1 10 °C for 60 min. The reaction mixture was cooled to room temperature, acidified with 1 N HCI solution to pH around 5. The organic layer was filtered and purified by HPLC

(Method A) to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) 5 8.19 - 8.10 (m, 1 H), 7.98 (dd, J = 8.2, 1 .3 Hz, 1 H), 7.94 - 7.86 (m, 2H), 7.66 (dt, J = 7.9, 1 .4 Hz, 1 H), 7.61 (dd, J = 2.5, 1 .4 Hz, 1 H), 7.45 - 7.35 (m, 2H), 7.28 (dt, J = 7.5, 1 .3 Hz, 1 H), 7.23 - 7.13 (m, 2H), 7.01 (td, J = 7.5, 1 .4 Hz, 1 H), 6.81 (s, 1 H), 4.22 (qd, J = 6.7, 3.9 Hz, 1 H), 4.18 - 4.04 (m, 2H), 3.83 (ddd, J = 8.2, 7.1 , 6.2 Hz, 1 H), 3.75 - 3.67 (m, 1 H), 3.45 (s, 2H), 3.40 (s, 2H), 2.1 1 - 1 .99 (m, 1 H), 1 .99 - 1 .79 (m, 2H), 1 .73 (ddt, J = 1 1 .8, 8.6, 6.7 Hz, 1 H). HRMS calcd. for C26H27N3O5 (M+H) 489.2026, found 489.201 1 .

Example 13-A. 2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)-4-chloropicolinamido)phenyl)acetic acid

The title compound was synthesized in a similar manner as described in Example 1 from fe/ -butyl 2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4-chloropicolinamido)phenyl)acetate (Intermediate 29-B). MS (ESI⁺) m/z 424.0, 426.0 (M+H).

Example 13-B. 2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)picolinamido)phenyl)acetic acid

A solution of 2-(2-(6-(3-(2-amino-2-oxoethyl)phenyl)-4-chloropicolinamido)phenyl)acetic acid (Intermediate 13-A) (88 mg, 0.208 mmol) in MeOH (15 ml) and acetic acid (5 ml) was circulated through H-Cube at room temperature under 10 bar for 2 hours (1 ml_/min). The mixture was concentrated. The residue was dissolved in DMSO and purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (d, J = 1 .9 Hz, 1 H), 8.15 (ddd, J = 7.7, 4.4, 1 .1 Hz, 2H), 8.10 - 8.01 (m, 2H), 7.97 (dd, J = 8.0, 1 .3 Hz, 1 H), 7.51 - 7.41 (m, 2H), 7.36 - 7.25 (m, 2H), 7.14 (td, J = 7.5, 1 .3 Hz, 1 H), 3.73 (s, 2H), 3.67 (s, 2H). HRMS calcd. for C₂2H₁₉N₃04 (M+H) 390.1454, found 390.1445.

Example 14. 2-(2-((3'-(2-Amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid

The title compound was synthesized in a similar manner as described in Example 12-D from methyl 2-(2-((3-bromobenzyl)oxy)phenyl)acetate (Intermediate 23) and 2-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0). ¹ H NMR (400 MHz, Methanol-d₄) δ 7.79 (q, J = 1 .3 Hz, 1 H), 7.68 (t, J = 1 .9 Hz, 1 H), 7.59 - 7.52 (m, 2H), 7.50 - 7.35 (m, 3H), 7.29 (ddd, J = 7.6, 3.7, 2.2 Hz, 1 H), 7.22 (dd, J = 7.5, 1 .7 Hz, 1 H), 7.17 - 7.08 (m, 1 H), 6.96 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.87 (td, J = 7.4, 1 .1 Hz, 1 H), 5.17 (s, 2H), 3.63 - 3.57 (m, 4H). HRMS calcd. for C₂₃H₂iN0₄ (M+H) 376.1549, found 376.1544.

Example 15. 2-(2-((3'-(1 ,2-Diamino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid

In a 2-5 ml_ microwave vial was placed methyl 2-(2-((3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate (Intermediate 24) (0.1 g, 0.21 mmol) and 2- amino-2-(3-bromophenyl)acetamide (0.072 g, 0.314 mmol) in MeCN (2.0 ml). Then K₃P0₄ (2 M solution, 0.523 ml, 1 .046 mmol) and PdCI₂(dppf) CH₂CI₂ adduct (7.66 mg, 10.46 μηιοΓ) was added. The vial was sealed and heated in a microwave at 140°C for 60 min. The reaction mixture was cooled to rt, acidifed with 1 N HCI solution to pH around 3. The organic layer was filtered and 0.5ml 1 N LiOH was added to the filtrate. The resulting mixture was stirred overnight. TFA was then added to adjust pH to around 5. The mixture was filtered and purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.85 (t, J = 1 .8 Hz, 1 H), 7.82 - 7.76 (m, 2H), 7.64 - 7.54 (m, 2H), 7.53 - 7.45 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1 H), 6.92 (td, J = 7.5, 1 .1 Hz, 1 H), 5.21 (s, 2H), 5.04 (s, 1 H), 3.69 (s, 2H). HRMS calcd. for C23H22N2O4 (M+H) 391 .1658, found 391 .1656.

Example 16. 2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid

To a solution of 2-(5-fluoro-3'-(hydroxymethyl)-[1 ,1 '-biphenyl]-3-yl)acetamide

(Intermediate 42-C) (50 mg, 0.193 mmol), fe/f-butyl 2-(2-hydroxyphenyl) acetate (Intermediate 2) (48.2 mg, 0.231 mmol) and PPh₃ (101 mg, 0.386 mmol) in THF (4 ml) at 0 °C in an ice/water bath under nitrogen was added DIAD (0.075 ml, 0.386 mmol) dropwise. The reaction was stirred at room temperature for 16 hours. The mixture was dilutied in EtOAc and washed with water. The water layer was extracted with EtOAc twice. The organic layers were combined and concentrated to provide crude fe/f-butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate. This was dissolved in DCM (1 mL) and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 30 min, then concentrated. The residue was purified by HPLC (Method A) to provide the title product. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (qd, J = 1 .5, 0.9 Hz, 1 H), 7.57 (tdd, J = 4.9, 2.9, 1 .5 Hz, 1 H), 7.48 - 7.44 (m, 3H), 7.30 (ddd, J = 10.1 , 2.5, 1 .6 Hz, 1 H), 7.27 - 7.20 (m, 2H), 7.07 - 7.02 (m, 2H), 6.92 (td, J = 7.4, 1 .1 Hz, 1 H), 5.19 (s, 2H), 3.68 (s, 2H), 3.60 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H) 394.1455, found 394.1455.

Example 17. 2-(2-((3'-(2-Amino-2-oxoethyl)-4'-fluoro-[1 ,1 ^,-biphenyl]-3- yl)methoxy)phenyl)acetic acid

In a 2-5 mL microwave vial was placed methyl 2-(2-((3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate (Intermediate 24, 100 mg, 0.262 mmol) and 2-(5- bromo-2-fluorophenyl)acetamide (Intermediate 33, 91 mg, 0.392 mmol) in DMF(2.0 ml). Then K3PO4 (2.0 M solution, 0.65 ml, 1 .31 mmol) and X-Phos palladacycle (9.66 mg, 0.013 mmol) were added. The vial was sealed and heated in a microwave at 140°C for 60 min. The reaction mixture was cooled to room temperature, acidifed withI N HCI solution to pH around 5. The organic layer was filtered, and LiOH (1 M solution, 0.5 ml) was added. The resulting mixture was stirred for 16 h. 1 N HCI was added to adjust pH to ~7. The resulting mixture was filtered and filtrate was purified by HPLC (Method A) to provide the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ 7.74 (d, J = 1 .8 Hz, 1 H), 7.66 (dd, J = 7.2, 2.4 Hz, 1 H), 7.61 - 7.51 (m, 2H), 7.47 - 7.40 (m, 2H), 7.24 - 7.12 (m, 3H), 6.99 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.89 (td, J = 7.4, 1 .1 Hz, 1 H), 5.17 (s, 2H), 3.66 (d, J = 1 .3 Hz, 2H), 3.63 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H) 394.1455, found 394.1451 . Example 18. 2-(2-((3'-(2-Amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)-3- fluorophenyl)acetic acid

The title compound was synthesized in a similar manner as described in Example 17 from methyl 2-(2-((3-bromobenzyl)oxy)-3-fluorophenyl)acetate (Intermediate 35) and 2-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0). ¹H NMR (400 MHz, Methanol-d₄) δ 7.71 (d, J = 1 .9 Hz, 1 H), 7.60 (dq, J = 5.5, 1 .9 Hz, 2H), 7.53 (dt, J = 7.7, 1 .5 Hz, 1 H), 7.47 - 7.38 (m, 3H), 7.30 (dt, J = 7.7, 1 .4 Hz, 1 H), 7.14 - 7.02 (m, 3H), 5.17 (s, 2H), 3.63 (s, 2H), 3.59 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H) 394.1455, found 394.1449. Example 19. 2-(2-(3'-(2-amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-ylcarboxamido)phenyl)acetic acid

A mixture of methyl 2-(2-(3-bromobenzamido)phenyl)acetate (Intermediate 36) (50 mg, 0.144 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS # 843646-72-0) (37.5 mg, 0.144 mmol), PdCI₂(dppf).CH₂CI₂ adduct (CAS # 95464-05-4) (5.9 mg, 0.0072 mmol), and 2M aq. K₃P0₄ (0.215 mL, 0.431 mmol) in 10:1 MeCN/H₂0 (1 .1 mL) was heated in a microwave reactor at 1 10 °C for 90 min. The organic layer was filtered and the filtrate was directly purified by reverse phase HPLC (Method A). Fractions containing the desired product were pooled, the pooled fractions were frozen and lyophilized to provide the title compound. ¹H NMR ¹H NMR (400 MHz, Methanol-c/₄) δ ppm 8.40 (t, J=1 .6 Hz, 1 H), 8.08 (d, J=7.8 Hz, 1 H), 7.94 (d, J=7.8 Hz, 1 H), 7.86 (ddd, J=7.8, 1 .8, 1 .0 Hz, 1 H), 7.72 (s, 1 H), 7.58 - 7.66 (m, 2 H), 7.43 (t, J=7.7 Hz, 1 H), 7.23 - 7.37 (m, 3 H), 7.1 1 (td, J=7.6, 1 .3 Hz, 1 H), 3.61 (s, 2 H), 3.60 (s, 2 H). HRMS calcd. for C₂₃H₂₀N₂O₄ (M+H)⁺ 389.1501 , found 389.1485.

Example 20. 2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid

To a solution of methyl 2-(2-((3-bromo-4-fluorobenzyl)oxy)phenyl)acetate (Intermediate 37) (60 mg, 0.170 mmol) and 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (66 mg, 0.255 mmol) in DMF (1 .0 mL) was added a 2.0M solution of K3PO4 (0.4 mL, 0.8 mmol); this mixture was degassed for 10 minutes with N₂(g), and then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll) (6.3 mg, 0.0085 mmol) added. The reaction mixture was sealed and heated at 1 10 °C in an oil bath for 1 hr. The reaction mixture was cooled to room temperature, filtered through a plug of Celite. The filtrate was partitioned between EtOAc/H₂0 and the layers separated; the organic phase was washed, dried over Na₂S0₄, and concentrated in vacuo. The resulting residue was purified by HPLC (Method A) to afford the title compound. ¹H NMR (600 MHz, METHANOL-cf₄) δ ppm 7.61 (dd, J=7.38, 2.06 Hz, 1 H) 7.54 (s, 1 H) 7.48 (d, J=6.79 Hz, 1 H) 7.43 - 7.46 (m, 1 H) 7.40 (t, J=7.70 Hz, 1 H) 7.33 (d, J=7.70 Hz, 1 H) 7.15 - 7.27 (m, 3 H) 7.03 (d, J=8.25 Hz, 1 H) 6.92 (t, J=7.43 Hz, 1 H) 5.14 (s, 2 H) 3.65 (s, 2 H) 3.59 (s, 2 H). HRMS calcd. for C23H20FNO4 (M+H)⁺ 394.1455, found 394.1450 .

Example 21. 2-(2-((3^,-(2-Amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid

A mixture of methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 39-D) (34.5 mg, 0.069 mmol) and LiOH (7.8 mg, 0.326 mmol) in THF (517 uL) / H₂0 (172 uL) was stirred at room temperature overnight. AcOH (19.7 ul) was added and the mixture was loaded on a SCX-2 cartridge (from Isolute, catalogue number 532-0050-CG, 1 g) and washed with CH₃CN (4 mL). The product was released with a mixture of 7N NH₃ in MeOH and ACN (3 / 10 mL). The filtrate was concentrated to afford the title compound. MS (ESI⁺) m/z 487.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-c/₆) δ (ppm) : 7.68 - 7.46 (m, 5H), 7.45 - 7.34 (m, 2H), 7.31 - 7.14 (m, 3H), 7.06 (m, 1 H), 6.91 (m, 2H), 5.18 (s, 2H), 3.87 (s, 2H), 3.60 (s, 2H), 3.45 (s, 2H), 3.21 (q, 2H).

Compounds of invention are active on factor D inhibition. Data on Table 1 collected using the assay of Biological Example 2.

Table 1.

Example Number IC₅₀ (μΜ)

Example 1 0.023

Example 2 -A 0.029

Example 2-B 0.078

Example 2-C 0.25

Example 2-D 0.074

Example 2-E 0.11

Example 2-F 0.12

Example 2-G 0.11

Example 2-H 0.13

Example 3 0.11

Example 4 0.14

Example 5 0.26

Example 6 0.33

Example 7 0.04

Example 8-A 0.039

Claims

What is claimed is:

1 . A compound of formula (I):

(I)

or a salt thereof, wherein

X is N or CH;

A is O or NH;

B is C(O) when A is NH, or B is CHR¹ when A is O;

R¹ is hydrogen;

R² is hydrogen; or

R¹ and R², taken in combination form a -CH₂CH₂- group;

R⁸ is hydrogen when A is NH and R⁸ is hydrogen or amino when A is O;

R⁹ is independently selected at each occurrence from the group consisting of hydrogen, C C₄alkyl, haloCrC₄alkyl, C₃-C₆cycloalkyl, benzyl, CrC₄alkanoyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from Ci-C₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C dalkoxy, and wherein each heterocycloalkyi or heteroaryl is optionally fused to a benzo ring and further optionally substituted by 0, 1 , or 2 substituents independently selected from C₁-C₄alkyl, C0₂ C₁-C₄alkyl, C(0)NH C C₄alkyl, C₃-C₆cycloalkyl, or C C₄alkoxy; and

heterocycloalkyi, heteroaryl, wherein C₁-C₄alkyl is optionally substituted with C C₄alkoxy, C₃- C₆cycloalkyl, cyano, 4 to 6 member heterocycloalkyi or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1 , or 2 substitutents selected from CrC₄alkyl, CH₂C0₂H, C₃- C₆cycloalkyl or C dalkoxy, and wherein each heterocycloalkyi or heteroaryl are optionally substituted by 0, 1 , or 2 substituents independently selected from C dalkyl, C0₂ C dalkyl, C(0)NH d-C₄alkyl, C₃-C₆cycloalkyl, or d-C₄alkoxy.

2. The compound of claim 1 or a salt thereof, wherein X is CH.

3. The compound of claim 1 or claim 2, or a salt thereof, wherein A is O and B is CH₂.

4. The compound of any one of claims 1 to 3, or a salt thereof, wherein R², R⁴ and R⁵ are hydrogen.

5. The compound of any one of claims 1 to 4, or a salt thereof, wherein R⁷ is hydrogen.

6. The compound of any one of claims 1 to 6, or a salt thereof, wherein R⁶ is fluorine.

7. The compound of any one of claims 1 to 7, or a salt thereof, wherein R⁸ is hydrogen.

8. The compound of any one of claims 1 to 8, or a salt thereof, wherein X is CH, A is O, B is CH₂, R², R⁴, R⁵, R⁷, and R⁸ are hydrogen and R⁶ is fluorine.

9. The compound of any one of claims 1 to 8, or a salt thereof, wherein R³ is NHR⁹, - C(0)NHR⁹, OR¹⁰, or five member heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, O and S and optionally substituted CrC₄alkyl or cyclopropyl;

R⁹ is C dalkyl, C₃-C₆cycloalkyl, or 5 or 6 member heterocycloalkyi, wherein the alkyl group is optionally substituted with CrC₄alkoxy, C₃-C₆cycloalkyl, 5 or 6 member heterocycloalkyi and wherein each heterocycloalkyi is optionally fused to a benzo ring and further optionally substituted by C dalkyl or cyclopropyl; and

R¹⁰ is CrC₄alkyl or C₃-C₆cycloalkyl wherein the alkyl group is optionally substituted with Crdalkoxy, C₃-C₆cycloalkyl, 5 or 6 member heterocycloalkyi and wherein each heterocycloalkyi is optionally fused to a benzo ring and further optionally substituted by Crdalkyl or cyclopropyl.

10. The compound of claim 1 , or a salt thereof, which is selected from the group consisting of:

2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4-yl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid; (S)-2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid;

(S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid;

(±)-2-(2-((6-(3-(2-Amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 -yl)oxy)phenyl)acetic acid;

2-(2-(3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid;

(S)-2-(2-(3'-(2-Amino-2-oxoethyl)-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid; 2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)picolinamido)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid; 2-(2-((3'-(2-Amino-2-oxoethyl)-4'-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid; 2-(2-((3'-(2-Amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-yl)methoxy)-3-fluorophenyl)acetic acid; 2-(2-(3'-(2-amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-ylcarboxamido)phenyl)acetic acid;

2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid; and 2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid; and salts, especially pharmaceutically acceptable salts, thereof.

1 1 . A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any one of claims 1 -10.

12. A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to any one of claims 1 -10 and a second therapeutically active agent.

13. A method of modulating complement alternative pathway activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 -10.

14. 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, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 -10.

15. The method of claim 14, in which the disease or disorder is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt- Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity.

16. A method of treating age related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of any one of claims 1 -10.

17. A method of treating glomerulonephritis comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of any one of claims 1 -10.

18. A compound according to any one of claims 1 -10, for use as a medicament.

19. Use of a compound according to any one of claims 1 -10 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.

20. Use of a compound according to any one of claims 1 -10, for the treatment of age-related macular degeneration.

21 . A compound according to any one of claims 1 -10 for use in the treatment of a disorder or disease in a subject mediated by complement activation or activation of the complement alternative pathway.