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NZ715780B2 - Piperidinyl indole derivatives and their use as complement factor b inhibitors - Google Patents
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NZ715780B2 - Piperidinyl indole derivatives and their use as complement factor b inhibitors - Google Patents

Piperidinyl indole derivatives and their use as complement factor b inhibitors Download PDF

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NZ715780B2
NZ715780B2 NZ715780A NZ71578014A NZ715780B2 NZ 715780 B2 NZ715780 B2 NZ 715780B2 NZ 715780 A NZ715780 A NZ 715780A NZ 71578014 A NZ71578014 A NZ 71578014A NZ 715780 B2 NZ715780 B2 NZ 715780B2
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New Zealand
Prior art keywords
methyl
indolyl
piperidinyl
methoxymethyl
benzoic acid
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NZ715780A
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NZ715780A (en
Inventor
Christopher Adams
Michael Paul Capparelli
Takeru Ehara
Rajeshri Ganesh Karki
Nello Mainolfi
Chun Zhang
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Novartis Ag
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Priority to NZ754317A priority Critical patent/NZ754317B2/en
Priority claimed from PCT/US2014/046515 external-priority patent/WO2015009616A1/en
Publication of NZ715780A publication Critical patent/NZ715780A/en
Publication of NZ715780B2 publication Critical patent/NZ715780B2/en

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Abstract

The present invention provides a compound of formula I: (I) a method for manufacturing the compounds of the invention, and its therapeutic uses as inhibitors of the complement alternative pathway, in particular of Factor B. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition. tive agents and a pharmaceutical composition.

Description

PIPERIDINYL INDOLE DERIVATIVES AND THEIR USE AS COMPLEMENT FACTOR B INHIBITORS FIELD OF THE INVENTION The invention relates to the tion of the complement alternative pathway and particularly to inhibition of Factor B, in patients suffering from conditions and diseases associated with complement alternative pathway activation such as lated macular degeneration, diabetic retinopathy and related lmic diseases.
BACKGROUND OF THE INVENTION 10 The ment 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: ples and ce, ed. R.R. Rich, Mosby Press; 1996, 363- 391). Molecules from microorganisms, antibodies or cellular components can activate these 15 pathways resulting in the formation of protease complexes known as the CB-convertase and the C5-convertase. The classical pathway is a calcium/magnesium-dependent cascade, which is normally ted by the formation of antigen-antibody xes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein xed to ligand and by many pathogens including gram-negative bacteria. The alternative pathway is a magnesium- 20 dependent cascade which is activated by deposition and activation of C3 on certain susceptible es (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
Factor B may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma tration in humans is typically about 200 ug/mL (or about 2 uM), and it has been shown to be a critical enzyme for activation of the alternative ment 25 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 30 retina is the macula lutea, which is about 1/3 to 1/2 cm in diameter. The macula provides detailed , particularly in the center (the fovea), because the cones are higher in density and because WO 2015/009616 PCT/US2014/046515 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. lated macular ration (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 10 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 l 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 ts progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD). 15 Neovascular AMD is characterized by the al growth of blood vessels under the macula and vascular leakage, resulting in displacement of the , 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. ln neovascular AMD, as the al blood vessels leak fluid and blood, 20 scar tissue is formed that destroys the central .
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 s as inflammation, ischemia, and local production of angiogenic factors are thought to be important. A published study suggests that CNV is caused by 25 complement activation in a mouse laser model (Bora P.S., J. l. 74; 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). icant associations have been found between AMD and polymorphisms in complement factor H (CFH) (Edwards AO, et al. ment factor H polymorphism and age-related macular 30 degeneration. Science. 2005 Apr 15;308(5720):421-4; Hageman GS, et al A common haplotype in the complement regulatory gene factor H FH) 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 ment factor H rphism in age-related WO 2015/009616 PCT/US2014/046515 macular degeneration. Science. 2005 Apr 15;308(5720):385-9; Lau Li, et al. Association of the Y402H polymorphism in ment factor H gene and neovascular age-related macular degeneration in Chinese ts. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3242-6; Simonelli F, et al. Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population.Br J lmol. 2006 Sep;90(9):1142-5; and rsi S, et al Strong association of the Y402H t in complement factor H at 1q32with 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 lated macular degeneration. Nat 10 Genet. 2006 Apr;38(4):458—62 and dottir 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 ment ent C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar;116(3):474-480.e2; Maller JB, et al Variation in complement factor 3 is associated with risk of lated r 15 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 er, the genetic variations in the alternative pathway components CFH, CFB, and C3 can predict clinical outcome in nearly 80% of cases. 20 Currently there is no proven medical therapy for dry AMD and many patients with neovascular AMD become legally blind despite t 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 es and particularly for the treatment of AMD.
SUMMARY OF THE INVENTION 25 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 B activity and/or Factor B ed complement pathway activation. Such Factor B modulators are preferably high affinity Factor B inhibitors that inhibit the catalytic activity of complement Factor B, such as primate Factor B and 30 particularly human Factor B.
The compounds of the present invention inhibit or suppress the amplification of the ment system caused by C3 activation irrespective of the initial mechanism of activation (including for example activation of the classical, Iectin or alternative pathways).
Various embodiments of the invention are described herein. It will be ized that features specified in each ment may be combined with other ied features to provide further embodiments.
Within certain aspects, Factor B modulators provided herein are compounds of Formula I and salts and tautomers thereof: In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound ing to the definition of formula (I) or subformulae thereof and one or more pharmaceutically acceptable carriers.
In r ment, the invention provides a combination, in particular a ceutical combination, sing a therapeutically effective amount of the compound according to the definition of formula (I) or subformulae thereof and one or more additional therapeutically active agents.
The invention further provides methods of treating or ting 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 es ding early or neovascular agerelated macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, toid arthritis), Respiratory diseases, cardiovascular diseases.
In a particular aspect, the present invention provides a compound of Formula (I) or a ceutically acceptable salt thereof, wherein: (I) n is 0, 1 or 2; R is hydrogen, C1-C4alkyl, or hydroxyC1-C4alkyl; R1 is halogen, hydroxy, C1-C6alkyl, lkenyl, C3-C6cycloalkyl, C1-C6alkoxy, haloC1- C6alkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C3- C6cycloalkylC1-C6alkoxy, haloC1-C6alkoxy, -S(O)pC1-C6alkyl, -CH2NHC(O)C1-C4alkyl, or - OCH2C(O)R7; p is 0, 1, or 2; R2 is C1-C6alkyl, C1-C6alkoxy, hydroxyC1-C6alkyl or halogen; R3 is hydrogen, halogen, cyano, C1-C4alkyl, haloC1-C4alkyl, -CH2C(O)R7, phenyl or 5- or 6- ed heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C1-C4alkyl groups, and wherein the alkyl and haloalkyl are optionally substituted with 0 or 1 hydroxy; [FOLLOWED BY 4a] - 4a - R4 is phenyl, naphthyl or heteroaryl, wherein the aryl is a 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, and S, and wherein the phenyl or heteroaryl is optionally substituted by R5 and r substituted by 0 or 1 substituents selected from n, C1-C4alkyl, C1-C4alkoxy, hydroxy C1-C4alkyl, hydroxy, and ethyl; R5 is -C(O)R8, -CH2C(O)R 8, R9, HSO2C1-C4alkyl, -SO2NHC(O)C 1-C4alkyl, - SO 2N(H) m(C 1-C4alkyl) 2-m, -SO2C1-C4alkyl, cyano, halogen, hydroxyC1-C4alkyl and 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring sulfur or oxygen atoms; m is 0, 1, or 2; W is O or ; each R6 is independently selected from hydrogen, hydroxy, amino, mono- and di- C1- C4alkylamino, C1-C4alkyl, hydroxyC1-C4alkyl, cyanoC1-C4alkyl, and C1-C4alkoxy; or C(R 6) 2, taken in combination, form a spirocyclic carbocycle having 3 to 6 ring atoms; R7 is hydroxy, C1-C4alkoxy, amino, or mono- and di-C1-C4alkylamino; R8 is hydroxy, C1-C4alkoxy, amino, or a 5- to ered saturated cycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; or R8 is mono- and di-C1-C4alkylamino, which is unsubstituted or substituted with halogen, hydroxy, or C1-C4alkyl; and R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atoms, which heterocycle is optionally substituted by 0 to 2 C1-C4alkyl groups.
Other s of the invention are discussed infra .
DETAILED DESCRIPTION OF THE INVENTION As noted above, the present ion provides compounds that modulate Factor B activation and/or Factor B-mediated signal transduction of the complement system. Such compounds may be used in vitro or in vivo to modulate (preferably inhibit) Factor B activity in a variety of contexts.
In a first embodiment, the ion provides compounds of Formula I and salts and tautomers thereof, which modulate the alternative pathway of the complement system.
Compounds of Formula I are represented by the structure: [FOLLOWED BY PAGE 5] WO 2015/009616 PCT/US2014/046515 / (I) Wherein n is 0, 1 or 2; R is hydrogen, lkyl, or hydroxyC1-C4alkyl; R1 is halogen, hydroxy, C1-Csalkyl, Cz-Csalkenyl, Cs-Cscycloalkyl, C1-Csalkoxy, haloC1- Csalkyl, hydroxyC1-Csalkyl, aminoC1-Csalkyl, C1-CsalkoxyC1-Csalkyl, lkoxyC1-Csalkoxy, Cs- oalkle1-Csalkoxy, haloC1-Csalkoxy, -S(O)pC1-Csalkyl, -CH2NHC(O)C1-C4alkyl or - O)R7, p is 0, 1, or 2; 10 R2 is C1-Csalkyl, C1-Caalkoxy, hydroxyC1-Caalkyl or halogen; R3 is hydrogen, halogen, cyano, C1-C4alkyl, haloC1-C4alkyl, -CHZC(O)R7, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring atoms ndently selected from N, O or 8, wherein the phenyl or heteroaryl is optionally tuted with 0, 1, or 2 C1-C4alkyl groups, and wherein alkyl and haloalkyl optionally substituted with 0 or 1 hydroxy; 15 R4 is phenyl, naphthyl or heteroaryl, where the heteroaryl is a five or six member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, and where the phenyl or heteroaryl is optionally substituted by R5 and further substituted by 0 or 1 substituents selected from halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy C1-C4alkyl, hydroxy, and cyanomethyl; R5 is -C(O)R8, -CHZC(O)R8, R9, -C(O)NHSOZC1-C4alkyl, -SOZNHC(O)C1-C4alkyl, - 20 SOZN(H)m(C1-C4alkyl)2-m, -SOZC1-C4alkyl, cyano, n, hydroxyC1-C4alkyl and 5 member heteroaryl having 1-4 ring en atoms and 0 or 1 ring sulfur or oxygen atoms; m is 0, 1, or 2; Wis 0 or C(R6)2; R6 is independently selected at each occurrence from the group consisting of hydrogen, 25 hydroxy, amino, mono- and di- C1-C4alkylamino, C1-C4alkyl, hydroxyC1-C4alkyl, cyanoC1-C4alkyl or C1-C4alkoxy; or WO 2015/009616 PCT/US2014/046515 _ 5 _ C(R6)2, taken in combination, form a spirocyclic carbocycle having 3 to 6 ring atoms; R7 is hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino; R8 is hydroxy, C1-C4alkoxy, amino or a 5 to 7 member saturated heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O or S; or R8 is mono- and C4alkylamino which is unsubstituted or substituted with halogen, hydroxy or C1-C4alkyl; and R9 is a 5 membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atoms, which heterocycle is optionally substituted by 0 to 2 Ci-C4alkyl groups.
In a second embodiment, the ion provides compounds, salts thereof and ers 10 thereof of the first embodiment, in which n is 0 or 1. In certain nds of the second embodiment, n is 1.
In a third embodiment, the ion provides compounds, salts thereof and tautomers thereof of the first or second embodiment in which W is CHR6 or C(CH3)R6.
In a fourth ment, the invention provides compounds, salts thereof and tautomers 15 f of any one of embodiments 1 to 3 in which R1 is hydrogen, C1-C4alkyl, C1-C4alkoxy, or cyclopropyl.
In a fifth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 4 in which R2 is C1-C4alkyl. In certain compounds of the fifth embodiment, R2 is methyl. 20 In a sixth embodiment, the invention es compounds, salts f and tautomers thereof of any one of embodiments 1 to 5 in which R3 is hydrogen, halogen or C1-C4alkyl. In certain compounds of the sixth embodiment, R3 is hydrogen or R3 is chloro or bromo or R3 is methyl. In certain other compounds of the sixth embodiment, R3 is hydrogen.
In a seventh embodiment, the invention provides compounds, salts thereof and ers 25 thereof of any one of embodiments 1 to 6 in which R3 is hydrogen.
In an eighth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 7 in which the compound is represented by Formula (Ila) or (llb): WO 2015/009616 PCT/US2014/046515 / N H (Ila) or R2 (llb). n preferred compounds of the eighth embodiment include nds represented by Formula (llc) (lld) or (lle): R4 R6 5 R2 (llc) or R2 (lld) or R2 (lle) In a ninth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 8 in which the compound is represented by Formula (Illa) 10 or (lllb): WO 2015/009616 2014/046515 _ 8 _ R5 / R5 / x R6 \ Me x R6 \ N R3 N R1 R3 / R1 N H N R2 H (Illa) or R2 (Illb) Wherein X is N or CH.
Certain preferred compounds of the ninth embodiment include compounds represented by Formula (Illc), (Illd) or (Ille): R2 (Illc) or R2 (Illd) or X 6 \ l], 1,, "\\\R R2 (Ille).
WO 2015/009616 2014/046515 In a tenth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 8 in which R4 is pyridinyl which is substituted para to the piperidine ring with R5.
In an eleventh embodiment, the invention es compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 8 in which R4 is phenyl substituted para to the dine ring with R5 and optionally substituted with fluoro, methoxy, ymethyl or y.
In a twelvth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 8 in which R4 is phenyl substituted para to the piperidine 10 ring with R5.
In a thirtheenth embodiment, the ion provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 8 in which Formula (lVa) or (lVb): / R1 N H N R2 H (We) or R2 (lVb).
Certain preferred compounds of the thirteenth embodiment include compounds represented 15 by Formula (ch), (lVd) or (We): WO 09616 PCT/US2014/046515 0Ill/I, R6 R5 R5 N R3 R3 R1 R1 N N H H R2 (ch) or R2 (lVd) or .
R5/Olllh, .\\\\R6 N R3 R1 N H R2 (We).
In a fourteenth embodiment, the invention provides compounds, salts thereof and tautomers thereof of any one of embodiments 1 to 13 in which R5 is COZH, COZNHZ, SOZNHZ or tetrazolyl.
In a fifteenth embodiment, the ion provides compounds, salts thereof and tautomers thereof of embodiment 1 in which compound is selected from the group consisting of: 1-((5,7-dimethyl-1H-indolyl)methyl)—2—phenylpiperidinol; 10 4-((4-methoxy-2—phenylpiperidinyl)methyl)—5,7-dimethyl-1H-indole; 5,7-dimethyl((2—phenylpiperidinyl)methyl)-1H-indole; 7-dimethyl-1H-indolyl)methyl)phenyl-piperidinyl)methanol; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; 15 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)—N-methylbenzenesulfonamide; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide; 4-((2-(4-fluorophenyl)methoxypiperidinyl)methyl)-5,7-dimethyl-1H-indole; (1 -((5,7-dimethyl-1 H-indolyl)methyl)—2—phenylpiperidinyl)methanol; WO 2015/009616 PCT/US2014/046515 (4-(1-((5,7-dimethy|—1H-indoIyl)methy|)piperidiny|)pheny|)methanol; 5,7-dimethyl((2—(4-(methy|su|fony|)pheny|)piperidiny|)methy|)—1H-indole; 4-((2-(4-(2H—tetrazoIyl)phenyl)piperidiny|)methy|)—5,7-dimethyI-1H-indole; 1-((5,7-dimethy|—1H-indoIyl)methyl)—2—pheny|piperidinamine; 4-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidinyl)benzamide; 4-(1-((5-ch|oro—7-methy|—1H-indoIyl)methyl)piperidinyl)benzamide; 4-(1-((5,7-dimethyI-1H-indoIyl)methyl)methoxypiperidin-2—y|)benzamide; 4-(4-methoxy((5-methoxymethy|—1H-indolyl)methyl)—4-methy|piperidinyl)benzamide; 4-(1-((5,7-dimethy|—1H-indoIyl)methy|)hydroxypiperidinyl)benzoic acid; 10 4-(1-((5-ch|oro—7-methy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; methyl 4-(1-((5,7-dimethy|—1H-indoIyl)methyl)methoxypiperidiny|)benzoate; 4-(1-((5-cyclopropyImethyl-1H-indoIy|)methy|)piperidinyl)—2—f|uorobenzoic acid; 4-(1-((5-cyclopropyImethyl-1H-indoIy|)methy|)pyrro|idinyl)benzoic acid; 5-(1-((5-cyclopropyImethyl-1H-indoIy|)methy|)piperidin-2—y|)pico|inic acid; 15 4-(1-((5-cyclopropyImethyl-1H-indoIy|)methy|)piperidinyl)—3-methoxybenzoic acid; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z-yl)benzoic acid; 5-methoxymethyl((2—(pyridinyl)piperidiny|)methy|)—1H-indole; 5-methoxymethyl((2—(pyridinyl)piperidiny|)methy|)—1H-indole; 3-fluoro—4-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzoic acid; 20 4-(4-((5-methoxymethyI-1H-indoIy|)methy|)morpholinyl)benzoic acid; 6-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidinyl)nicotinic acid; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)propoxypiperidin-2—y|)benzoic acid; 4-(4-hydroxy((5-methoxymethy|—1H-indolyl)methyl)piperidin-Z-yl)benzoic acid; (5-methoxymethy|—1H-indoIy|)methy|)piperidinyl)—3-methy|benzoic acid; 25 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)methy|piperidiny|)benzoic acid; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)ethy|piperidinyl)benzoic acid; 2-(4-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)pheny|)acetic acid; 2-(3-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)pheny|)acetic acid; (5-cyclopropyImethyl-1H-indoIy|)methy|)methoxypiperidiny|)pico|inic acid; 30 2-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)thiazole—4-carboxylic acid; 2-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)methy|thiazole—5-carboxylic acid; (5,7-dimethy|—1H-indoIyl)methyl)piperidin-Z-yl)benzoic acid; 4-(1-((5-methoxymethy|—1H-indoIyl)methyl)azepanyl)benzoic acid; 4-((2-(4-(1H-pyrazoIyl)phenyl)piperidiny|)methyl)methoxymethy|—1H-indole; WO 2015/009616 PCT/US2014/046515 _ 12 _ 4-((2-(4-(1H-pyrazoIyl)phenyl)piperidiny|)methyl)methoxymethy|—1H-indole; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidin-2—y|)naphthoic acid; 1-(2,2,2—trif|uoro—1-(5-methoxymethy|—1H-indoIyl)ethyl)piperidin-Z-yl)benzoic acid; 2-methoxy(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzoic acid; 2-(1-((5,7-dimethyI-1H-indoIyl)methyl)—2—pheny|piperidinyl)acetonitrile; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)methy|piperidiny|)benzoic acid; 4-(4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; 5-(4-ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidin-Z-yl)picolinic acid; 4-(1-((5-methoxymethy|—1H-indoIy|)methy|)-4,4-dimethy|piperidin-Z-yl)benzoic acid; 10 4-(4-ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzonitrile; 4-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidin-Z-yl)benzoic acid; 4-((4-ethoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z-yl)benzoic acid; 4-(1-((5,7-dimethy|—1H-indoIyl)methyl)—4-methoxypiperidinyl)benzoic acid; 4-(1-((5,7-dimethy|—1H-indoIyl)methyl)ethoxypiperidin-2—y|)benzoic acid; 15 4-(1-((5,7-dimethyI-1H-indoIyl)methyl)ethoxypiperidin-2—y|)benzoic acid; 4-(1-((5-cyclopropyImethyl-1H-indoIy|)methy|)methoxypiperidinyl)benzoic acid; 4-(1-((5-cyc|opropyImethyl-1H-indoIy|)methy|)ethoxypiperidin-2—y|)benzoic acid; 4-(1-((5-cyc|opropyImethyl-1H-indoIy|)methy|)ethoxypiperidin-2—y|)benzoic acid; 4-(5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; 20 4-(5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzamide; 4-(5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; 4-(5-hydroxy((5-methoxymethy|—1H-indolyl)methyl)piperidin-Z-yl)benzoic acid; 1-((5,7-dimethy|—1H-indoIy|)methy|)-N-methy|—2—phenylpiperidinamine; (4-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidiny|)pheny|)methanamine; 25 (4-(4-methoxy((5-methoxy—7-methy|—1H-indoIyl)methyl)piperidin-2—y|)phenyl)methanol; 4-((2-(3-(2H—tetrazoIyl)phenyl)piperidiny|)methy|)—5,7-dimethyI-1H-indole; (5,7-dimethyI-1H-indoIyl)methyl)piperidinyl)benzamide; (3-(1-((5,7-dimethy|—1H-indoIy|)methy|)piperidiny|)pheny|)methanol; -(4-(1H-tetrazoIyl)phenyl)—4-ethoxypiperidiny|)methyl)methoxy—7-methyI-1H-indole; 30 4-(4-ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)—N- (methylsu|fony|)benzamide; ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)-N-methy|benzamide; 4-(4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)-N,N-dimethylbenzamide; WO 2015/009616 PCT/US2014/046515 (4-(4-methoxy((5-methoxymethy|—1H-indoIyl)methy|)piperidin y|)pheny|)(morpho|ino)methanone; N-(2—hydroxyethyl)(4-methoxy((5-methoxymethy|—1H-indo|y|)methy|)piperidin y|)benzamide; 4-(4-methoxy((5-methoxymethy|—1H-indo|y|)methy|)piperidiny|)-N-(2- methoxyethyl)benzamide; (1-((5-cyc|opropyImethyl-1H-indo|y|)methyl)piperidiny|)pheny|)sulfony|)acetamide; 4-(6-((5-methoxymethyI-1H-indo|y|)methy|)azaspiro[2.5]octanyl)benzoic acid; 4-ethyI((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)benzoic acid; 10 ethyl 4-((28,4R)—1-((5-methoxymethy|—1H-indoIyl)methy|)methy|piperidiny|)benzoate; ethyl 4-((28,4S)—4-ethoxy((5-methoxymethy|—1H-indo|y|)methy|)piperidiny|)benzoate and salts, stereoisomers and tautomers f.
In a sixteenth embodiment, the invention provides compounds, salts thereof and tautomers thereof of embodiment 1 in which compound is selected from the group consisting of: 15 (-)((5,7-dimethy|—1H-indo|y|)methy|)pheny|piperidinol (diastereomer—2); (i)((4-methoxy-2—pheny|piperidiny|)methy|)-5,7-dimethyI-1H-indole (diastereomer—1); (-)((4-methoxyphenylpiperidiny|)methy|)-5,7-dimethy|—1H-indole (diastereomer—2); (i)—5,7-dimethyI((2-pheny|piperidiny|)methy|)-1H-indole; (i)—1-((5,7-dimethy|—1H-indo|y|)methyl)pheny|-piperidiny|)methano| (diastereomer—1); 20 ((5,7-dimethy|—1H-indo|y|)methyl)pheny|-piperidiny|)methano| ereomer—2); (i)—4-(1-((5,7-dimethy|—1H-indo|y|)methyl)piperidinyl)benzenesulfonamide; (i)—3-(1-((5,7-dimethy|—1H-indo|y|)methyl)piperidinyl)benzenesulfonamide; (i)—4-(1-((5,7-dimethy|—1H-indo|y|)methy|)piperidinyl)-N-methy|benzenesu|fonamide; (1-((5,7-dimethy|—1H-indo|y|)methy|)piperidinyl)-N-methy|benzenesu|fonamide; 25 (i)—4-((2—(4-f|uoropheny|)methoxypiperidiny|)methy|)-5,7-dimethyI-1H-indole; (i)—(1-((5,7-dimethy|—1H-indo|y|)methy|)pheny|piperidiny|)methano|; (4-(1-((5,7-dimethy|—1H-indo|y|)methy|)piperidiny|)pheny|)methano|; (i)—5,7-dimethyl((2-(4-(methy|su|fony|)pheny|)piperidiny|)methy|)-1H-indole; (i)—4-((2—(4-(2H—tetrazoIyl)phenyl)piperidiny|)methy|)-5,7-dimethyI-1H-indole; 30 (i)—1-((5,7-dimethy|—1H-indo|y|)methyl)pheny|piperidinamine (diastereomer—1); (i)—1-((5,7-dimethy|—1H-indo|y|)methyl)pheny|piperidinamine (diastereomer—2); (i)—4-(1-((5,7-dimethy|—1H-indo|y|)methyl)piperidiny|)benzamide; (i)—4-(1-((5-ch|oromethy|—1H-indoIyl)methy|)piperidiny|)benzamide; (i)—4-(re/—(28,4S)—1-((5,7-dimethy|—1H-indo|y|)methyl)methoxypiperidiny|)benzamide; WO 2015/009616 PCT/US2014/046515 (i)—4-(4-methoxy((5-methoxymethy|—1H-indoIyl)methy|)methy|piperidinyl)benzamide (single diastereomer); (i)—4-(rel—(28,4S)—1-((5,7-dimethy|—1H-indoIyl)methy|)hydroxypiperidinyl)benzoic acid; (i)—4-(rel—(28,4R)—1-((5,7-dimethy|—1H-indoIy|)methy|)hydroxypiperidiny|)benzoic acid; (i)—4-(1-((5-ch|oro—7-methy|—1H-indoIyl)methyl)piperidinyl)benzoic acid; (i)—methy| 4-(re/-(28,4S)—1-((5,7-dimethy|—1H-indoIy|)methy|)methoxypiperidinyl)benzoate; (i)—methy| 4-(rel-(28,4R)—1-((5,7-dimethy|—1H-indoIyl)methyl)methoxypiperidinyl)benzoate; (-)-(S)—4-(1-((5-cyc|opropyImethyl-1H-indoIyl)methyl)piperidinyl)—2—fluorobenzoic acid; (-)-(S)—4-(1-((5-cyc|opropy|—7-methyl-1H-indoIyl)methyl)piperidiny|)benzoic acid; 10 (i)—4-(1-((5-cyclopropyImethyl-1H-indoIyl)methyl)pyrrolidin-Z-yl)benzoic acid; (-)-(S)—5-(1-((5-cyc|opropy|—7-methyl-1H-indoIyl)methyl)piperidiny|)pico|inic acid; (-)-(S)—4-(1-((5-cyc|opropyImethyl-1H-indoIyl)methyl)piperidinyl)—3-methoxybenzoic acid; (-)-(S)—4-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidin-Z-yl)benzoic acid; (i)methoxymethyl((2—(pyridinyl)piperidiny|)methy|)—1H-indole; 15 (i)methoxymethyl((2—(pyridinyl)piperidiny|)methy|)—1H-indole; (+)-(S)—3-f|uoro—4-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; (-)-(R)—4-(4-((5-methoxymethyI-1H-indoIyl)methyl)morpholinyl)benzoic acid; (-)-(S)—6-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)nicotinic acid; (-)((28,4S)—1-((5-methoxymethy|—1H-indoIyl)methyl)propoxypiperidin-2—y|)benzoic acid; 20 (-)((2S,4S)—4-hydroxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; (i)—4-(1-((5-methoxymethy|—1H-indoIyl)methy|)piperidinyl)—3-methy|benzoic acid; (i)—4-(1-((5-methoxymethy|—1H-indoIyl)methyl)—5-methy|piperidiny|)benzoic acid (single reomer); (i)—4-(re/—(2S,4R)—4-ethy|—1-((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid); 25 (4-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)pheny|)acetic acid; (i)—2-(3-(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)pheny|)acetic acid; (i)—5-(rel-(28,4S)—1-((5-cyclopropyImethyl-1H-indoIyl)methyl)—4-methoxypiperidinyl)picolinic acid; (i)—2—(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)thiazole—4-carboxylic acid; 30 (i)—2-(1-((5-methoxymethy|—1H-indoIyl)methy|)piperidinyl)—4-methylthiazole—5-carboxylic acid; (i)—3-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidin-Z-yl)benzoic acid; (i)—4-(1-((5-methoxymethy|—1H-indoIyl)methy|)azepan-Z-yl)benzoic acid; (-)-(S)—4-((2—(4-(1H-pyrazoIyl)phenyl)piperidiny|)methyl)methoxymethy|—1H-indole; WO 2015/009616 PCT/US2014/046515 (-)-(S)—4-((2—(4-(1H-pyrazoIy|)pheny|)piperidiny|)methyl)methoxymethy|—1H-indole; (i)—4-(1-((5-methoxymethy|—1H-indoIyl)methy|)piperidinyl)—1-naphthoic acid; 4-((28)—1-(2,2,2—trif|uoro—1-(5-methoxy—7-methy|—1H-indoIy|)ethy|)piperidiny|)benzoic acid (diastereomer—1); (i)—2—methoxy(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; (i)—4-(6-((5-methoxymethyI-1H-indoIyl)methyl)—6-azaspiro[2.5]octany|)benzoic acid; (i)—4-(rel—(2S,4S)—4-ethy|—1-((5-methoxy—7-methy|—1H-indoIyl)methyl)piperidinyl)benzoic acid; (i)—2—(1-((5,7-dimethy|—1H-indoIyl)methyl)—2—phenylpiperidinyl)acetonitrile (diastereomer—1); (+)((28,4R)—1-((5-methoxymethy|—1H-indoIyl)methyl)methylpiperidinyl)benzoic acid; 10 (-)((2R,4S)—1-((5-methoxymethyI-1H-indolyl)methyl)—4-methy|piperidinyl)benzoic acid; (+)((2R,4R)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzoic acid; (-)((2S,4S)—4-methoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidinyl)benzoic acid; (-)(re/—(28,4S)—4-ethoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidinyl)picolinic acid; (rel—(2S,4S)—4-ethoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)pico|inic 15 acid; (+)(1-((5-methoxymethy|—1H-indoIyl)methyl)-4,4-dimethy|piperidiny|)benzoic acid; (-)(1-((5-methoxymethy|—1H-indoIyl)methy|)-4,4-dimethylpiperidiny|)benzoic acid; (rel-(28,4S)—4-ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzonitri|e; (+)(re/-(2S,4S)—4-ethoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)benzamide; 20 (+)(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid; (-)(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidin-Z-yl)benzoic acid; (+)((28,4S)—(4-ethoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|))benzoic acid; (-)((2R,4R)—(4-ethoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z-yl))benzoic acid; (re/—(28,4S)—1-((5,7-dimethy|—1H-indoIy|)methy|)methoxypiperidin-2—yl)benzoic acid; 25 (-)(rel-(28,4S)—1-((5,7-dimethy|—1H-indoIyl)methyl)methoxypiperidin-2—y|)benzoic acid; (+)(rel—(28,4S)—1-((5,7-dimethy|—1H-indoIy|)methy|)ethoxypiperidinyl)benzoic acid; (-)(rel-(28,4S)—1-((5,7-dimethy|—1H-indolyl)methyl)—4-ethoxypiperidiny|)benzoic acid; (-)(re/—(28,4S)—1-((5-cyc|opropyImethyl-1H-indoIyl)methyl)—4-methoxypiperidiny|)benzoic acid; 30 (+)(rel—(28,4S)—1-((5-cyc|opropy|—7-methyl-1H-indoIyl)methyl)methoxypiperidin-2—y|)benzoic acid; (+)(re/—(28,4S)—1-((5-cyc|opropy|—7-methyl-1H-indolyl)methyl)—4-ethoxypiperidiny|)benzoic acid; WO 2015/009616 PCT/US2014/046515 (-)(rel-(28,4S)—1-((5-cyc|opropyImethyl-1H-indoIyl)methyl)ethoxypiperidinyl)benzoic acid; (i)—4-(5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid (diastereomer—1); (i)—4-(5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidin-2—y|)benzamide (diastereomer—1); (5-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)benzoic acid (diastereomer—Z); (i)—4-(5-hydroxy((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z-yl)benzoic acid 10 (diastereomer—1); (i)—4-(5-hydroxy((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z-yl)benzoic acid ereomer—Z); (i)—1-((5,7-dimethyI-1H-indoIyl)methyl)-N-methy|—2—phenylpiperidinamine—(diastereomer—1 ); (i)—1-((5,7-dimethyI-1H-indoIyl)methyl)-N-methy|—2-phenylpiperidinamine ereomer—Z); 15 (i)—(4-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidinyl)phenyl)methanamine; (4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)pheny|)methanol; (i)—4-((2—(3-(2H—tetrazoIyl)phenyl)piperidiny|)methy|)—5,7-dimethyI-1H-indole; (i)—3-(1-((5,7-dimethy|—1H-indoIyl)methyl)piperidin-2—y|)benzamide; (i)— (3-(1-((5,7-dimethyI-1H-indoIyl)methyl)piperidinyl)phenyl)methanol; 20 (i)—(4-(rel-(28,4S)—(2—(4-(1H-tetrazoIyl)phenyl)—4-ethoxypiperidiny|)methy|)—5-methoxy methyl-1H—indole; (+)((28,4S)—4-ethoxy—1-((5-methoxymethy|—1H-indoIy|)methy|)piperidiny|)-N- (methylsu|fony|)benzamide; 4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidiny|)—N- 25 methylbenzamide; 4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidin-2—y|)—N,N- dimethylbenzamide; (4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIy|)methy|)piperidin-Z- y|)pheny|)(morpholino)methanone; 30 N-(2—hydroxyethyl)((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidin y|)benzamide; 4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidin-Z-yl)—N-(2— methoxyethyl)benzamide; (i)—N-((4-(1-((5-cyc|opropyImethyI-1H-indoIyl)methyl)piperidin-2—y|)pheny|)su|fony|)acetamide; WO 2015/009616 2014/046515 ethyl 4-((28,4R)—1-((5-methoxymethyl-1H-indolyl)methyl)—4-methylpiperidinyl)benzoate; ethyl 4-((28,4S)—4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoate and salts, stereoisomers and tautomers f.
In another 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 formulae I, II, III or IV, or a subformulae thereof.
In another embodiment, combinations, in particular pharmaceutical combinations, are provided which comprise a therapeutically effective amount of the compound any one of formulae I, II, III or IV or a subformulae thereof. 10 In another embodiment, methods of modulating complement alternative pathway activity in a subject are provided which methods comprise administering to the subject a therapeutically effective amount of any one of formulae I, II, III or IV, or a mulae thereof.
In yet other embodiments, s of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the ment alternative 15 pathway, are provided, which methods comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae I, II, III, IV, or a subformulae thereof.
In another embodiment, methods of treating age related macu|ar degeneration in a subject are provided which methods comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae I, II, III, IV, or a subformulae thereof. 20 In another , the invention provides for the use of compounds of any one of formulae I, II, III, IV, or a subformulae thereof for use in the ation of a ment and more particularly for use in the manufacture of a medicament for the treatment of a disorder or disease in a subject mediated by complement activation or activation of the complement alternative pathway. In certain other aspects, the invention es for the use of a compound according of any one of formulae I, 25 II, III, IV, or a subformulae thereof in the ent of age-related macu|ar degeneration.
In one embodiment, the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to the tion of formula (I), (la) or subformulae thereof or any one of the specificaIIy disclosed compounds of the invention and one or more therapeutically active agents (preferably ed 30 from those listed infra).
For purposes of interpreting this ication, the following tions 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 othenNise provided, aIkyI refers to WO 2015/009616 PCT/US2014/046515 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, iso—propyl, n-butyl, sec-butyl, tyl, tert—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 "a|ky|ene" refers to divalent alkyl group as defined herein above having 1 to 20 carbon atoms. It comprises 1 to 20 carbon atoms, Unless othenNise provided, a|ky|ene 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 a|ky|ene include, but are not limited to, 10 methylene, ethylene, n—propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert- butylene, n—pentylene, isopentylene, neopentylene, lene, 3-methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n—heptylene, n—octylene, n—nonylene, n-decylene and the like.
As used herein, the term lkyl" refers to an alkyl as defined herein, that is tuted 15 by one or more halo groups as d herein. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A loalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl 20 include methyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, oromethyl, 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 25 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 ic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused er.
Non-limiting examples include phenyl, naphthyl or ydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, 30 hydroxy, , acyl, alkyl-C(O)-O-, aryl-O-, aryl-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 es of alkoxy include, but are not limited to, methoxy, , propoxy, 2- WO 09616 PCT/US2014/046515 propoxy, butoxy, tert—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-, 11-, or 12—membered bicyclic or 10-, 11-, 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 . 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. es of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1, 4- 10 dioxane, morpholine, thiane, piperazine, piperidine, 1,3-dioxolane, olidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, opyran, oxathiolane, lane, 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: 15 (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo, i.e., =0; (e) amino, alkylamino or lamino; 20 (f) alkoxy; (g) cycloalkyl; (h) carboxyl; (i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded h an oxygen bridge; 25 (j) alkyl-O-C(O)—; (k) mercapto; (l) nitro; (m) cyano; (n) sulfamoyl or sulfonamido; 30 (o) aryl; (I0) alkyl-C(O)-O-; (<1) aryI-C(O)-O-; (r) aryl-S-; (s) aryloxy; WO 2015/009616 PCT/US2014/046515 _ 20 _ (t) alkyl-S-; (u) formyl, i.e., HC(O)—; (v) oyl; (w) aryl-alkyl-; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, C(O)—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 othenNise provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring 10 carbon atoms, each of which can be ally substituted by one, or two, or three, or more substituents ndently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, 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 arbon groups include, but are not limited to, ropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl 15 and cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, ydronaphthyl, 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. 20 As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic— or lic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or 8. Typically, the heteroaryl is a 5-10 ed ring system (e.g., 5-7 membered monocycle or an 8-10 memberred e) or a 5-7 membered ring system. Typical heteroaryl groups e 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- 25 isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2, zolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2—pyrazinyl, and 2-, 4-, or 5- pyrimidinyl.
The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the 30 heteroaromatic ring. Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5- , 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6- , 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, WO 2015/009616 PCT/US2014/046515 7-, or 8—4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8—carbzaolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8—, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8—, 9-, or 10-phenanthridinyl, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8—, or 9- acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8—, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8—, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4-, 6-, 7-, 8—, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8—, 9-, or nothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8—, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or l-, 3-, 4-, 5-, 6-, 7-, 8—, 9-, or 10- benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8—, 9-, 10 -, or 11-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-, or 7-2H- furo[3,2-b]—pyranyl, 2-, 3-, 4-, 5-, 7-, or 8—5H-pyrido[2,3-d]—o-oxazinyl, 1-, 3-, or 5- 1H-pyrazolo[4,3-d]—oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8—pyrazino[2,3- d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2,1-b] thiazolyl, 1-, 3-, 6-, 7-, 8—, or 9-furo[3,4-c]cinnolinyl, 1-, 10 2-, 3-, 4-, 5-, 6-, 8—, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or azo[1,2— b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- idazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8—, or 9- benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8—benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8—, 9-, 10-, or 11-1H-pyrrolo[1,2- b][2]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7- 15 , or 8—quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8—isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
A aryl group may be substituted with 1 to 5 tuents independently selected from the groups consisting of the following: 20 (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo, i.e., =0; (e) amino, mino or dialkylamino; 25 (f) alkoxy; (g) cycloalkyl; (h) carboxyl; (i) heterocyclooxy, wherein heterocyclooxy denotes a cyclic group bonded through an oxygen bridge; 30 (j) alkyl-O-C(O)—; (k) mercapto; (l) nitro; (m) cyano; WO 2015/009616 2014/046515 (n) sulfamoyl or sulfonamido; (o) aryl; (I0) alkyl-C(O)-O-; (<1) aryl-C(O)-O-; 5 (r) aryl-S-; (s) aryloxy; (t) alkyl-S-; (u) formyl, i.e., ; (v) carbamoyl; 10 (w) aryl-alkyl-; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—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 othenNise ied refers to a group 15 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; 20 (d) oxo, i.e., =0; (e) amino, alkylamino or dialkylamino; (f) alkoxy; (g) cyc|oa|ky|; (h) yl; 25 (i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge; (j) a|ky|-O-C(O)—; (k) mercapto; (l) nitro; 30 (m) cyano; (n) sulfamoyl or sulfonamido; (o) aryl; (I0) alkyl-C(O)-O-; WO 2015/009616 PCT/US2014/046515 (<1) aryl-C(O)-O-; (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(O)—NH-, alkylamino, dialkylamino or halogen. 10 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 ion and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a 15 carbon atom. Therefore, the invention es enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. The use of "rel" indicates that the reomeric orientation is known but the absolute stereochemistry is not. For example, the moniker "rel-28,48", 20 as used herein, indicates the relative stereochemistry at the 2 and 4 positions is either 28,48 or in the alternative 2R,4R. The absolute chemistry has not been determined but the optical rotation and/or chiral chromatography conditions will indicate which isomer is present.
"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is ied according to the Cahn- 25 lngold- Prelog R-S system. When a nd is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or 8. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) ing on the ion (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line or retention time on chiral chromatography separation. Certain of the compounds described herein 30 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)—, or with the (+) or (-) sign. The t invention is meant to include all such possible isomers, including c mixtures, optically pure forms and intermediate mixtures. lly active (R)— and (S)— isomers may be prepared using chiral synthons or chiral WO 2015/009616 PCT/US2014/046515 _ 24 _ reagents, or resolved using conventional techniques. If the compound ns a double bond, the tuent 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 , the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the invention. "Salts" include in particular "pharmaceutical acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and ties 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 10 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. lnorganic acids from which salts can be derived include, for example, hydrochloric acid, 15 hydrobromic acid, ic acid, nitric acid, phosphoric acid, and the like.
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, 20 benzenesuflonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. lnorganic bases from which salts can be derived include, for e, ammonium salts and metals from s | to XII of the periodic table. In certain embodiments, the salts are derived 25 from sodium, potassium, ammonium, calcium, magnesium, iron, , zinc, and copper; particularly suitable salts e ammonium, ium, sodium, calcium and magnesium salts. c bases from which salts can be d 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, 30 benzathine, ate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
In r aspect, the present invention es compounds of formula I in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, WO 2015/009616 PCT/US2014/046515 ethandisulfonate, fumarate, gluceptate, gluconate, onate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, , maleate, malonate, mandelate, te, methylsulphate, mucate, naphthoate, ate, nate, nitrate, octadecanoate, oleate, oxalate, ate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another , the present invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
In another aspect, the present invention provides (-)-(S)—4-(1-((5-cyclopropylmethyl-1H- 10 indolyl)methyl)piperidinyl)benzoic acid in acetate, ate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, te, 15 methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the present ion provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1- 20 l substituted e sufonic acid addition salt form.
In another , the t invention provides (-)((28,4S)—1-((5-methoxymethyl-1H- indolyl)methyl)propoxypiperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, 25 fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, e, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, lacturonate, nate, sebacate, stearate, succinate, sulfosalicylate, sulfate, 30 tartrate, tosylate trifenatate, trifluoroacetate or ate salt form. In yet another aspect, the present invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted e sufonic acid addition salt form.
In another aspect, the present invention es (+)((28,4R)—1-((5-methoxymethyl- 1H-indolyl)methyl)—4-methylpiperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, WO 2015/009616 PCT/US2014/046515 _ 25 _ benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, te, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, e, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, te, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet r aspect, the t invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid 10 or mono-, di- or tri- C1-C4alkyl substituted e sufonic acid addition salt form.
In another aspect, the t invention provides (-)((2S,4S)—4-methoxy((5-methoxy- 7-methyl-1H-indolyl)methyl)piperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, benzoate, te, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, de/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, 15 fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, odide/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, sebacate, stearate, succinate, sulfosalicylate, sulfate, 20 tartrate, tosylate trifenatate, trifluoroacetate or ate salt form. In yet another aspect, the present invention provides compounds of a I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted e sufonic acid addition salt form.
In another aspect, the present invention provides (-)(rel—(2S,4S)—4-ethoxy((5-methoxy- 25 7-methyl-1H-indolyl)methyl)piperidinyl)picolinic acid in acetate, ascorbate, adipate, ate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, ate, glycolate, hippurate, odide/iodide, onate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, 30 ate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, , oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, lacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or ate salt form. In yet another aspect, the WO 09616 PCT/US2014/046515 _ 27 _ present ion provides compounds of a I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
In another aspect, the present invention provides (1-((5-methoxymethyl-1H-indol yl)methyl)—4,4-dimethylpiperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, te, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, ate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, 10 octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the present invention provides compounds of formula I in C1-C4alkyl sufonic acid, esulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene c acid addition salt form. 15 In another , the t invention provides 4-((28,4S)—(4-ethoxy((5-methoxy methyl-1H-indolyl)methyl)piperidinyl))benzoic acid ((+)-as TFA salt) in e, ate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, isulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, 20 hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, te, methylsulphate, , naphthoate, napsylate, nate, nitrate, canoate, oleate, oxalate, palmitate, e, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the 25 present invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
In another aspect, the present ion provides (-)(rel-(28,4S)—1-((5,7-dimethyl-1H- indolyl)methyl)—4-methoxypiperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, 30 camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, isulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, onate, e, lactobionate, laurylsulfate, malate, maleate, te, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen WO 2015/009616 PCT/US2014/046515 _ 28 _ phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the present invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- lkyl tuted benzene sufonic acid addition salt form.
In another aspect, the present ion provides 4-(rel-(28,4S)—1-((5,7-dimethyl-1H-indol yl)methyl)—4-ethoxypiperidinyl)benzoic acid ((+)- as TFA salt) in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, onate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, 10 hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, , maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, ate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, ate, sulfosalicylate, e, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the 15 present invention provides compounds of a I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
In r aspect, the present invention es (-)(re/-(28,4S)—1-((5-cyclopropyl methyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid in acetate, ascorbate, adipate, aspartate, te, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, 20 camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, isulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, ate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, , maleate, malonate, mandelate, mesylate, methylsulphate, mucate, oate, napsylate, nate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen 25 phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, te, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet another aspect, the present invention es compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
In another aspect, the present invention es (+)(rel-(28,4S)—1-((5-cyclopropyl 30 methyl-1H-indolyl)methyl)—4-ethoxypiperidinyl)benzoic acid in acetate, ascorbate, adipate, ate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, tate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, WO 09616 2014/046515 mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, e, phosphate/hydrogen phosphate/dihydrogen ate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form. In yet r aspect, the present invention provides compounds of formula I in C1-C4alkyl sufonic acid, benzenesulfonic acid or mono-, di- or tri- C1-C4alkyl substituted benzene sufonic acid addition salt form.
Any a given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom 10 having a selected atomic mass or mass number. Examples of isotopes that can be orated into compounds of the invention e isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and ne, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 358, 36Cl, 124l, 125l respectively. The invention includes s isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H, 13C, and 14C , are present. Such 15 isotopically labelled compounds are useful in lic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging ques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive ent of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. lsotopically d 20 compounds of this invention and salts 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, ularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in 25 vivo ife or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is ed as a substituent of a compound of the a (I). The concentration of such a heavier isotope, specifically deuterium, may be d by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the l abundance of a specified isotope. If a substituent 30 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% ium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% WO 2015/009616 2014/046515 _ 30 _ deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% ium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
In certain embodiments, selective deuteration of compounds of Formula (I) include deuteration of R1, R3, R5 and/or R6, for example when any of R1, R3, R5 and/or R6 are methyl, methoxy, or ethoxy, the alkyl residue is preferably deuterated, e.g. CD3, OCD3 or OC2D5. when R3 is alkanoyl, e.g., C(O)CD3. lsotopically-labeled nds 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 10 place of the beled reagent previously employed.
The compounds of the present invention may inherently or by design form es with solvents (including water). ore, 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 ion (including salts thereof) with one or more solvent molecules. Such solvent molecules are 15 those commonly used in the pharmaceutical art, which are known to be innocuous to a recipient, e.g., water, ethanol, ylsulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a lar complex comprising a compound of the invention and water.
Pharmaceutically acceptable solvates in ance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d5-acetone, O. 20 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 ures include ng, heating, co-subliming, co- melting, or ting in solution compounds of formula (I) with the co-crystal former under 25 crystallization conditions and isolating co-crystals y formed. Suitable co-crystal s 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 30 agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug izers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and ations thereof, as would be known to those d in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, WO 2015/009616 PCT/US2014/046515 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 ive amount" of a compound of the present invention refers to an amount of the compound of the t invention that will elicit the biological or medical response of a t, 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 miting 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 10 disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) ed by Factor B, or (ii) associated with Factor B activity, or (iii) characterized by ty (normal or abnormal) of the complement alternative pathway; or (2) reducing or inhibiting the activity of Factor B; or (3) reducing or inhibiting the expression of Factor B; or (4) reducing or inhibiting activation of the complement system and particularly reducing or inhibiting generation of C3a, iCBb, C5a or the 15 membrane attack complex generated by activation of the complement alternative pathway. In r non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the nd of the present invention that, when administered to a cell, or a tissue, or a non- ar biological material, or a , is effective to at least partially reducing or inhibiting the activity of Factor B and/or the complement alternative pathway; or at least partially reducing or 20 inhibiting the expression of Factor B and/or the complement alternative pathway. The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for Factor B and/or the ment alternative y.
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, 25 rabbits, rats, mice, fish, birds and the like. In certain embodiments, the t is a primate. In yet other ments, the subject is a human.
As used herein, the term "inhibit", ition" 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. 30 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 e or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to ating or rating at least one physical parameter including those which may not be discernible by the patient. In yet another WO 2015/009616 PCT/US2014/046515 _ 32 _ embodiment, "treat", ing" or "treatment" refers to modulating the disease or disorder, either ally, (e.g., ization 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 ise indicated herein or clearly contradicted by the context. 10 All methods described herein can be performed in any suitable order unless ise ted herein or othenNise clearly contradicted by context. The use of any and all es, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the ion 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 15 can be t in racemic or enantiomerically enriched, for e the (R)—, (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 , at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)— or (S)— configuration. Substituents at atoms with 20 rated bonds may, if possible, be present in cis- (Z)— or trans— (E)- form. ingly, 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), tes or mixtures thereof. 25 Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or ntially 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 30 an optically active acid or base, and liberating the optically active acidic or basic compound. In ular, 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, oyl tartaric acid, diacetyl tartaric acid, di-0,0’-p-toluoyl tartaric acid, ic acid, malic acid or camphor—10-sulfonic acid. Racemic products can also be resolved by WO 2015/009616 PCT/US2014/046515 chiral chromatography, e.g., high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) using a chiral adsorbent.
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 llization.
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 , unless the context indicates otherwise. The tion of functional groups by such protecting groups, the protecting groups lves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups 10 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. ofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/l, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, 15 "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, ns), Verlag , Weinheim, Deerfield Beach, and Basel 1982, and in Jochen n, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme , Stuttgart 1974. A characteristic of ting groups is that they can be removed readily (i.e. t the occurrence of undesired ary reactions) for example by 20 so|vo|ysis, reduction, photolysis or atively under physiological ions (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 25 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 nds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt- 30 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. al 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 WO 2015/009616 PCT/US2014/046515 _ 34 _ neutralisation 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 le basic agent.
Mixtures of isomers obtainable according to the invention can be ted 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, tallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid 10 chromatography over a reversed phase column, and racemates can be separated, for e, 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 crystallisation, or by chromatography over optically active column materials.
Intermediates and final products can be worked up and/or purified according to standard 15 methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
The following applies in l to all processes mentioned herein before and hereinafter.
All the above-mentioned process steps can be carried out under reaction ions that are known to those d in the art, including those mentioned specifically, in the absence or, 20 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 e or presence of catalysts, condensation or lizing agents, for e ion exchangers, such as cation gers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or ed ature, for example in a temperature range of from about -100 0C to about 250 25 00, including, for example, from approximately -80 °C to approximately 250 °C, for example at from -80 to -60 0C, at room temperature, at from -20 to 40 0C 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 30 individual isomers, for example reoisomers 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 ts from which those solvents that are suitable for any particular reaction may be selected include those mentioned ically or, for example, water, esters, such as lower alkyl- WO 2015/009616 PCT/US2014/046515 _ 35 _ 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 ol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as ene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidinone, carboxylic acid ides, such as lower alkanoic acid anhydrides, for e acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless othenNise indicated in the description of the processes. Such solvent 10 mixtures may also be used in working up, for example by chromatography or partitioning.
The compounds, ing their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the t used for crystallization. Different lline forms may be present.
The invention relates also to those forms of the process in which a compound obtainable as 15 an intermediate at any stage of the process is used as starting material and the remaining s 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 nd obtainable by the s according to the ion is produced under the process conditions and processed further in situ. 20 All starting materials, building blocks, reagents, acids, bases, dehydrating , solvents and catalysts utilized to synthesize the compounds of the present invention are either cially 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 c Synthesis, Thieme, Volume 21).
GENERAL SYNTHETIC ASPECTS 25 The following Examples serve to illustrate the invention without limiting the scope thereof.
Typically, the compounds of formula (I) can be prepared according to the Schemes provided below.
Compounds such as A-5, wherein PG is a protecting group (preferably Boc or Ts), R:11 is halo or alkyl, and Rb is alkoxy, and G:11 is hydrogen or fluoro can be ed by the general method 30 outlined in Scheme 1.
WO 2015/009616 PCT/US2014/046515 _ 35 _ Scheme 1 I I H O OH OH Rb Rb / / / / __ __ __ __ N Ga N Ga N Ga N Ga N Ga H Ra H Ra H Ra PG Ra PG Ra A-1 A-2 A-3 A-4 A-5 Transformation of ne A-1 to the corresponding 5-hydroxyindole A-2 can be accomplished by treatment with potassium nitrosodisulfonate preferably in a t mixture of acetone/aq. buffer at pH=7 either at 0 0C or at room ature. The hydroxy group of A-2 can then be alkylated utilizing a Mitsunobu-type reaction with a||y| alcohol in a suitable solvent such as toluene. The product can then be converted to C-allyl derivatives such as A-3 by thermally ed ropic rearrangement at temperatures between 200 oC and 250 oC without the use of solvent. Compound A-3 can then be reacted with alcohols (e.g. MeOH, BnOH) utilizing 10 Mitsunobu-type conditions permitting differentiation at Rb. Subsequent protection of the nitrogen of the indole employing TsCl and an appropriate base, preferably NaH, or atively with Boc20 in the presence of a catalytic amount of DMAP can afford compounds such as A-4. Isomerization of the double bond of A-4 can be accomplished via treatment with )2 in hexafluoroisopropyl alcohol (HFIPA). Cleavage of the olefin can then be ed by reaction with osmium tetraoxide 15 and sodium periodate to afford A-5.
Alternatively, compounds such as A-5, wherein PG is a protecting group (preferably Boc), R:11 is alkyl, Rb is alkoxyl, and G:11 is hydrogen can be also prepared by formylation of indole A-5a using Vilsmeier—type reagents such as N-(chloromethylene)—N-methylbenzenaminium chloride in acetonitrile at temperatures between 0°C and room temperature as shown in Scheme 1b. 20 Scheme 1b WO 2015/009616 PCT/US2014/046515 _ 37 _ Compounds such as A-10, wherein is X:11 is Cl, Br, or SMe, can be prepared ing to Scheme 2.
Scheme 2 CN Br No2 va Va A-6 xa xa xEl , / _. / COOH N NO [\1 2 Cl PG Ra Ra PG Ra A-8 A-9 A-10 N02 A-7 Nucleophilic aromatic substitution of A-6 (CAS: 8—65-8) can be achieved by sodium thiomethoxide in DMF at 60 0C to afford 8 (Xa=SMe). Alternatively, A-7 (CAS: 1015805) can be transformed into A-8 (X3: Cl, Va: CHZOTHP) by ion employing 1,1,1-trichloro methylpropanyl carbonochloridate and NaBH4, followed by protection of the ing hydroxy with 3,4-dihydro—2H—pyran in the presence of TsOH. Transformation of A-8 (Va is either ON or CH2- 10 OTHP) to the indole A-9 can be achieved by Bartoli reaction using vinylmagnesium e in THF at temperatures ranging from -78 °C to room temperature, followed by protection of the indole.
Protection can be effected by employing TsCl and an appropriate base preferably NaH, or alternatively tion can be accomplished with BocZO in the presence of a catalytic amount of DMAP. The aldehyde A-10 can be accessed when V:11 = ON by reduction with DIBAL followed by 15 acid hydrolysis, preferably employing aq. HCI. Alternatively, when Va=CHZOTHP, A-10 can be accessed by deprotection of the THP protecting group via acid mediated hydrolysis preferably employing TsOH in EtOH, followed by oxidation preferably using Mn02 or 802-pyridine complex.
Compounds such as A-14, wherein RC is alkyl and Rd is lkyl, or CH2-phthaloyl, can be prepared according to Scheme 3.
WO 2015/009616 PCT/US2014/046515 _ 38 _ Scheme 3 Va V3 R0 R =VIny|c - / / OH A-9 N N PG Ra PG Ra A-11 A-12 H 0 Va d Rc or Rd N l" Pd PG Ra Ra A-13 A-14 lndole A-9 (X3: Cl or Br, Va: ON or CHZOTHP) can be transformed to A-11 wherein RC: alkyl or vinyl utilizing a -coupling with an riate boronate (such as alkyl trifluoroborates, or 2,4,6-trivinylcyclotriboroxane-pyridine complex). Alternatively a Negishi-type coupling employing an alkylzinc halide can be used in place of the Suzuki reaction. A-11 (RC = vinyl) can be further transformed into A-12 by a dihydroxyation preferably employing ADmix-o, followed by oxidative cleavage using NalO4 and reduction of the resulting aldehyde with NaBH4. Alkylation of the hydroxy group of A-12 can be achieved by deprotonation with an appropriate base, preferably NaH, 10 and on with an appropriate electrophile such as Mel or SEM-Cl to afford A-13. Alternatively A- 12 can undergo Mitsunobu reaction with phthalimide. , indoles of type A-13 can be converted to A-14 in accordance with Scheme 2 (Le. A-9 9 A-10).
Aldehyde such as A-18 can be prepared as described in Scheme 4.
Scheme 4 / / / l" i" i" R Me PG PG A-15a; R=H A-16 A1- A-18 15 A-15b; R=Ts Indole A-15a (CAS: 11903142) can be protected by ing TsCl and an appropriate base, preferably NaH, to afford A-15b. Reduction of the nitro onality, preferably by employing WO 2015/009616 2014/046515 zinc metal in a solvent e of EtOAc/MeOH, can afford aniline A-16, which can be converted to iodide A-17 upon treatment with NaNOz, followed by l2. Treatment of A-17 with butyl lithium in the presence of DMF can provide the aldehyde A-18.
Compounds such A-25 where Xb = Cl, or Br, can be prepared by the sequence described in Scheme 5.
Scheme5 N02 NH2 NHBoc CE) a CE) aBr Me / .N .N .N R PG PG A-20a; R=H A-21 A-22 A-20b;R=Ts NH2 I H 0 Me Me Me / / _. _. _. / l" l" N PG xb PG xb PG, Xb A-23 A-24 A-25 lndole A-20a (CAS: 47695) can be protected by employing TsCl and an appropriate base, preferably NaH, to afford A-20b. Reduction of the nitro onality of A-20b, preferably 10 employing zinc metal in a solvent mixture of EtOAc/MeOH, followed by bromination, preferably with NBS, can afford A-21. Boc protection of the aniline A-21 followed by Suzuki-coupling using potassium methyltrifluoroborate can afford A-22. Acid mediated deprotection of the Boc group of A- 22, followed by halogenation using NBS or NCS can yield halides of type A-23. Transformation of the e A-23 to aldehyde A-25 can be accomplished in ance with Scheme 4 (Le. A479 15 A-18).
Compounds such as B-5a, wherein Rf is H, F, Cl, Br, SMe, or CN; and R9: H or C1-C4 alkyl; and L:11 is an aryl group optionally substituted with -Rf; can be prepared by the general method outlined in Scheme 6.
WO 2015/009616 PCT/US2014/046515 Scheme 6 ow:prororor B-5a |:B-4a; R9: HB-4b; R9: C1-C4-alkyl 4-Methoxypyridine B-1 can be transformed to compound B-2, wherein Re is an alkoxy group (preferably -OPh, -OBn or -OtBu), by in situ N-acylation with a chloroformate such as benzyl or phenyl chloroformate, followed by addition of an arylmagnesium halide, and subsequent acid mediated hydrolysis, preferably employing aqueous HCI. Alternatively, B-2 when Re: OtBu can be synthesized by the following sequence: reaction of B-1 with phenyl formate; treatment with an aryl Grignard reagent to install La; ent with KOtBu to convert the phenyl chloroformate to the Boc protecting group; and then acid mediated hydrolysis to reveal the ketone. The double bond 10 of B-2 can then undergo reduction ing a suitable choice of reagents such as L-Selectride®, or a reducing metal such as zinc, to afford ketone B-3. The reduction may also be effected by the hydrogenation over Pd/C under a pressurized hydrogen here ranging up to 20 bar. B-3 can then be converted to the corresponding alcohol B-4a (R9=H) employing a ng reagent such as NaBH4 or LiBH4. Alkylation of B-4a can be achieved by reaction with an electrophile such as Mel 15 or Etl in the presence of a base such as NaH in a suitable solvent such as DMF, to provide B-4b (R9: C 1.4alkyl). , deprotection of B-4a and B-4b can h B-5a by employing conditions such as s basic hydrolysis (Re: OPh), catalytic hydrogenation (Re: OBn), or acid treatment (Re: OtBu). 20 Compounds such as B-5b, wherein Yb is C1-C4-alkyl, CHZOH, CHZCN or NH-Cbz; can be prepared by the l method outlined in Scheme 7.
Scheme-7 fitaoU"U 36- 3-7 B-5b B-3 can undergo a Wittig-type reaction utilizing an hosphonium halide such as 25 methyltriphenylphosphonium bromide (Ya: CH2), ethyltriphenylphosphoniym bromide (Ya: CHCH3), or a Horner—Wadsworth-Emmons type reaction employing diethyl cyanomethylphosphonate (Ya: WO 2015/009616 PCT/US2014/046515 CHCN) to furnish B-6. B-6, when Ya =CH2, can undergo hydroboration ing 9-BBN, followed by the treatment with hydrogen peroxide, to afford B-7 (Yb: CHZOH). In addition, hydrogenation of B-6, when Ya: CHCH3 or CHCN, can afford B-7 (Yb: CHchs or CHZCN, respectively), which can be a mixture of diastereomer. atively, compound B-7 (when Yb: NHCbz) can be obtained by a sation of B-3 with tert—butyl sulfinylamide in the presence of a dehydrating reagent, such as Ti(OiPr)4 or Zr(OtBu)4, followed by reduction of the sulfinylimine with NaBH4_ The resulting ylamide can then be treated with an riate acid such as HCI in methanol to afford the corresponding primary amine, which can then be reacted with Cbz—Cl to provide B-7 (Yb: NHCbz).
Transformation from B-7 to B-5b can be achieved by the standard methods as mentioned above 10 (e.g. B-4 to B-5a). atively, compounds such as 3-11 and B-5c, wherein: Lb: L3, or a heterocycle which is optionally substituted with Rf; Ri= -CH2-, -CH(OTBDPS)—, -CH(OH)—, or -C(Me)2-; and n= 0 or 1; can be ed according to Scheme 8a. 15 Scheme 8a R>\"5f f f f \L. R\ R\ R\< OvRi Ri LL‘Bx . L . m .
NM; 0 W—r am _. now _. flow 800’ n NHn N HN n n OYN n BOC/ Re 3-8 3-9 3-10 B-5c B-11 B-8 can be reacted with the appropriate Grignard ts such as (4- (methylthio)phenyl)magnesium bromide, to furnish B-9. ection of the Boc group of B-9 can be achieved by treatment with a suitable acid and solvent such as HCI in dioxane. Subsequent 20 dehydration employing a reagent such as Ti(OiPr)4 can afford the corresponding cyclic imine B-10.
Alternatively, B-10 can be accessed directly by a treatment of B-9 with TMSOTf in the presence of 2,6-lutidine. B-10 can then be reduced employing reagents such as NaBH4, to afford B-5c.
Compounds such as B-5c when R: -CH(OTBDPS)— can then be transformed to the corresponding alcohol (B-11 when R: -CH(OH)—) as s: protection of the nitrogen with an 25 appropriate group such as Boc or Cbz; deprotection of the TBDPS group by a treatment with nucleophilic fluoride anion preferably via the use of TBAF in THF or by hydrolysis with HCI in MeOH; and then by methods described in Scheme 6 (e.g. B-4a to B-5a) to liberate the amine.
Alternatively, compounds such as B-11b and B-5d, wherein: R]: OTBDPS or 0R9; can be prepared according to Scheme 8b.
WO 2015/009616 PCT/US2014/046515 _ 42 _ Scheme 8b REEF».f RR R\ RR< O R1 HF" (03‘. {LB} 0 Fr fl "0% "0% 0C /NH RJ' R’ R1 ".13R1 800 B-5d B-8b B-9b B-10b . .3 50'- (RJ=-OTBDPS) H or B 11b_ _ORC) (R: CORe) B-8b (when R]: CH(OTBDPS)) can be reacted with the appropriate Grignard reagents such as (4-cyanopheny|)magnesium e, to furnish B-9b. Deprotection of the Boc group of B-9b, followed by the imine formation can be achieved by treatment with TMSOTf in the presence of 2,6- lutidine to afford B-5d (Rj= OTBDPS), which can then be transformed to B-11b. B-11b (when R]: OTBDPS) can then be tansformed to B-5d (where R]: OH, or ORC) by the standard methods described in Scheme 6. 10 nds such as B-4a or 3-11 can be transformed to the corresponding diastereomer as shown in Scheme 9. Of note, the ve chemistry shown in Scheme 9 is intended for illustrative purposes only and does not specify a particular te configuration. Typically, reactions provide a mixture of diastereomers generally with one diastereomer in excess of the other. 15 Scheme 9 RI"?f R>3f szf RX}f ‘HUOH ‘5} _.\OBz ‘\E_ \OH \th .0 RC a D a 0 a O CYN oY OYN R,N Re Re Re B-4a or 3-13 B-14 B-15 ; R= CORe B-11 B-5e ; R: H Stereochemical inversion of the hydroxy of B-4a or 3-11 can be achieved by reaction with a carboxylic acid such as benzoic acid under Mitsunobu-type reaction conditions in a suitable solvent, preferably in THF, to provide B-13. Subsequent saponification employing conditions such as 20 K2003 in methanol can give B-14. B-14 can then be transformed to B-15, and then to amine B-5e employing similar methods as bed in Scheme 6 (e.g. B-4a to B-5a).
Compounds such as B-5f; wherein Rf'2 is COO-alkyl; and Ri'2 is -CH(OR9)- or -C(Me)2-; can be prepared according to Scheme 10.
WO 2015/009616 PCT/US2014/046515 _ 43 _ Scheme 10 Rf Rf 2 kuvRI 2 >‘LbY\ R ff; - ‘~ , ‘\, Ri—Z 'be~ ‘ 2 ‘ WR' o NQ o Nd Y Y HNQ Re Re :1? 3T1"? B-4c B-5f B-4a, B-4b, B-11, or 3-15 when Rf: CN can undergo hydrolysis of the nitrile group by employing a source of hydroxide, preferably barium hydroxide, in a suitable solvent preferably a mixture of iPrOH/HZO, at temperatures between 80 oC and 110 °C. The subsequent acid can then be transformed to corresponding alkyl esters B-4c ing reagents such as trimethylsilyldiazomethane in a solvent mixture of toluene/methanol (Rf'2= COZMe), or via ent with an anhydrous alcoholic solvent with an acid such as methanolic HCI. Alternatively B-4b, B-11, or B-15 when Rf: Cl or Br can be transformed to B-4c respectively by a ylation employing 10 carbon monooxide in the presence of a base, such as ylamine and a palladium catalysts with an appropriate ligand such as (rac—BlNAP)PdC|2 in a suitable solvent such as methanol.
Deprotection of B-4c can be accomplished by applying methods as described in Scheme 6 to afford B-5f. 15 Compounds such as B-5g n Rk= alkyl, can be prepared according to Scheme 11.
Scheme 11 //Rk Rf—Z fj >13" \"j‘B’OH xb \N I OH R f—2 R f2 B-16a B-17a I\., Rk .\-~~ Rk \ La I / \ La I / Rk R f—2 N \ HN f/J >131; 3-18 3-59 Sn(Bu)3 N Xb B-16b B-17b nds of type B-16a (when Xb= Cl, Br or I) can be reacted with an appropriately substituted organoboronate (B-17a) utilizing Suzuki-type reaction conditions to provide B-18. 20 Alternatively, B-18 can be prepared from compounds type B-16b and B-17b via Stille type ng method. A reduction of the pyridine ring of B-18 can be accomplished by treatment with a st such as PtOz under a hydrogen atmosphere in a suitable solvent such as methanol in the presence of an acid such as HCl, to afford piperidine B-5g.
WO 2015/009616 PCT/US2014/046515 Compounds such as B-5h; can be prepared by the route depicted in Scheme 12 wherein R""1 and R""2 are independently selected from hydrogen or alkyl.
Scheme 12 Rk Rk Rm-1 Rk j CI—SQZ j \lN—sc\)2 j Rf Rf Rf 5 B-19 B-20 B-5h ylation of compounds such as B-19 when Rf: H, Br, Cl, or F, can be accomplished by employing a reagent such as chlorosulfonic acid to afford B-20, which can subsequently be treated with a wide variety of primary (Rm'1-NH2) and secondary amines (Rm'1Rm'2-NH) such as a or methylamine, to furnish B-5h. 10 Compounds such as C-2 wherein R": -Rf, R", or -SOZNRm'1Rm'2; and Q: R, Ri'2 or O; and Rb and RC are ndent groups respectively; can be prepared as outlined in Scheme 13.
Scheme 13 A-5, A-10, A-14 borc _’ A-18, A-25 :1 R 15 lndole aldehydes such as A-5, A-10, A-14, A-18 or A-25, can be d by a hydride donating reagent in a suitable solvent such as NaBH4 in a mixture of methanol/THF, to provide C- 1a. Subsequent, conversion of the resulting hydroxy to chloride C-1b can be accomplished by treatment with methanesulfonyl de and Et3N, or by directly reacting with (chlormethylene)dimethylammonium chloride. C-1b can be reacted with a cyclic amine such as B- 20 5a, B-5b, B-5c, B-5d, B-5e B-5f, B-5g, B-5h, or commercially available cyclic amines such as 4- (morpholinyl)benzoic acid ester in the presence of a base such as potassium carbonate in a solvent such as DMSO at temperatures ranging from 0 0C to 100 0C to afford C-2. Alternatively, aldehydes A-5, A-10, A-14, A-18 or A-25 can be d with the cyclic amines described above employing ive alkylation conditions, e.g. treatment with sodium triacetoxyborohydride in 25 DCE, to provide C-2.
WO 2015/009616 PCT/US2014/046515 Compounds such as D-1 wherein R°= R", CONH2, or COOH, can be prepared according to Scheme 14.
Scheme 14 R0 X \‘->j/\QI NM>RK Rb 2r c C-2 —’ / N Ga D-1 H Ra or Xb Deprotection of PG (PG: Ts or Boc) in compound C-2 can be achieved by a ent with a base such as KOH in a suitable solvent such as l at temperatures ranging from 80 to 120°C under microwave irradiation, to afford D-1. Deprotection of PG from C-2 when R°= CN can also result in concomitant reaction of the nitrile to e D-1 n R°= -COOH or -CONH2. 10 Alternatively, transformation of C-2, when (PG: Boc), to D-1 can be accomplished by a treatment with a source of hydroxide such as KOH or LiOH in a suitable solvent system such as a e of THF/methanol/HZO at temperatures ranging from room temperature to 100 °C. In addition, treatment of C-2, when PG: Boc, with an appropriate acid such as TFA in a solvent such as CHZCIZ at temperature preferably 0°C can provide D-1. 15 Compounds such as D-1b wherein Rp= CHZOH, CH2NH2, CONRm'1Rm'2, or tetrazole, can be prepared according to Scheme 15.
Scheme 15 R0 RP :L‘b" >53; ‘ \_’ Q ‘~_ Q NM>R"n "14>"n Rb or c Rb or c —> / / N G8 N Ga H D-1 H D-1b Ra orb Ra orb 20 D-1 when R°= COOR, COOH, or CN, can be further elaborated utilizing a reducing reagent such as LiAlH4 in a suitable solvent such as THF at temperatures between 0 and 50 °C, to provide D1-b (Rp= CHZOH, CH2NH2). Alternatively, D-1, when R°= COOH, can also be coupled with a wide variety of primary and secondary amines (HNRm'1Rm'2) such as methylamine, or sulfonamides such as methanesulfonamide by employing amide bond forming conditions of those that are well known WO 2015/009616 PCT/US2014/046515 to those skilled in the art, to provde amides of type D-1b. In addition, D-1 when R°= CN can be transformed to D-1b (Rp= tetrazole) by a treatment with azide containing reagents such as sodium azide in the ce of catalysts such as triethylamine hydrochloride in a suitable solvent such as chlorobenzene at elevated temperatures between 100°C and 150°C.
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 10 materials.
Compounds of the invention and intermediates can also be ted into each other according to methods lly known to those skilled in the art. All tautomeric forms are also intended to be included.
In another aspect, the present invention provides a pharmaceutical composition comprising 15 a compound of the present invention, or a pharmaceutically able salt f, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For es of the present invention, unless designated othenNise, solvates and hydrates are generally considered compositions. ably, ceutically acceptable carriers are sterile. The ceutical 20 composition can be formulated for particular routes of administration such as oral administration, eral administration, and rectal stration, etc. In addition, the pharmaceutical compositions of the present ion 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 or ons). The pharmaceutical compositions can be 25 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, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: 30 a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, c acid, its magnesium or m salt and/or polyethyleneglycol; for tablets also c) s, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired WO 2015/009616 PCT/US2014/046515 d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or escent mixtures; and e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to s 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 ceutical 10 compositions and such compositions can contain one or more agents ed from the group consisting of ning 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 15 carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for e, corn starch, or alginic acid; binding agents, for example, starch, n or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are ed 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 e, a 20 time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can be presented as hard gelatin es n the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft n capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 25 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, izing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may 30 also n other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, tively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
WO 2015/009616 PCT/US2014/046515 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 , 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 s ons, 10 suspensions, ointments, creams, gels or ble formulations, e.g., for ry by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like.
They are thus particularly suited for use in topical, including ic, formulations nown in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and 15 preservatives.
As used herein a topical application may also pertain to an inhalation or to an asal 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) 20 from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or ser, with or without the use of a suitable lant.
Ophthalmic formulations, eye ointments, powders, solutions, suspensions and the like, for topical stration are also contemplated as being within the scope of this invention.
The present invention further es anhydrous pharmaceutical compositions and dosage 25 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 ed using anhydrous or low re containing ingredients and low moisture or low ty conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its 30 anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be ed in suitable formulary kits. Examples of le packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
WO 2015/009616 PCT/US2014/046515 The ion further provides pharmaceutical compositions and dosage forms that se 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 ed to herein as "stabilizers," include, but are not d to, antioxidants such as ic acid, pH buffers, or salt buffers, etc.
Prophylactic and eutic Uses The compounds of formula I in free form or in ceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. Factor B modulating properties, complement pathway ting 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 ted for 10 therapy.
The present ion 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 s, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the 15 complement pathway. In certain embodiments, methods of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
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 f an effective 20 amount of the compound of Formula (I) of the invention. In certain ments, patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration d disorder are le for administration with a compound of the invention. The methods of ng 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 25 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. 30 The compound of Formula (I) of the invention can be used, inter alia, to prevent the onset of AMD, to t the progression of early AMD to advanced forms of AMD including cular 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 al or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve WO 2015/009616 PCT/US2014/046515 vision lost due to pre-existing early or advanced AMD. It can also be used in combination with anti- VEGF ies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD. The t invention further provides methods of ng a complement related disease or disorder by administering to a subject in need thereof an ive amount of the compound(s) of the invention, wherein said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot -chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion. 10 In some embodiments, the present invention provides methods of treating a complement related disease or er 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, in Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, 15 hemodialysis complications, cute allograft ion, xenograft rejection, interleukin-2 induced ty during lL-2 therapy, inflammatory disorders, inflammation of mune diseases, Crohn's disease, adult respiratory distress me, 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 20 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, 25 asthma, chronic obstructive pulmonary disease (COPD), ema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and ls (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary is, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen e, ammonia, and hydrochloric acid), smoke injury, l injury (e.g., burn, freeze), asthma, allergy, 30 bronchoconstriction, ensitivity pneumonitis, parasitic diseases, sture'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 ment, the present ion es methods of treating a ment related disease or disorder by administering to a subject in need thereof an effective amount of the WO 2015/009616 PCT/US2014/046515 compounds of the invention, wherein said disease or disorder is asthma, tis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia- reperfusion injuries, Barraquer—Simons Syndrome, hemodialysis, anca vasculitis, cryoglobulinemia, ic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system such as mer's e and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), dense deposit disease, blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.
In a ic embodiment, the present invention provides methods of treating 10 glomerulonephritis by administering to a t 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 ion resulting in hypertension and edema; hematuria and abnormal urinary 15 sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific embodiment, the present invention provides methods of treating paroxysmal nal hemoglobinuria (PNH) by administering to a subject in need thereof an ive 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. 20 In a ic embodiment, the present invention provides methods of reducing the dysfunction of the immune and/or hemostatic systems ated with extracorporeal circulation by administering to a subject in need thereof an effective amount of a composition sing an nd of the t invention. The compounds of the present invention can be used in any ure which involves circulating the patient's blood from a blood vessel of the patient, through 25 a conduit, and back to a blood vessel of the patient, the t 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 ECG, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a t. More particularly, such procedures include, but 30 are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell lant procedures.
In other ments, the compounds of the invention are suitable for use in the treatment of diseases and ers associated with fatty acid metabolism, including obesity and other metabolic disorders.
WO 2015/009616 PCT/US2014/046515 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 y associated with blood sampling.
The pharmaceutical ition 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 t, the body weight, age and 10 individual ion, the disorder or e 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 cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated , s and 15 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 enously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range n 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 20 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 t invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may 25 be administered tely, 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 ed preparation for aneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or 30 condition mediated by alternative complement pathway. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other eutic agent(s) together in the same ceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
WO 2015/009616 2014/046515 In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the ceutical 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 . An example of such a kit is a blister pack, as typically used for the packaging of tablets, es and the like.
The kit of the invention may be used for administering different dosage forms, for e, 10 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 ies of the invention, the nd of the ion and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. 15 Moreover, the compound of the invention and the other therapeutic may be t 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 ian) shortly before administration; (iii) in the patient themselves, e.g. during sequential stration of the compound of the invention and 20 the other therapeutic agent.
Accordingly, the invention es the use of a compound of formula (I) for treating a disease or ion mediated by the complement alternative y, 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 25 alternative pathway, wherein the medicament is administered with a compound of formula (I).
The invention also es a compound of formula (I) for use in a method of treating a e or condition mediated by the complement alternative pathway, wherein the compound of formula (I) is prepared for administration with another eutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated 30 by the complement alternative pathway and/or Factor B, 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 B, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent WO 2015/009616 PCT/US2014/046515 for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor B, 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 ion mediated by the complement alternative y and/or Factor B, wherein the patient has previously (e.g. within 24 hours) been treated with r therapeutic agent. The invention also provides the use of another therapeutic agent for treating a e or condition mediated by the complement alternative pathway and/or Factor B n the patient has previously (e.g. within 24 hours) been d with a compound of formula (I). 10 The pharmaceutical compositions can be administered alone or in ation 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 e complement inhibitors (such as inhibitors of Factor D, C5a receptor and antibody or Fabs t C5, CB, properidin, factor H, and the like), anti-VEGF 15 agents (such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin), basic last growth factor (bFGF), ciliary neurotrophic factor (CNTF), e (a mutein of CNTF), leukemia inhibitory factor (LlF), 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 20 and antifungal agents and analgesics and anesthetics. Suitable agents for combination treatment with the compounds of the invention e 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 25 agents). In some embodiments, the present invention provide a combination y 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 Avastin and VEGF-R2 inhibitors including pazopanib, sutent, inifanib, and VEGF-R2 inhibitors disclosed in W02010/066684) or ynamic therapy (such as as verteporfin). 30 In some embodiments, the present ion provide a combination therapy for ting and/or treating autoimmune disease as described above with a compound of the invention and a B- Cell or T-Cell ting agent (for example cyclosporine or analogs f, rapamycin, RAD001 or analogs thereof, and the like). In particular, for multiple sclerosis therapy may include the WO 2015/009616 PCT/US2014/046515 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 B, n the method comprises administering to the subject a therapeutically effective amount of the compound ing to the definition of Formula (I). 10 In one embodiment, the invention provides a compound according to the definition of a (I), (la), or any subformulae thereof, for use as a medicament.
In one embodiment, the ion provides the use of a compound according to the definition of formula (I), (la), or any subformulae f, for the treatment of a disorder or disease in a t mediated by complement activation. In particular, the invention provides the use of a 15 compound according to the definition of formula (I), (la), or any subformulae thereof, for the treatment of a disorder or disease mediated by activation of the complement alternative pathway.
In one ment, the invention provides the use of a compound according to the definition of formula (I), (la), or a subformulae thereof in the manufacture of a medicament for the treatment of a er or disease in a subject terized by activation of the complement 20 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 mulae thereof for the treatment of a disorder or disease in a t characterized by tion of the complement . More particularly, the invention 25 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 ed from retinal es (such as age-related macular degeneration).
The present ion provides use of the compounds of the invention for treating a disease 30 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 ication loop of the complement pathway. In certain embodiments, uses of treating or preventing compelment mediated diseases are provided in which the complement activation is WO 2015/009616 PCT/US2014/046515 _ 55 _ induced by dy-antigen interactions, by a ent of an autoimmune disease, or by ischemic damage.
In a specific embodiment, the present invention provides use of the compounds of the invention for ng or ting age-related r degeneration (AMD). In certain embodiments, patients who are currently asymptomatic but are at risk of developing a symptomatic macu|ar ration related disorder are suitable for administration with a compound of the invention. The use in treating or ting 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 eceptor cells, loss of vision (including loss of 10 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 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 15 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 macu|ar edema from AMD or other conditions (such as diabetic pathy, 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 ed AMD. It can also be used in combination with anti- 20 VEGF ies for the treatment of neovascular AMD patients or for the tion 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, adu|t macuar degeneration, diabetic pathy, retinitis pigmentosa, macu|ar edema, ’s uveitis, ocal choroiditis, 25 Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and l vein ion.
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: 30 neurological disorders, multiple sis, stroke, Guillain Barre Syndrome, tic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during |L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress me, thermal injury including burns or frostbite, myocarditis, WO 2015/009616 PCT/US2014/046515 post-ischemic reperfusion conditions, myocardial infarction, balloon lasty, post-pump syndrome in pulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, eric artery reperfusion after aortic reconstruction, ious disease or , 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, c obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, enic dust es, inert dusts and minerals (e.g., n, coal dust, 10 ium, 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, tic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis 15 (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 , arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer—Simons Syndrome, 20 hemodialysis, systemic lupus, lupus erythematosus, sis, le sclerosis, lantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic me (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular ical pemphigoid or MPGN II. 25 In a ic embodiment, the present invention provides use of the compounds of the invention for treating glomerulonephritis. ms 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; ria and abnormal urinary sediments 30 including red cell casts; hypoalbuminemia; hyperlipidemia; and ria. In a specific ment, the present invention provides methods of treating paroxysmal nal 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.
WO 2015/009616 PCT/US2014/046515 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 l surface comprising a material e of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion. Such procedures include, but are not d to, all forms of ECG, 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 e, but are not 10 limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell lant ures.
In one embodiment of the present invention, there is (-)-(S)(1-((5-cyclopropylmethyl- 1H-indolyl)methyl)piperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the 15 complement alternative pathway. In certain embodiments, the disease or disorder mediated by complement tion is selected from age-related macular degeneration, geographic y, ic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular icial pemphigoid, ocular pemphigus, nonartertic ischemic optic 20 athy, perative mation, retinal vein occlusion, neurological ers, multiple sclerosis, , 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 lL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult atory 25 ss syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal , sclerosis, 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 30 anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic ctive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, oconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune itis, immune complex-associated inflammation, WO 2015/009616 PCT/US2014/046515 antiphospholipid syndrome, glomerulonephritis and obesity. In certain preferred embodiments, the disease or disorder mediated by ment activation is selected from age-related macular degeneration, geographic atrophy, ic retinopathy, uveitis, retinitis pigmentosa, or macular edema.
In one embodiment of the t invention, there is (-)((28,4S)—1-((5-methoxymethyl- 1H-indolyl)methyl)propoxypiperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in ular mediated by activation of the complement alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is selected from age-related r degeneration, geographic y, 10 diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, oyangi-Harada syndrome, imtermediate 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, tic brain injury, Parkinson's disease, disorders of 15 inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during lL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, ditis, post-ischemic reperfusion conditions, myocardial infarction, n lasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, sclerosis, 20 hemodialysis, renal ischemia, mesenteric artery usion after aortic truction, 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, c obstructive pulmonary disease (COPD), emphysema, ary embolisms and 25 ts, pneumonia, enic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated mation, antiphospholipid syndrome, glomerulonephritis and obesity. In certain preferred embodiments, the disease or disorder ed by complement activation is selected from age-related macular 30 degeneration, geographic atrophy, diabetic retinopathy, s, retinitis pigmentosa, or macular edema.
In one embodiment of the present invention, there is (+)((28,4R)—1-((5-methoxymethyl- 1H-indolyl)methyl)—4-methylpiperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject ed by complement tion, in particular mediated by activation of the WO 2015/009616 PCT/US2014/046515 _ 50 _ ment alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, r edema, Behcet’s uveitis, ocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular icial goid, 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, cute allograft rejection, xenograft rejection, interleukin-2 induced ty during lL-2 therapy, 10 inflammatory ers, inflammation of autoimmune diseases, Crohn's disease, adult atory distress syndrome, myocarditis, schemic reperfusion conditions, myocardial infarction, balloon lasty, 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, 15 ic lupus matosus (SLE), SLE tis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural ration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and ts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, 20 pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, ulonephritis and obesity. In certain preferred embodiments, the disease or er mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, or macular edema. 25 In one embodiment of the present invention, there is (-)((2S,4S)—4-methoxy((5- methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway. In certain embodiments, the disease or disorder mediated by ment activation is selected from age-related macular degeneration, geographic 30 atrophy, diabetic pathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, ediate s, birdshot retino- chorioditis, sympathetic lmia, ocular dicatricial goid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multi ple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain in'uJ ry, Parkinson's WO 2015/009616 PCT/US2014/046515 e, disorders of opriate or undesirable complement activation, alysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during lL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, s disease, adult respiratory ss 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 matosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, tic anemia, myasthenia gravis, tissue regeneration, neural 10 ration, a, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary is, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's me, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity. In 15 n preferred embodiments, the disease or disorder mediated by complement activation is selected from lated macular degeneration, geographic y, diabetic retinopathy, uveitis, retinitis pigmentosa, or macular edema.
In one embodiment of the present ion, there is (-)(rel-(2S,4S)—4-ethoxy((5- methoxymethyl-1H-indolyl)methyl)piperidinyl)picolinic acid for use in the ent of a 20 disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic pathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, ocal choroiditis, Vogt-Koyangi-Harada me, imtermediate uveitis, birdshot retino- 25 chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein ion, neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable ment activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity 30 during lL-2 therapy, inflammatory disorders, mation 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 ia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune WO 2015/009616 PCT/US2014/046515 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 ctive ary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust es, ary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, immune vasculitis, immune x-associated inflammation, antiphospholipid syndrome, ulonephritis and obesity. In certain preferred embodiments, the disease or disorder mediated by complement activation is selected from age-related r degeneration, geographic atrophy, diabetic retinopathy, uveitis, 10 retinitis tosa, or r edema.
In one embodiment of the present ion, there is (-)(1-((5-methoxymethyl-1H-indol- 4-yl)methyl)-4,4-dimethylpiperidinyl)benzoic acid for use in the treatment of a disorder or a e in a subject mediated by complement activation, in ular mediated by activation of the complement alternative pathway. In n ments, the disease or disorder mediated by 15 complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis tosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial goid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, ogical disorders, multiple 20 sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft ion, xenograft rejection, interleukin-2 induced toxicity during lL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon 25 angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, erative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, 30 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, ary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and y. In certain preferred embodiments, the WO 2015/009616 PCT/US2014/046515 disease or disorder mediated by ment activation is selected from age-related r degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, or macular edema.
In one embodiment of the present invention, there is 4-((28,4S)—(4-ethoxy—1-((5-methoxy methyl-1H-indolyl)methyl)piperidinyl))benzoic acid ((+)-as TFA salt) for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the ment alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is ed from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, 10 multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot - chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, l vein occlusion, neurological disorders, le sclerosis, stroke, in Barre Syndrome, traumatic brain , son's disease, disorders of inappropriate or undesirable complement activation, hemodialysis 15 complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during lL-2 y, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, ump syndrome in cardiopulmonary bypass or renal , atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after 20 aortic reconstruction, infectious disease or sepsis, immune complex ers and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE tis, 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, enic dust diseases, 25 pulmonary fibrosis, asthma, allergy, bronchoconstriction, ensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity. In certain preferred embodiments, the disease or disorder ed by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, 30 retinitis pigmentosa, or macular edema.
In one embodiment of the present ion, there is (-)(rel-(28,4S)—1-((5,7-dimethyl-1H- indolyl)methyl)—4-methoxypiperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject mediated by complement tion, in ular mediated by activation of the ment alternative pathway. In certain embodiments, the disease or disorder mediated by WO 2015/009616 PCT/US2014/046515 _ 54 _ complement activation is ed from age-related macular degeneration, geographic y, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, ertic 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, alysis cations, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during lL-2 therapy, matory disorders, mation of autoimmune diseases, s disease, adult respiratory 10 distress me, myocarditis, schemic 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 15 anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, nia, fibrogenic dust es, pulmonary fibrosis, asthma, allergy, bronchoconstriction, ensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary itis, Pauci-immune vasculitis, immune complex-associated inflammation, 20 ospholipid syndrome, glomerulonephritis and obesity. In certain preferred embodiments, the disease or disorder mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, or macular edema.
In one embodiment of the present invention, there is -(28,4S)—1-((5,7-dimethyl-1H- 25 indolyl)methyl)ethoxypiperidinyl)benzoic acid ((+)- as TFA salt) for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, ic retinopathy, uveitis, retinitis tosa, macular edema, Behcet’s uveitis, 30 multifocal ditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, ogical disorders, le sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement tion, hemodialysis WO 2015/009616 2014/046515 _ 55 _ complications, hyperacute aft rejection, xenograft rejection, interleukin-2 induced toxicity during |L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress me, ditis, post-ischemic reperfusion conditions, myocardial infarction, n 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 tis, ic lupus erythematosus (SLE), SLE nephritis, erative nephritis, liver fibrosis, hemolytic , myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease 10 (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust es, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity. In certain preferred embodiments, the e or disorder mediated by complement tion is 15 selected from age-related macular ration, geographic atrophy, diabetic retinopathy, uveitis, retinitis tosa, or macular edema.
In one embodiment of the present invention, there is (-)(rel-(28,4S)—1-((5-cyclopropyl methyl-1H-indolyl)methyl)—4-methoxypiperidinyl)benzoic acid for use in the treatment of a disorder or a disease in a subject mediated by complement activation, in particular mediated by 20 activation of the complement alternative pathway. In certain embodiments, the disease or disorder mediated by complement activation is selected from age-related r degeneration, geographic atrophy, diabetic pathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, ot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular gus, nonartertic 25 ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, son's disease, disorders of inappropriate or undesirable complement activation, hemodialysis cations, hyperacute allograft ion, xenograft rejection, interleukin-2 induced toxicity during |L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's 30 disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump me 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 WO 2015/009616 PCT/US2014/046515 _ 55 _ nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue ration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive ary disease (COPD), emphysema, pulmonary embolisms and infarcts, nia, fibrogenic dust diseases, pulmonary fibrosis, , allergy, bronchoconstriction, hypersensitivity nitis, parasitic diseases, sture's me, pulmonary vasculitis, Pauci-immune vasculitis, immune x-associated inflammation, antiphospholipid syndrome, glomerulonephritis and y. In certain preferred embodiments, the disease or disorder mediated by complement activation is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, or macular edema. 10 In one embodiment of the present invention, there is (+)(rel-(28,4S)—1-((5-cyclopropyl methyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid for use in the ent of a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway. In certain embodiments, the disease or er ed by complement activation is selected from lated macular degeneration, geographic 15 y, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, le sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's 20 disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during |L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's e, adult atory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or 25 renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or , immune complex ers and autoimmune diseases, rheumatoid arthritis, systemic lupus matosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease 30 , 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. In certain preferred embodiments, the e or disorder ed by complement activation is WO 2015/009616 PCT/US2014/046515 selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, or r edema.
The following examples are intended to rate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees grade (°C). If not mentioned othenNise, all evaporations are performed under d pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The ure 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, ating agents, ts, 10 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 ed by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. 15 Inter Alia the following in vitro tests may be used.
The following Examples, while representing preferred embodiments of the invention, serve to illustrate the invention without limiting its scope.
Abbreviations 9-BBN 9-Borabicyclo[3.3.1]nonane 20 Ac acetyl AcOH acetic acid APCI heric-pressure al ionization app apparent aq. aqueous 25 atm here BINAP 2,2’-Bis(diphenylphosphino)—1,1’-binaphthy| Boc tertiary butyloxy carboxy br. Broad Bu butyl 30 BuOH butanol Bz benzoyl calcd. Calculated Cbz carboxybenzyl WO 2015/009616 PCT/US2014/046515 _ 68 _ d doublet dd doublet of doublets DCE chloroethane DEA diethylamine DEAD diethyl arboxylate DlBAL-H diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMAP 4,4-dimethylaminopyridine DME methoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane EDC-HCI 1-ethyl(3-dimethylaminopropyl)carbodiimide hloride ESI electrospray ionization EtOAc ethyl acetate Et ethyl EtOH ethanol g grams h, hr hour(s) HATU 2—(1Hazabenzotriazolyl)--1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium HC HPLC condition HFIP 1,1,1,3,3,3-hexafluoro—2—propanol HPLC high performance liquid chromatography IPA, iPrOH 2—propanol IR infrared spectroscopy L liter(s) M molar MHz mega Hertz m multiplet Me methyl Mel iodomethane MeOH methanol WO 2015/009616 PCT/US2014/046515 mg milligram(s) min minutes mL milliliter(s) mmol mi||imo|es MS mass spectrometry Ms methyanesulfonyl m/z mass to charge ratio normal NMR nuclear magnetic resonance 10 PBS phosphate buffered saline Pd/C ium on carbon Ph phenyl ppm parts per million rac racemic 15 rel relative stereochemical information (e.g., trans or cis) and does not denote absolute stereochemistry of accompanying stereochemical information r.t. room temperature RP- reverse phase s singlet 20 satd. saturated SFC Supercritical Fluid Chromatography SOs.Py, SOs-Py sulfur trioxide pyridine complex t triplet 25 TBAF tetra-n-butylammonium fluoride TBDPS utyldiphenylsilyl I, TBDPS—Cl tert—butyldiphenylsilyl chloride TEA, Et3N ylamine 30 tert- tertiary TFA trif|uoroacetic acid TFE 2,2,2-trifluoroethanol THF tetrahyd rofu ran TMS trimethylsilyl WO 2015/009616 PCT/US2014/046515 _ 70 _ TMSOTf trimethylsilyl trifluoromethanesulfonate TMSP sodium 3-trimethylsilylpropionate-2,2,3,3-d4 tr retention time Tris tris(hydroxymethyl)aminomethane Ts p-toluenesulfonyl TsOH p-toluenesulfonic acid v/v volume per volume w/v weight per volume 10 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 eric forms of nds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples bed hereafter should be considered to be disclosed.
Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are 15 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 als is med by standard analytical methods, e.g., microanalysis and spectroscopic teristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.
All starting materials, ng blocks, reagents, acids, bases, ating agents, ts, 20 and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be ed by c synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic sis, 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. 25 All reactions are carried out under nitrogen or argon unless othenNise stated. Optical rotations were ed in MeOH, using D line of a sodium lamp.
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. 30 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.
WO 2015/009616 2014/046515 Following ation methods were used for RP-HPLC.
HC-A: - Stationary phase: Waters SunFireTM Prep C18 OBDTM 5pm, 30x100 mm - Mobile phase: gradient, water with 0.1% TFA / acetonitrile HC-B - Stationary phase: Gemini® NX 5p C18 110A 100x30 mm - Mobile phase: gradient, water with 0.1% (28% ammonium hydroxide) / acetonitrile Absolute stereochemistry and/or optical rotations are ed for the embodiments of the 10 ion where applicable. The invention contemplates all chemical forms of the nds 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 15 ed via NMR studies and/or X-ray diffraction. In these cases the compounds are fied with the prefix "rel" followed by R/S nomenclature. Of note, in ces where "ref’ is used the R/S only provides relative stereochemical information (e.g., trans or cis) and does not denote absolute stereochemistry. 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 20 delineated HPLC conditions and the monikers "diastereomer—1" or "diastereomer—2", or "single reomer" when only one isomer is isolated and/or available.
In the case of a racemic samples, including intermediates, enantiomers are ted 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- 25 2", and/or by a specific "+" or "-" sign referring to the on of polarized light when this data is available.
In instances when individual diastereomers, that are racemic, are identified but relative stereochemistry is not determined, then the compounds are designated with the symbol "(i ) along with the moniker "diastereomer—1" or "diastereomer—2", or "single diastereomer" if only one isomer is 30 isolated and/or available.
In instances where a ative specific rotation is available, but relative stereochemistry is not determined, individual diastereomers are identified as "+" or "-" along with the designation "diastereomer—1" or "diastereomer—2", or "single diastereomer" when only one isomer is isolated and/or available.
WO 2015/009616 PCT/US2014/046515 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.
Intermediate 1-1: Intermediate 1A; 5,7-dimethyInitrotosyI-1H-indole No2 / IN Ts 10 To a solution of methylnitro-1H-indole (CAS; 11903142, 10 g, 52.6 mmol) in DMF (200 mL) was added nwise NaH (3.2 g, 60% in mineral oil, 79 mmol) at 0 °C, and then the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 0 °C. To the red suspension was added TsCl (15.0 g, 79 mmol) at 0 °C, and then the mixture was stirred at room temperature for 22 h. At this point, the reaction was quenched with half saturated aq. KHSO4. 15 The mixture was diluted with H20, and then the whole mixture was d at room temperature for 1h. The ing solid was collected by filtration. The obtained brown solid was successively washed with H20, MeOH, and heptane. The solid was dried to give the title compound. MS (ESI+) m/z 345.1 (M+H).
Intermediate 1B; 5,7-dimethyItosyI-1H-indolamine NH2 / IN 20 Ts To a solution of 5,7-dimethylnitrotosyl-1H-indole , Intermediate 1A, (17 g, 49.4 mmol) in MeOH (50 mL)/EtOAc (300 mL) was added Zn (16.1 g, 247 mmol). The suspension was cooled down to 0 °C. To the suspension was added dropwise AcOH (30 mL) over 30 min, and then the mixture was stirred at 0 °C for 0.5 h. The flask was removed from the ice bath, and the mixture 25 left stirring at room temperature for 18.5 h. The reaction e was poured into a mixture of Celite®/5% aq. /EtOAc, and then the basic e was vigorously stirred for 0.5 h. The mixture was ed through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 5% aq. NaHCOs, H20, and brine, dried over NaZSO4, and then filtered. Concentration of the filtrate gave the title compound, 30 which was used without the need for r purification. MS (ESI+) m/z 315.1 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 1C; 4-iodo-5,7-dimethyltosy|-1H-indole l / ,N Ts To a suspension of 5,7-dimethyltosyl-1H-indolamine, Intermediate 1B, (7.70 g, 24.5 mmol) in H20 (80 OAc (150 mL) was added conc. aq. HCI (4.3 mL, 49.0 mmol) at 0 °C, and then the mixture was d at 0 °C. To the suspension was added dropwise a solution of NaN02 (2.0 g, 29.4 mmol) in H20 (20 mL) over 15 min while keeping the temperature below 5 oC.
Once the addition was complete, the mixture was stirred at 0 °C for 1h. To the mixture was added dropwise a solution of Kl (12.2 g, 73.5 mmol) in H20 (20 mL) over 15 min, and then the e was stirred at 0 °C for 1hr. The reaction was quenched with half saturated Na28203, and then the whole 10 mixture was stirred at room temperature for ca. 16h. The e was diluted with EtOAc, and then the layers were partitioned. The organic layer was successively washed with H20 and brine, dried over Na2804, and then filtered and concentrated. The resulting residue was purified by silica gel flash column tography [heptane/(30% EtOAc in CH2C|2) = 91/9 to 85/15)]. The resulting residue was triturated with EtZO, and then the solid was collected by filtration to give the title 15 compound. 1H NMR (400 MHz, DMSO-ds) 6 7.92 (d, J=3.80 Hz, 1H), 7.61 (d, J=8.60 Hz, 2H), 7.40 (dd, J=0.50, 8.60 Hz, 2H), 7.04 (s, 1H), 6.72 (d, J=3.79 Hz, 1H), 2.41 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H).
Intermediate 1-1; 5,7-dimethyltosy|-1H-indolecarbaldehyde H o / ,N Ts 20 To a solution of 4-iodo-5,7-dimethyltosyl-1H-indole, ediate 1C, (950 mg, 2.1 mmol) and DMF (0.33 mL, 4.2 mmol) in cyclopentyl methyl ether (22 mL), was added n-butyllithium in hexane (2.2 M, 1.3 mL, 2.8 mmol) at -78 °C. After stirring for 1 h, additional n-butyllithium in hexane (2.2 M, 0.19 mL, 0.42 mmol) was added. After stirring for 15 min, the reaction was quenched with MeOH (2 mL) and 1M aq. NaHSO4 (4.5 mL), and diluted with EtOAc and brine. The 25 layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaZSO4, filtered, and concentrated. The resulting e was purified by silica gel flash column tography [(10% CH2C|2/heptane)/(20%EtOAc/ CH2C|2) = 100/0 to 50/50] to afford the title compound. MS (ES|+) m/z 328.2 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 1-2: lntermediatelnt2-A; 5-bromomethyI-1H-indoIecarbonitrile N | | Br / N H To a suspension of 1 M vinylmagnesium e in THF (249 mL, 249 mmol) was added 2- bromomethylnitro-benzonitrile (15 g, 62.2 mmol) in THF (100 mL) dropwise while keeping the reaction temperature below -20 °C. After completion of the on, the mixture was placed at room temperature and stirred at for 1.5h. The reaction mixture was then cooled to below -20 °C and quenched with MeOH while maintaining the internal reaction temperature below 0 °C. To the mixture was added Celite®, and 5% aq. NaHCOs (50 mL). The mixture was diluted with CHZCIZ, 10 and filtered through a Si02 pad, which was rinsed with a mixture of CHZCIZ/EtOAc (ca. 1/1). The filtrate was trated to give the title compound, which was used in the next reaction without the need for further purification. MS (ESl-) m/z 233.1, 235.1. (M-H).
Intermediate 1B; 5-bromomethyItosyI-1H-indoIecarbonitrile N Br / Ts’ 15 To a suspension of 5-bromomethyl-1H-indolecarbonitrile, ediate 1A, (11.99 g, 51 mmol), TsCl (14.58 g, 77 mmol), and triethylbenzylammonium chloride (1.162 g, 5.10 mmol) in CHZCIZ (300 mL) was added NaOH (3.06 g, 77 mmol), and then the mixture was stirred at room temperature for 19h. The reaction mixture was quenched with H20, and the mixture was vigorously stirred for 1h. The mixture was further diluted with CHZCIZ and the mixture was successively 20 washed with H20 and brine, and the organic layer then dried over NaZSO4, filtered, and concentrated. The resulting e was triturated with MeOH and the solid was collected by filtration to afford the title compound, which was used in the next on without the need for further purification. MS (ESl-) m/z 387.2, 389.2. (M-H).
Intermediate 1C; 5-bromomethyltosy|-1H-indolecarbaldehyde H 0 Br ‘2 25 WO 2015/009616 PCT/US2014/046515 To a solution of 5-bromomethyltosyl-1H-indolecarbonitrile, Intermediate 1B, (10 g, 25.7 mmol) in toluene (500 mL) at -78 °C was added 1 M DIBAL-H (38.5 mL, 38.5 mmol) in toluene over 10 min. The mixture was then stirred at -78 °C for ca. 75 minutes. The reaction was then quenched with MeOH at -78 °C. To the mixture was then added 5 N aq. HCI (100 mL), and the on mixture was then placed at room temperature for 2 h at which time an excess of solid Na+/K+ te (Rochelle’s Salt) was added followed by H20 (100 mL). The mixture was then vigorously stirred at room temperature for ca. 3h and then diluted with EtOAc. The mixture was filtered h a plug of Celite®, and the filtrate was ioned. The organic phase was successively washed with 5% aq. NaHC03, H20, and brine, dried over Na2804, filtered, and 10 concentrated to furnish the title compound without the need for further purification. MS (ES|+) m/z 392.0; 394.0 (M+H).
Intermediate 1D; 5-bromomethyl-1H-indolecarbaldehyde H 0 Br / N H To a solution of 5-bromomethyltosyl-1H-indolecarbaldehyde, Intermediate 1C, 15 (6.5 g, 16.57 mmol) in 1,4-dioxane (50 mL)/H20 (5 mL) was added KOH (2 g, 35.6 mmol). The mixture was stirred at 100 °C for ca. 3 h. The reaction mixture was then diluted with CH2C|2, and the mixture was washed with H20 and brine, and the c layer dried over , filtered, and concentrated to furnish the title compound t the need for further purification. MS (ESl-) m/z 235.9, 238.0 (M-H). 20 Intermediate 1E; tert-butyl 5-bromoformylmethyl-1H-indolecarboxylate H 0 Br / N / Boc To a solution of 5-bromomethyl-1H-indolecarbaldehyde, Intermediate 1D, (3.6 g, 15.12 mmol) in CH3CN was added Boc20 (7.02 mL, 30.2 mmol), followed by DMAP (0.185 g, 1.512 mmol). The mixture was stirred at room ature for ca. 1h. Then the reaction was quenched 25 with H20. The whole mixture was vigorously stirred for 0.5h. The mixture was then diluted with CH2C|2. The organic phase was then washed successively with H20 and brine, dried over Na2804, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography ne/30% EtOAc in CH2C|2= 85/15] to give the title compound. MS (ESI+) m/z 338.0, 340.0 (M+H)+.
WO 2015/009616 PCT/US2014/046515 ediate 1-2; tert-butyl 5-cyclopropylformylmethyl-1H-indolecarboxylate H o / N I Boc To a suspension of tert—butyl 5-bromo—4-formylmethyl-1H-indolecarboxylate, Intermediate 1E, (9.5 g, 14.05 mmol) in toluene (50 mL)/H20 (20 mL) at room temperature was added Cs2C03 (27.5 g, 84 mmol), ium cyclopropyltetrafluoroborate (4.16 g, 28.1 mmol), and s (CAS: 7876188) (2.62 g, 5.62 mmol), ed by )2 (0.631 g, 2.81 mmol).
The whole mixture was then stirred at 100 °C for 2 h. The reaction mixture was cooled down to room temperature and diluted with CH2C|2. The organic layer was washed successively with H20 and brine, dried over NaZSO4, filtered and concentrated. The resulting residue was ed by 10 silica gel flash column chromatography [heptane/(30% EtOAc in CH2C|2) =82/18]. The resulting solid was triturated with heptane to furnish the title compound. MS (ES|+) m/z 300.3 (M+H)+.
Intermediate 1-3: Intermediate 1A; tert-butyl 5-methoxymethyl-1H-indolecarboxy|ate O\ / l‘ Boc 15 To a on of 5-methoxymethyl-1H-indole (CAS: 610194, 9.69 g, 60.1 mmol) in CH2C|2 (200 mL) at room ature was added Boc20 (19.54 mi, 84 mmol), DMAP (0.734 g, 6.01 mmol), and Et3N (10.05 mi, 72.1 mmol). The mixture was then stirred for 16h. The reaction was diluted with CH2C|2 and saturated NH4CI. The aqueous phase was extracted three times with CH2C|2. The organic phase was washed with brine, dried over NaZSO4, filtered, and concentrated. 20 The resulting residue was purified by silica gel flash column chromatography (EtOAc/heptanes) to provide the title compound. MS (ESI+) m/z 262.2 (M+H).
Intermediate 1-3; tert-butyl 4-formylmethoxymethy|-1H-indolecarboxylate H o \ / N / Boc To a solution of N-methylformanilide (10.49 mi, 85 mmol) in CH2C|2 (68 mL) at room 25 temperature was added oxalyl chloride (7.44 ml, 85 mmol) dropwise over 30 min. The mixture was then stirred for 16h at room temperature. The mixture was then added dropwise over 45 min to a on of tert—butyl 5-methoxymethyl-1H-indole—1-carboxylate, Intermediate 1A, (16.99 g, 65 mmol) in CH2C|2 (70 mL) at -14 °C. The resulting mixture was stirred for 1.5h at -14 °C. The WO 2015/009616 PCT/US2014/046515 on was quenched with ice water and then extracted three times with CH2C|2. The organic phase was then washed with brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (EtOAc/heptanes) to provide the title compound. MS (ES|+) m/z 290.1 (M+H).
Intermediate 1-4: Intermediate 1A; (2-chloromethylnitrophenyl)methanol CI To a solution of 2-chloromethylnitrobenzoic acid (CAS; 1015805, 15 g, 69.6 mmol) and triethylamine (11.1 mL, 80 mmol) in THF (200 mL) was added 1,1,1-trichloromethylpropan- 10 2-yl carbonochloridate (19.2 g, 80 mmol) at 0 °C, and then the mixture was d at 0 °C for 1hr.
The resulting white solid was filtered off through a plug of Celite®, which was rinsed with THF (20 mL). To the filtrate was added NaBH4 (3.2 g, 83 mmol) at 0 °C, followed by H20 (50 mL). The mixture was stirred at 0 °C for 0.5h, and then stirred at room temperature for 1.25h. The reaction was quenched by half satd. aq. KHSO4. The layers were separated and the aqueous layer was 15 ted with CH2C|2. The combined organic layers were washed successively with H20 and brine, dried over , and then filtered h a plug of SiOz, which was rinsed with EtOAc.
The residue was concentrated and then triturated with e. The resulting solid was collected by filtration to give the title compound. 1H NMR (400 MHz, CD3CN) 6 8.11 (s, 1H), 7.47 (s, 1H), 4.68 (s, 2H), 2.53 (s, 3H). 20 Intermediate 1B; 2-((2-chloromethylnitrobenzyl)oxy)tetrahydro-2H-pyran CI To a solution of (2-ch|oromethylnitrophenyl)methanol, Intermediate 1A, (23 g, 114 mmol) and 3,4-dihydro-2H—pyran (20.9 mL, 228 mmol) in CH2C|2 (500 mL) was added nium p- toluenesulfonate (5.7 g, 22.8 mmol), and then the mixture was stirred at room temperature for 11h. 25 The reaction was quenched with 5% aq. NaHC03. The layers were separated and the aqueous layer was extracted with CH2C|2. The combined organic layers were washed successively with H20 and brine, dried over NaZSO4, ed and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 96/4) to give the title compound. 1H NMR (400 MHz, CD3CN) 5 8.10 (s, 1H), 7.49 (s, 1H), 4.81 (d, J=13.64 Hz, 1H), 4.72 - 4.78 (m, 1H), 30 4.59 (d, J=13.64 Hz, 1H), 3.77 - 3.92 (m, 1H), 3.34 - 3.60 (m, 1H), 2.54 (s, 3H), 1.68 - 1.91 (m, 2H), 1.43 - 1.68 (m, 4H).
WO 2015/009616 PCT/US2014/046515 _ 78 _ Intermediate 1C; 5-chloromethyl(((tetrahydro-2H-pyranyl)oxy)methyI)-1H-indole 9 Cl / N H To a suspension of vinylmagnesium bromide (1M in THF, 200 mL, 200 mmol) was added dropwise 2-((2-chloromethylnitrobenzyl)oxy)tetrahydro-2H-pyran, Intermediate 1B, (14 g, 49.0 mmol) in THF (40 mL) below -20 °C. After completion of the on, the flask was removed from the ice bath. The mixture was then stirred at room temperature. After 2h, the reaction mixture was cooled to below -20 °C. The reaction was quenched with MeOH while maintaining the temperature below 0 °C. The mixture was diluted with CH2C|2 and H20. The e was filtered through a plug of Celite®, which was rinsed with CH2C|2. The layers were separated and the 10 organic phase was washed with H20 and brine, dried over NaZSO4, and then filtered.
Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. For the terization e, the product was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2C|2)] = 69/31] to afford the title compound. 1H NMR (400 MHz, CD3CN) 6 9.43 (br. s., 1H), 7.29 - 7.36 (m, 1H), 6.99 (s, 1H), 6.58 - 15 6.70 (m, 1H), 5.05 (d, J=11.12 Hz, 1H), 4.84 (d, J=11.10 Hz, 1H), 4.67 - 4.77 (m, 1H), 3.89 - 4.03 (m, 1H), 3.46 - 3.60 (m, 1H), 2.47 (s, 3H), 1.59 - 1.75 (m, 2H), 1.43 - 1.59 (m, 4H).
Intermediate 1D; 5-chloromethyl(((tetrahydro-2H-pyranyl)oxy)methyI)tosyI-1H- indole © 0 Cl / IN Ts 20 To a solution of 5-chloromethyl(((tetrahydro-2H—pyranyl)oxy)methyl)—1H-indole, lntermediate1C, (8.95 g, 32 mmol) in CH2C|2 (150 mL), at 0 °C was added NaOH (2.56 g, 64.0 mmol), followed by triethylbenzylammonium chloride (0.729 g, 3.20 mmol) and TsCl (12.20 g, 64.0 mmol). The mixture was then stirred at room temperature. After 17h, additional NaOH (1.28 g, 32.0 mmol), and TsCl (6.10 g, 32.0 mmol) were added. The mixture was stirred at room 25 temperature for 1.5h. The on mixture was diluted with H20, and was vigorously stirred for 1h.
The mixture was diluted with CH2C|2 and the organic layer was successively washed with H20 and WO 2015/009616 PCT/US2014/046515 _ 7g _ brine, dried over NaZSO4, filtered, and then trated. The resulting residue was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2C|2) = 82/18 then 79/21] to give the title compound. 1H NMR (400 MHz, CD3CN) 6 7.84 (d, J=3.79 Hz, 1H), 7.67 (d, J=8.20 Hz, 1H), 7.59 (d, J=8.59 Hz, 1H), 7.48 (d, J=8.20 Hz, 1H), 7.33 (d, J=8.50 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J=3.79 Hz, 1H), 4.97 (d, J=11.37 Hz, 1H), 4.76 (d, J=11.37 Hz, 1H), 4.61 - 4.70 (m, 1H), 3.79 - 3.91 (m, 1H), 3.40 - 3.52 (m, 1H), 2.53 (s, 3H), 2.36 (s, 3H), 1.58 - 1.75 (m, 2H), 1.38 - 1.58 (m, 4H). ediate 1E; (5-chloromethyItosyI-1H-indoIyl)methanol OH Cl / ,N Ts 10 A solution of 5-chloromethyl(((tetrahydro-2H-pyranyl)oxy)methy|)tosyl-1H-indole, lntermediate1D, (4.1 g, 9.5 mmol) and TsOH H20 (359 mg, 1.9 mmol) in EtOH (50 mL) was stirred at room ature for 21h. The reaction mixture was concentrated. The mixture was diluted with CH2C|2. The organic phase was successively washed with 5% aq. , H20 and brine, dried over Na2804, and then filtered. Concentration of the filtrate gave the title compound 15 without the need for further purification. 1H NMR (400 MHz, CD3CN) 6 7.84 (d, J=3.79 Hz, 1H), 7.59 (d, J=8.34 Hz, 2H), 7.33 (d, J=8.34 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J=3.79 Hz, 1H), 4.84 (d, J=5.81 Hz, 2H), 3.14 (t, J=5.81 Hz, 1H), 2.52 (s, 3H), 2.37 (s, 3H).
Intermediate 1-4; 5-chloromethyltosy|-1H-indolecarbaldehyde H 0 Cl / IN Ts 20 To a solution of (5-chloromethyltosyl-1H-indoly|)methano|, Intermediate 1E, (3.3 g, 9.5 mmol) and N-ethyl-diisopropylamine (8.3 mL, 47.3 mmol) in CH2C|2 (20 mL)/DMSO (1 mL) was added SOgPy (4.5 g, 28.4 mmol) at 0 °C. The mixture was d at 0 °C for 2.5h, and then stirred at room temperature for 15h. The reaction was quenched by MeOH. The mixture was stirred for 1h. The mixture was partially concentrated. The mixture was diluted with H20, and then 25 the resulting solid was collected by filtration. The resulting residue was triturated with MeOH to give the title compound. 1H NMR (400 MHz, CD3CN) 6 10.56 (s, 1H), 8.00 (d, J=3.80 Hz, 1H), 7.62 (d, J=3.80 Hz, 1H), 7.60 (d, J=8.60 Hz, 2H), 7.35 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 2.60 (s, 3H), 2.37 (s, 3H).
WO 2015/009616 2014/046515 _ 80 _ Intermediate 1-5: Intermediate 1A; 5,7-dimethyl-1H-indolecarbaldehyde H o / N H To a solution of 5,7-dimethyltosyl-1H-indolecarbaldehyde, ediate 1-1, (2 g, 6.11 mmol) in THF (6 mL) was added TBAF in THF (12 mL, 12 mmol). The mixture was then stirred at 60 °C for 4h, and then cooled to room temperature. The e was then diluted with EtOAc. The organic phase was then washed successively with H20 (twice), and brine, dried over NaZSO4, filtered, and concentrated to afford the title compound, which was used in the next reaction without the need for further purification. MS (ESI+) m/z 174.3 (M+H). 10 Intermediate 1-5; tert-butyl 4-formyl-5,7-dimethyl-1H-indolecarboxy|ate H o / N I Boc The title compound was synthesized from 5,7-dimethyI-1H-indoIecarbaldehyde, Intermediate 1A, analogously to the preparation of Intermediate 1E. MS (ESI+) m/z 274.4 (M+H). 15 Intermediate 1-6: Intermediate 1A; (5,7-dimethyItosyI-1H-indoIyl)methano| OH / I" Ts To a solution of methyItosyI-1H-indoIecarbaldehyde, Intermediate 1-1, (3 g, 9.16 mmol) in THF (50 mL)/MeOH (50 mL) at room temperature was added NaBH4 (1 g, 26.4 20 mmol). The mixture was then stirred at room temperature for 1.5h, and then quenched with half satd. aq. KHSO4. The mixture was then extracted with EtOAc/TFE (ca. 9/1). The organic layer was then washed successively with H20, and brine, dried over NaZSO4, and then concentrated to furnish the title compound without the need for further purification. MS (ESl-) m/z 328.2 (M-H), (ESI+) m/z 312.3 (M-OH).
WO 2015/009616 PCT/US2014/046515 _ 81 _ ediate 1-6; oromethyI)-5,7-dimethyltosyI-1H-indole CI / IN Ts To a solution of (5,7-dimethyltosyl-1H-indolyl)methanol, Intermediate 1A, (3 g, 9.11 mmol) in CH2C|2 (80 mL) at room temperature was added N-(chloromethylene)—N- methylmethanaminium chloride (CAS: 37244, 2 g, 15.62 mmol). The mixture was then stirred at room temperature for 0.75h, and then was cooled to 0 °C. The reaction was then quenched with 5% aq. NaHCOs at 0 oC. The mixture was then extracted with EtOAc/CHZCIZ. The organic layer was washed successively with 0.2M aq. LiCI, and brine, dried over NaZSO4, and then concentrated.
The resulting residue was triturated with EtZO, and then the resulting solid was collected by filtration 10 to afford the title compound. MS (ESI+) m/z 312.4 (M-Cl)+.
Intermediate 1-7: tert-Butyl 4-(chloromethyl)-5,7-dimethyl-1H-indolecarboxylate CI / N I Boc The title nd was synthesized from terf-butyl 4-formyl-5,7-dimethyl-1H-indole 15 carboxylate, Intermediate 1-5, ously to the preparation of Intermediate 1-6. 1H NMR (400 MHz, CD2C|2) 5 7.50 (d, J=3.79 Hz, 1H), 6.87 (s, 1H), 6.56 (d, J=3.79 Hz, 1H), 4.80 (s, 2H), 2.49 (s, 3H), 2.36 (s, 3H), 1.54 (s, 9H).
Intermediate 1-8: tert-Butyl 4-(chloromethyl)cyc|opropylmethy|-1H-indolecarboxylate CI / N I 20 Boc The title compound was synthesized from terf-butyl 5-cyclopropylformylmethyl-1H- indoIecarboxylate, Intermediate 1-2, analogously to the preparation of Intermediate 1-6. 1H NMR (400 MHz, CD3CN) 6 7.63 (d, J=3.79 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J=3.80 Hz, 1H), 5.13 (s, 2H), 2.53 (d, J=0.76 Hz, 3H), 2.11 - 2.16 (m, 1H), 1.60 (s, 9H), 0.93 - 1.03 (m, 2H), 0.67 - 0.74 (m, 25 2H).
WO 2015/009616 PCT/US2014/046515 _ 82 _ Intermediate 1-9: 5-Ch|oro(chIoromethyI)methyltosyI-1H-indole Cl Cl / IN Ts The title compound was sized from (5-chloromethyltosyl-1H-indolyl)methanol, Intermediate 1E, analogously to the preparation of Intermediate 1-6. 1H NMR (400 MHz, CD3CN) 6 7.92 (d, J=3.79 Hz, 1H), 7.59 (d, J=8.60 Hz, 2H), 7.33 (d, J=8.60 Hz, 2H), 7.14 (s, 1H), 6.95 (d, J=3.79 Hz, 1H), 2.51 (s, 3H), 2.36 (s, 3H). ediate 1-10 tert-Butyl 4-(hydroxymethyl)methoxymethyl-1H-indolecarboxylate OH O\ / IN 10 Boc To a solution of tert—butyl 4-formylmethoxymethyl-1H-indolecarboxylate, lntermediate1-3, (1 g, 3.46 mmol) in MeOH (10 mL) at 0 °C was added NaBH4 (0.3 g, 7.93 mmol).
The mixture was then stirred at 0 °C for 5h. The reaction mixture was diluted with H20. The mixture was then extracted twice with EtZO. The organic layer was washed successively with H20, 15 and brine, dried over NaZSO4, and then concentrated to afford the title compound, which was used in the next reaction without the needs of further purification. 1H NMR (400 MHz, CDscN) 6 7.57 (d, J=3.79 Hz, 1H), 6.82 (s, 1H), 6.68 (d, J=3.79 Hz, 1H), 4.72 - 4.77 (m, 2H), 3.84 (s, 3H), 2.56 (s, 3H), 1.60 (s, 9H).
Intermediate 2-1: 20 ediate 2A; (i)-tert-butyl 4-hydroxyphenylpiperidinecarboxy|ate (diastereomeric e) Boc\ OH diastereomeric_ . mixture To a solution of tert—butyl 4-oxophenylpiperidinecarboxylate (CAS: 8499289, 500 mg, 1.816 mmol) in THF (10 mL) at -78 °C was added L-Selectride® (2.2 mL, 2.2 mmol). The 25 mixture was then stirred at -78 °C for ca. 1.75h. The reaction was then quenched with 7N NH3 in MeOH at -78 °C, and then stirred at -78 °C for 5min. To the mixture was then added satd. aq.
NH4CI, and then stirred at room temperature for 1.5h. The e was then extracted with EtOAc.
WO 2015/009616 2014/046515 _ 83 _ The organic layer was washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column tography [heptane/(30% EtOAc in CHZCIZ) = 82/18] to afford the title compound as a diastereomeric mixture, which was used in the next reaction without the need for further purification. MS (ES|+) m/z 278.4 (M+H).
Intermediate 2-1; (i)phenylpiperidinol (diastereomeric mixture) HN OH diastereomeric. . mixture A mixture of (i)—ten‘-butyl oxyphenylpiperidinecarboxylate (diastereomeric mixture), Intermediate 2A, (200 mg, 0.721 mmol) in 4M HCI in dioxane (2 mL) was stirred at 10 room temperature for 1h. The mixture was concentrated to afford a HCI salt of the title compound as a diastereomeric mixture, which was used in the next reaction without the need for further purification. MS (ESl-) m/z 211.1 (M-H).
Intermediate 2-2: Intermediate 2A; (i)-tert-butyl 4-methoxyphenylpiperidinecarboxylate ereomeric 15 mixture) 0 diastereomeric. . mixture To a solution of (i)—ten‘-butyl 4-hydroxyphenylpiperidine—1-carboxylate (diastereomeric mixture), Intermediate 2A, (220 mg, 0.793 mmol) and Mel (100 uL, 1.6 mmol) in DMF (3 mL) at 0 °C was added NaH (70 mg, 1.750 mmol). The mixture was then stirred at 0 °C for 3h, and then 20 quenched with satd. aq. KHSO4. The e was then stirred at the same temperature for 5min.
The mixture was then extracted with EtZO. The organic layer was washed sively with H20, and brine, dried over NaZSO4, ed, and concentrated to afford the title compound as a diastereomeric mixture, which was used in the next reaction without the need for further purification. MS (ES|+) m/z 292.4 (M+H). 25 Intermediate 2-2; (i)methoxyphenylpiperidine (diastereomeric mixture) HN / 0 reomeric mixture WO 2015/009616 2014/046515 The title compound was synthesized from (i)—ten‘-butyl 4-methoxyphenylpiperidine carboxylate (diastereomeric mixture), Intermediate 2A, analogously to the preparation of Intermediate 2-1. MS (ES|+) m/z 192.3 (M+H).
Intermediate 2-3: Intermediate 2A; rt-butyl 4-(cyanomethylene)pheny|piperidinecarboxy|ate To a solution of l cyanomethylphosphonate (1.2 g, 6.77 mmol) in THF (10 mL) at 0 °C was added NaH (60% in oil, 0.27 g, 6.75 mmol). The mixture was then stirred at 0 °C for ca. 1h.
The resulted suspension was diluted with THF (25 mL). To the suspension 0 °C was added a 10 solution of tert—butyl 4-oxo—2-phenylpiperidinecarboxylate (CAS: 9, 1.2 g, 4.36 mmol) in THF (10 mL). The mixture was then d at room temperature for 2h. The reaction was then quenched with satd. aq. KHSO4. The mixture was then extracted with EtZO. The organic layer was washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by SiOZ flash column tography (heptane/EtOAc = 78/22) to 15 afford the title compound as a e of isomers. MS (ES|+) m/z 299.7 (M+H).
Intermediate 2B; (i)-tert-butyl 4-(cyanomethyl)phenylpiperidinecarboxy|ate (diastereomer—1) and (i)-tert-butyl 4-(cyanomethyl)phenylpiperidinecarboxy|ate (diastereomer—2) o" a" diastereomer-1 diastereomer-2 20 A suspension of (i)—ten‘-butyl 4-(cyanomethylene)—2-phenylpiperidinecarboxylate, Intermediate 2A, (1 g, 3.35 mmol) and Pd/C (5%) (300 mg, 3.35 mmol) in MeOH (20 mL) was stirred at room temperature under H2 atmosphere for 15.5h. The H2 gas was replaced with N2. The catalyst was removed by filtration h a plug of Celite®, which was rinsed with MeOH. The filtrate was concentrated. The resulting residue was purified by silica gel flash column 25 chromatography (heptane/EtOAc = 80/20) to afford in respective elution order (i)—tert—buty| 4- (cyanomethyl)pheny|piperidinecarboxylate (diastereomer—1) and (i)—ten‘-butyl 4- (cyanomethyl)pheny|piperidinecarboxylate (diastereomer—2).
WO 09616 PCT/US2014/046515 (diastereomer—1); 1H NMR (400 MHz, CD3CN) 6 7.34 - 7.39 (m, 2H), 7.19 - 7.28 (m, 3H), 5.48 (br. s., 1H), 4.08 (d, J=13.39 Hz, 1H), 2.74 (br. dd, J=12.10, 12.60 Hz, 1H), 2.40 - 2.48 (m, 1H), 2.36 (d, J=6.10 Hz, 2H), 1.56 - 1.82 (m, 3H), 1.43 (br. s., 9H), 1.18 - 1.26 (m, 1H). (diastereomer—2); 1H NMR (400 MHz, CD3CN) 6 7.29 - 7.35 (m, 2H), 7.19 - 7.26 (m, 3H), 4.85 (dd, J=5.94, 9.73 Hz, 1H), 3.90 - 3.97 (m, 1H), 3.25 - 3.34 (m, 1H), 2.23 - 2.35 (m, 2H), 1.96 - 2.10 (m, 2H), 1.66 - 1.77 (m, 1H), 1.34 - 1.43 (m, 1H), 1.26 (s, 9H), 0.78 - 0.91 (m, 1H).
Intermediate 2-3; (i)(2-phenylpiperidinyl)acetonitriIe (diastereomer—1) HN //N diastereomer-1 The title compound was prepared from (i)—ten‘-butyl 4-(cyanomethyl)—2-phenylpiperidine 10 carboxylate (diastereomer—1), Intermediate 2B, analogously to the preparation of Intermediate 2-1. MS (ESI+) m/z 201.3 (M+H).
Intermediate 2-4: (i)-(2-(2-Pheny|piperidiny|)acetonitri|e (diastereomer—2) HN //N diastereomer-2 15 The title compound was synthesized from (i)—ten‘-butyl 4-(cyanomethyl)—2-phenylpiperidine- 1-carboxylate (diastereomer—2), ediate 2B, analogously to the preparation of Intermediate 2-1. MS (ESI+) m/z 201.2 (M+H).
Intermediate 2-5: Intermediate 2A; (i)-tert-butyl 4-((tert-butylsulfinyl)imino)phenylpiperidine 20 carboxylate >LOJLNo 9 \NflsK A mixture of (i)—ten‘-buty| 4-oxophenylpiperidinecarboxylate (CAS: 8499289, 1 g, 3.63 mmol) and (i)—2-methylpropanesulfinamide (0.6 g, 4.95 mmol) in Zr(O-tBu)4 in toluene (15 mL, 7.50 mmol) was stirred at 100 °C for 1.75h. The reaction mixture was cooled to room 25 temperature, and diluted with . To the mixture was then added Celite®, followed by 5% aq.
NaHC03. The e was stirred for 0.25h, and then filtered through a plug of Celite®. The filtrate was then extracted with . The organic phase was then successively washed with 5% aq.
NaHC03, H20, and brine, dried over NaZSO4, filtered, and trated to afford the title compound, WO 2015/009616 PCT/US2014/046515 which was used in the next reaction without the needs of further purification. MS (ESI+) m/z 379.4 (M+H).
Intermediate 2B; (i)-tert-butyl 4-(1,1-dimethylethylsulfinamido)phenylpiperidine carboxylate A O OJLN 9 3 "MN/ H K diastereomeric mixture To a solution of n‘-butyl 4-((tert-butylsulfinyl)imino)—2-phenylpiperidinecarboxylate, Intermediate 2A, (600 mg, 1.585 mmol) in MeOH (15 mL) at 0 °C was added NaBH4 (600 mg, 15.86 mmol). The mixture was then stirred at room temperature for ca. 1h, and then diluted with H20. The mixture was then extracted with EtOAc. The organic phase was sively washed 10 with 5% aq. NaHCOs, H20, and brine, dried over NaZSO4, ed, and concentrated to afford the title compounds as a diastereomeric mixture, which was used in the next reaction t the need for further purification. MS (ESI+) m/z 381.4 (M+H).
Intermediate 2C; (i)-tert-butyl 4-aminophenylpiperidinecarboxy|ate H2 diastereomeric. . mixtu re 15 A solution of (i)—ten‘-butyl 4-(1,1-dimethylethylsulfinamido)—2-phenylpiperidinecarboxylate, Intermediate 2B, (60 mg, 1.579 mmol) in 0.5M HCI in MeOH (20 mL) was stirred at room temperature for 0.5h, and then quenched with 5% aq. NaHCOs. The mixture was then extracted with CHZCIZ, and then was successively washed with 5% aq. Nchog, H20, and brine, dried over NaZSO4, filtered, and concentrated to afford the title compounds as a diastereomeric mixture, which 20 was used in the next reaction without the need for further cation. MS (ESI+) m/z 277.4 (M+H).
Intermediate 2D; (i)-tert-butyl 4-(((benzy|oxy)carbonyl)amino)—2-phenylpiperidine ylate (diastereomer—1) and (i)-tert-butyl 4-(((benzy|oxy)carbonyl)amino) phenylpiperidinecarboxy|ate (diastereomer—2) RANO O N,CbZ N,Cbz H H diastereomer-1 diastereomer-2 25 To a suspension of (i)—ten‘-butyl 4-aminophenylpiperidinecarboxylate, Intermediate 2- 5-C, (434 mg, 1.57 mmol) in CHZCIZ (10 mL)/5% aq. NaHCOs (10 mL) was added Cbz-CI (500 uL, WO 09616 PCT/US2014/046515 3.50 mmol). The mixture was then stirred at room temperature for 0.5h. The reaction was quenched with N,N-dimethylethylenediamine (0.25 mL). The mixture was then stirred at room temperature for 0.5h. The e was then extracted with EtOAc. The organic phase was then washed successively with H20, 1M HCIaq, H20, 5% aq. NaHC03, and brine, dried over NaZSO4, filtered, and concentrated. The ing residue was purified by silica gel flash column chromatography [heptane/(10% MeOH in EtOAc) = 74/26] to afford in respective elution order (i)- tert—butyl 4-(((benzyloxy)carbonyl)amino)phenylpiperidinecarboxylate (diastereomer—1) and (i)—ten‘-butyl 4-(((benzyloxy)carbonyl)amino)phenylpiperidinecarboxylate (diastereomer—2). (diastereomer—1); 1H NMR (400 MHz, CD3CN) 5 7.17 - 7.41 (m, 10H), 5.61 (br. d, J=6.10 Hz, 1H), 10 5.49 (br. s., 1H), 5.02 (s, 2H), 4.06 (br. d, J=13.40 Hz, 1H), 3.41 - 3.53 (m, 1H), 2.75 (br. dd, J=12.90, 13.10 Hz, 1H), 2.60 (br. d, J=13.10 Hz, 1H), 1.71 - 1.79 (m, 1H), 1.60 -1.71 (m, 1H), 1.43 (s, 9H), 1.28 - 1.40 (m, 1H). (diastereomer—2); 1H NMR (400 MHz, CD3CN) 5 7.10 - 7.46 (m, 10H), 5.01 - 5.17 (m, 2H), 4.92 (s, 2H), 3.89 - 4.00 (m, 1H), 3.72 - 3.82 (m, 1H), 3.21 - 3.32 (m, 1H), 2.19 - 2.30 (m, 1H), 2.04 - 2.11 15 (m, 1H), 1.95 - 2.01 (m, 1H), 1.50 - 1.59 (m, 1H), 1.32 (s, 9H).
Intermediate 2-5; (i)-benzyl (2-phenylpiperidinyl)carbamate (diastereomer—1) HN Cbz H diastereomer—1 The title compound was synthesized from (i)—tert—butyl 4-(((benzyloxy)carbonyl)amino) phenylpiperidinecarboxylate (diastereomer—1), ediate 2D, analogously to the 20 preparation of Intermediate 2-1. MS (ES|+) m/z 311.4 (M+H).
Intermediate 2-6: (i)-Benzyl (2-phenylpiperidinyl)carbamate (diastereomer—2) HN ,Cbz N H diastereomer-Z The title compound was synthesized from (i)—tert—butyl enzyloxy)carbonyl)amino) 25 phenylpiperidinecarboxylate (diastereomer—2), Intermediate 2D, analogously to the preparation of Intermediate 2-1. MS (ES|+) m/z 311.4 (M+H).
WO 2015/009616 PCT/US2014/046515 _ 88 _ ediate 2-7: Intermediate 2A; (i)-tert-buty| 4-methylenephenylpiperidinecarboxy|ate >l\OJLO N To a solution of methyl triphenylphosphonium bromide (5 g, 14 mmol) in THF (30 mL) at -78 0C was added n-BuLi (2.5 M, 5.5 mL, 13.75 mmol). The mixture was then stirred at -78 °C for 5 min, and then stirred at 0 0C for 0.5h. To the mixture at -78 °C was then added a solution of (i)- terf—butyl 4-oxophenylpiperidinecarboxylate (2 g, 7.26 mmol) in THF (10 mL). The mixture was stirred at room temperature for 15h, and then stirred at 40 °C for 3h. The reaction was quenched with MeOH (10 mL), and then d with EtZO. The mixture was then filtered through a 10 plug of Celite®, which was rinsed with EtZO. The filtrate was concentrated. The resulting residue was purified by silica gel flash column chromatography ne/EtOAc = 81/19) to afford the title compound. MS (ES|+) m/z 274.4 (M+H). ediate 2B; rt-butyl 4-(hydroxymethyI)phenylpiperidinecarboxylate (diastereomer—1) and (i)-tert-buty| 4-(hydroxymethy|)pheny|piperidinecarboxy|ate 15 (diastereomer—2) >|\OJLNO XOJLNO OH OH diastereomer-1 diastereomer-2 A mixture of (i)—ten‘-butyl ylenephenylpiperidinecarboxylate, Intermediate 2 A, (580 mg, 2.122 mmol) and 9—BBN in THF (12 mL, 6 mmol) was stirred at room temperature for 2.75h. The mixture was then cooled to 0 °C. To the e was then added H202 (1 mL, 32.6 20 mmol) dropwise. The mixture was then stirred at 0 °C for 0.5h. The mixture was then diluted with EtOAc. The mixture was then washed successively with H20, aq. Na28203, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting e was purified by silica gel flash column chromatography (heptane/EtOAc = 68/32) to afford, in respective elution order, (i)—ten‘-buty| 4-(hydroxymethyl)—2-phenylpiperidinecarboxylate (diastereomer—1) and (i)—tert—butyl 4- 25 (hydroxymethyl)pheny|piperidinecarboxylate (diastereomer—2). (diastereomer—1); 1H NMR (400 MHz, CD3CN) 6 7.32 - 7.38 (m, 2H), 7.18 - 7.26 (m, 3H), 5.44 (br. s., 1H), 4.24 - 4.37 (m, 1H), 4.05 (br. d, J=12.60 Hz, 1H), 3.27 - 3.34 (m, 1H), 2.67 - 2.80 (m, 1H), 2.38 (br. d, J=10.90 Hz, 1H), 1.47 - 1.85 (m, 18H),1.41 (br.s,12H),1.02 - 1.15 (m, 1H).
WO 2015/009616 PCT/US2014/046515 (diastereomer—2); 1H NMR (400 MHz, CD3CN) 6 7.26 - 7.35 (m, 2H), 7.14 - 7.26 (m, 3H), 4.78 (dd, J=6.06, 10.36 Hz, 1H), 3.88 - 3.98 (m, 1H), 3.28 - 3.37 (m, 1H), 3.18 - 3.27 (m, 2H), 2.58 (t, J=5.43 Hz,1H), 1.97 - 2.06 (m, 1H), 1.69 - 1.89 (m, 2H), 1.49 - 1.61 (m, 1H), 1.28 - 1.39 (m, 1H), 1.26 (s, 9H).
Intermediate 2-7; (i)-(2-phenylpiperidinyl)methanol (diastereomer—1) HN OH diastereomer-1 The title compound was synthesized from (i)—tert—butyl 4-(hydroxymethyl)—2- phenylpiperidinecarboxylate (diastereomer—1), Intermediate 2B, analogously to the preparation of Intermediate 2-1. MS (ES|+) m/z 192.3 (M+H). 10 Intermediate 2-8: (i)-(2-Phenylpiperidinyl)methano| (diastereomer—2) HN OH diastereomer-2 The title nd was synthesized from (i)—ten‘-butyl 4-(hydroxymethyl)—2- piperidinecarboxylate (diastereomer—2), Intermediate 2B, analogously to the 15 preparation of Intermediate 2-1. MS (ES|+) m/z 192.3 (M+H).
Intermediate 2-9: Intermediate 2A; (i)-tert-butyl 2-(3-sulfamoylphenyl)piperidinecarboxy|ate and (i)-tert- butyl ulfamoylphenyl)piperidinecarboxy|ate Q9 ,8 N H N2 N A J< "2" A J< o o ’/S\ O O \ O o 20 At 0 °C, chlorosulfonic acid (0.536 mL, 8.00 mmol) was added dropwise to (i) phenylpiperidine (0.322 g, 2 mmol). The reaction mixture was stirred at 60 °C for 0.5h. The reaction mixture was then cooled to 0 °C. To the mixture was then added dropwise 7N NH3 in MeOH (30 mL) at 0 °C. The mixture was then stirred at room temperature for 1 h, and then concentrated. The resulting residue was suspended in CH3CN (20 mL). To the e were 25 added Boc20 (1.393 mL, 6.00 mmol) and DMAP (200 mg, 1.64 mmol). The mixture was stirred at 60 0C for 3 hr, and then concentrated. The resulting residue was then dissolved in H20, and extracted twice with EtOAc. The combined organic layers were dried over , ed and concentrated. The resulting e was purified by silica gel flash column chromatography WO 2015/009616 PCT/US2014/046515 _ go _ (heptane/EtOAc = 1/0 to 2/8) to afford the title compounds as a mixture of regioisomers, which was used in the next on without the need for further purification. MS (ESl-) m/z 339.4 (M-H).
Intermediate 2-9; (i)(piperidinyl)benzenesulfonamide and (i)(piperidin yl)benzenesu|fonamide HZN N H2N\ H o’ ‘b The title compounds (a mixture of regioisomer) were prepared from a mixture of (i)—tert— butyl ulfamoylphenyl)piperidinecarboxylate and (i)—tert—butyl 2-(3- sulfamoylphenyl)piperidinecarboxylate, Intermediate 2A, analogously to the ation of Intermediate 2-1. MS (ESI+) m/z 241.3 (M+H). 10 Intermediate 2-10: (i)-N-methyI(piperidinyl)benzenesulfonamide and (i)-N-methyl(piperidin yl)benzenesu|fonamide 0. ,9 H IZ N N H H / \ ’/ o "o The title compounds (as a e of somers) were synthesized analogously to the 15 preparation of ediate 2-9 by using 33% MeNH2 in EtOH in the place of 7N ammonia in MeOH. MS (ESI+) m/z 255.3 (M+H).
Intermediate 2-11: Intermediate 2A; (i)-phenyl 2-(4-fluorophenyl)oxo-3,4-dihydropyridine-1(2H)- carboxylate OYN / 20 Go To a solution of4-methoxypyridine (1.1 g, 10 mmol) in THF (20 mL) at -40 °C was added 4- fluorophenylmagnesium bromide in THF (1M, 11 mL, 11 mmol), followed by phenyl chloroformate (1.566 g, 10.00 mmol) in THF (10 mL) dropwise. The mixture was then stirred at the same temperature for 0.25h, and then stirred at room temperature for_ca. 15h. The reaction was then 25 quenched with 10% HCI (30 mL), and the whole mixture was stirred for 0.5h. The reaction is diluted with brine and EtOAc, and the organic layer was then separated. The aqueous layer was WO 2015/009616 PCT/US2014/046515 extracted three times with EtOAc. The combined organic layers were washed with sat. aq.
NaHC03, and dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 1/1) to afford the title nd.
MS (ES|+) m/z 277.4 (M+H).
Intermediate 2B; (i)-phenyl 2-(4-f|uorophenyl)oxopiperidinecarboxylate F o N Go A solution of (i)—phenyl 2-(4-fluorophenyl)—4-oxo-3,4-dihydropyridine-1(2H)-carboxylate, Intermediate 2A, (1.090 g, 3.5 mmol) in MeOH (150 mL) was hydrogenated over 10% Pd/C cartridge at 10 bar in an H-cube®. The reaction mixture was concentrated to afford the title 10 compound, which was used in the next on without the need for further purification. MS (ES|+) m/z 314.3 (M+H). ediate ; (i)-phenyl 2-(4-f|uorophenyl)—4-hydroxypiperidinecarboxylate F OH O N Y go single diastereomer To a solution of (i)—phenyl 2—(4-fluorophenyl)—4-oxopiperidinecarboxy|ate, Intermediate 15 , (1.1 g, 3.51 mmol) in MeOH (20 mL) at room temperature, NaBH4 (0.266 g, 7.02 mmol) was added. The reaction mixture was stirred at r.t. for 0.5h, and then quenched with sat. aq. NH4CI.
The mixture was partially concentrated. The resulting residue was then diluted with brine, and then extracted with EtOAc. The s layer was extracted twice with EtOAc. The combined organic layers were dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by 20 silica gel flash column chromatography (heptane/EtOAc = 1/0 to 4/6) to afford the title compound.
MS (ESI+) m/z 316.4 (M+H).
Intermediate 2D; (i)-phenyl 2-(4-f|uorophenyl)—4-methoxypiperidinecarboxylate F O N GO single diastereomer WO 2015/009616 PCT/US2014/046515 _ 92 _ To a solution of (i)—phenyl 2-(4-fluorophenyl)hydroxypiperidinecarboxylate, Intermediate 2C, (1.37 g, 4.34 mmol) in DMF (20 mL), was added NaH (0.261 g, 6.52 mmol).
The reaction mixture was then stirred for 0.25h at room temperature. To the mixture was then added methyl iodide (0.407 mL, 6.52 mmol). The mixture was stirred at room temperature for 1.5h, 5 and then quenched with satd. aq. NH4CI. The on mixture was extracted with EtOAc. The organic layer was then concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 6/4) to afford the title compound as a single diastereomer. 1H NMR (400 MHz, CD2C|2) 6 7.30 - 7.37 (m, 4H), 7.16 - 7.21 (m, 1H), 7.00 - 7.08 (m, 4H), 5.33 - 5.38 (m, 1H), 4.10 - 4.18 (m, 1H), 3.60 - 3.66 (m, 1H), 3.44 (ddd, J=4.04, 12.22, 13.42 Hz, 1H), 10 3.11 (s, 3H), 2.39 - 2.46 (m, 1H), 2.12 - 2.20 (m, 1H), 1.81 - 1.98 (m, 2H); MS (ES|+) m/z 330.4 (M+H).
Intermediate 2-11; (i)(4-fluorophenyl)methoxypiperidine F 0\ HN single diastereomer_ To a solution of phenyl 2-(4-fluorophenyl)methoxypiperidinecarboxylate, Intermediate 15 2D, (290 mg, 0.88 mmol) in iPrOH (4 mL), KOH (400 mg) was added. The on is heated to 100 0C for 2 hr, and then cooled to room temperature. The reaction mixture was diluted with H20.
The mixture was extracted four times with EtOAc. The combined organic layers were dried over , filtered, and concentrated to afford the title compound, which was used in the next reaction without the need for further purification. MS (ES|+) m/z 210.3 (M+H). 20 Intermediate 2-12: Intermediate ; (i)-benzyl 2-(4-cyanophenyI)oxo-3,4-dihydropyridine-1(2H)- carboxylate Cbz\ N// To a solution of 4-bromobenzonitrile (17 g, 93 mmol) in THF (50 mL) at room temperature 25 was added isopropylmagnesium chloride lithium de complex solution (1.3M in THF, 70 mL, 91 mmol) dropwise over 0.25h. The mixture was then stirred at room temperature for 2h. The mixture was diluted with THF (300 mL), and then cooled to -5 °C. To the mixture was then added 4- methoxypyridine (8.37 mL, 82 mmol), followed by Cbz—Cl (12 mL, 84 mmol) while in the internal temperature below 0 °C. The mixture was then stirred at 0 °C for 1.5h, and then stirred at 30 room ature for 16h. The reaction was then quenched with 5M aq. HCl. The mixture was WO 2015/009616 PCT/US2014/046515 then stirred at room temperature for 0.5h. The mixture was then diluted with EtOAc. The mixture was then washed with H20 twice, 5% aq. NaHCOs, and brine, dried over NaZSO4. The extract was then ed through a plug of silica gel, which was rinsed with EtOAc. The filtrate was trated. The resulting residue was then triturated with EtZO (ca. 100 mL). The resulted solid was collected by filtration to give the title compound. MS (ESI+) m/z 333.3 (M+H).
Intermediate 2B; (i)-benzyl 2-(4-cyanophenyI)oxopiperidinecarboxylate A suspension of nzyl 2-(4-cyanophenyl)oxo-3,4-dihydropyridine-1(2H)—carboxylate, Intermediate 2A, (13 g, 39.1 mmol) and zinc (5 g, 76 mmol) in AcOH (50 mL) was d at 10 100 °C for 1h. The reaction mixture was cooled to room temperature. The mixture was filtered through a plug of Celite®, which was rinsed with EtZO. The filtrate was diluted with EtZO. The EtZO layer was then washed successively with H20, 5% aq. NaHCOs (twice), H20 (twice), and brine, dried over , ed, and concentrated to furnish the title compound t the need for further purification. MS (ESI+) m/z 335.3 (M+H). 15 Intermediate 2C; (i)-benzyl 2-(4-cyanophenyl)hydroxypiperidinecarboxylate (diastereomeric mixture) Cbzt OH // diastereomeric N mixtu re To a solution of (i)—benzyl 2-(4-cyanophenyl)—4-oxopiperidinecarboxylate, Intermediate 2B, (8 g, 23.93 mmol) in THF (100 mL) at room temperature was added LiBH4 in THF (20 mL, 20 40.0 mmol) dropwise. The mixture was then stirred at room temperature for 0.5h. The reaction was then quenched with half satd. aq. KHSO4. The mixture was then extracted with EtOAc. The organic phase was then washed with brine, dried over NaZSO4, filtered, and concentrated to afford the title compounds as a diastereomeric mixture, which was used in the next reaction without the need for further purification. MS (ESI+) m/z 337.3 (M+H).
WO 2015/009616 PCT/US2014/046515 _ g4 _ Intermediate ; (i)-reI-(2S,4S)-benzyl 4-((tert-butyldiphenylsilyl)oxy)(4- cyanophenyl)piperidinecarboxylate and (i)-reI-(2S,4R)-benzyl 4-((tertbutyldiphenylsiIyl 2-(4-cyanophenyl)piperidinecarboxylate CbZ‘N CbZ‘N O/TBDPS O/TBDPS / / N / rel-(28,48) N / rel-(28,4R) To a solution of (i)—benzyl 2-(4-cyanophenyl)—4-hydroxypiperidinecarboxylate (diastereomeric mixture), Intermediate 2C, (8.04 g, 23.9 mmol) in DMF (40 mL) at room temperature were added imidazole (5 g, 73.4 mmol) and TBDPS—CI (8.5 mL, 33.1 mmol). The mixture was then stirred at room temperature for 20.5h. The reaction was then ed with MeOH. The mixture was then ted with EtOAc. The organic phase was then washed 10 successively with H20, 5% aq. NaHC03, and brine, dried over , ed, and concentrated.
The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 86/14) to afford in the respective elution order (i)—rel—(2S,4S)—benzyl 4-((ten‘-butyldiphenylsilyl)oxy)— 2-(4-cyanophenyl)piperidinecarboxylate and (i)—re/—(2S,4R)—benzyl 4-((tert— butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate. 15 (i)—rel—(2S,4S)—Benzyl 4-((ten‘-butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate; 1H NMR (400 MHz, CD3CN) 6 7.62 - 7.67 (m, 2H), 7.57 - 7.62 (m, 2H), 7.27 - 7.53 (m, 13H), 6.79 - 6.83 (m, 2H), 5.43 (br. d, J=4.50 Hz, 1H), 5.06 - 5.15 (m, 2H), 4.04 - 4.12 (m, 1H), 3.54 - 3.63 (m, 1H), 2.60 (dt, J=3.03, 13.64 Hz, 1H), 2.23 - 2.30 (m, 1H), 1.79 - 1.89 (m, 2H), 1.59 (ddt, J=5.05, 10.48, 12.82 Hz, 1H), 1.01 (s, 9H). 20 (i)—re/—(2S,4R)—Benzyl 4-((ten‘-butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate; 1H NMR (400 MHz, CD3CN) 6 7.60 - 7.64 (m, 2H), 7.22 - 7.47 (m, 17H), 5.37 (br. d, J=6.60 Hz, 1H), 5.02 - 5.12 (m, 2H), 4.16 - 4.21 (m, 1H), 3.99 - 4.06 (m, 1H), 3.49 (dt, J=3.03, 13.14 Hz, 1H), 2.34 - 2.41 (m, 1H), 2.01 - 2.08 (m, 1H), 1.47 - 1.56 (m, 1H), 1.35 - 1.41 (m, 1H), 0.73 (s, 9H).
Intermediate 2E; (i)-reI-(2S,4S)-benzyl 2-(4-cyanophenyl)hydroxypiperidine 25 carboxylate N\\ OH ,N Cbz rel-(28,48) To a solution of TBAF in THF (1 M, 20 mL, 20 mmol) was added (i)—rel—(2S,4S)—benzyl 4- ((terf—butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate, Intermediate 2D, (3.5 30 g, 6.09 mmol). The mixture was then stirred at room temperature for 1.5h, and then diluted with WO 2015/009616 PCT/US2014/046515 _ g5 _ EtZO. The mixture was then washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated to give the title compound. 1H NMR (400 MHz, CD30N) 6 7.64 - 7.73 (m, 2H), 7.37 - 7.42 (m, 2H), 7.28 - 7.36 (m, 5H), 5.57 (br. d, J=5.00 Hz, 1H), 5.09 - 5.18 (m, 2H), 4.12 - 4.19 (m, 1H), 3.45 - 3.55 (m, 1H), 2.89 (d, J=4.52 Hz, 1H), 2.82 (dt, J=3.06, 13.51 Hz, 1H), 2.45 - 2.53 (m, 1H), 1.71 - 1.84 (m, 2H), 1.31 - 1.44 (m, 1H).
Intermediate ; (i)-reI-(2S,4S)-benzyl 2-(4-cyanophenyl)methoxypiperidine carboxylate N\\ 0\ Cbz’N rel-(28,48) The title compound was sized from l—(2S,4S)—benzyl 2-(4-cyanophenyl)—4- 10 hydroxypiperidinecarboxy|ate, Intermediate 2E, analogously to the preparation of Intermediate 2A. MS (ESI+) m/z 351.4 (M+H).
Intermediate 2G; (i)(reI-(2S,4S)((benzy|oxy)carbonyl)—4-methoxypiperidin yl)benzoic acid HO 0\ Cbz’N rel-(28,48) 15 A mixture of l—(2S,4S)—benzyl yanophenyl)methoxypiperidinecarboxylate, Intermediate 2F, (9 g, 14.38 mmol) and Ba(OH)2 hydrate (16 g, 57.3 mmol) in iPrOH/HZO (15 mL/50 mL) was stirred at 80 °C for 15h, and then 100 °C for 8h. The reaction mixture was cooled to room temperature. The precipitate was filtered off through a plug of Celite®. The filtrate was then acidified by 5M aq. HCI (by pH ca. 3). The mixture was then extracted with EtOAc. The 20 organic layer was washed successively with H20 twice, and brine, dried over NaZSO4, filtered, and concentrated to afford the title compound. MS (ESI+) m/z 370.3 (M+H).
Intermediate 2H; (i)-reI-(2S,4S)-benzyl oxy(4- (methoxycarbonyl)phenyl)piperidinecarboxy|ate O \o 0\ Cbz’N rel-(28,48) 25 To a solution of (i)—4-(re/—(2S,4S)—1-((benzy|oxy)carbony|)methoxypiperidiny|)benzoic acid, Intermediate 2G, (10 g, 15.16 mmol) in MeOH (15 mL) was added HCI in MeOH, which WO 2015/009616 PCT/US2014/046515 was prepared by addition of SOCIZ (6 mL, 82 mmol) in MeOH (15 mL). The mixture was then stirred at 40 °C for 1.75h. The reaction mixture was then diluted with CHZCIZ. The organic phase was then washed successively with 5% aq. NaHCOs (twice), H20, and brine, dried over NaZSO4, ed, and concentrated. The resulting e was purified by silica gel flash column chromatography (heptane/EtOAc = 68/32) to afford the title nd. MS (ES|+) m/z 384.3 (M+H).
Intermediate 2-12; (i)-methyl 4-(reI-(ZS,4S)methoxypiperidinyl)benzoate O \o 0\ HN rel-(28,48) A mixture of rel-(2S,4S)—benzyl methoxy(4-(methoxycarbonyl)phenyl)piperidine 10 carboxylate, Intermediate 2H, (6 g, 15.65 mmol) and Pd/C (5%) (19, 15.65 mmol) in MeOH (30 mL) was stirred at room temperature under H2 atmosphere for 2h. The H2 gas was replaced with N2. The catalyst was then removed by tion through a plug of ®, which was rinsed with MeOH. The filtrate was then concentrated to afford the title compound. MS (ES|+) m/z 250.3 (M+H). 15 Intermediate 2-12b; (+)-methy| 4-(((2$,4S)methoxypiperidinyl))benzoate and (-)-methyl 4- (((2R,4R)methoxypiperidinyl))benzoate \o \o HN (28,48) HN (2R,4R) Resolution of the enantiomers of (i)—methyl 4-(rel-(2S,4S)—(4-methoxypiperidin yl))benzoate, Intermediate 2-12, was achieved by chiral SFC using a CHIRALPAK® AS—H column 20 with 5% (MeOH with 5mM NH4OH) in 002 to give (+)—methyl 4-((2S,4S)—4-methoxypiperidin yl)benzoate (peak 1, tr = 2.8 min) and (-)-methyl 4-((2R,4R)—4-methoxypiperidinyl)benzoate (peak 2, tr = 4.1 min). Absolute chemistry of (+)—methyl 4-((2S,4S)—4-methoxypiperidin yl)benzoate was confirmed by X—ray single crystal ction.
Intermediate 2-13: 25 Intermediate 2A; (-)-(2$,4S)-benzyl 2-(4-cyanophenyl)hydroxypiperidinecarboxylate N\\\©,,,, N\\ OH "\OH Cbz (28, 4S) Cbz (2R, 4R) WO 2015/009616 PCT/US2014/046515 _ g7 _ Resolution of the enantiomers of (i)—rel—(2S,4S)—benzyl 2-(4-cyanophenyl)—4- hydroxypiperidinecarboxy|ate, Intermediate 2E, was achieved by chiral SFC using a CHIRALPAK® AD-H column with 25% (MeOH with 5mM NH4OH) in 002 to give (+)—(2R,4R)—benzyl 2-(4-cyanophenyl)—4-hydroxypiperidinecarboxylate (peak-1, tr = 2.8 min) and (-)-(2S,4S)—benzyl 2-(4-cyanophenyl)—4-hydroxypiperidinecarboxylate (peak-2, tr = 4.5 min).
Intermediate 2B; (28,4S)-benzy| 2-(4-cyanophenyl)ethoxypiperidinecarboxy|ate NQ\© CbZ’UQS,0\/48) To a solution of (-)—(2S,4S)—benzyl 2-(4-cyanophenyl)—4-hydroxypiperidinecarboxylate, Intermediate 2A, (2 g, 5.95 mmol) in DMF (20 mL) at 0 °C was added Etl (1 mL, 12.37 mmol), 10 followed by NaH (60% in oil, 400 mg, 10 mmol). The mixture was then stirred at 15 °C for 1.5h.
The reaction was quenched with MeOH. The mixture was then stirred for 0.25h. The mixture was then diluted with half satd. aq. KHSO4, and then extracted with EtOAc. The organic phase was then washed successively with H20, 0.5M aq. LiCI, and brine, dried over NaZSO4, filtered, and concentrated to furnish the title compound without further purification. MS (ESI+) m/z 365.3 (M+H). 15 ediate ; 4-((2$,4S)((benzyloxy)carbonyI)ethoxypiperidinyl)benzoic acid 0 HO I," 0V CbZ (28,48) A suspension of (2S,4S)—benzyl 2-(4-cyanophenyl)—4-ethoxypiperidinecarboxylate, ediate 2B, (2.17 g, 5.95 mmol) and Ba(OH)2 hexahydrate (6 g, 21.5 mmol) in iPrOH/HZO (15 mL/40 mL) was stirred at 100 °C for 20h, and then cooled to room temperature. 20 The reaction mixture was then acidified with half satd. aq. KHSO4. The mixture was then extracted with EtOAc. The organic layer was washed successively with H20 twice, and brine, dried over NaZSO4, ed, and concentrated to furnish the title compound t further purification. MS (ES|+) m/z 384.3 (M+H). ediate 2D; (28,4S)-benzyl 4-ethoxy(4-(methoxycarbonyl)phenyl)piperidine 25 carboxylate WO 2015/009616 2014/046515 _ 98 _ To a solution of 4-((28,4S)—1-((benzyloxy)carbonyl)ethoxypiperidinyl)benzoic acid, Intermediate 2C (1.0 g, 2.68 mmol) in toluene (10 mL)/MeOH (3 mL) was added TMSCHN2 in EtZO (3 mL, 6 mmol) dropwise. The mixture was then stirred at room temperature for 0.5h. The reaction was then ed with AcOH. The mixture was then diluted with EtOAc. The organic phase was then washed successively with 5% aq. NaHCOs twice, H20, brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 66/34) to afford the title compound. MS (ES|+) m/z 398.3 (M+H).
Intermediate 2-13a; methyl 4-((2$,4S)ethoxypiperidinyl)benzoate: \o "U0v 10 (23,43) A mixture of (28,4S)-benzyl xy-2—(4-(methoxycarbonyl)phenyl)piperidine carboxylate, Intermediate 2D, (1.8 g, 4.53 mmol) and Pd/C (5%) (200 mg, 4.53 mmol) in MeOH (20 mL) was stirred at room temperature under H2 atmosphere for 5h. The H2 gas was replaced to N2. The catalyst was then removed by filtration h a plug of Celite®, which was 15 rinsed with MeOH. The filtrate was then trated to furnish the title compound without further purification. MS (ESI+) m/z 264.3 (M+H).
Intermediate 2-13b; (i)-methyl 4-(reI-(ZS,4S)ethoxypiperidinyl)benzoate O \o 0v "N rel-(28,48) The title compound was synthesized from l—(28,4S)—benzyl 2—(4-cyanophenyl)—4- 20 hydroxypiperidinecarboxy|ate, Intermediate 2E, by following methods sequence described in the synthesis of Intermediate 2B, Intermediate 2C,and then Intermediate 2D. ical data; same as Intermediate 2-13.
Intermediate 2-14: Intermediate 2A; (i)-benzyl 2-(4-cyanophenyl)hydroxymethylpiperidine 25 carboxylate ereomeric mixture) N\\ OH Cbz WO 2015/009616 PCT/US2014/046515 _ gg _ To a mixture of CeCI3 (516 mg, 2.093 mmol) and THF (10 mL) at 0°C was added MeMgBr (3 M in EtZO) (0.698 ml, 2.093 mmol). The mixture was then stirred at the same temperature for 3h.
To the mixture at 0°C was then added a solution of (i)—benzyl 2-(4-cyanophenyl)oxopiperidine carboxylate, Intermediate 2B, (500 mg, 1.495 mmol) in THF (6 mL). The mixture was then stirred at room temperature for ca. 16h, and then quenched with satd. aq. NH4C| with 10% citric acid. The mixture was then extracted two times with EtOAc. The combined organic layers were then washed with brine, dried over Na204, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 0/1) to afford the title compound as a single diasteremer, which was used in the next on without the need for further 10 purification. MS (ES|+) m/z 351.0 (M+H).
Intermediate 2B; (i)-benzyl 2-(4-cyanophenyl)methoxymethylpiperidine ylate (single diastereomer) N\\ / o ,N single Cbz diastereomer The title compound was synthesized from (i)—benzyl 2-(4-cyanophenyl)hydroxy 15 methylpiperidinecarboxylate (single reomer), Intermediate 2A, (70mg, 0.200 mmol) ously to the preparation of ediate 2A. The product was characterized as follow; 1H NMR (400MHz, CD3CN) 6 7.65 (d, J=8.4 Hz, 2H), 7.39 - 7.35 (m, 3H), 7.35 - 7.24 (m, 4H), 5.38 (d, J=6.2 Hz, 1H), 5.14 - 5.08 (m, 2H), 4.10 (app. ddd, J=2.5, 5.0, 13.4 Hz, 1H), 3.33 (app. dt, J=3.1, 13.2 Hz, 1H), 2.64 (s, 3H), 2.41 (app. td, J=2.3, 14.6 Hz, 1H), 1.54 (app. dt, J=5.0, 13.4 Hz, 1H), 20 1.32 - 1.30 (m, 1H), 1.13 (s, 3H), 0.93 - 0.89 (m, 1H).
Intermediate 2-14; (i)(4-methoxymethylpiperidinyl)benzonitriIe (single diastereomer) N\\ HN single diastereomer.
The title compound was synthesized from nzyl 2-(4-cyanophenyl)methoxy methylpiperidinecarboxy|ate (single diastereomer), Intermediate 2B, analogously to the 25 preparation of Intermediate 2-12. MS (ES|+) m/z 231.0 (M+H).
Following ediates were ed from appropriate starting materials by similar methods described above.
WO 2015/009616 PCT/US2014/046515 lnterme chemical name MS (ESI+) structure diate starting al (m/z) (i)—4-(rel—(2 4-hyd roxypiperidin-2— yl) benzonitrile 203.3 OH (M+H) rel-(28, 4S) Intermediate 2E (i)—4-(rel—(2 S,4R)—4-hyd roxypiperidin-2— yl) benzonitrile OH /—(28,4S)—isomer in rel-(2S, 4R) ediate 2D (i)—4-(rel—(2S,4S)—4-methoxypiperidin yl) benzonitrile \ rel-(28,48) Intermediate 2F (i)—4-(rel—(2S,4R)—4-methoxypiperidin-Z- yl) benzonitrile 0\ (i)—re/—(28,4S)—isomer in rel-(28,4R) Intermediate 2D (i)—4-(rel—(2 S,4S)—4-eth oxypiperidin-Z- yl) benzonitrile 0v rel-(28, 4S) Intermediate 2E methyl 4-((28,4S)—4-propoxypiperidin-2— yl)benzoate (28,4S)-isomer in Intermediate 2A methyl 4-((28,4S)—4-hydroxypiperidin yl) benzoate (28,4S)-isomer in Intermediate 2A WO 2015/009616 PCT/US2014/046515 Intermediate 2-16: Intermediate 2A; methyl 4-(4-methylpyridinyl)benzoate O \o / N\ To a sion of 2-chloromethylpyridine (5 g, 39.2 mmol) and (4- (methoxycarbonyl)phenyl)boronic acid (8 g, 44.5 mmol) in toluene (50 mL) was added 2M aq.
Na2C03 (30 mL) followed by PdC|2(dppf).CH2C|2 adduct (4 g, 4.90 mmol). The whole mixture was then stirred at 100 °C for 17h, and then cooled to room temperature. The reaction e was then diluted with EtZO, and then ted. The organic layer was dried over NaZSO4, ed, and concentrated. The resulting residue was purified by silica gel flash column chromatography 10 (heptane/EtOAc = 76/24) to afford the title compound. MS (ESI+) m/z 228.1 (M+H).
Intermediate 2-16; (i)-methyl 4-(reI-(2S,4R)methylpiperidinyl)benzoate HN rel-(28, 4R) A e of methyl 4—(4umethylpyriclin~2~yl)benzoate. Intermediate 2A, (3 g, 13.20 15 mmol) and Pt02 (500 mg, 13.20 mmol) in MeOH (50 mL)/1M HCI in MeOH (2 mL) was stirred at room temperature under H2 atmosphere (50 psi) for 20 h. The H2 gas was replaced with N2. The catalyst was filtered through a plug of Celite®, which was rinsed with MeOH and concentrated. The resulting residue was then dissolved in CH2C|2, and then washed with 5% aq. NaHCOs and brine, dried over Na2804, filtered, and then concentrated. The resulting residue was purified by silica gel 20 flash column chromatography (0.5% Et3N in CH2C|2/MeOH = 1/0 to 95/5) to afford the title nd isolated as a single diastereomer. 1H NMR (400 MHz, CDgOD) 6 7.98 (d, J=8.30 Hz, 2H), 7.47 (d, J=8.30 Hz, 2H), 3.89 (s, 3H), 3.69-3.75 (m, 1H), 3.14 - 3.21 (m, 1H), 2.74 - 2.83 (m, 1H), 1.80 - 1.87 (m, 1H), 1.64 - 1.76 (m, 2H), 1.12 - 1.27 (m, 2H), 0.98 (d, J=6.36 Hz, 3H), MS (ESI+) m/z 234.3 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 2-17: Intermediate 2A; methyl 2-methoxy(pyridinyl)benzoate O O A mixture of methyl omethoxybenzoate (1 g, 4.07 mmol), 2- 5 (tributylstanny|)pyridine (1.84 g, 5.01 mmol), Cul (155 mg, 0.81 mmol), and Pd(PPh3)4 (235 mg, 0.203 mmol) in DMF (8 mL) was stirred at 80 °C for 2h, and then concentrated. The resulting residue was purified by silica gel flash column tography (heptane/EtOAc = 8/2) to afford the title compound. MS (APC|+) m/z 244.1 (M+H).
Intermediate 2-17; (i)-methyl 2-methoxy(piperidinyl)benzoate oo/ \o 10 HN The title compound was synthesized form methyl 2-methoxy(pyridiny|)benzoate, Intermediate 2A, analogously to the preparation of Intermediate 2-16. ) 250.2 (M+H).
Following intermediates were prepared from appropriate starting materials by similar 15 methods described above. chemical name IntermedIate_ structure + starting materials (i)—methy| 3-methyI(piperidinyl) benzoate (APCH) 234.0 methyl 4-bromomethylbenzoate (M+H) and 2-(tributylstanny|)pyridine (i)—methy| 4-(5-methylpiperidinyl) benzoate (single diastereomer) (APCH) —234.0 (4-(methoxycarbonyl)pheny|)boronic acid (M+H) and o—5-methylpyridine thy| 4-(re/-(2S,4R)—4- 0 ethylpiperidiny|)benzoate o—4-ethylpyridine and HN (4-(methoxycarbonyl)pheny|)boronic acid rel-(28.4R) WO 2015/009616 PCT/US2014/046515 (i)—methyl 2-(4-(piperidinyl)phenyl) acetate (APC|+) 234.1 2-bromopyridine and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2- (M+H) dioxaborolanyl)phenyl)acetate (i)—methyl 2-(3-(piperidinyl)phenyl) o acetate (APC|+) w \0 234'0 2-bromopyridine and "N methyl 2-(3-(4,4,5,5-tetramethyl-1,3,2- (M+H) orolanyl)phenyl)acetate (i)—methyl 4-(piperidinyl)—1- 0 na hthoate \O 9—(APC|+) 26 O opyridine and 270-1 0 methyl 4-(4,4,5,5-tetramethyl-1,3,2- (M+H) HN dioxaborolanyl)—1-naphthoate Intermediate 2-19: Intermediate 2A; tert-butyl (5-(4-(methylthio)phenyl)oxopentyl)carbamate s o o / W11K 0 To a on of tert—butyl 2-oxopiperidinecarboxylate (CAS: 85908~96—9, 4.98 g, 25 mmol) in THF (75 mL) at -78 °C under nitrogen, was added 0.5N (4-(methylthio)phenyl)magnesium e in THF (50 mL, 25 mmol) slowly over 10 min. The mixture was stirred at -78 °C for 0.5h, and then the reaction was quenched with MeOH and half satd. aq. KHSO4. The mixture was then ted with EtOAc. The organic layer was concentrated. The resulting residue was purified by 10 silica gel flash column chromatography (heptane/EtOAc = 1/0 to 6/4) to afford the title compound.
MS (ESl-) m/z 322.3 (M-H).
Intermediate 2B; 5-amino(4-(methy|thio)phenyl)pentanone /S NH2 0 The title compound was prepared from tert—butyl (5-(4-(methylthio)pheny|) 15 oxopentyl)carbamate, Intermediate , analogously to the preparation of Intermediate 2-1.
MS (ES|+) m/z 224.2 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 2C; (i)(4-(methylthio)phenyl)piperidine /S HN To the suspension of 5-amino(4-(methylthio)phenyl)pentanone, Intermediate 2B, (3.9 g, 15 mmol) in toluene (50 mL), Ti(O-iPr)4 (12.79 mL, 45.0 mmol) was added slowly. The e was stirred at r.t. for 15 min, then heated at 85 0C for 2.5 hr, and then cooled to 0 °C. To the mixture was then added a suspension of NaBH4 (2.27 g, 60 mmol) in MeOH (50 mL) dropwise.
After completion of the addition, to the mixture was successively added H20, CH2C|2, and Celite®.
The mixture was then filtered through a plug of ®, which was rinsed with CH2C|2. The organic layer was then separated. The aqueous layer was then extracted twice with . The 10 combined organic layers were dried over NaZSO4, filtered, and concentration to furnish the title compound without the need for further purification. MS (ES|+) m/z 208.3 (M+H).
Intermediate 2D; (i)-tert-butyl 2-(4-(methylthio)phenyl)piperidinecarboxylate /S 01,; To a solution of (i)—2-(4-(methylthio)phenyl)piperidine, Intermediate 2C, (3 g, 14.47 15 mmol) in acetonitrile (30 mL), Boc20 (4.03 mL, 17.36 mmol) and DMAP (0.088 g, 0.723 mmol) were added. The reaction mixture was stirred at 45 0C for 0.5h, and then concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 4/6) to afford the title compound. MS (ESI+) m/z 308.4 (M+H).
Intermediate 2E; (i)-tert-butyl 2-(4-(methylsuIfonyl)phenyl)piperidinecarboxylate o o \\ I/ /S O N E 20 To a solution of (i)—ten‘-butyl 2-(4-(methylthio)phenyl)piperidinecarboxylate, Intermediate , (307 mg, 1 mmol) in EtOH (5 mL) at 0 0C was added a e of um molybdate tetrahydrate (371 mg, 0.300 mmol) and 50% H202 in H20 (1.4 mL) slowly. The mixture was then stirred at room temperature during over ca. 72h. The reaction mixture was then d with H20 25 and CH2C|2, and then quenched with Na28203. The e was partitioned. The aqueous layer WO 09616 PCT/US2014/046515 was extracted with CHZCIZ. The combined organic layers were dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 0/1) to afford the title compound. MS (ESI+) m/z 340.4 (M+H).
Intermediate 2-19; (i)(4-(methylsuIfonyl)phenyl)piperidine o o \\ I/ /S HN The title compound was prepared from (i)—ten‘-butyl 2-(4-(methylsulfonyl)phenyl)piperidine- 1-carboxylate, Intermediate 2E, analogously to the preparation of Intermediate 2-1. MS (ESI+) m/z 240.3 (M+H).
Intermediate 2-20: 10 Intermediate 2A; (i)((tert-butyldiphenylsiIyl)oxy)piperidinone In TBDPS o 0’ To a solution of (i)—4-hydroxypiperidinone (7.5 g, 65.1 mmol) in DMF (60 mL) at room temperature were added ole (6 g, 88 mmol) and TBDPS—Cl (22 mL, 86 mmol). The mixture was then stirred at room temperature for 1.25h. The e was then diluted with H20. The 15 mixture was then extracted with EtOAc. The organic phase was then washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated to give the title compound, which was used in the next on without the need for further purification. MS (ES|+) m/z 354.3 (M+H).
Intermediate 2B; (i)-tert-butyl 4-((tert-butyldiphenylsi|y|)oxy)oxopiperidine ylate OX 0%O 20 O,TBDPS To a solution of (i)—4-((ten‘-butyldiphenylsilyl)oxy)piperidinone, Intermediate 2A, (23 g, 65 mmol) in CHZCIZ (30 mL) at room ature were added Boc20 (21.28 mL, 92 mmol) and Et3N (13 mL, 94 mmol), followed by DMAP (0.2 g, 1.637 mmol). The mixture was then stirred at room temperature for 7h. The reaction was then ed with H20. The mixture was then 25 extracted with CHZCIZ. The organic phase was then washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was ed by silica gel column chromatography (heptane/EtOAc = 77/23) to afford the title compound. MS (ESI+) m/z 454.4 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 2C; (i)-tert-butyl (3-((tert-butyldiphenylsilyl)oxy)(6-chloropyridinyl) oxopentyl)carbamate To a solution of 2—chloro—5-iodopyridine (14 g, 58.5 mmol) in THF (50 mL) at 0 °C was added isopropylmagnesium chloride lithium de complex in THF (1.3 M, 45 mL, 58.5 mmol).
The mixture was then stirred at 0 °C for 1h. To a on of (i)—ten‘-butyl n‘- butyldiphenylsilyl)oxy)—2—oxopiperidinecarboxylate, Intermediate , (20 g, 44.1 mmol) in THF (100 mL) at -78 °C was added the mixture above over 15 min. The mixture was then stirred at -78 °C for 10min. The mixture was then warmed to 0 °C, and then stirred for 1h. The reaction was 10 ed with MeOH, followed by half satd. aq. KHSO4. The mixture was warmed to room temperature. The mixture was then extracted with EtOAc. The organic layer was then washed successively with 5% aq. NaHCOs and brine, dried over NaZSO4, filtered, and concentrated to give the title compound, which was used in the next reaction without the need for further purification.
MS (ESI+) m/z 567.2, 569.19 (M+H). 15 Intermediate 2D; (i)(rel-(2$,4R)((tert-butyldiphenylsiIyl)oxy)piperidinyI) chloropyridine / l TBDPS N\ O "N rel-(28,4R) To a solution of (i)—ten‘-butyl (3-((ten‘-butyldiphenylsilyl)oxy)—5-(6-chloropyridinyl)—5- oxopentyl)carbamate, Intermediate 2C, (25 g, 44.1 mmol) in CHZCIZ (200 mL) at 0 °C was 20 added 2,6-lutidine (10 mL, 86 mmol), followed by TMSOTf (15 mL, 83 mmol). The mixture was then stirred at 0 °C for 2h. To the mixture was added an additional amount of 2,6-lutidine (6 mL, 51.5 mmol), followed by TMSOTf (6 mL, 33.2 mmol). The mixture was then stirred at 0 °C for 1h.
The reaction at 0 °C was then quenched with MeOH (50 mL). The mixture was then stirred at the same temperature for 0.25h. To the mixture was then added NaBH4 (3g, 79 mmol). The mixture 25 was then stirred at 0 °C for 1h. The reaction was then diluted with H20. The mixture was then ted with CHZCIZ. The aqueous layer was ted with CHZCIZ. The ed organic layers were then dried over NaZSO4, filtered, and concentrated to give the title compound as a single diastereomer, which was used in the next reaction without the need for further purification.
MS (ESI+) m/z 451.1, 453.1 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 2E; (i)-reI-(2S,4R)-benzyl 4-((tert-butyldiphenylsiIyl)oxy)(6-chloropyridin- 3-y|)piperidinecarboxy|ate CI / | TBDPS N \ O ,N Cbz rel-(28,4R) To a solution of (i)—5-(re/—(2S,4R)—4-((terf—butyldiphenylsilyl)oxy)piperidinyl)—2- chloropyridine, Intermediate 2D, (19.85 g, 44 mmol) in CH2C|2 (100 mL) at 0 °C was added Et3N (10 mL, 72.1 mmol), followed by Cbz—Cl (10 mL, 70.0 mmol) over 0.25h. The mixture was then stirred at 0 °C for 2h. The on was then quenched with 1M NH4OH. The mixture was then stirred at room temperature for 0.5h and d with CH2C|2. The organic phase was then washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated to give the 10 title compound, which was used in the next reaction without the need for further purification. MS (ES|+) m/z 595.3, 587.2 (M+H).
Intermediate 2F; (i)-reI-(2S,4R)-benzyl hloropyridinyI)hydroxypiperidine carboxylate Cl N \ l / OH ,N CbZ rel-(28,4R) 15 To a on of (i)—rel—(2S,4R)—benzyl 4-((ten‘-butyldiphenylsilyl)oxy)—2-(6-chloropyridin eridinecarboxylate, Intermediate 2E, (25.7 g, 44 mmol) in MeOH (100 mL) was added a solution of HCI in MeOH, which was prepared by SOCIZ (6.5 mL, 89 mmol) and MeOH (100 mL).
The mixture was stirred at room temperature for 16h, and then 2h at 40 °C. The mixture was diluted with CH2C|2. The mixture was then washed successively with 5% aq. NaHC03, and brine, 20 dried over , filtered, and concentrated. The resulting residue was purified by silica gel flash column tography (CH2C|2/EtOAc = 61/39 to 25/75) to afford the title compound. MS (ES|+) m/z 347.2, 349.0 (M+H).
Intermediate 2G; (i)-reI-(2S,4S)-benzyl 4-(benzoyloxy)(6-chloropyridinyl)piperidine- 1-carboxylate / 0\ Bz 25 Cbz’N rel-(28,48) To a solution of (i)—re/—(2S,4R)—benzyl 2-(6-chloropyridinyl)hydroxypiperidine carboxylate, Intermediate 2F, (7 g, 20.18 mmol), benzoic acid (4.2 g, 34.4 mmol), and PPh3 (8 g, 30.5 mmol) in THF (200 mL) at 0 °C was added DEAD (4.2 mL, 26.5 mmol) over 0.25h. The WO 2015/009616 PCT/US2014/046515 mixture was then stirred at 0 °C for 1h. The reaction was quenched with MeOH. The mixture was then absorbed on silica gel, which was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2C|2) = 1/0 to 3/7] to afford the title compound. MS (ESI+) m/z 451.1, 453.0 (M+H).
Intermediate ; (i)-reI-(2S,4S)-benzyl 2-(6-chIoropyridinyI)hydroxypiperidine carboxylate CI N \ I / OH ,N Cbz rel-(28,48) A suspension of (i)—rel—(2S,4S)—benzyl 4-(benzoyloxy)—2-(6-chloropyridinyl)piperidine—1- carboxylate, Intermediate 2G, (9.02 g, 20 mmol) and K2C03 (5 g, 36.2 mmol) in MeOH (100 10 mL) was stirred at 60 °C for 1.5h. The reaction mixture was cooled to room temperature. The e was diluted with CH2C|2. The organic phase was then washed successively with H20 and brine, dried over NaZSO4, filtered, and concentrated. The ing residue was ed by silica gel flash column chromatography (CH2CIZ/MeOH = 93/7) to afford the title nd. 1H NMR (400 MHz, CD3CN) 6 8.23 - 8.26 (m, 1H), 7.59 (ddd, J=0.92, 2.66, 8.41 Hz, 1H), 7.26 - 7.39 (m, 6H), 15 5.57 (br. d, J=4.90 Hz, 1H), 5.09 - 5.18 (m, 2H), 4.10 - 4.17 (m, 1H), 3.54 - 3.65 (m, 1H), 2.91 (d, J=4.65 Hz, 1H), 2.75 - 2.85 (m, 1H), 2.43 - 2.50 (m, 1H), 1.69 - 1.85 (m, 2H), 1.31 - 1.43 (m, 1H).
Intermediate 2l; (i)-reI-(2S,4S)-benzyl 2-(6-chloropyridinyI)ethoxypiperidine carboxylate CI N \ I / O\/ ,N CbZ rel-(2S, 48) 20 The title compound was sized from (i)—rel—(2S,4S)—benzyl 2-(6-chloropyridinyl)—4- hydroxypiperidinecarboxylate, Intermediate 2H, by using Etl in the place of Mel analogously to the preparation of Intermediate 2A. MS (ESI+) m/z 375.1, 377.4 (M+H).
Intermediate 2J; (i)-methyl 5-(reI-(2S,4S)((benzyloxy)carbonyI)ethoxypiperidin yl)pico|inate 25 rel-(28,48) A solution of (i)—rel—(2S,4S)—benzyl 2-(6-chloropyridinyl)—4-ethoxypiperidine carboxylate, ediate 2l, (1.8 g, 4.80 mmol) and Et3N (1.2 mL, 8.66 mmol) in MeOH (4 mL) WO 2015/009616 PCT/US2014/046515 was sparged with CO gas for 5min in a vial. (rac)—B|NAP (400 mg, 0.642 mmol) and PdC|2 (100 mg, 0.564 mmol) was added to the mixture, and the vial was capped under CO atmosphere. The mixture was then stirred at 100 °C under the microwave irradiation for 1 hr. To the mixture was added additional amount of (rac)—B|NAP (400 mg, 0.642 mmol), followed by PdC|2 (100 mg, 0.564 mmol). The vial was filled with CO gas. The mixture was then stirred at 120 °C under the microwave irradiation for 1 hr. The reaction mixture was then diluted with H20. The mixture was then extracted with EtOAc. The organic phase was then washed with H20 and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel f|ash column chromatography (heptane/EtOAc = 55/45) to afford the title compound. MS (ESI+) m/z 399.2 10 (M+H). ediate 2-20; (i)-methyl 5-(reI-(2S,4S)ethoxypiperidinyl)picolinate HN rel-(28,48) The title compound was sized from (i)—methyl -(28,4S)—1-((benzyloxy)carbonyl)- 4-ethoxypiperidiny|)pico|inate, ediate 2J, analogously to the preparation of 15 Intermediate 2-12. MS (ESI+) m/z 265.1 (M+H).
Intermediate 2-21: Intermediate 2A; (i)-tert-buty| 5-((tert-buty|diphenylsi|y|)oxy)oxopiperidine carboxylate 20 The title compound was synthesized from hydroxypiperidinone (CAS: 193652) by following procedures described in the synthesis of Intermediate 2A and then Intermediate 2B. MS (ESI+) m/z 454.3 (M+H).
Intermediate 2B; (i)-tert-buty| ert-buty|diphenylsilyl)oxy)(4-cyanopheny|) oxopentyl)carbamate 25 WO 2015/009616 2014/046515 To a solution of iPngCl-LiCl complex solution in THF (15 mL, 19.50 mmol) in THF (15 mL) at -78 °C was added a solution of 4-bromobenzonitrile (4 g, 21.98 mmol) in THF (10 mL). The e was then stirred at room temperature for 1.5h. To a solution of (i)—ten‘-butyl 5-((tert— butyldiphenylsilyl)oxy)—2-oxopiperidinecarboxylate, Intermediate 2A, (6 g, 13.23 mmol) in THF (25 mL) at -78 °C was added the reaction mixture above over 15 min. The mixture was then stirred at -78 °C for 10 min, and then at 0 °C for 0.5h. The reaction was then quenched with MeOH, followed by half satd. aq. KHSO4. The mixture was then extracted with EtOAc. The organic layer was then washed sively with 5% aq. NaHCOs and brine, dried over NaZSO4, ed, and concentrated. The resulting residue was used in the next on without the need for further 10 purification. MS (ESI+) m/z 557.4 (M+H).
Intermediate 2C; (i)(5-((tert-butyldiphenylsilyl)oxy)piperidinyl)benzonitrile (diastereomeric mixture) diastereomeric HN S mixture The title compounds was synthesized from (i)—ten‘-butyl (2-((tert—butyldiphenylsilyl)oxy)—5-(4- 15 cyanophenyl)—5-oxopenty|)carbamate, Intermediate , analogously to the preparation of Intermediate 2D. MS (ESI+) m/z 441.1 (M+H).
Intermediate 2D; (i)-benzyl 5-((tert-butyldiphenylsiIyl)oxy)(4-cyanophenyl)piperidine- 1-carboxylate ereomer—1); and (i)-benzy| rt-butyldiphenylsi|y|)oxy)(4- cyanophenyl)piperidinecarboxy|ate (diastereomer—2).
N\\ N\\ Cbz’N O/TBDPS CbZ’N O/TBDPS 20 diastereomer-1 diastereomer—Z To a solution of (i)—4-(5-((tert—butyldiphenylsilyl)oxy)piperidinyl)benzonitrile (diastereomeric mixture), Intermediate 2C, (5.77 g, 13 mmol) in CHZCIZ (100 mL) at 0 °C was added Et3N (5 mL, 36.1 mmol), followed by Cbz-Cl (5 mL, 35.0 mmol) over 0.25h. The mixture was then stirred at 0 °C for 2.5h. The reaction was quenched with 28% NH4OH. The mixture was 25 diluted with CHZCIZ. The organic phase was then washed successively with H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 87/13) to afford, in respective elution order, (i)—benzy| WO 2015/009616 PCT/US2014/046515 5-((tert—butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate (diastereomer—1); and (i)- benzyl 5-((ten‘-butyldiphenylsilyl)oxy)—2-(4-cyanophenyl)piperidinecarboxylate (diastereomer—2). (diastereomer—1); 1H NMR (400 MHz, CD30D) 6 7.58 - 7.70 (m, 6H), 7.20 - 7.45 (m, 13H), 5.58 (br. d, J=2.00 Hz, 1H), 5.18 (d, J=11.98 Hz, 1H), 4.89 - 5.01(m, 1H), 4.04 (br. d, J=13.90 Hz, 1H), 3.89 (br. s., 1H), 2.75 (dd, J=1.47, 14.06 Hz, 1H), 2.53 - 2.64 (m, 1H), 2.12 - 2.21 (m, 1H), 1.58 - 1.68 (m, 1H), 1.36 - 1.47 (m, 1H), 1.06 (s, 9H). (diastereomer—2); 1H NMR (400 MHz, CD30D) 6 7.71 (d, J=8.31 Hz, 2H), 7.56 - 7.64 (m, 4H), 7.27 - 7.46 (m, 11H), 7.23 (br. s., 2H), 5.31 (br. d, J=2.70 Hz, 1H), 5.01 - 5.13 (m, 2H), 4.14 (br. d, J=10.80 Hz, 1H), 3.66 - 3.76 (m, 1H), 2.61 (dd, J=10.64, 12.84 Hz, 1H), 2.33 (d, J=14.31 Hz, 1H), 10 1.70 - 1.83 (m, 2H), 1.30 - 1.43 (m, 1H), 1.00 (s, 9H).
Intermediate 2E; (i)-benzyl 2-(4-cyanophenyl)hydroxypiperidinecarboxylate (diastereomer—1) N Cbz diastereomer-1 OH The title compound was synthesized from (i)—benzyl 5-((ten‘-butyldiphenylsilyl)oxy)—2-(4- 15 henyl)piperidinecarboxylate ereomer—1), Intermediate 2D, analogously to the preparation of Intermediate 2E. MS (ESI+) m/z 337.1 (M+H).
Intermediate 2F; nzy| 2-(4-cyanopheny|)methoxypiperidinecarboxy|ate (diastereomer—1) N\\ diastereomer-1 Cbz’N 0/ 20 The title compound was synthesized from (i)—benzyl 2-(4-cyanophenyl)—5- hydroxypiperidinecarboxylate (diastereomer—1), Intermediate 2E, analogously to the preparation of Intermediate 2A. MS (ESI+) m/z 351.2 (M+H).
Intermediate 2-21; (i)(5-methoxypiperidinyl)benzonitriIe (diastereomer—1) N\\ HN . / dlastereomer-1 O 25 The title compound was synthesized from nzyl yanophenyl)—5- methoxypiperidinecarboxylate (diastereomer—1), Intermediate 2F, analogously to the preparation of Intermediate 2-12. MS (ESI+) m/z 217.1 (M+H).
WO 2015/009616 PCT/US2014/046515 ediate 2-22: ediate 2A; tert-butyl 4,4-dimethylpiperidinecarboxylate Y ()4 T 0 To a solution of 4,4-dimethylpiperidine hydrochloride (6 g, 40.1 mmol) and Boc20 (12.77 mL, 55.0 mmol) in CH2C|2 (100 mL) was added Et3N (12 mL, 87 mmol). The e was then stirred at room temperature for 13h. The reaction was quenched with H20. The mixture was then extracted with EtZO. The mixture was then washed successively with 1M aq. HCI, 5% aq. NaHCOs, and brine, dried over NaZSO4, filtered, and concentrated to afford the title compound, which was used in the next reaction without the need for further purification. 1H NMR (400 MHz, CDCI3) 6 3.33 10 - 3.40 (m, 4H), 1.45 (s, 9H), 1.26 - 1.33 (m, 4H), 0.94 (s, 6H).
Intermediate 2B; (i)-tert-buty| 4,4-dimethyloxopiperidinecarboxy|ate To a suspension of tert—butyl 4,4-dimethylpiperidine—1-carboxy|ate, Intermediate 2A, (8.5 g, 40.0 mmol) and Na|O4 (13 g, 60.8 mmol) in EtOAc (50 mL)/H20 (100 mL) was added RuCIs 15 (1 g, 4.82 mmol). The mixture was then stirred at room temperature for 4.5h. To the mixture was then added additional amount of NalO4 (8 g, 37.4 mmol). The mixture was then stirred at room temperature for 2.5h. The on mixture was then diluted with EtOAc. The mixture was then ed through a plug of Celite®, which was rinsed with EtOAc. The organic phase was then washed sively with H20, 1% aq. Na28203, and brine, dried over NaZSO4, filtered, and 20 concentrated. The resulting e was absorbed onto silica gel. The silica gel was rinsed with EtZO. The filtrate was then concentrated to afford the title compound. MS (ESI+) m/z 228.2 (M+H).
Intermediate 2C; (i)-tert-buty| cyanophenyl)—3,3-dimethyloxopenty|)carbamate N\ The title compound was synthesized from (i)—ten‘-butyl 4,4-dimethyloxopiperidine—1- 25 carboxylate, Intermediate 2B, analogously to the preparation of Intermediate 2B. MS (ESI+) m/z 331.2 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate ; (i)(4,4-dimethylpiperidinyl)benzonitriIe N \ \ HN The title compound was analogously synthesized form n‘-butyl (5-(4-cyanophenyl)—3,3- dimethyloxopentyl)carbamate, Intermediate 2C, by following s described in the sis of Intermediate 2B, and then Intermediate 2C. MS (ESI+) m/z 215.3 (M+H).
Intermediate 2E; (i)-benzyl 2-(4-cyanophenyI)-4,4-dimethylpiperidinecarboxylate N \ \ N Cbz’ The title compound was synthesized from (i)—4-(4,4-dimethylpiperidinyl)benzonitrile, Intermediate 2D, analogously to the preparation of Intermediate 2E. MS (ESI+) m/z 349.1 10 (M+H).
Intermediate 2-22; (i)-methyl 4-(4,4-dimethylpiperidinyl)benzoate O \o HN The title compound was synthesized from (i)—benzyl 2-(4-cyanophenyl)—4,4- dimethylpiperidinecarboxylate, ediate 2E, by following procedures described in the 15 synthesis of Intermediate 2C, Intermediate 2D, and then Intermediate 2-13. MS (ESI+) m/z 248.1 (M+H).
Following intermediates were prepared from appropriate starting materials by similar methods described above. lnterme al name ure MS (m/z) dIate starting material 0 (i)—methyl 5-(re/-(28,4S)—4- \o \ methoxypiperidin-2—yl) picolinate (ESI+) 21 N' / ('3 2'31;+ _ WO 2015/009616 PCT/US2014/046515 (5-((terf—butyldiphenylsilyl)oxy) dinyl)benzonitrile (diastereomer—1) HN ,TBDPS dIastereomer-1 described as Intermediate. . .
O diastereomer-1 2D N\\ (5-((terf—butyldiphenylsilyl)oxy) piperidinyl)benzonitrile (dIas ereomer- t _2 ) (ESI+) 2_23_3 441-0 HN ,TBDPS 0 diastereomer—2 described as (M+H) diastereomer-2 Intermediate 2D N\\ (i)—4-(5-methoxypiperidin-2—yl)benzonitrile (diastereomer—Z) (ESI+) 24 217.1 "N o/ diastereomer—2 described as (M+H) diastereomer-2 Intermediate 2D Intermediate 2-24: (i)-Ethyl 2-(piperidiny|)thiazolecarboxylate A mixture of n‘-butyl 2-carbamothioylpiperidinecarboxylate (CAS: 569348-09—0, 99 mg, 0.405 mmol) and bromoethylpyruvate (79 mg, 0.405 mmol) in EtOH (3 mL) was stirred at room temperature for 4 days. The mixture was concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc) to afford the title compound. MS (ESI+) m/z 241.3 (M+H). 10 Intermediate 2-25: Intermediate 2A; (i)-methyl 2-(1-(tert-butoxycarbonyl)piperidinyI)methylthiazole carboxylate /Niko O O= Intermediate 2-25; (i)-methyl 4-methyl(piperidinyl)thiazolecarboxylate N /0 "H3 S HN 0 To a solution of (i)—methyl tert—butoxycarbonyl)piperidinyl)methylthiazole—5- carboxylate, Intermediate 2A, (115mg, 0.338 mmol) in CH2C|2 (2 mL) was added TFA. The whole mixture was then d at room temperature for 1h. The reaction mixture was diluted with EtOAc, and then washed successively with aq. , brine, dried over NaZSO4, filtered, and 10 concentrated to furnish the title compound without further purification. MS (ESI+) m/z 240.9 (M+H).
Intermediate 2-26: (i)-N-((4-(piperidinyl)phenyl)sulfonyl)acetamide I IZ YER o 0 To a solution of a mixture of (i)—tert—butyl 2-(3-sulfamoylphenyl)piperidine—1-carboxylate and 15 (i)—ten‘-butyl ulfamoylphenyl)piperidinecarboxylate, Intermediate 2A, (0.11 g, 0.25 mmol) in CH2C|2 (3 mL) at room temperature was added Et3N (0.14 mL, 0.97 mmol), followed by Ac20 (0.09 mL, 0.97 mmol). The mixture was then stirred for 20 min. The reaction mixture was then diluted with CH2C|2 and satd. aq. NaHC03. The organic phase was then washed sively with brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was used in the 20 following step without any purification.
To a solution of the residue in CH2C|2 (3 mL) at room temperature was added TFA (0.25 mL, 3.2 mmol. The mixture was then stirred at room temperature for 60 hr. The reaction mixture was concentrated to give the title compound as TFA salt, which was used in the next reaction t the need for r purification. MS (ESI+) m/z 283.1 (M+H). 25 Intermediate 2-27: Intermediate 2A; (i)benzoyl(4-bromophenyl)-2,3-dihydropyridin-4(1H)-one Br 82’ WO 09616 PCT/US2014/046515 To a suspension of Mg (1.2 g, 50 mmol) in THF (50 mL) at room temperature was added iodine (50 mg), and then the mixture was d at room temperature for 5 min. To the mixture was then added 1,4-bibromobenzene (11.8 g, 50 mmol) portionwise , and the mixture was stirred at 70 °C for 2h. The mixture was cooled to room temperature to furnish ophenylmagnesium bromide in THF.
To a solution of4-methoxypyridine (1.52 g, 13.9 mmol) in THF (40 mL) at room temperature was added benzoyl chloride (1.6 mL, 13.9 mmol), followed by trimethylsilyl trifluoromethanesulfonate (3.06 g, 13.8 mmol). The mixture was then stirred at room temperature for 0.5h, and then cooled to -78 °C. To the mixture at -78 0C was then added the 4- 10 bromophenylmagnesium brimide in THF, and then the e was stirred at the same temperature for 1h. The mixture was then quenched with 2M HCI (50 mL). The mixture was then extracted with EtOAc. The organic layer was then dried over Na2804, filtered, and then concentrated. The resulting residue was purified by si|ca gel flash cholumn chromatography (heptane/EtOAc = 1/0 to 4/1) to afford the titled compound. MS (ESI+) m/z 357.8 (M+H). 15 Intermediate 2B; (i)-tert-butyl 2-(4-bromophenyl)oxo-3,4-dihydropyridine-1(2H)- carboxylate Br A e of Intermediate 2A (700 mg, 1.97 mmol) and 25% NaOMe in MeOH (5 mL) was stirred at room temperature for 2h, and then diluted with H20. The mixture was then extracted 20 with EtOAc. The oeganic phase was then dried over , filtered, and then concentrate. The resulting residue in THF (8 mL) were added Boc20 (955 mg, 4.38 mmol) and Et3N (0.5 mL, 3.28 mmol), followed by DMAP (130 mg, 1.06 mmol). The mixture was then stirred at room temperature for 1h, and then concentrated. The resulting residue was purified by silica gel flash column chromatography ne/EtOAc = 1/0 to 7/3) to afford the title compound. MS (ES|+) m/z 294.9 25 (M-tBu)+.
Intermediate 2C; (i)-tert-butyl 2-(4-(methoxycarbonyl)phenyl)oxo-3,4-dihydropyridine- 1(2H)-carboxylate WO 2015/009616 PCT/US2014/046515 A mixture of Intermediate 2B (7.8 g, 22.2 mmol), iPr2NEt (10 mL, 57.4 mmol), Pd(OAc)2 (1.2 g, mmol, 5.34 mmol), and dppp (4.2 g, 10.2 mmol) in DMSO/MeOH (60 mL/60 mL) was stirred at 80 0C for 16h under CO gas here (100 psi). The reaction mixture was diluted with H20. The mixture was then extracted with EtOAc. The organic layer was then concentrated.
The resulting residue and Et3N (10 mL, 71 mmol) in THF (50 mL) was added Boc20 (8 g, 36.7 mmol) in THF (10 mL), followed by catalytic amount of DMAP. The mixture was then stirred at room temperature for 2h, and then concentrated. The resulting mixture was ed by silica gel flash column chromatography ne/EtOAc = 1/0 to 4/1) to afford the titled compound. MS (ESI- 10 )m/z 331.0 (M-H), (ESI+) m/z 231.95 (M-Boc)+. ediate 2D; (i)-tert-butyl 2-(4-(methoxycarbonyl)phenyI)oxopiperidine carboxylate A mixture of Intermediate 2C (4.5 g, 13.6 mmol) and Pd/C (10%, 800 mg) in MeOH 15 (25 mL) was stirred at room temperature under H2 atmosphere (40psi) for 2h. The H2 gas was replaced to N2, and then the catalyst was removed by filtration through a plug of Celite®, which was rinsed with MeOH. The filtrate was then concentrated. The resulting residue was purified by silica gel flash column tography (heptane/EtOAc = 1/0 to 3/1) to afford the titled compound. MS (ESI-) m/z 333.1 (M-H). 20 Intermediate 2E; rt-butyl 2-(4-(methoxycarbonyl)phenyI)methylenepiperidine carboxylate WO 2015/009616 PCT/US2014/046515 To a suspension of methyltriphenylphosphonium bromide (480 mg, 1.34 mmol) in THF (5 mL) at 0 0C was added KOtBu (153 mg, 1.36 mmol). The mixture was then stirred at the same temperature for 0.5h. To the mixture was then added a solution of Intermediate 2D (300 mg, 0.90 mmol) in THF (5 mL). The mixture was then stirred at room temperature for 16h, and then quenched with H20. The mixture was then extracted with EtOAc. The organic phase was then dried over , ed, and then concentrated. The resulting residue was purified by silica gel flash column tography (heptane/EtOAc = 1/0 to 9/1) to afford the titled compound. 1H NMR (300 MHz, CDCI3) 6 7.98 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4Hz, 2H), 5.53 (brd, J=3.8 Hz, 1H), 4.83 (br. s, 2H), 4.02-4.10 (m, 1H), 3.90 (s, 3H), 2.61-2.87 (m, 3H), 2.16-2.38 (m, 2H), 1.46 (s, 9H). 10 Intermediate 2-27; (i)-methyl 4-(6-azaspiro[2.5]octanyl)benzoate O \o HN To a solution of diethylzinc (1M in hexane, 14 mmol) in CH2C|2 (30 mL) at -40 0C was added diiodomethane (1.1 mL, 13.8 mml). The mixture was then stirred at the same temperature for 0.5h.
To the mixture was then added a solution of Intermediate 2E (1.52 g, 4.6 mml) in CH2C|2 (20 15 mL). The mixture was then d at room temperature for 16h. The mixture was then quenched with HZO/brine. The e was then extracted with CH2C|2. The organic phase was then dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 1/4) to afford the titled nd. MS (ES|+) m/z 246.0 (M+H). 20 ediate 2-28: Intermediate 2A; (i)-tert-butyl 4-ethylidene(4-(methoxycarbonyl)phenyl)piperidine carboxylate The title compound was synthesized from Intermediate 2D (220mg, 0.66 mmol) and 25 ethyl triphenylphosphonium bromide (344mg, 0.92 mmol) analogoulsy to the ation of Intermediate 2E. MS (ES|+) m/z 246.0 (M-tBu).
WO 2015/009616 PCT/US2014/046515 Intermediate 2B; (i)-reI-(2S,4S)-tert-butyl 4-ethyl(4- (methoxycarbony|)phenyl)piperidinecarboxy|ate O \o N Boc’ rel- (23,43) A mixture of Intermediate 2A (110 mg, 0.3 mmol) and Pd/C (10%, 30 mg) in MeOH (2 mL) was stirred at room temperature under H2 here (50 psi) for 5h. The H2 gas was replaced to N2, and then the catalyst was removed by tion through a plug of Celite®, which was rinsed with MeOH. The filtrate was then concentrated. The ing residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 3/1) to afford the titled compound. 1HNMR (300 MHz, CDCI3) 5 8.00 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.49 (brs, 1H), 4.03- 10 4.22 (m, 1H), 3.91 (s, 3H), 2.68-2.83 (m, 1H), 2.34 (br, d, J=14 Hz, 1H), 1.52-1.69 (m, 3H), 1.46 (s, 9H), 10-134 (m, 3H), 0.88 (t, J=7.1Hz, 3H).
Intermediate 2-28; (i)-methyl 4-(reI-(2S,4S)ethylpiperidinyl)benzoate O \o HN re/-(28,48) 15 To a solution of Intermediate 2B (40 mg, 0.115 mmol) in CH2C|2/MeOH (1 mL/1 mL) at 0 0C was added 4M HCl in dioxane (2 mL). The mixture was then stirred at room temperature for 6h. The e was then partially concentrated. The mixture was then diluted with H20. The e was then rendered basic by NaHCOs (pH~8). The mixture was then extracted with EtOAc.
The organic phase was dried over NaZSO4, filtered, and concentrated to afford the title compound. 20 1HNMR (300 MHz, CD30D) 5 ppm: 7.97 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 3.94 (dd, J’=3 Hz, J"=7.4 Hz, 1H), 3.88 (s, 3H), 2.84-2.97 (m, 2H), 1.50-1.89 (m, 7H), 0.96 (t, J=8.0 Hz, 3H).
WO 2015/009616 PCT/US2014/046515 Intermediate 3-1: (i)((5,7-DimethyItosyI-1H-indolyl)methyI)phenylpiperidinol ereomeric mixture) OH N / ,N diastereomeric TS mixture To a solution of (i)—2—phenylpiperidinol (diastereomeric mixture), Intermediate 2-1, (154 mg, 0.72 mmol) in DMSO (2 mL) was added K2003 (350 mg, 2.53 mmol). The mixture was then d for 10 min. To the mixture was then added 4-(chloromethyl)—5,7-dimethyltosyl-1H-indole, Intermediate 1-6, (170 mg, 0.489 mmol). The mixture was then stirred at 80 °C for 1h. The reaction mixture was cooled to room ature, and then poured into H20. The mixture was then 10 extracted with EtOAc. The organic phase was washed sively with H20 (twice) and brine, dried over K2003, filtered, and concentrated. The resulting residue was purified by slica gel flash column chromatography (heptane/EtOAc ) to afford the title compound as a mixture of diastereomers, which was used in the next on without the need for further purification. MS (ESI+) m/z 489.4 (M+H). 15 Following intermediates were prepared from appropriate starting materials by similar methods described above. lnterm chemical name MS stru ctu re ediate starting material (i)—4-((4-methoxyphenylpiperidin-1 - 0 \ yl)methyl)—5,7-dimethyltosyl-1H—indole N {1152/ (diastereomeric mixture) / IntermedIate 1-6 andI diastereomeric Ts’ mixture Intermediate 2-2 nzyl (1-((5,7-dimethyltosyl-1H- indolyl)methyl)phenylpiperidin y|)carbamate (diastereomer—1) Intermediate 1-6 and diastereomer—1 Intermediate 2-5 WO 2015/009616 2014/046515 (i)—benzy| (1-((5,7-dimethyItosy|—1H- indoIyl)methyl)pheny|piperidin y|)carbamate (diastereomer—Z) Intermediate 1-6 and diastereomer-2 Intermediate 2-6 (i)—5,7-dimethyl((2-phenylpiperidin-1 - y|)methyl)—1-tosy|—1H-indole Intermediate 1-6 and ylpiperidine (i)—(1-((5,7-dimethy|—1-tosy|—1H-indoI y|)methyl)pheny|piperidinyl)methanol (diastereomer—1) Intermediate 1-6 and diastereomer-1 Intermediate 2-7 (i)—(1-((5,7-dimethy|—1-tosy|—1H-indoI y|)methyl)pheny|piperidinyl)methanol (diastereomer—Z) Intermediate 1-6 and diastereomer-Z Intermediate 2-8 (i)—4-(1-((5,7-dimethy|—1-tosy|—1H—indo|—4- y|)methy|)piperidin zenesulfonamide and (i)—3-(1-((5,7-dimethy|—1-tosy|—1H—indo|—4- y|)methyl)piperidin-2— y|)benzenesulfonamide (mixture of regioisomer) Intermediate 1-6 and (mixture of regioisomer) Intermediate 2-9 WO 2015/009616 PCT/US2014/046515 (i)—4-(1-((5,7-dimethy|—1-tosy|—1H—indo|—4- y|)methyl)piperidin-Z-yl)—N- methylbenzenesulfonamide and (i)—3-(1-((5,7-dimethy|—1-tosy|—1H—indo|—4- hyl)piperidin-Z-yl)—N- methylbenzenesulfonamide T Intermediate 1-6 and Intermediate 2-10 (i)—4-((2-(4-f|uorophenyl)—4- methoxypiperidiny|)methy|)—5,7- dimethyItosyI-1H-indole Intermediate 1-6 and Intermediate 2-11 (i)—(1-((5,7-dimethy|—1-tosy|—1H-indoI hy|)phenylpiperidin-Z-yl)methanol Intermediate 1-6 and (2-phenylpiperidinyl)methanol (CAS: 1614990) (i)—4-(1-((5,7-dimethy|—1-tosy|—1H—indo|—4- y|)methyl)piperidiny|)benzonitrile Intermediate 1-6 and 4-(piperidinyl)benzonitrile HCI (CAS: 12036851) (i)—4-(1-((5-ch|oro—7-methy|—1-tosy|—1 H- indoIyl)methyl)piperidinyl)benzonitrile Intermediate 1-9 and 4-(piperidinyl)benzonitrile HCI WO 2015/009616 PCT/US2014/046515 N\\ (i)—4-(rel—(28,4S)—1-((5,7-dimethy|—1 -tosy|— OH 1H-indoIyl)methyl)hydroxypiperidin- N 2-y|)benzonitri|e (1%/ Intermediate 1-6 and N Intermediate 21.
TS; "9,423,43) N \\ (i)—4-(re/—(28,4R)—1-((5,7-dimethy|—1 -tosy|— 1H-indoIyl)methyl)hydroxypiperidin- N 2-y|)benzonitri|e / Intermediate 1-6 and TS/N Intermediate 2'15'2 rel-(28,4R) N \\ (i)—4-(rel—(28,4S)—1-((5,7-dimethy|—1 -tosy|— 1H-indoIyl)methyl)methoxypiperidin- N 2-y|)benzonitri|e (15/ Intermediate 1-6 and N IntermedIate 23.
TS! rel-(28,48) N\\ (i)—4-(re/—(28,4R)—1-((5,7-dimethy|—1 -tosy|— (I) 1H-indoIyl)methyl)methoxypiperidin- N 2-y|)benzonitri|e (15/ ediate 1-6 and N .
N \\ (rel—(28,4S)—1-((5,7-dimethy|—1 — O\/ 1H-indoIyl)methyl)—4-ethoxypiperidin N y|)benzonitri|e / Intermediate 1-6 and N / Intermediate 25 Ts reI-(28, 4S) WO 2015/009616 PCT/US2014/046515 (i)—5,7-dimethyl((2—(4- (methylsu|fony|)pheny|)piperidin y|)methy|)—1-tosy|—1H-indole Intermediate 1-6 and Intermediate 2-19 (S)—ten‘-buty| 5-cyclopropyI((4- (methoxycarbonyl)phenyl)piperidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and thy| 4-(piperidin-Z-yl)benzoate HCI (CAS: 1391547-09—3) (i)—tert—buty| 5-cyclopropyl((2—(4- (methoxycarbonyl)phenyl)pyrrolidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and methyl 4-(pyrrolidinyl)benzoate (CAS: 9083344) (S)—ten‘-buty| 5-cyclopropyl((2—(6- (methoxycarbonyl)pyridinyl)piperidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and (S)—methy| 5-(2—piperidy|)pyridine-2— ylate (CAS: 12136062) (S)—tert—buty| opropyl((2—(3-f|uoro- hoxycarbonyl)pheny|)piperidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and (S)—methy| 2-fluoro— 4-(piperidinyl)benzoate (CAS: 13365715) WO 2015/009616 PCT/US2014/046515 (S)—ten‘-buty| 5-cyclopropyl((2—(2- methoxy xycarbonyl)phenyl)piperidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and thy| 6-(piperidy|)pyridine carboxylate (CAS: 12699961) (i)—ten‘-buty| 4-(rel-(28,4S)—(4-ethoxy-2—(4- \o (methoxycarbonyl)phenyl)piperidin y|)methy|)—5,7-dimethyI-1 H-indoIe carboxylate Intermediate 1-7 and Intermediate 2-13b (i)—ten‘-buty| 5-cyclopropyl(rel—(28,48)- (4-methoxy-2—(4- (methoxycarbonyl)phenyl)piperidin y|)methy|)—7-methy|—1 H-indoIe carboxylate Intermediate 1-8 and Intermediate 2-12 (i)-tert—buty| 4-((2-(4-(N- acetylsulfamoyl)phenyl)piperidin y|)methyl)cyc|opropyImethyl-1H- indoIecarboxylate single Intermediate 1-8 and $94323" Intermediate 2-26 WO 2015/009616 2014/046515 Intermediate 3-3: Intermediate 3A; 1-((5,7-dimethyltosyl-1H-indolyl)methyl)(4- (hydroxymethyl)phenyl)pyridinium chloride HO NK CI- / I" Ts To a solution of (4-(pyridiny|)pheny|)methano| (CAS: 880813286, 70 mg, 0.378 mmol) in CH3CN (0.5 mL) was added 4-(chloromethyl)-5,7-dimethy|—1-tosy|—1H-indole, Intermediate 1-6, (100 mg, 0.287 mmol). The mixture was then d at 70 °C for 23h. The reaction mixture was concentrated to give the title nd, which was used in the next reaction without the need for further purification. MS (ESI+) m/z 497.5 (M)+. 10 Intermediate 3-3; (i)-(4-(1-((5,7-dimethyltosyl-1H-indolyl)methyl)piperidin yl)phenyl)methanol Ho A mixture of 1-((5,7-dimethy|—1-tosy|—1H-indoIyl)methyl)—2-(4-(hydroxymethyl)pheny|)— pyridinium chloride, Intermediate 3A, and Pt02 (20 mg, 0.088 mmol) in MeOH (2 mL) was 15 stirred at room temperature under H2 atmosphere for ca. 4h. The H2 gas was replaced with N2.
The catalyst was then removed by filtration through a plug of Celite®, which was rinsed with MeOH.
The filtrate was then concentrated, which was purified by silica gel flash column tography (heptane/EtOAc = 4/1 to 1/1) to afford the title nd. MS (ESI+) m/z 503.5 (M+H).
Intermediate 4-1: 20 (i)-tert-Butyl 4-((4-(cyanomethyl)phenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole carboxylate (diastereomer—1) Boc diastereomer-1 WO 09616 PCT/US2014/046515 To a mixture of (i)—2-(2-phenylpiperidinyl)acetonitrile (diastereomer—1), Intermediate 2-3, (46.7 mg, 0.233 mmol) and Ti(OiPr)4 (1 mL, 3.38 mmol) was added terf-butyl 4-formyl-5,7-dimethyl- 1H—indole—1-carboxylate, Intermediate 1-5, (55 mg, 0.201 mmol). The mixture was then stirred at 90 °C for 1h. The reaction mixture was cooled to room temperature, and then diluted with CH2C|2 (ca. 2 mL). The mixture was then poured into a suspension of NaBH4 (500 mg, 13.22 mmol) in MeOH (20 mL) at 0 °C dropwise. The mixture was then stirred at room temperature for 1h. The e was then diluted with CH2C|2, and added ® and H20. The mixture was filtered through a plug of Celite®, which was rinsed with CH2C|2. The organic phase was successively washed with H20, and brine, dried over NaZSO4, filtered, and concentrated to h the title compound without 10 any purification MS (ESI+) m/z 458.5 (M+H).
Intermediate 4-2: (i)-tert-Butyl 4-((4-(cyanomethyI)phenylpiperidinyl)methyI)-5,7-dimethyl-1H-indoIe carboxylate (diastereomer—2) \ N N / IN 15 800 diastereomer-Z The title compound was synthesized from (i)—2-(2-phenylpiperidinyl)acetonitrile (diastereomer—2), Intermediate 2-4, and terf-butyl 4-formyl-5,7-dimethyl-1H-indolecarboxylate, Intermediate 1-5, ously to the preparation of ediate 4-2. MS (ES|+) m/z 458.5 (M+H). 20 Intermediate 4-3: (i)-tert-Butyl 4-(reI-(2S,4S)-(4-ethoxy(4-(methoxycarbonyl)phenyl)piperidiny|)methyI) methoxymethyl-1H-indolecarboxy|ate O \O l/ O N 0‘ / N 800/ rel-(28,48) To a solution of tert—butyl 4-formylmethoxymethyl-1H-indole—1-carboxylate, 25 Intermediate 1-3, (1.5 g, 5.18 mmol) and (i)—methyl 4-(rel-(2S,4S)—4-ethoxypiperidin WO 2015/009616 PCT/US2014/046515 yl)benzoate, Intermediate 2-13b, (1.185 g, 4.5 mmol) in DOE (20 mL) was added NaBH(OAc)3 (3 g, 14.15 mmol). The mixture was then stirred at room temperature for 20h. The reaction mixture was then diluted with EtOAc. The e was then washed successively with 5% aq. Nchog, H20, and brine, dried over NaZSO4, filtered, and concentrated to afford the title compound, which was used in the next reaction t the needs of further purification. MS (ESI+) m/z 537.4 (M+1).
Following intermediates were ed from appropriate starting materials by similar methods described above. e chemical name structure + dIate. starting material (i)—ten‘-butyl 5-methoxymethyl((2-(pyridin yl)piperidinyl)methyl)-1H-indolecarboxylate (APCI) 436.1 Intermediate 1-3 and (M+H) (i)—2-(4-pyridinyl)piperidine (CAS: 143924-51—8) n‘-butyl 5-methoxymethyl((2-(pyridin yl)piperidinyl)methyl)-1H-indolecarboxylate (APCI) 436.1 Intermediate 1-3 and (M+H) (i)—2-(3-pyridinyl)piperidine (CAS: 130781) (S)—ten‘-butyl 4-((2-(2-fluoro (methoxycarbonyl)phenyl)piperidinyl)methyl) methoxymethyl-1H-indolecarboxylate (APCI) 511.2 Intermediate 1-3 and (M+H) (S)—methyl 4-((2-piperidyl))—3-fluorobenzoate (CAS: 121 33201) (R)—ten‘-butyl 5-methoxy((3-(4- (methoxycarbonyl)phenyl)morpholino)methyl)—7- -1H-indolecarboxylate (ES|+) Intermediate 1-3 and (M+H) (R)—methyl 4-(morpholinyl)benzoate (CAS: 12134508) WO 2015/009616 PCT/US2014/046515 (S)—tert—buty| 5-methoxy((2-(5- (methoxycarbonyl)pyridinyl)piperidin y|)methy|)—7-methyI-1H-indoIecarboxylate Intermediate 1-3 and (S)—methy| 6-(2-piperidyl)pyridinecarboxylate (CAS: 12699961) (S)—tert—buty| 4-((2-(4-bromopheny|)piperidin hy|)methoxymethy|—1 H-indoIe (APC|+) carboxylate 513.2, 515.1 Intermediate 1-3 and (M+H) (S)—2-(4-bromopheny|)piperidine (i)—ten‘-buty| 4-((2-(4-bromopheny|)azepan y|)methy|)methoxymethy|—1 H-indoIe carboxylate (APC|+) 527.2 Intermediate 1-3 and (M+H) 2-(4-bromophenyl)azepane (CAS: 383129u24m6) (i)—ten‘-buty| 4-((2-(3-bromopheny|)piperidin hy|)—5,7-dimethyI-1H-indole—1-carboxylate (APC|+) 497.0 Intermediate 1-3 and (M+H 2-(3-bromophenyl)piperidine (CAS: 3831283453) (i)—tert—buty| 4-((2-(4-cyanophenyl)—4-methoxy methylpiperidiny|)methyl)methoxymethy|— MS 1H—indoIecarboxylate e diastereomer) (ESI+) m/z 504.2 ediate 1-3 and (M+H) Intermediate 2-14 diastereomer-1 WO 2015/009616 PCT/US2014/046515 o (i)—tert—buty| 5-cyclopropyI(rel-(2S,4S)—(4- \o ethoxy(4-(methoxycarbonyl)pheny|)piperidin 0v hy|)—7-methyI-1H-indoIecarboxylate N / Intermediate 1-2 and N / Boc rel-(28,48) Intermediate 2-13b tert—butyl 5-methoxy((28,4S)—(2—(4- (methoxycarbonyl)phenyl)propoxypiperidin y|)methy|)—7-methyI-1H-indoIecarboxylate ediate 1-3 and Intermediate 26 tert—butyl 4-((28,4S)—(4-hydroxy-2—(4- (methoxycarbonyl)phenyl)piperidiny|)methy|)—5- methoxymethyI-1H-indole—1-carboxylate Intermediate 1-3 and Intermediate 27 o \ o (i)—ten‘-buty| 5-methoxy((2-(4- (methoxycarbonyl)methy|pheny|)piperidin (APC|+) N y|)methy|)—7-methyI-1H-indoIecarboxylate 507.2 (M+H) ediate 1-3 and Intermediate 21 Boc(fixNI o (i)—ten‘-buty| 5-methoxy((2-(4- \o (methoxycarbonyl)phenyl)methy|piperidin y|)methy|)—7-methyI-1H-indoIecarboxylate (APC|+) N (single diastereomer) 507.4 O\ / (M+H) I" Intermediate 1-3 and Boc Intermediate 22 single diastereomer WO 2015/009616 PCT/US2014/046515 (i)—ten‘-buty| 4-((re/-(2S,4R)—4-ethy|—2—(4- (methoxycarbonyl)phenyl)piperidiny|)methy|)—5- methoxymethyI-1H-indole—1-carboxylate Intermediate 1-3 and Intermediate 23 (i)—ten‘-buty| oxy((2—(4-(2—methoxy oxoethyl)phenyl)piperidiny|)methy|)—7-methy|— ) 1H—indole—1-carboxylate 507-3 (M+1) Intermediate 1-3 and Intermediate 24 (i)—ten‘-buty| 5-methoxy((2—(3-(2—methoxy oxoethyl)phenyl)piperidiny|)methy|)—7-methy|— (APC|+) 1H—indole—1-carboxylate 507-2 (M+1) Intermediate 1-3 and Intermediate 25 (i)—tert—buty| 5-cyclopropyI(rel-(2S,4S)—(4- \o / methoxy-2—(6-(methoxycarbonyl)pyridin | N \ o\ y|)piperidiny|)methy|)—7-methy|—1 H-indoIe N carboxylate / Intermediate 1-2 and ,N Intermediate 21 B re,_(2s 48) OC ’ n‘-buty| 4-((2-(4-cyanopheny|)—5- methoxypiperidiny|)methy|)—5-methoxy methyl-1H-indoIecarboxylate (diastereomer—1) Intermediate 1-3 and Intermediate 2-21 diastereomer-1 WO 2015/009616 PCT/US2014/046515 N \ \ (i)—ten‘-buty| 4-((2-(4-cyanopheny|)—5- methoxypiperidiny|)methy|)—5-methoxy N -1H-indoIecarboxylate (diastereomer—Z) 0/ O\ / /N ediate 1-3 and 306 Intermediate 24 diastereomer-Z (i)—tert—buty| 4-((5-((ten‘-buty|diphenylsilyl)oxy)—2— (4-cyanophenyl)piperidiny|)methy|)—5-methoxy- 7-methyI-1H-indole—1-carboxylate (diastereomer— 1) Intermediate 1-3 and Intermediate 22 (i)—tert—buty| 4-((5-((ten‘-buty|diphenylsilyl)oxy)—2— (4-cyanophenyl)piperidiny|)methy|)—5-methoxy- 7-methyI-1H-indole—1-carboxylate (diastereomer— 2) Intermediate 1-3 and Intermediate 23 (i)—ethy| 2—(1-((1-(tert—butoxycarbony|)methoxy- 7-methyI-1H-indoIyl)methyl)piperidin-2— y|)thiazole—4-carboxylate Intermediate 1-3 and Intermediate 2-24 (i)—methy| 2-(1-((1-(tert—butoxycarbonyI) methoxymethyI-1H-indoIyl)methyl)piperidin- 4-methylthiazole—5-carboxylate Intermediate 1-3 and Intermediate 2-25 WO 2015/009616 PCT/US2014/046515 rt—buty| oxy((2—(4- (methoxycarbonyl)phenyl)piperidiny|)methy|)—7- methyl-1H-indoIecarboxylate Intermediate 1-3 and (S)—methyl 4-(piperidinyl)benzoate (CAS: 12134555) (i)—ten‘-buty| 5-methoxy((2—(3-methoxy (methoxycarbonyl)phenyl)piperidiny|)methy|)—7- -1H-indole—1-carboxylate Intermediate 1-3 and Intermediate 2-17 (i)—ten‘-buty| 5-methoxy((5-(4- (methoxycarbonyl)pheny|)azaspiro[2.5]octan y|)methy|)—7-methyI-1H-indoIecarboxylate (APC|+) 519.1 Intermediate 1-3 and (M+1) Intermediate 2-27 (i)—tert—buty| 4-((re/-(28,4S)—4-ethy|—2-(4- (methoxycarbonyl)phenyl)piperidiny|)methy|)—5- methoxymethyI-1H-indole—1-carboxylate (APC|+) 521.1 Intermediate 1-3 and (M+1) Intermediate 2-28 WO 2015/009616 PCT/US2014/046515 Intermediate 4-5: (i)-tert-Butyl 4-((2-(4-cyanophenyI)hydroxypiperidiny|)methyl)methoxymethyl-1H- indolecarboxylate (diastereomer—1) N\\ N OH O\ / l‘ 800 diastereomer-1 The title compound was sized from (i)—ten‘-butyl 4-((5-((ten‘-butyldiphenylsilyl)oxy)—2— (4-cyanophenyl)piperidiny|)methyl)methoxymethyl-1H-indolecarboxylate ereomer- 1), Intermediate 421 (diastereomer—1), analogously to the preparation of Intermediate 2E.
MS (ESI+) m/z 476.4 (M+H).
Intermediate 4-6: 10 rt-Butyl 4-((2-(4-cyanophenyI)hydroxypiperidiny|)methyl)methoxymethyl-1H- carboxylate (diastereomer—Z) N\\ N OH O\ / IN Boc diastereomer-2 The title compound was synthesized from (i)—ten‘-butyl 4-((5-((tert-butyldiphenylsilyl)oxy)—2— (4-cyanophenyl)piperidiny|)methyl)methoxymethyl-1H-indolecarboxylate (diastereomer- 15 2), Intermediate 422 (diastereomer—Z),analogously to the preparation of Intermediate 2E.
MS (ESI+) m/z 476.3 (M+H).
Intermediate 4-7: (i)-tert-Butyl 4-((2-(3-cyanophenyl)piperidiny|)methyI)-5,7-dimethyl-1H-indoIe carboxylate 20 WO 2015/009616 PCT/US2014/046515 To a on of (i)—ten‘-butyl 4-((2-(3-bromophenyl)piperidinyl)methyl)-5,7-dimethyl-1H- indole—1-carboxylate, Intermediate 48, (200 mg, 0.402 mmol) and zinc cyanide (10.16 mg, 0.087 mmol) in DMF (1.5 mL) was added Pd(PPh3)4 (50 mg, 0.043 mmol). The mixture was then stirred at 80 °C for 6 h, and then cooled to room temperature. The mixture was diluted with EtOAc. The organic phase was then washed successively with H20 (twice), and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography ne/EtOAc) to afford the title compound. MS (APC|+) m/z 444.1 (M+H).
Intermediate 4-8: (i)-Methyl 3-(1-((5,7-dimethyI-1H-indoly|)methyl)piperidinyl)benzoate 10 To a solution of (i)—ten‘-butyl 4-((2-(3-bromophenyl)piperidiny|)methyl)—5,7-dimethyl-1H- indole—1-carboxylate, Intermediate 48, (580 mg, 1.166 mmol), Et3N (1 mL, 7.21 mmol), and Pd(OAc)2 (52.4 mg, 0.233 mmol) in DMSO (18 mL)/MeOH (18 mL) was added 1,3- bis(diphenylphosphino)propane (192 mg, 0.466 mmol). The mixture was then stirred at 80 °C 15 under carbon monoxide atmosphere (100 psi) for ca. 16h. The on mixture was diluted with EtOAc. The e was then washed successively with H20 (twice) and brine, dried over NaZSO4, filtered, and concentrated. The resulting e was purified by silica gel flash column chromatography (heptane/EtOAc) to afford the title compound. MS (APC|+) m/z 377.1 (M+H).
Intermediate 4-9: 20 (i)-tert-Butyl 5-methoxy((2-(4-(methoxycarbonyl)phenyl)azepany|)methyI)methyI-1H- indolecarboxylate / Bee The title compound was synthesized from (i)—ten‘-butyl 4-((2-(4-bromophenyl)azepan y|)methyl)methoxymethy|—1H-indoIecarboxylate, ediate 47, analogously to the 25 preparation of Intermediate 4-8. MS (APC|+) m/z 507.2 (M+1) WO 2015/009616 PCT/US2014/046515 Intermediate 4-10: (S)-tert-Butyl 4-((2-(4-(1H-pyrazolyl)phenyl)piperidiny|)methyl)methoxymethyl-1H- indolecarboxylate / \ N Boc/ 5 To a suspension of (S)—ten‘-butyl 4-((2-(4-bromophenyl)piperidinyl)methyl)methoxy methyl-1H-indolecarboxylate, Intermediate 46 (153 mg, 0.298 mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)—1H-pyrazole (89 mg, 0.46 mmol), and K2C03 (124 mg, 0.9 mmol) in dioxane (8 mL)/H20 (2 mL) was added Pd(PPh3)4 (30 mg, 0.026 mmol). The mixture was then stirred at 90 °C for ca. 16h. The reaction mixture was then cooled down to room temperature, and 10 then diluted with EtOAc. The e was then washed successively with 5% aq. NaHC03, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 1/1) to afford the title compound.
MS (ES|+) m/z 501.3 (M+H).
Intermediate 4-11: 15 (S)-tert-Butyl 4-((2-(4-(1H-pyrazolyl)phenyl)piperidiny|)methyl)methoxymethyl-1H- indolecarboxylate HN~N % NO / \ The title compound was synthesized from n‘-butyl (4-bromophenyl)piperidin yl)methyl)methoxymethyl-1H-indolecarboxylate, Intermediate 46, and 3-(4,4,5,5- 20 tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole analogously to the ation of Intermediate 4- 10. MS (ESI+) m/z 501.3 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 4-12: (i)-tert-Butyl 5-methoxy((2-(4-(methoxycarbonyl)naphthaleny|)piperidiny|)methyI) methyl-1H-indolecarboxylate To a solution of tert—butyl 4-(hydroxymethyl)methoxymethyl-1H-indolecarboxylate, Intermediate 1-10, (50 mg, 0.172 mmol) in DMSO (1 mL) at room temperature was added cyanuric chloride (63 mg, 0.344 mmol). The mixture was then d at room temperature for 2h, and then quenched with H20. The mixture was then extracted with EtOAc. The organic layer was washed successively with H20 and brine, dried over NaZSO4, filtered, and then concentrated. The resulting 10 residue was dissolved in DMF (3 mL). To the DMF on was added (i)—methy| 4-(piperidin naphthoate HCI salt, Intermediate 26, (79mg, 0.26 mmol) and iPr2NEt (0.13 mL, 0.777 mmol), followed by potassium iodide (21.6 mg, 0.13 mmol). The e was then stirred at room temperature for 4 days. The reaction mixture was then diluted with EtOAc. The organic phase was washed successively with H20 and brine, dried over NaZSO4, ed, and concentrated. The 15 resulting residue was purified by silica gel flash column chromatography (heptane/EtOAc = 1/0 to 8/2) to afford the title compound. MS (APC|+) m/z 543.2 (M+H).
Intermediate 4-13 and Intermediate 4-14: Intermediate 4A; (i)-tert-buty| 5-methoxymethyl(2,2,2-trif|uorohydroxyethy|)-1H- indolecarboxylate CF3 OH O\ / ,N 20 Boc To a on of tert—butyl 4-formylmethoxymethyl-1H-indole—1-carboxylate, Intermediate 1-3, (1.34 g, 4.6 mmol) and hyl(trifluoromethyl)silane (900 mg, 4.88 mmol) in THF (10 mL) was added TBAF (1M in THF, 92 uL, 0.09 mmol) at -20°C. The mixture was then stirred at room temperature for 2h, and then concentrated. The resulting residue was purifies by 25 silica gel flash column chromatography (heptane/EtOAc = 1/0 to 8/2) to afford the title compound.
WO 2015/009616 PCT/US2014/046515 1H NMR (300 MHz, CDCI3) 6 7.54 (d, J=3.0 Hz, 1H), 6.79 (s, 1H), 6.58 (d, J=3.0 Hz, 1H), 5.30 - 5.46 (m, 1H), 4.63 (br. d, J=5.4 Hz, 1H), 3.93 (br. s., 3H), 2.63 (s, 3H), 1.62 (s, 9H). ediate 4-13; methyl -(1-(2,2,2-trifluoro(5-methoxymethyI-1H-indol yl)ethyl)piperidinyl)benzoate (diastereomer-1): and Intermediate 4-14; methyl 4-(2S)-(1- (2,2,2-trifluoro(5-methoxymethyI-1H-indoly|)ethyl)piperidinyl)benzoate (diastereomer—2): o 0 CF3 [‘0 CFs IO 0 O / \ / \ N N H diastereomer-1 H diastereomer-Z To a solution of (i)—ten‘-buty| 5-methoxymethyI(2,2,2-trif|uorohydroxyethy|)—1H- indoIecarboxylate, Intermediate 4A, (350 mg, 0.974 mmol) in CH2C|2 (5 mL) at 0 °C was 10 added Et3N (162 uL, 1.169 mmol), followed by MsCI (91 uL, 1.169 mmol). The mixture was then stirred at room temperature for 16h. The mixture was then diluted with CH2C|2. The mixture was then washed successively with 5% aq. NaHC03, H20, and brine, dried over Na2804, filtered, and concentrated. To a solution of the ing residue in CH3CN (5 mL) was added Et3N (1 mL, 7.21 mmol), followed by methyl (S)—4-(piperidiny|)benzoate (125 mg, 0.487 mmol). The mixture was 15 then stirred at 130 °C for 16h in the sealed tube. The reaction e was then trated. The resulting residue was purified by RP-HPLC (stationary phase; XbridgeTMC-18: mobile phase; 0.05% TFA in HZO/CH3CN: gradient; 5% to 90% B in 40 min) to afford, in respective elution order, tert- butyl 5-methoxymethyI(2,2,2-trif|uoro((S)—2-(4-(methoxycarbonyl)phenyl)piperidin y|)ethy|)-1H-indoIecarboxylate (diastereomer—1, tr = 23.8 min) as Intermediate 4-13, MS (APC|-) 20 m/z 459.16 (M-H); and utyl 5-methoxymethyI(2,2,2-trifluoro((S)—2-(4- (methoxycarbonyl)pheny|)piperidiny|)ethy|)-1H-indoIecarboxylate (diastereomer—2, tr = 26.1 min) as Intermediate 4-14, MS (APC|-) m/z 459.15 (M-H).
WO 2015/009616 PCT/US2014/046515 ediate 4-15: (i)((2-(4-(2H-tetrazolyl)phenyl)piperidiny|)methyI)-5,7-dimethyltosyI-1H-indole ,N=N HN\ / N A mixture of (i)—4-(1-((5,7-dimethyltosyl-1H-indolyl)methyl)piperidinyl)benzonitrile, Intermediate 311, (80 mg, 0.161 mmol), sodium azide (15.68 mg, 0.241 mmol), and triethylamine hydrochloride (33.2 mg, 0.241 mmol) in chlorobenzene (2 mL) was stirred at 110 °C for 1 hr, and then at 130 0C for 5 hr. To the mixture were added additional amounts of sodium azide (29 mg) and triethylamine hydrochloride (63 mg) at room temperature. The mixture was then stirred at 130 °C for 3 hr, and then cooled to room ature. The mixture was then diluted with 10 H20, and then acidified with 1 mL of AcOH. The mixture was then extracted three times with EtOAc. The combined organic layers were then dried over NaZSO4, filtered, and then concentrated.
The resulting residue was purified by silica gel flash column chromatography [heptane/(5% MeOH in EtOAc = 1/0 to 0/1) to afford the title compound. MS (ESI+) m/z 541.5 (M+H).
Intermediate 5-1: N xfloN xfloN 15 Intermediate 5-1a; rt-butyl 5-methoxy((reI-(2S,4R)(4-(methoxycarbonyl)phenyl) methylpiperidiny|)methy|)methyl-1H-indolecarboxylate To a solution of tert—butyl 4-formylmethoxymethyl-1H-indolecarboxylate, Intermediate 1-3, (1.8 g, 6.22 mmol) and (i)—methyl 4-(rel-(2S,4R)—4-methylpiperidin 20 yl)benzoate, Intermediate 2-16, (1.2 g, 5.14 mmol) in DOE (15 mL) was added Ac)3 (3 g, 14.15 mmol). The mixture was then stirred at room temperature for 14h. The reaction e was d with EtOAc. The mixture was then washed successively with 5% aq. NaHC03, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel WO 2015/009616 PCT/US2014/046515 flash column chromatography (heptane/EtOAc = 91/1) to afford the title compound. (ESI+) m/z 507.1 (M+H).
Intermediate 5-1b; tert-butyl 5-methoxy(((2S,4R)(4-(methoxycarbonyl)phenyl)—4- methylpiperidiny|)methy|)methyl-1H-indolecarboxylate and tert-butyl 5-methoxy (((2R,4S)(4-(methoxycarbonyl)phenyI)methylpiperidinyl)methyI)methyI-1H-indole- 1-carboxylate Resolution of the enantiomers of Intermediate 5-1a was achieved by chiral SFC using a CHIRALPAK® IA column with 20% iPrOH in C02 to give tert—butyl oxy(((28,4R)—2-(4- 10 (methoxycarbonyl)phenyl)—4-methylpiperidinyl)methyl)methyl-1H-indolecarboxylate (peak- 1, tr = 4.1 min) and utyl 5-methoxy(((2R,4S)—2-(4-(methoxycarbonyl)phenyl) methylpiperidinyl)methyl)methyl-1H-indolecarboxylate (peak-2, tr = 5.8 min).
Intermediate 5-2: Intermediate 5-2a; (i)-tert-butyl 5-methoxy(reI-(2S,4S)-(4-methoxy(4- 15 (methoxycarbonyl)phenyl)piperidinyl)methyI)methyI-1H-indoIecarboxylate O O N O\ / N Boc/ reI-(28, 48) To a solution of tert—butyl 4-formylmethoxymethyl-1H-indolecarboxylate, Intermediate 1-3, (120 mg, 0.415 mmol) and thyl -(2S,4S)—4-methoxypiperidin yl)benzoate, Intermediate 2-12, (100 mg, 0.401 mmol) in DOE (2 mL) was added NaB(OAc)3H 20 (400 mg, 1.887 mmol). The mixture was then stirred at room temperature for 17h. The mixture was then diluted with CH2C|2. The e was then washed successively with 5% aq. NaHC03, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography on aminopropyl-functionalized silica gel (heptane/EtOAc = 94/6) to afford the title compound. MS (ESI+) m/z 523.4 (M+H).
WO 2015/009616 PCT/US2014/046515 Intermediate 5-2b; tert-butyl 5-methoxy((2R,4R)-(4-methoxy(4- (methoxycarbonyl)phenyl)piperidiny|)methyl)methyl-1H-indolecarboxylate: and tertbutyl 5-methoxy((2S,4S)-(4-methoxy(4-(methoxycarbonyl)phenyl)piperidiny|)methyl)- 7-methyl-1H-indolecarboxylate: o o \O \O I I MO N 0’o O 0\ / \ / IN IN Boo 800 Resolution of the enantiomers of Intermediate 5-2a was ed by chiral SFC using a CHIRALPAK® AD-H column with 15% (5mM NH4OH in MeOH) in 002 to afford tert—butyl 5- methoxy((2R,4R)—(4-methoxy(4-(methoxycarbonyl)phenyl)piperidinyl)methyl)methyl-1H- indolecarboxylate (peak-1, tr = 2.8 min) and tert—butyl 5-methoxy((2S,4S)—(4-methoxy(4- 10 xycarbonyl)phenyl)piperidinyl)methyl)methyl-1H-indolecarboxylate (peak-2, tr = 5.5 min).
The following compounds were prepared from riate starting materials by similar methods described above: chemical name lnterme structure MS (m/z) ng material_ _ diate Conditions for the enantiomer separation (i)—tert—butyl 4-(rel—(2S,4S)—(4-ethoxy-2—(6- (methoxycarbonyl)pyridinyl)piperidin yl)methyl)methoxymethyl-1H-indole carboxylate Intermediate 1-3 and Intermediate 2-20 Resolution of the omers of Intermediate 51a was achieved by chiral SFC using a (R,R) Whelk-O®1 column with 40% MeOH in 002 to afford utyl 4-(rel- (28,4S)—(4-ethoxy(6-(methoxycarbonyl)pyridinyl)piperidinyl)methyl)methoxy- 7-methyl-1H-indole—1-carboxylate (enantiomer-1 ) (peak-1, tr = 4.9 min) and tert—butyl 4- (rel-(2S,4S)—(4-ethoxy(6-(methoxycarbonyl)pyridinyl)piperidinyl)methyl) methoxymethyl-1H-indolecarboxylate (enantiomer-2) (peak-2, tr = 6.0 min).
WO 2015/009616 PCT/US2014/046515 (i)—ten‘-butyl 5-methoxy((2-(4- (methoxycarbonyl)phenyl)—4,4- dimethylpiperidinyl)methyl)methyl-1H- indolecarboxylate Intermediate 1-3 and Intermediate 2-22 Resolution of the enantiomers of Intermediate 52a was achieved by chiral SFC using a CHIRALPAK® AD column with 20% (5mM NH4OH in MeOH) in 002 to afford tert—butyl 5-methoxy((2-(4-(methoxycarbonyl)phenyl)-4,4-dimethylpiperidin yl)methyl)—7-methyl-1H-indolecarboxylate (enantiomer-1) (peak-1, tr = 2.4 min) and tert—butyl oxy((2-(4-(methoxycarbonyl)phenyl)-4,4-dimethylpiperidin yl)methyl)—7-methyl-1H-indolecarboxylate (enantiomer—2) (peak-2, tr = 4.4 min). (i)—ten‘-butyl 4-(re/-(28,4S)—(2—(4- cyanophenyl)ethoxypiperidinyl)methyl)- 5-methoxymethyl-1H-indolecarboxylate Intermediate 1-3 and ediate 2-13b Resolution of the enantiomers of Intermediate 53a was achieved by chiral SFC using a CHIRALPAK® AD-H column with 20% (10mM NH4OH in MeOH) in 002 to afford tert—butyl 4-(rel-(28,4S)—(2—(4-cyanophenyl)ethoxypiperidinyl)methyl)methoxy methyl-1H-indolecarboxylate )enantiomer—1) (peak-1, tr = 1.7 min) and tert—butyl 4- (rel-(2S,4S)—(2—(4-cyanophenyl)ethoxypiperidiny|)methyl)methoxy—7-methyl-1 H- indolecarboxylate (enantiomer—2) (peak-2, tr = 3.4 min). ediate 6-1: / N H Intermediate 6-1a; (i)-methyl 4-(1-((5,7-dimethyI-1H-indoly|)methyl)piperidinyl)benzoate A mixture of (i)—4-(1-((5,7-dimethyltosyl-1H-indolyl)methyl)piperidinyl)benzonitrile, Intermediate 311, (550 mg, 1.105 mmol) and KOH (500 mg, 8.91 mmol) in EtOH (8 mL) was stirred at 130 °C under the microwave irradiation for 2.5 hr. The on mixture was acidified by said. aq. citric acid. The e was then extracted with CHZCIZ/TFE (ca. 9/1) two times. The WO 2015/009616 PCT/US2014/046515 combined organic layers were then dried over NaZSO4, filtered, and concentrated. The resulting residue was dissolved in toluene/MeOH (50mL/15 mL). To the mixture at 0 °C was added trimethylsilyldiazomethane EtZO (2M, 5 ml, 10 mmol). The mixture was then stirred at 0 °C for 1.5h.
The reaction was then quenched with acetic acid. The mixture was then diluted with EtOAc. The e was then washed successively with 5% aq. NaHCOs twice, H20, and brine, dried over NaZSO4, filtered, and then concentrated. The resulting e was purified by silica gel column chromatography (heptane/EtOAc = 76/24) to afford the title compound. MS (ESI+) m/z 377.5 (M+H).
Intermediate 6-1b; 10 Resolution of the enantiomers of (i)—methyl 4-(1-((5,7-dimethyl-1H-indol yl)methyl)piperidinyl)benzoate, Intermediate 6-1 a, was achieved by chiral SFC using a CHIRALCEL® OJ-H column with 30% (0.2% DEA in MeOH) in 002 to give methyl 4-(1-((5,7- dimethyl-1H-indolyl)methyl)piperidinyl)benzoate (enantiomer—1) (peak-1, tr = 2.6 min) and methyl 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoate iomer—2) 2, tr = 15 4.1 min).
Intermediate 6-2: Intermediate 6-2a; (i)-methyl 4-(reI-(2S,4S)ethoxy((5-methoxymethyI-1H-indoI yl)methyl)piperidinyl)benzoate O O N O\ / N H rel-(28,48) 20 A mixture of (i)—ten‘-butyl 4-((rel-(2S,4S)—4-ethoxy(4-(methoxycarbonyl)phenyl)piperidin- 1-y|)methyl)methoxymethyl-1H-indolecarboxylate, Intermediate 4-3, (310 mg, 0.578 mmol) in MeOH (15 mL) and K2003 (639 mg, 4.62 mmol) was d for 3h under the reflux condition, and then trated. The resulting residue was then diluted with satd. aq. citric acid. The mixture was then extracted three times with EtOAc. The combined organic layers were then dried over 25 , filtered, and then concentrated. The resulting residue in toluene (15 mL) and MeOH (5 mL) was added hylsilyldiazomethane (2M in EtZO, 2 mL, 2 mmol) dropwise. The mixture was stirred at room temperature for 0.25h. The reaction was then quenched with AcOH at 0 °C. The reaction mixture was diluted with 5% aq. NaHCOs. The mixture was then extracted three times with EtOAc. The combined organic layers were concentrated. The resulting residue was purified by WO 2015/009616 PCT/US2014/046515 silica gel flash column chromatography (heptane/EtOAc = 1/0 to 1/7) to afford the title compound.
MS (ESI+) m/z 437.5 (M+H).
Intermediate 6-2b; methyl 4-((2$,4S)ethoxy((5-methoxymethyl-1H-indol yl)methyl)piperidinyl)benzoate and methyl 4-((2R,4R)ethoxy((5-methoxymethyl-1H- 5 indolyl)methyl)piperidinyl)benzoate O O \O K \O K 0,,UO "‘0 N O\ O\ / / N N H H Resolution of the enantiomers of (i)—methyl 4-(rel-(28,4S)—4-ethoxy((5-methoxymethyl- 1H-indoIyl)methy|)piperidiny|)benzoate, Intermediate 6-2a, was ed by chiral SFC using a CHIRALPAK® AD-H column with 35% (5mM NH4OH in iPrOH) in 002 to afford methyl 4-((28,4S)— 10 4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoate (peak-1, tr = 1.9 min) and methyl 4-((2R,4R)—4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin-2— y|)benzoate (peak-2, tr = 3.4 min).
The following compounds were ed from the appropriate intermediate by similar 15 methods as described in the examples above: chemical name ure MS (m/z) startIng materIal. .
Conditions for the enantiomer separation (i)—methy| 4-(re/-(28,4S)—1-((5,7- dimethyl-1H-indolyl)methyl) ethoxypiperidinyl)benzoate Resolution of the enantiomers of (i)—methyl 4-(reI-(28,4S)((5,7-dimethyl-1H-indol hyl)ethoxypiperidinyl)benzoate was achieved by chiral SFC using a CHIRALPAK® AD-H column with 40% (5mM NH4OH in iPrOH) in 002 to afford methyl 4- (rel-(28,4S)((5,7-dimethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoate (enantiomer-1) 1, tr = 1.7 min) and methyl 4-(re/-(28,4S)—1-((5,7-dimethyl-1H-indol- 4-yl)methyl)—4-ethoxypiperidinyl)benzoate (enantiomer-2) (peak-2, tr = 4.4 min).
WO 2015/009616 PCT/US2014/046515 O (i)—methy| 4-(rel-(2S,4S)—1-((5- /J) cyclopropyImethyI-1H-indoI yl)methyl)methoxypiperidin N y|)benzoate / fl Intermediate 325 rel-(28,48) Resolution of the enantiomers of (i)—methyl 4-(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H- 4-yl)methyl)methoxypiperidiny|)benzoate was achieved by chiral SFC using a CEL® OJ-H column with 30% (5mM NH4OH in MeOH) in C02 to give methyl 4- 2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidin y|)benzoate (enantiomer—1) (peak-1, tr = 2.0 min) and methyl 4-(rel-(2S,4S)—1-((5- cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoate (enantiomer—2) (peak-2, tr = 4.3 min). 0 (i)—methy| 4-(re/-(2S,4S)—1-((5- \o 0K cyclopropyImethyI-1H-indoI yl)methyl)—4-ethoxypiperidin N y|)benzoate / N lntermedIate 410.
H rel-(28,48) Resolution of the enantiomers of (i)—methyl 4-(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H- indoIyl)methyl)—4-ethoxypiperidiny|)benzoate was achieved by chiral SFC using a CHIRALPAK® AD-H column with 40% (5mM NH4OH in iPrOH) in C02 to give methyl 4- 64b (rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)ethoxypiperidin zoate (enantiomer—1) (peak-1, tr = 1.3 min) and methyl 4-(rel-(2S,4S)—1-((5- cyclopropylmethyl-1H-indolyl)methyl)—4-ethoxypiperidinyl)benzoate (enantiomer- 2) (peak-2, tr = 2.9 min).
Example-1: (i)((5,7-Dimethyl-1H-indoly|)methyl)phenylpiperidinol (diastereomer—1) OH N / N H diastereomer-1 A mixture of (i)—1-((5,7-dimethyltosyl-1H-indolyl)methyl)—2-phenylpiperidinol ereomeric mixture), Intermediate 3-1, (200 mg, 0.409 mmol), KOH (100 mg, 1.782 mmol), and isoamylamine (200 uL, 1.721 mmol) in EtOH (5 mL) was stirred at 100 °C under the microwave WO 2015/009616 PCT/US2014/046515 ation for 1 hr. The reaction mixture was diluted with . The mixture was ed through a plug of silica gel, which was rinsed with a mixture of CH2C|2/MeOH (ca. 6/1 ). The filtrate was concentrated. The resulting residue was purified by silica gel flash column chromatography 2/MeOH = 93/7to 85/15) to afford, in respective elution order, (i)—1-((5,7-dimethyl-1H-indol yl)methyl)pheny|piperidinol (diastereomer—1) as e-1 and diastereomer—2. 1H NMR (400 MHz, CD3CN) 6 9.12 (br. s., 1H), 7.53 (d, J=7.33 Hz, 2H), 7.38 (dd, J=7.33, 7.80 Hz, 2H), 7.26 - 7.32 (m, 1H), 7.16 (dd, J=2.80, 3.03 Hz, 1H), 6.71 (s, 1H), 6.56 (dd, J=2.02, 3.03 Hz, 1H), 3.63 (d, J=12.13 Hz, 1H), 3.53 - 3.60 (m, 1H), 3.14 - 3.19 (m, 1H), 3.12 (d, J=12.13 Hz, 1H), 2.80 (br. s., 1H), 2.59 - 2.65 (m, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 1.96 - 2.05 (m, 1H), 1.87 - 1.91 (m, 1H), 1.68 - 10 1.75 (m, 1H), 1.56 - 1.67 (m, 1H), 1.21 - 1.34 (m, 1H); HRMS calcd. for C22H27N20 (M+H)+ 335.2123, found 335.2119.
Example-2: OH N / N H diastereomer-2 e-2a; (i)((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinol (diastereomer—2) 15 The title compound was isolated as the diastereomer—2 in the preparation of Example-1. 1H NMR (400 MHz, CD3CN) 6 9.09 (br. s., 1H), 7.54 (d, J=7.30 Hz, 2H), 7.37 (dd, J=7.30, 7.80 Hz, 2H), 7.23 - 7.32 (m, 1H), 7.12 - 7.21 (m, 1H), 6.71 (s, 1H), 6.55 - 6.63 (m, 1H), 3.91 - 4.00 (m, 1H), 3.66 (d, J=12.13 Hz, 1H), 3.53 (br. d, J=8.80 Hz, 1H), 3.23 (br. d, J=10.90 Hz, 1H), 2.64 (br. s., 1H), 2.31 - 2.48 (m, 5H), 2.27 (s, 3H), 1.84 -1.91 (m, 1H), 1.68 - 1.78 (m, 1H), 1.43 - 1.66 (m, 2H); HRMS 20 calcd. for N20 (M+H)+ 335.2123, found 335.2123.
Example-2b; (+) and (-)((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinol (diastereomer—2).
Resolution of the enantiomers of (i)—1-((5,7-dimethyl-1H-indolyl)methyl) phenylpiperidinol (diastereomer—2), Example-2a, was achieved by chiral SFC using a 25 CHIRALPAK® AD-H column with 30% (10mM NH4OH in MeOH) in C02 to afford, in respective order, (+)((5,7-dimethyl-1H-indolyl)methyl)—2-phenylpiperidinol (diastereomer—2) (peak-1, tr = 1.6 min) and (-)((5,7-dimethyl-1H-indolyl)methyl)—2-phenylpiperidinol (diastereomer—2) (peak-2, tr = 3.0 min).
WO 2015/009616 PCT/US2014/046515 Example-3: (i)((5,7-Dimethyl-1H-indolyl)methyl)phenylpiperidinol (diastereomer—1) 0\ N / N H reomer-1 The title compound was sized from (i)—4-((4-methoxyphenylpiperidinyl)methyl)- 5,7-dimethyltosyl-1H-indole (diastereomeric mixture), Intermediate 31, by similar manner to the preparation of Example-1. Separation of the diastereomers were achieved by silica gel flash column chromatography ne/(10% MeOH in EtOAc) = 77/23] to afford, in tive elution order, Example-3 (diastereomer—1), and diastereomer—2. 1H NMR (400 MHz, CD3CN) 5 9.09 (br. s., 1H), 7.54 (d, J=7.20 Hz, 2H), 7.38 (dd, J=7.20, 7.80 Hz, 2H), 7.26 - 7.31 (m, 1H), 7.16 (dd, 10 J=2.80, 3.00 Hz, 1H), 6.71 (s, 1H), 6.54 - 6.57 (m, 1H), 3.62 (d, J=12.13 Hz, 1H), 3.19 - 3.29 (m, 4H), 3.10 - 3.18 (m, 2H), 2.64 (td, J=3.54, 11.87 Hz, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 2.02 - 2.10 (m, 1H), 1.97 - 2.02 (m, 1H), 1.79 - 1.90 (m, 1H), 1.55 (dd, J=11.40, 12.13 Hz, 1H), 1.14 - 1.25 (m, 1H); HRMS calcd. for C23H29N20 (M+H)+ 349.2280, found 349.2278.
Example-4: 0\ N / N 15 H diastereomer—2 Example-4a; (i)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer—2) The title compound was isolated as the diastereomer—2 in the preparation of Example-3. 1H NMR (400 MHz, CD3CN) 5 9.08 (br. s., 1H), 7.54 (d, J=7.33 Hz, 2H), 7.37 (dd, J=7.33, 7.80 Hz, 2H), 20 7.25 - 7.30 (m, 1H), 7.14 - 7.17 (m, 1H), 6.70 (s, 1H), 6.58 (dd, J=2.02, 3.03 Hz, 1H), 3.63 (d, 3 Hz, 1H), 3.45 - 3.50 (m, 1H), 3.41 (dd, J=3.41, 11.24 Hz, 1H), 3.27 (s, 3H), 3.19 (d, J=12.13 Hz, 1H), 2.38 (s, 3H), 2.32 - 2.37 (m, 1H), 2.21 - 2.31 (m, 4H), 1.78 - 1.91 (m, 2H), 1.70 - 1.77 (m, 1H), 1.45 - 1.54 (m, 1H); HRMS calcd. for C23H29N20 (M+H)+ 349.2280, found 349.2276.
WO 2015/009616 2014/046515 Example-4b; (+) and (-)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer—2) Resolution of the enantiomers of (i)—4-((4-methoxyphenylpiperidinyl)methyl)-5,7- dimethyl-1H—indole (diastereomer—2), Example-4a, was achieved by chiral SFC using a CHIRALPAK® lB column with 30% (10mM NH4OH in iPrOH) in C02 to afford, in respective elution order, (+)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer-2) (peak-1, tr = 3.1 min) and (-)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer—2)(peak-2, tr = 4.3 min). 10 The following Examples were synthesized from appropriate starting als by ng similar methods described in the examples above: Chemical name Exam starting materials Chemical p_|e structure NMR; HRMS (i)—5,7-dimethyl((2-phenylpiperidinyl)methyl)-1H-indole Intermediate 34 1H NMR (400 MHz, CD2C|2) 6 ppm 8.04 (br. s., 1 H), 7.53 (d, J=7.1 Hz, 2 H), 7.36 , J=7.3 Hz, 2 H), 7.26 (app.t, J=7.2 Hz, 1 H), 5_1 — N 7.16 (br. s., 1 H), 6.74 (s, 1 H), 6.68 (br. s., 1 H), 3.72 (d, J=12.4 Hz, 1 H), 3.15 (d, J=12.4 Hz, 1 H), 3.00 - 3.10 (m, 1 H), 2.72 (d, J=10.9 / Hz, 1 N H), 2.40 (s, 3 H), 2.31 (s, 3 H), 1.94 (t, J=11.4 Hz, 1 H), 1.65 - H 1.79 (m, 3 H), 1.26 - 1.47 (m, 3 H); HRMS ca|cd. for N2 (M+H)+ 318.2096, found 318.2105. (i)—1-((5,7-dimethyl-1H-indolyl)methyl)phenyl-piperidinyl)methanol (diastereomer—1) Intermediate 35 1H NMR (TFA salt, 400 MHz, D20) 6 7.47-7.67 (m, 5H), 7.25 (d, 5-2 @waN J=3.03 Hz, 1H), 6.78 (s, 1H), 6.12 (br. s., 1H), 4.40 (br. dd, J=2.90, 12.30 Hz, 1H), 4.23 (d, J=13.60 Hz, 1H), 4.07 (d, J=13.60 Hz, 1H), 3.39 (d, J=6.32 HZ, 2H), 3.33-3.38 (m, 1H), 3.18-3.29 (m, 1H), 2.32 / (s, 3H), 2.05-2.13 (m, 1H), 1.91-2.03 (m, 4H), 1.77-1.89 (m, 2H), N H 1.24-1.38 (m, 1H); HRMS ca|cd. for C23H29N20 (M+H)+ 349.2280, reomer-1 found 349.2265.
WO 2015/009616 PCT/US2014/046515 (i)—1-((5,7-dimethy|—1H-indoIyl)methyl)pheny|—piperidiny|)methano| (diastereomer—2) Intermediate 36 QC)OH 1H NMR (TFA salt, 400 MHZ, D20) 6 7.49-7.63 (m, 5H), 7.26 (d, N J=3.03 Hz, 1H), 6.78 (s, 1H), 6.12 (br. s., 1H), 4.46 (dd, J=2.65, 13.26 Hz, 1H), 4.20 (d, J=13.40 Hz, 1H), 4.10 (d, J=13.40 Hz, 1H), L 3.77 (d, J=7.83 Hz, 2H), 3.15-3.29 (m, 2H), 2.26-2.40 (m, 4H), 1.95- H 2.14 (m, 5H), 1.70-1.90 (m, 2H); HRMS calcd. for C23H29N20 diastereomer-Z (M+H)+ 349.2280, found 349.2270. (i)—4-(1-((5,7-dimethyI-1H-indoIyl)methyl)piperidiny|)benzenesu|fonamide Intermediate 37 (isolated as a single somer) 1H NMR (400 MHz, CD2C|2) 5 8.11 (br. s., 1H), 7.91 (d, J=8.46 Hz, 2H), 7.75 (br. d, J=8.10 Hz, 2H), 7.22 (dd, J=2.70, 2.80 Hz, 1H), 6.79 (s, 1H), 6.66-6.74 (m, 1H), 4.84 (br. s., 2H), 3.71 (d, J=12.25 Hz, 1H), 3.26 (d, J=12.38 Hz, 1H), 3.22 (dd, , 10.74 Hz, 1H), 2.74-2.83 (m, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 1.96-2.05 (m, 1H), 1.64-1.85 (m, 3H), 1.38-1.54 (m, 2H), 1.37 (d, J=4.55 Hz, 1H); HRMS calcd. for C22H28N3038 (M+H)+ 398.1902, found 398.1893. (i)—3-(1-((5,7-dimethyI-1H-indoIyl)methyl)piperidiny|)benzenesu|fonamide Intermediate 37 (isolated as a single somer) 1H NMR (TFA salt, 400 MHz, CD30D)610.79(br.s., 1H), 8.21 (s, 1H), 8.11 (td, J=1.47, 7.80 Hz, 1H), 7.87 (br. d, J=7.80 Hz, 1H), .82 (m, 1H), 7.30-7.33 (m, 1H), 6.83 (s, 1H), 6.34 (d, J=3.03 Hz, 1H), 4.58-4.65 (m, 1H), 4.26- 4.35 (m, 2H), 3.54 (br. d, J=11.40 Hz, 1H), 3.36-3.41 (m, 1H), 2.45 (s, 3H), 2.10-2.22 (m, 5H), 1.76-2.02 (m, 4H); HRMS calcd. for C22H28N3038 (M+H)+ 398.1902, found 398.1884.
Intermediate 38 (isolated as a single regioisomer) 1H NMR (TFA salt, 400 MHz, CD30D) 6 8.05 (d, J=8.59 Hz, 2H), 7.86 (d, J=8.46 Hz, 2H), 7.32 (d, J=3.16 Hz, 1H), 6.83 (s, 1H), 6.34 (d, J=3.03 Hz, 1H), 4.58-4.64 (m, 1H), 4.34 (d, J=13.40 Hz, 1H), 4.27 (d, 0 Hz, 1H), 3.50-3.60 (m, 1H), 3.33-3.42 (m, 1H), 2.58 (s, 3H), 2.45 (s, 3H), 2.08-2.21 (m, 5H), 1.73-2.04 (m, 4H); HRMS calcd. for N3028 (M+H)+ 412.2059, found 412.2048.
WO 2015/009616 PCT/US2014/046515 (i)—3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide Intermediate 38 (isolated as a single regioisomer) 1H NMR (400 MHz, CD30D) 6 10.80 (br. s., 1H), 8.18 (s, 1H), 8.00-8.06 (m, 1H), 7.90 (br. d, J=7.70 Hz, 1H), 7.83 (app. t, J=7.70 Hz, 1H), 7.31 (dd, J=2.80, 2.90 Hz, 1H), 6.83 (s, 1H), 6.32-6.38 (m, 1H), 4.59-4.66 (m, 1H), 4.34 (d, J=13.30 Hz, 1H), 4.28 (d, J=13.30 Hz, 1H), 3.54 (br. d, J=12.80 Hz, 1H), .42 (m, 1H), 2.51 (s, 3H), 2.45 (s, 3H), 2.11-2.20 (m, 5H), 1.75-2.02 (m, 4H); HRMS calcd. for C23H30N3028 (M+H)+ 412.2059, found 412.2048. (i)—4-((2-(4-fluorophenyl)—4-methoxypiperidiny|)methyl)—5,7-dimethyl-1H-indole Intermediate 39 1H NMR (400 MHz, CD2C|2) 6 8.08 (br. s., 1 H), 7.44 - 7.57 (m, 2 H), 7.17 (t, J=2.8 Hz, 1 H), 7.07 (t, J=8.8 Hz, 2 H), 6.75 (s, 1 H), 6.62 (dd, J=3.2, 2.1 Hz, 1 H), 3.68 (d, J=12.4 Hz, 1 H), 3.28 (s, 3 H), 3.19 - 3.26 (m, 1 H), 3.08 - 3.17 (m, 2 H), 2.74 (dt, J=11.9, 3.5 Hz, 1 H), 2.41 (s, 3 H), 2.28 (s, 3 H), 2.04 - 2.15 (m, 1 H), 1.98 (td, J=12.3, 2.3 Hz, 1 H), 1.80 - 1.90 (m, 1 H), 1.50 - 1.64 (m, 2 H), 1.23 - 1.39 (m, 1 H); HRMS calcd. for C23H28FN20 (M+H)+ 367.2186, found 367.2174. (i)—(1-((5,7-dimethyl-1H-indolyl)methyl)—2-phenylpiperidinyl)methanol Intermediate 310 1H NMR (400 MHz, DMSO-da) 510.78 (br. s., 1 H), 7.71 (d, J=7.6 Hz, 2 H), 7.31 (t, J=7.7 Hz, 2 H), 7.15 - 7.24 (m, 2 H), 5.55 - 5.71 (m, 1 H), 5.54 (s, 1 H), 4.52 (t, J=4.7 Hz, 1 H), 3.90-4.07 (m, 3 H), 3.80 - 3.89 (m, 2 H), 2.37 (s, 3 H), 2.29 (s, 3 H), 1.98 - 2.13 (m, 1 H), 1.71 - 1.85 (m, 1 H), 1.52- 1.57 (m, 2 H), 1.41 - 1.51 (m, 1 H), 1.25 - 1.35 (m, 1 H), 1.05 - 1.20 (m, 1 H) (i)—(4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol Intermediate 3-3 1H NMR (TFA salt, 400 MHZ, CD3CN) 6 9.45 (br. s., 1H), 9.10 (br. s., 1H), 7.71 - 7.89 (m, 2H), 7.50 (d, J=8.34 Hz, 2H), 7.29 (app. t, J=2.91 Hz, 1H), 6.80 (s, 1H), 6.37 - 6.46 (m, 1H), 4.64 (s, 2H), 4.26 - 4.33 (m, 1H), 4.24 (d, J=13.50 Hz, 1H), 4.01 - 4.12 (m, 1H), 3.34 (d, J=12.38 Hz, 1H), 3.03 - 3.17 (m, 1H), 2.42 (s, 3H), 2.30 - 2.39 (m, 1H), 2.13 (s, 3H), 1.95 - 2.05 (m, 2H), 1.83 - 1.90 (m, 1H),1.71 - 1.79 (m, 1H), 1.55 (td, , 13.23 Hz, 1H); HRMS calcd. for o (M+H)+ 80, found 349.2278.
WO 2015/009616 PCT/US2014/046515 (i)—5,7-dimethyl((2-(4-(methylsulfonyl)phenyl)piperidinyl)methyl)-1H-indole Intermediate 318 Q"? /S\©\© 1H NMR (400 MHz, CDZCIZ) 6 8.12 (br. s., 1H), 7.91 (d, J=8.34 Hz, 2H), 7.78 (d, J=8.08 Hz, 2H), 7.22 (dd, , 3.00 Hz, 1H), 6.78 ‘1" A A (s, 1H), 6.70 (dd, J=2.27, 3.03 Hz, 1H), 3.70 (d, J=12.38 Hz, 1H), 3.27 (d, J=12.38 Hz, 1H), 3.20 - 3.24 (m, 1H), 3.06 (s, 3H), 2.74 - / 2.82 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 1.96 - 2.05 (m, 1H), 1.75 - N 1.85 (m, 2H), 1.64 - 1.75 (m, 1H), 1.38 - 1.53 (m, 3H); HRMS calcd.
H for CstngzOzS (IVI'I'H)+ 397.1950, found 397H1936 (i)((2-(4-(2H-tetrazo|y|)pheny|)piperidiny|)methyI)-5,7-dimethyl-1H-indole ,N=N Intermediate 4-15 HN\ / N 1H NMR (TFA salt, 400 MHz, CD30D) 6 10.80 (br. s., 1H), 8.28 (d, I A N J=8.34 HZ, 2H), 7.86 (d, J=8.34 HZ, 2H), 7.32 (dd, , 2.90 HZ, N 1H), 6.83 (s, 1H), 6.35 - 6.40 (m, 1H), 4.57 - 4.63 (m, 1H), 4.31 - / 4.40 (m, 2H), 3.55 (br. d, J=12.50 Hz, 1H), 3.36 - 3.42 (m, 1H), 2.45 N (S, 3H), 2.11 - 2.25 (m, 5H), 1.77 - 2.04 (m, 4H); HRMS calcd. for H C23H27N5 (M+H)+ 97, found 387.2281.
Example-6: (i)((5,7-DimethyI-1H-indoly|)methyI)pheny|piperidinamine (diastereomer—1) NH2 N / N H diastereomer-1 A mixture of (i)—benzyl (1-((5,7-dimethyltosyl-1H-indolyl)methyl)—2-phenylpiperidin y|)carbamate (diastereomer—1), Intermediate 32, (100 mg, 0.161 mmol) and KOH (100 mg, 1.782 mmol) in EtOH (5 mL)/H20 (0.7 mL) was stirred at 130°C under the microwave irradiation for 0.5h. The on mixture was diluted with CH2C|2. The mixture was filtered through a plug of silica gel, which was rinsed with a mixture of /MeOH (ca. 6/1 ). The combined organic layers 10 were concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. 1H NMR (400 MHz, CD30D) 6 7.54 (br. d, J=7.30 Hz, 2H), 7.36 (dd, J=7.30, 7.60 Hz, 2H), 7.25 - 7.31 (m, 1H), 7.15 (d, J=3.03 Hz, 1H), 6.68 (s, 1H), 6.55 (d, J=3.03 Hz, 1H), 3.77 (d, J=12.38 Hz, 1H), 3.55 (dd, J=2.91, 11.49 Hz, 1H), 3.30 (d, J=12.38 Hz, 1H), 3.17 - 3.22 (m, 1H), 2.64 (td, J=3.92, 12.38 Hz, 1H), 2.46 (dt, J=2.78, 12.51 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 2.04 - WO 2015/009616 PCT/US2014/046515 2.12 (m, 1H), 1.78 - 1.88 (m, 1H), 1.71 - 1.78 (m, 1H), 1.48 - 1.58 (m, 1H); HRMS calcd. for czszgN3 (M+H)+ 334.2283, found 72.
Example-7: (i)((5,7-Dimethyl-1H-indoly|)methyl)phenylpiperidinamine (diastereomer—2) NH2 N / N H diastereomer—2 The title compound was synthesized from (i)—benzyl (1-((5,7-dimethyltosyl-1H-indol y|)methy|)pheny|piperidiny|)carbamate (diastereomer—2), Intermediate 33, analogously to the preparation of Example-6. 1H NMR (400 MHz, CD30D) 6 7.53 (br. d, J=7.10 Hz, 2H), 7.37 (dd, J=7.10, 8.10 Hz, 2H), 7.26 - 7.32 (m, 1H), 7.14 (d, J=3.15 Hz, 1H), 6.67 (s, 1H), 6.50 (d, J=3.15 Hz, 10 1H), 3.71 (d, 0 Hz, 1H), 3.17 (dd, J=2.65, 11.49 Hz, 1H), 3.13 (d, J=12.10 Hz, 1H), 2.75 - 2.87 (m, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 2.08 (dt, J=2.53, 12.25 Hz, 1H), 1.88 - 1.95 (m, 1H), 1.68 - 1.76 (m, 1H), 1.57 - 1.68 (m, 1H), 1.29 - 1.41 (m, 1H); HRMS calcd. for C22H28N3 (M+H)+ 334.2283, found 334.2271.
Example-8: 15 (1-((5,7-Dimethyl-1H-indolyl)methyl)piperidinyl)benzamide o H2N N / N H A mixture of (i)—4-(1-((5,7-dimethyltosyl-1H-indolyl)methy|)piperidinyl)benzonitrile, Intermediate 311, (100 mg, 0.201 mmol) and KOH (100 mg, 1.782 mmol) in EtOH (2 mL) was stirred at 100 °C under the microwave irradiation for 1 hr. The reaction mixture was then acidified 20 with AcOH by pH= ca. 6. The ed mixture was directly purified by C (HC-A) to afford (i)—4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzamide as Example-8, and the corresponding carboxylic acid. 1H NMR (TFA salt, 400 MHz, D20) 6 7.81 (d, J=8.34 Hz, 2H), 7.60 (br. d, J=7.80 Hz, 2H), 7.20 (d, J=3.03 Hz, 1H), 6.68 - 6.73 (m, 1H), 6.08 (br. s., 1H), 4.32 - 4.39 (m, 1H), 4.12 (d, J=13.60 Hz, 1H), 4.06 (d, J=13.60 Hz, 1H), 3.28 (d, J=12.13 Hz, 1H), 3.08 - 3.17 (m, WO 2015/009616 PCT/US2014/046515 1H), 2.25 (s, 3H), 1.89 - 2.03 (m, 5H), 1.74 - 1.82 (m, 1H), 1.65 - 1.74 (m, 1H), 1.45 - 1.62 (m, 2H); HRMS calcd. for o (M+H)+ 32, found 362.2221.
The following Examples were synthesized from appropriate starting materials by applying similar methods described in the examples above: Chemical name a Starting material Chemical_ mple Strucwre NMR and HRMS (i)—4-(1-((5-chloromethyl-1H-indolyl)methyl)piperidinyl)benzamide O Intermediate 312 H2N 1 H NMR (TFA salt, 400 MHz, 611.20(br.s., 1H), 8.07 94 — (d, J=8.40 Hz, 2H), 7.75 (d, J=8.34 Hz, 2H), 7.41 - 7.46 (m, 1H), N 7.04 (s, 1H), 6.44 (br. s., 1H), 4.58 (dd, J=4.55, 10.86 Hz, 1H), Cl / 4.37 - 4.46 (m, 2H), 3.49 - 3.55 (m, 1H), 3.38 - 3.46 (m, 1H), N 2.49 (s, 3H), 2.07 - 2.24 (m, 2H), 1.72 - 2.03 (m, 4H); HRMS H calcd. for 022H25N300| (M+H)+ 382.1686, found 382.1679. (i)—4-(rel—(28,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)—4-methoxypiperidin y|)benzamide 0 Intermediate 315 H2N l 0 1H NMR (TFA salt, 400 MHz, CDsCN)610.82(br.s., 1H), 8.10 Q N (br. d, J=8.10 Hz, 2H), 7.76 (br. d, J=8.30 Hz, 2H), 7.32 (br. s., 1H), 6.83 (s, 1H), 6.36 (br. s., 1H), 4.40 (d, J=13.30 Hz, 1H), / 4.27 (d, J=13.30 Hz, 1H), 3.74 (br. s., 1H), 3.54 - 3.65 (m, 1H), N H 3.45 (s, 3H), 3.36 - 3.42 (m, 1H), 2.45 (s, 3H), 2.27 - 2.35 (m, rel-(28,48) 2H), 2.08 - 2.20 (m, 4H), 1.88 - 1.99 (m, 1H); HRMS calcd. for Cz4H30N302 (IVI'I'H)+ 392.2338, found 392H2328 WO 09616 PCT/US2014/046515 e-10: (i)(4-Methoxy((5-methoxymethyl-1H-indoly|)methyl)methylpiperidin yl)benzamide (single diastereomer) O H2N / O N O\ / N single H diastereomer A mixture of Ba(OH)2 (97 mg, 0.347 mmol) and (i)—ten‘-butyl 4-((2-(4-cyanophenyl) methoxymethylpiperidiny|)methyl)methoxymethyl-1H-indolecarboxylate (single diastereomer), Intermediate 49, (35 mg, 0.069 mmol) in iPrOH/HZO (2 mL/2 mL) was stirred at 100 °C for 2h under the microwave irradiation. The reaction mixture was then acidified with AcOH until pH around 7. The resulting mixture was ed by C (HC-B) to afford the title 10 compound. 1H NMR (400MHz, CD30D) 6 7.93 (d, J=7.7 Hz, 2H), 7.67 (d, J=7.7 Hz, 2H), 7.19 (d, J=2.6 Hz, 1H), 6.68 (s, 1H), 6.43 (d, J=2.9 Hz, 1H), 3.76 (s, 3H), 3.43 - 3.39 (m, 2H), 3.21 - 3.16 (m, 3H), 2.95 (br. s., 1H), 2.45 (s, 3H), 2.26 (br. s., 1H), 1.88 - 1.68 (m, 3H), 1.67 - 1.57 (m, 1H), 1.37 (s, 3H); HRMS calcd. for C25H31N303 (M+H)+ 422.2444, found 422.2459.
Example-11 15 (i)(reI-(2S,4S)((5,7-dimethyl-1H-indoly|)methyl)hydroxypiperidinyl)benzoic acid 0 HO OH N / N H rel-28,48 A e of (i)—4-(rel—(2S,4S)—1-((5,7-dimethyltosyl-1H-indolyl)methyl)—4- hydroxypiperidinyl)benzonitrile, Intermediate 313, (144 mg, 0.28 mmol), KOH (100 mg, 1.782 mmol), and isoamylamine (100 uL, 0.860 mmol) in EtOH (2 mL) was stirred at 130 °C under the 20 microwave irradiation for 2.5 hr. The reaction mixture was then acidified by AcOH by pH around 6.
The mixture was purified by RP HPLC (HC-A) to afford the title compound. 1H NMR (TFA salt, 400 MHz, D20) 6 8.02 (br. d, J=8.60 Hz, 2H), 7.65 (br. d, J=7.80 Hz, 2H), 7.26 (d, J=3.03 Hz, 1H), 6.77 (s, 1H), 6.17 (br. s., 1H), 4.72 - 4.79 (m, 1H), 4.15 - 4.21 (m, 3H), 3.46 - 3.57 (m, 1H), 3.15 - 3.26 WO 2015/009616 PCT/US2014/046515 (m, 1H), 2.27 - 2.39 (m, 4H), 2.05 - 2.14 (m, 1H), 2.01 (s, 3H), 1.71 - 1.94 (m, 2H); HRMS calcd. for N203 (M+H)+ 379.2022, found 379.2012.
Example-12: (i)(reI-(2S,4R)((5,7-dimethyl-1H-indoly|)methyl)hydroxypiperidinyl)benzoic acid 0 HO OH N / N H rel-2S,4R The title compound was synthesized from (i)—4-(rel—(2S,4R)—1-((5,7-dimethyltosyl-1 H- indolyl)methyl)hydroxypiperidinyl)benzonitrile, Intermediate 314, analogously to the preparation of Example-11. H NMR (400 MHz, D20) 6 8.07 (d, J=8.60 Hz, 2H), 7.65 (br. d, J=7.60 Hz, 2H), 7.23 (d, J=3.03 Hz, 1H), 6.71 (s, 1H), 6.07 (br. s., 1H), 4.53 (dd, J=2.65, 12.76 Hz, 1H), 10 3.95 - 4.12 (m, 3H), 3.32 - 3.41 (m, 1H), 3.20 - 3.32 (m, 1H), 2.25 - 2.33 (m, 4H), 1.98 - 2.12 (m, 2H), 1.94 (br. s, 3H), 1.51 - 1.69 (m, 1H); HRMS calcd. for C23H27N203 (M+H)+ 379.2022, found 379.2014.
M (i)(1-((5-Chloromethyl-1H-indolyl)methyl)piperidinyl)benzoic acid 0 HO N CI / N 15 H The title nd was synthesized from (i)—4-(1-((5-chloromethyltosyl-1H-indol yl)methyl)piperidinyl)benzonitrile, Intermediate 312, analogously to the preparation of Example-11. 1H NMR (TFA salt, 400 MHz, CD30D) 6 8.21 (d, J=8.34 Hz, 2H), 7.76 (d, J=8.34 Hz, 2H), 7.44 (d, J=3.03 Hz, 1H), 7.04 (s, 1H), 6.44 (d, J=3.03 Hz, 1H), 4.59 (dd, , 10.36 Hz, 1H), 20 4.41 (s, 2H), 3.49 - 3.55 (m, 1H), 3.38 - 3.46 (m, 1H), 2.49 (s, 3H), 2.08 - 2.22 (m, 2H), 1.69 - 2.02 (m, 4H); HRMS calcd. for C22H24N202C| (M+H)+ 383.1526, found 383.1525.
WO 2015/009616 PCT/US2014/046515 Example-14: o \o O\ N / N H rel-28,48 Example-14a; (i)-methyl 4-(reI-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl) methoxypiperidinyl)benzoate A mixture of (rel—(2S,4S)—1-((5,7-dimethyltosyl-1H-indolyl)methyl)—4- methoxypiperidinyl)benzonitrile, Intermediate 315, (320 mg, 0.606 mmol), KOH (400 mg, 7.13 mmol), and isoamylamine (0.5 mL, 4.30 mmol) in EtOH (5 mL) was stirred at 130 °C under the microwave irradiation for 2.5 hr. The reaction mixture was diluted with H20. The mixture was then acidified by half satd. aq. citric acid. The mixture was then extracted three times with CH2C|2/TFE 10 (ca. 9/1). The combined organic layers were then dried over NaZSO4, ed, and concentrated.
The ing residue was dissolved in toluene (4 mL)/MeOH (1 mL). To the mixture was then added trimethylsilyldiazomethane in EtZO (1 mL, 2 mmol) dropwise. The e was then stirred at room temperature for 2h. The reaction was quenched with AcOH. The mixture was then diluted with EtOAc. The c phase was then washed successively with 5% aq. NaHCOs twice, H20, 15 brine, dried over Na2804, filtered, and concentrated. The resulting e was purified by silica gel flash column chromatography (heptane/EtOAc = 67/33) to afford the title compound. 1H NMR (400 MHz, CD3CN) 6 9.09 (br. s., 1H), 7.99 (d, J=8.34 Hz, 2H), 7.65 (br. d, J=8.10 Hz, 2H), 7.17 (app. t, J=2.78 Hz, 1H), 6.71 (s, 1H), 6.57 (dd, J=2.02, 3.03 Hz, 1H), 3.85 (s, 3H), 3.60 (d, J=12.10 Hz, 1H), 3.45 - 3.54 (m, 2H), 3.21 - 3.29 (m, 4H), 2.34 - 2.40 (m, 4H), 2.23 - 2.33 (m, 4H), 1.86 - 1.91 (m, 20 1H), 1.79 - 1.85 (m, 1H), 1.70 - 1.78 (m, 1H), 1.45 - 1.56 (m, 1H); HRMS calcd. for N203 (M+H)+ 407.2335, found 407.2326.
Example-14b; (+) and (-)-methyl 4-(reI-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl) methoxypiperidinyl)benzoate Resolution of the enantiomers of (i)—methyl 4-(rel-(2S,4S)—1-((5,7-dimethyl-1H-indol 25 yl)methyl)methoxypiperidinyl)benzoate was achieved by chiral SFC using a CEL® OJ- H column with 30% (10mM NH4OH in MeOH) in C02 to afford methyl 4-(re/-(2S,4S)—1-((5,7- dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoate (enantiomer-1) (peak-1, tr = 2.4 min) and methyl 4-(rel-(2S,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidin yl)benzoate (enantiomer—2) (peak-2, tr = 3.4 min).
WO 2015/009616 PCT/US2014/046515 Example-15: (i)-Methyl 4-(reI-(28,4R)((5,7-dimethyl-1H-indoly|)methyl)methoxypiperidin yl)benzoate N H rel-2S,4R The title compound was synthesized from (i)—4-(re/—(2S,4R)—1-((5,7-dimethyltosyl-1H- indolyl)methyl)methoxypiperidinyl)benzonitrile, Intermediate 316, analogously to the preparation of Example-14. 1H NMR (400 MHz, CD3CN) 6 9.03 (br. s., 1H), 7.92 (d, J=8.59 Hz, 2H), 7.57 (br. d, J=8.08 Hz, 2H), 7.09 (app. t, J=2.78 Hz, 1H), 6.63 (s, 1H), 6.46 (dd, J=2.02, 3.03 Hz, 1H), 3.77 (s, 3H), 3.50 (d, J=12.25 Hz, 1H), .22 (m, 5H), 3.09 (d, J=12.25 Hz, 1H), 2.52- 10 2.62 (m, 1H), 2.30 (s, 3H), 2.17 (s, 3H), .03 (m, 2H), 1.73-1.82 (m, 1H), 1.38-1.49 (m, 1H), 1.06-1.20 (m, 1H); HRMS calcd. for C25H31N203 (M+H)+ 407.2335, found 407.2334.
Example-16: (-)-(S)(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)fluorobenzoic acid 0 HO)E©F "ON / N H 15 A mixture of (S)—ten‘-butyl opropyl((2-(3-f|uoro(methoxycarbonyl)phenyl)piperidin- 1-yl)methyl)methyl-1H-indolecarboxylate, Intermediate 322, (370 mg, 0.711 mmol) and LiOH in H20 (2 mL, 2 mmol) in THF (1 mL)/MeOH (1 mL) was stirred at 70 °C for 6.5h. The reaction mixture was cooled down to room temperature. The mixture was then acidified with AcOH.
The mixture was then partially trated. The resulting residue was purified by RP-HPLC (HC- 20 B) to afford the title compound. 1H NMR (400 MHz, D20) 6 7.77 (app. t, J=7.83 Hz, 1H), 7.42 - 7.53 (m, 2H), 7.41 (d, J=3.28 Hz, 1H), 6.74 (s, 1H), 6.36 (br. s., 1H), 4.50 (br. d, J=12.60 Hz, 1H), 4.09 - 4.37 (m, 2H), 3.41 (br. d, J=11.90 Hz, 1H), 3.11 (br. s., 1H), 2.44 (s, 3H), 2.09 (br. s, 2H), 1.90 - 1.98 (m, 1H), 1.79 - 1.89 (m, 1H), 1.62 - 1.79 (m, 3H), 0.91 (br. s., 1H), 0.76 (br. s., 1H), 0.49 (br. s., 1H), 0.21 (br. s., 1H); HRMS calcd. for C25H28N202F (M+H)+ 35, found 407.2124.
WO 2015/009616 PCT/US2014/046515 The following examples were synthesized from the appropriate starting material by applying similar methods described in the examples above: Chemical name Exam M Starting material Chemical structure NMR and MS (-)-(S)—4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)benzoic acid Intermediate 319 1H NMR (400 MHz, D20) 6 7.78 (br. d, J=8.00 Hz, 2H), 7.48 (br. d, J=8.00 Hz, 2H), 7.18 (d, J=2.90 Hz, 1H), 6.49 (s, 1H), 8.20 (br. d, J=2.90 Hz, 1H), 3.99 - 4.19 (m, 1H), 3.55 - 3.85 (m, 2H), 3.07 (br. d, J=11.10 Hz, 1H), 2.88 (br. s, 1H), 2.23 (s, 3H), 1.79 (br. s., 2H), 1.84 - 1.74 (m, 1H), 1.47 - 1.83 (m, 2H), 1.32 - 1.48 (m, 2H), 0.59 - 0.72 (m, 1H), 0.45 - 0.59 (m, 1H), 0.07 - 0.21 (m, 1H), 0.22 - 0.03 (m, 1H); HRMS calcd. for CZ5H29N202 (M+H)+ 29, found 389.2216.
Intermediate 320 1H NMR (400 MHz, D20) 6 7.88 (d, J=8.20 Hz, 2H), 7.50 (d, J=8.20 Hz, 2H), 7.37 (d, J=3.28 Hz, 1H), 6.64 (s, 1H), 6.30 (br. s., 1H), 4.54 (d, J=13.39 Hz, 1H), 4.41 (d, J=7.07 Hz, 2H), 3.50 (d, J=7.58 Hz, 1H), 3.40 (br. s., 1H), 2.47 - 2.65 (m, 1H), 2.39 (s, 3H), / 1.99 - 2.32 (m, 3H), 1.54 (br. s., 1H), 0.75 - 0.88 (m, 1H), 0.61 - N 0.74 (m, 1H), 0.46 (br. s., 1H), 0.12 - 0.33 (m, 1H); HRMS calcd. for CZ4H27N202 (M+H)+ 375.2073, found 375.2071.
Intermediate 321 1H NMR (600 MHz, CDgOD) o 8.66 (s, 1H), 7.81 - 8.07 (m, 2H), 7.16 (d, J=3.12 Hz, 1H), 6.56 (d, J=3.10 Hz, 1H), 6.52 (s, 1H), 3.89 (d, J=12.29 Hz, 1H), 3.41 (d, 0 Hz, 1H), 3.22 - 3.27 (m, 1H), 2.92 (d, J=11.28 Hz, 1H), 2.39 (s, 3H), 1.99 - 2.22 (m, 2H), 1.88 - 1.89 (m, 3H), 1.51 - 1.85 (m, 2H), 1.38 - 1.50 (m, 1H), 0.77 - 0.89 (m, 1H), 0.64 - 0.74 (m, 1H), 0.49 - 0.59 (m, 1H), 0.11 - 0.19 (m, 1H). HRMS calcd. for N302 (M+H)+ 390.2182, found 390.2168.
WO 2015/009616 PCT/US2014/046515 (-)-(S)—4-(1-((5-cyc|opropyImethyl-1H-indoIyl)methyl)piperidinyl)—3-methoxybenzoic acid Intermediate 323 1H NMR (HCI salt, 400 MHz, 00300003) 6 9.99 (br. s., 1H), 7.83 (d, J=7.80 Hz, 1H), 7.74 (dd, J=1.30, 8.00 Hz, 1H), 7.71 (d, J=1.34 Hz, 1H), 7.20 - 7.31 (m, 1H), 6.76 (dd, J=2.02, 3.12 Hz, 1H), 6.57 (s, 1H), 3.95 - 4.03 (m, 4H), 3.85 (dd, J=3.18, 10.51 Hz, 1H), 3.45 (d, J=12.23 Hz, 1H), 2.90 (d, J=11.74 Hz, 2H), 2.43 (s, 3H), 2.28 - 2.38 (m, 1H), 1.62 - 1.82 (m, 3H), 1.35 - 1.60 (m, 3H), 0.80 - 0.92 (m, 1H), 0.62 - 0.79 (m, 2H), 0.19 - 0.29 (m, 1H); HRMS calcd. for 025H31N203 (M+H)+ 419.2335, found 419.2318.
Intermediate 425 1H NMR (400 MHz, 020) 6 7.81 (d, J=8.20 Hz, 2H), 7.44 (d, I7.A 01 J=8.20 Hz, 2H), 7.15 (d, J=3.03 Hz, 1H), 6.55 (s, 1H), 6.06 (d, J=3.03 Hz, 1H), 3.70 - 3.92 (m, 2H), 3.46 (s, 3H), 3.41 (d, J=12.63 Hz, 1H), 3.02 (br. d, 0 Hz, 1H), 2.49 - 2.74 (m, J=11.00, 11.00 Hz, 1H), 2.23 (s, 3H), 1.62 - 1.85 (m, 3H), 1.25 - 1.62 (m, 3H); HRMS calcd. for 023H27N203 (M+H)+ 379.2022, found 21.
Intermediate 41 1H NMR (400 MHz, ) 6 8.55 (d, J=4.55 Hz, 2H), 8.10 (br. s., 1H), 7.50 (br. s., 2H), 7.21 (dd, J=2.50, 2.80 Hz, 1H), 6.69 (s, 1H), 6.55 - 6.66 (m, 1H), 3.76 (s, 3H), 3.69 (d, J=11.90 Hz, 1H), 3.25 (d, J=12.13 Hz, 1H), 3.11 (d, J=10.36 Hz, 1H), 2.87 (d, J=10.86 Hz, 1H), 2.45 (s, 3H), 1.90 - 2.13 (m, 1H), 1.68 - 1.82 (m, 2H), 1.50 - 1.68 (m, 2H), 1.30 - 1.50 (m, 2H); HRMS calcd. for 021H26N30 (M+H)+ 336.2076, found 67.
Intermediate 42 1H NMR (400 MHz, CDZCIZ) 5 8.69 (s, 1H), 8.48 (dd, J=1.30, 4.60 Hz, 1H), 8.04 (br. s., 1H), 7.91 (d, J=7.58 Hz, 1H), 7.30 (dd, J=4.60, 7.58 Hz, 1H), 7.20 (dd, J=2.50, 3.03 Hz, 1H), 6.68 (s, 1H), 6.58 (dd, J=2.02, 3.03 Hz, 1H), 3.75 (s, 3H), 3.68 (d, J=12.13 Hz, 1H), 3.23 (d, J=12.13 Hz, 1H), 3.14 (dd, J=2.53, 11.12 Hz,1H), 2.89 (d, J=11.87 Hz, 1H), 2.45 (s, 3H), 1.94 - 2.12 (m, 1H), 1.70 - 1.84 (m, 2H), 1.49 - 1.69 (m, 2H), 1.25 - 1.48 (m, 2H); HRMS calcd. for 023H30N3028 (M+H)+ 412.2059, found 412.2072.
WO 2015/009616 PCT/US2014/046515 (+)-(S)—3-f|uoro—4-(1-((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)benzoic acid Intermediate 43 1H NMR (HCI salt, 400 MHz, 020) 5 7.82 (br. d, J=7.60 Hz, 1H), F HO 7.72 (br. d, J=11.10 Hz, 1H), 7.61 (br. dd, J=7.10, 7.30 Hz, 1H), '7.A m 0 7.29 (d, J=3.03 Hz, 1H), 6.55 (s, 1H), 6.18 (d, J=3.03 Hz, 1H), N 4.63 (br. s., 1H), 3.88 (br. d, J=12.90 Hz, 1H), 3.78 (br. d, J=12.90 0\ Hz, 1H), 3.57 (s, 3H), 3.37 (br. d, J=11.80 Hz, 1H), 3.08 - 3.24 (m, 1H), 2.32 (s, 3H), 2.06 (br. s., 2H), 1.86 - 1.97 (m, 1H), 1.83 (br. d, H J=9.10 Hz, 1H), 1.55 - 1.75 (m, 2H); HRMS calcd. for N203F (M+H)+ 397.1927, found 397.1916.
Intermediate 44 1H NMR (400 MHz, 00300) 5 8.01 (d, J=8.46 Hz, 2H), 7.59 (br. d, J=7.30 Hz, 2H), 7.18 (d, J=3.16 Hz, 1H), 6.68 (s, 1H), 6.44 (d, J=3.16 Hz, 1H), 3.76 - 3.84 (m, 5H), 3.74 (s, 1H), 3.65 - 3.70 (m, 1H), 3.45 - 3.52 (m, 1H), 3.39 - 3.45 (m, 1H), 3.33 - 3.37 (m, 2H), 2.73 (s, 1H), 2.45 (s, 3H), 2.34 - 2.42 (m, 1H); HRMS calcd. for 022H25N204 (M+H)+ 381.1809, found 381.1797.
Intermediate 45 1H NMR (HCI salt, 400 MHz, 020) 5 8.91 (d, J=2.02 Hz, 1H), 8.16 (dd, J=2.10, 8.08 Hz, 1H), 7.41 (d, J=8.08 Hz, 1H), 7.25 (d, J=3.03 Hz, 1H), 6.49 (s, 1H), 6.16 (br. s., 1H), 4.35 (br. d, J=9.30 Hz, 1H), 3.76 - 3.85 (m, 1H), 3.67 - 3.75 (m, 1H), 3.64 (s, 3H), 3.39 (br. d, J=10.60 Hz, 1H), 3.00 - 3.20 (m, 1H), 2.29 (s, 3H), 2.02 (d, J=12.88 Hz, 1H), 1.79 - 1.92 (m, 3H), 1.56 - 1.75 (m, 2H); HRMS calcd. for 022H25N303 (M+H)+ 380.1974, found 380.1960. (-)((28,4S)—1-((5-methoxymethy|—1H-indoIyl)methyl)—4-propoxypiperidin y|)benzoic acid Intermediate 411 1H NMR (400 MHz, 020) 5 8.06 (d, J=8.07 Hz, 2H), 7.62 (d, J=8.07 Hz, 2H), 7.32 (d, J=2.93 Hz, 1H), 6.60 (s, 1H), 6.18 (br. s., 1H), 4.54 (br. d, J=9.20 Hz, 1H), 3.84 - 3.95 (m, 2H), 3.74 (d, 6 Hz, 1H), 3.59 (s, 3H), 3.52 (t, J=6.66 Hz, 2H), 3.27 - 3.38 (m, 1H), 3.21 (br. d, J=10.90 Hz, 1H), 2.36 (s, 3H), 2.15 - 2.32 (m, 2H), 1.98 - 2.08 (m, 1H), 1.80 - 1.94 (m, 1H), 1.60 - 1.72 (m, 2H), 0.98 (t, J=7.27 Hz, 3H); HRMS calcd. for 025H33NZO4 (M+H)+ 40, found 437.2436.
WO 2015/009616 PCT/US2014/046515 (-)((2S,4S)—4-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoic acid Intermediate 412 0 HOJKQ 1H NMR (400 MHz, 00300) 5 7.99 (d, J=8.31 Hz, 2H), 7.55 (br. d, H OH J=7.70 Hz, 2H), 7.16 (d, J=3.18 Hz, 1H), 6.67 (s, 1H), 6.41 (d, N J=3.18 Hz, 1H), 4.02 (br. s., 1H), 3.81 (d, J=11.86 Hz, 1H), 3.75 (s, 3H), 3.66 (dd, J=2.81, 11.62 Hz, 1H), 3.23 (d, J=11.86 Hz, 1H), o \ / 2.76 (d, J=11.37 Hz, 1H), 2.55 - 2.65 (m, 1H), 2.45 (s, 3H), 1.86 - 3 1.96 (m, 1H), 1.75 -1.86(m,2H), 1.61 (d, J=14.06 ; (28 48)' HRMS calcd. for N204 (M+H)+ 395.1971, found 395.1967. (i)—4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)—3-methylbenzoic acid Intermediate 413 0 1H NMR (HCI salt, 400 MHz, D20) 6 7.94 HO (d, J=8.13 Hz, 1H), 7.88 17-13 (s, 1H), 7.59 (d, J=8.13 Hz, 1H), 7.25 (d, J=3.06 Hz, 1H), 6.49 (s, N 1H), 6.09 (d, J=3.06 Hz, 1H), 4.43 - 4.57 (m, 1H), 3.65 (d, J=12.70 Hz, 1H), 3.50 - 3.59 (m, 4H), 3.22 - 3.33 (m, 1H), 3.05 - 3.19 (m, 0 \ / 1H), 2.48 (s, 3H), 2.28 (s, 3H), 1.74 - 2.02 (m, 4H), 1.65 (br. s., 2H); HRMS calcd. for C24H29N203 (M+H)+ 393.2178, found 393.2172. (i)—4-(1-((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid (single diastereomer) Intermediate 414 1H NMR (HCI salt, 400 MHz, 020) 5 7.93 HO (d, J=8.38 Hz, 2H), 7.55 (d, J=8.38 Hz, 2H), 7.32 (d, J=3.10 Hz, 1H), 5.70 (s, 1H), 5.20 (br. d, J=2.80 Hz, 1H), 4.37 (br. d, J=9.70 Hz, 1H), 4.18 N (d, J=13.20 Hz, 1H), 4.05 (d, J=13.20 Hz, 1H), 3.75 (s, 3H), 3.31 (dd, J=3.00, \ / 12.55 Hz, 1H), 3.15 (dd, J=2.51, 12.55 Hz, 1H), 2.41 (s, 3H), 2.22 N - 2.33 (m, 2H), 1.88 - 2.08 (m, 2H), 1.72 (dd, J=3.00, 13.88 Hz, 1H), 1.05 (d, J=7.21 Hz, 3H); HRMS calcd. for N203 (M+H)+ single diastereomer 393.2178, found 393.2175.
WO 2015/009616 PCT/US2014/046515 (i)—4-(rel—(2S,4R)—4-ethyI((5-methoxymethy|—1H-indoIy|)methy|)piperidin y|)benzoic acid ediate 415 0 1H NMR (400MHz, D20) 6 8.02 (br. d, J=8.20 Hz, 2H), 7.62 (br. d, HO J=7.70 Hz, 2H), 7.35 (d, J=3.18 Hz, 1H), 6.73 (S, 1H), 6.18 - 6.28 (m, 1H), 4.13 (br. 8., 1H), 4.02 (d, J=12.84 Hz, 1H), 3.59 - 3.78 (m, N 4H), 3.29 (br. d, J=12.50 Hz, 1H), 2.89 - 3.03 (m, 1H), 2.42 (s, 0\ / 3H), 2.03 - 2.14 (m, 1H), 1.79 - 1.89 (m, 1H), 1.57 - 1.71 (m, 2H), N 1.20 - 1.41 (m, 3H), 0.87 (t, J=7.46 Hz, 3H); HRMS calcd. for H rel-(2814'?) 025H31N203 (M+H)+ 407.2335, found 407.2358. (i)—2-(4-(1-((5-methoxymethyI-1H-indoIyl)methyl)piperidinyl)phenyl)acetic acid Intermediate 416 1H NMR (HCI salt, 400 MHz, 00300) 5 7.48 - 7.59 (m, 4H), 7.31 (d, J=3.18 Hz, 1H), 8.78 (s, 1H), 6.29 (d, J=3.18 Hz, 1H), 4.33 - 4.43 (m, 2H), 4.10 (d, J=12.72 Hz, 1H), 3.75 (s, 3H), 3.87 (s, 2H), 3.49 - 3.57 (m, 1H), 3.20 - 3.27 (m, 1H), 2.50 (s, 3H), 2.04 - 2.14 (m, 2H), 1.90 - 1.99 (m, 1H), 1.88 - 1.90 (m, 3H); HRMS calcd. for CZ4H29N203 (M+H)+ 393.2178, found 393.2181.
Intermediate 417 1H NMR (HCI salt, 400 MHz, 00300) 5 7.53 (s, 1H), 7.37 - 7.50 (m, 3H), 7.31 (d, J=3.06 Hz, 1H), 8.75 (s, 1H), 6.25 (br. s., 1H), 4.24 - 4.45 (m, 2H), 4.10 (d, J=12.72 Hz, 1H), 3.78 (s, 3H), 3.58 (s, 2H), 3.41 - 3.52 (m, 1H), 3.17 - 3.25 (m, 1H), 2.50 (s, 3H), 2.01 - 2.20 (m, 2H), 1.83 - 2.00 (m, 4H); HRMS calcd. for N203 (M+H)+ 393.2178, found 393.2175. (i)—5-(rel—(28,4S)—1-((5-cyc|opropyImethyI-1H-indoIyl)methyl)methoxypiperidin o|inic acid Intermediate 418 1H NMR (400 MHz, 020) 5 8.67 (s, 1H), 8.06 (br. d, J=8.10 Hz, 1H), 7.94 (br. d, J=8.10 Hz, 1H), 7.37 (d, J=2.90 Hz, 1H), 8.87 (s, 1H), 8.48 (d, J=2.81 Hz, 1H), 4.05 (br. d, J=11.60 Hz, 1H), 3.81 - 3.93 (m, 1H), 3.77 (br. s., 1H), 3.59 - 3.73 (m, 1H), 3.41 (s, 3H), 2.86 - 2.98 (m, 1H), 2.70 - 2.84 (m, 1H), 2.41 (s, 3H), 1.91 - 2.17 (m, 3H), 1.72 - 1.84 (m, 2H), 0.80 - 0.91 (m, 1H), 0.88 - 0.79 (m, 1H), 0.28 - 0.38 (m, 1H), 0.06 - 0.18 (m, 1H); HRMS calcd. for 025H30N303 (M+H)+ 420.2287, found 420.2281.
WO 2015/009616 PCT/US2014/046515 (i)—2-(1-((5-methoxymethyI-1H-indoIyl)methyl)piperidinyl)thiazoIecarboxylic acid ediate 423 0MN:8 1H NMR (400 MHz, 00300) 5 8.00 (s, 1H), 7.19 (d, J=3.16 Hz, N 1H), 6.68 (s, 1H), 6.53 (d, J=3.16 Hz, 1H), 3.84 (d, J=12.00 Hz, 1H), 3.70 - 3.79 (m, 4H), 3.45 (d, J=11.87 Hz, 1H), 3.33 - 3.38 (m, \ / 1H), 2.96 - 3.05 (m, 1H), 2.46 (s, 3H), 2.16 - 2.25 (m, 1H), 1.97 (d, N J=11.24 Hz, 1H), 1.75 - 1.84 (m, 2H), 1.40 - 1.62 (m, 2H); HRMS calcd. for CZOH24N3038 (M+H)+ 386.1533, found 386.1514. (i)—2-(1-((5-methoxymethyI-1H-indoIyl)methyl)piperidinyl)methy|thiazo|e carboxylic acid Intermediate 424 1H NMR (600 MHz, DMSO-ds) 5 10.84(s, 1 H) 7.27 (t, J=2.75 Hz, 1 H)6.66 (s, 1 H)6.65 (dd, J=2.89, 2.06 Hz, 1 H) 3.75 (d, J=12.10 Hz, 1 H)3.71 (s, 3 -3.63 (m, 1 H)3.53 (d, 0 Hz, 1 H) 2.71 - 2.81 (m, 1 H) 2.57 (s, 3 H) 2.42 (s, 3 H) 2.08 (t, J=10.36 Hz, 1 H) 1.91 (dd, J=9.22, 4.72 Hz, 1 H) 1.59 - 1.71 (m, 2 H) 1.52 (d, J=12.84 Hz, 1 H) 1.25 - 1.42 (m, 2 H); HRMS calcd. for 021H26N3038 (M+H)+ 400.1702, found 400.1687.
Intermediate 4-8 1H NMR (HCI salt, 400 MHz, DMSO - d5)610.82(br.s., 1H), 8.06 (br. s., 1H), 7.80 (d, J=7.33 Hz, 1H), 7.62 (br. d, J=8.10 Hz, 1H), 7.33 - 7.49 (m, 1H), 7.19 (t, J=2.80 Hz, 1H), 6.62 (s, 1H), 6.42 - 6.55 (m, 1H), 3.54 (d, J=12.13 Hz, 1H), 3.06 - 3.16 (m, 2H), 2.62 (br. d, J=11.40 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 1.86 - 1.96 (m, 1H), 1.54 - 1.75 (m, 3H), 1.48 (d, J=8.59 Hz, 1H), 1.26 - 1.41 (m, 2H), HRMS calcd. for 023H27N202 (M+H)+ 363.2073, found 363.2075.
Intermediate 4-9 O 1H NMR (HCI salt, 400 MHz, 00300) 5 8.11 (d, J=8.40 Hz, 2H), 17-22 "0% 7.59 (br. d, J=8.30 Hz, 2H), 7.27 (d, J=3.06 Hz, 1H), 6.69 (s, 1H), N 6.06 (d, J=3.18 Hz, 1H), 4.45 - 4.58 (m, 2H), 4.41 (d, J=12.80 Hz, 0\ 1H), 3.58 (s, 3H), 3.44 (d, J=6.97 Hz, 1H), 3.33 - 3.39 (m, 1H), / 2.48 (s, 3H), 2.36 - 2.54 (m, 1H), 2.19 - 2.35 (m, 1H), 1.92 - 2.14 (m, 4H), 1.71 - 1.87 (m, 1H), 1.46 - 1.64 (m, 1H); HRMS calcd. for CZ4H29N203 (M+H)+ 393.2178, found 393.2172.
WO 2015/009616 PCT/US2014/046515 (-)-(S)—4-((2-(4-(1H-pyrazoIyl)phenyl)piperidiny|)methyl)methoxymethy|—1H- indole ediate 4-10 1H NMR (400 MHz, DMSO-ds) 6 12.88 (br. s., 1H), 10.77 (br. s., 1H), 8.16 (br. s., 1H), 7.91 (br. s., 1H), 7.80 (d, J=8.31 Hz, 2H), 17-23 7.49 (br. d, J=7.70 Hz, 2H), 7.23 (dd, J=2.70, 2.80 Hz, 1H), 8.84 (s, 1H), 6.49 - 8.53 (m, 1H), 3.70 (s, 3H), 3.62 (d, J=12.00 Hz, 1H), 3.17 (d, J=11.98 Hz, 1H), 3.05 (br. dd, J=2.00, 10.50 Hz, 1H), 2.78 (br. d, J=10.40 Hz, 1H), 2.41 (s, 3H), 1.87 - 1.96 (m, 1H), 1.84 - 1.74 (m, 2H), 1.53 - 1.82 (m, 1H), 1.43 - 1.53 (m, 1H), 1.29 - 1.39 (m, 2H); HRMS calcd. for C25H28N4O (M - H) 401.2328, found 401.2343. indole Intermediate 4-11 % 1H NMR (400 MHz, 00300003) 6 12.08 (br. s., 1H), 9.92 (br. s., 17-24 1H), 7.87 (br. d, J=8.30 Hz, 2H), 7.88 (br. s., 1H), 7.83 (br. d, J=7.80 Hz, 2H), 7.24 (app.t, J=2.81 Hz, 1H), 8.88 - 8.72 (m, 3H), 3.80 (d, J=12.10 Hz, 1H), 3.77 (s, 3H), 3.30 (d, J=12.10 Hz,1H), 3.13 (dd, J=2.63, 10.70 Hz, 1H), 2.91 (br. d, J=11.74 Hz, 1H), 2.76 / (S, 3H), 2.44 (S, 3H), 1.95 - 2.02 (m, 1H), 1.72 - 1.80 (m, 2H), 1.63 - 1.72 (m, 1H), 1.50 - 1.56 (m, 1H), 1.37 - 1.50 (m, 2H); HRMS calcd. for C25H28N4O (M - H) 401.2328, found 401.2334. 0 ediate 4-12 HO O 1H NMR (rotamer exists, 400 MHz, DMSO - .77(br.s., 17-25 0 1H), 8.90 (br. s., 1H), 8.38 (br. m), 7.82 - 8.14 (br. m), 7.51 (br. s., N 2H), 7.23 (m, 1H), 6.25 - 8.78 (m), 4.07 (br. s), 3.53 - 3.76 (m), o\ 3.22 (br. s), 2.86 (br. s., 1H), 2.40 (s, 3H), 2.03 -2.21 (m, 1H), 1.73 (br. s., 2H), 1.33 - 1.81 (m, 4H); HRMS calcd. for czyHZQNzo3 (M+H)+ 429.2178, found 429.2180.
WO 09616 PCT/US2014/046515 4-((28)(2,2,2-trif|uoro—1-(5-methoxymethy|—1H-indoIy|)ethy|)piperidinyl)benzoic acid (diastereomer—1) 119190"? Intermediate 4-13 1H NMR (400 MHz, CDgCOCD3)610.12(br.s., 1H), 8.03 (d, J=8.32 Hz, 2H), 7.64 (d, J=8.32 Hz, 2H), 7.30 (app. t, J=2.90 Hz, 1H), 6.82 (s, 1H), 6.56 - 6.62 (m, 1H), 5.36 (q, J=10.39 Hz, 1H), 4.01 - 4.08 (m, 1H), 3.80 (s, 3H), 3.37 - 3.46 (m, 1H), 3.00 - 3.10 (m, 1H), 2.50 (d, J=0.73 Hz, 3H), 1.55 - 1.81 (m, 4H), 1.41 - 1.52 (m, 1H), 1.21 - 1.33 (m, 1H); HRMS ca|cd. for 024st F3N203 reomer-1 (M+H) 447.1896, found 447.1895. 4-((28)(2,2,2-trif|uoro—1-(5-methoxymethy|—1H-indoIy|)ethy|)piperidinyl)benzoic acid (diastereomer—Z) 165 Intermediate 4-14 1H NMR (400 MHz, CDsCOCD3)61O.16(br.s., 1H), 8.09 (d, 17-27 @659 J=8.19 Hz, 2H), 7.70 (d, J=8.19 Hz, 2H), 7.34 (br. s., 1H), 6.86 (s, 1H), 6.66 (br. s., 1H), 5.07 - 5.25 (m, 1H), 3.64 (br. s., 3H), 3.51 - 3.61 (m, 2H), 2.53 (s, 3H), 1.94 - 2.03 (m, 1H), 1.45 - 1.74 (m, 5H), 1.02 - 1.18 (m, 1H); HRMS ca|cd. for 024st F3N203 (M+H) 447.1896, found 447.1921. diastereomer-2 (i)methoxy(1-((5-methoxymethy|—1H-indoIy|)methy|)piperidinyl)benzoic acid Intermediate 426 1H NMR (HCI salt, 400 MHz, 020) 5 7.63 (d, J=7.70 Hz, 1H), 7.34 (d, J=2.87 Hz, 1H), 7.17 - 7.28 (m, 2H), 6.68 (s, 1H), 6.18 (d, J=2.87 Hz, 1H), 4.33 (br. dd, J=3.40, 11.60 Hz, 1H), 4.10 (d, J=12.96 Hz, 1H), 3.92 (s, 3H), 3.87 (d, J=12.96 Hz, 1H), 3.65 (s, 3H), 3.40 (d, J=12.35 Hz, 1H), 3.09 - 3.21 (m, 1H), 2.40 (s, 3H), 1.99 - 2.16 (m, 2H), 1.78 - 1.97 (m, 2H), 1.61 - 1.75 (m, 2H); HRMS ca|cd. for N204 (M+H)+ 409.2127, found 409.2116.
Intermediate 427 1H NMR (400 MHz, 00300) 5 8.11 (d, J=8.20 Hz, 2H), 7.61 (d, J=8.20 Hz, 2H), 7.30 (d, J=3.06 Hz, 1H), 6.75 (s, 1H), 6.33 (br. s., 1H), .62 (m, 1H), 4.36 (br. d, J=12.70 Hz, 1H), 4.14 (d, J=12.72 Hz, 1H), 3.75 (s, 3H), 3.44-3.58 (m, 1H), 3.33-3.42 (m, 1H), 2.52-2.64 (m, 1H), 2.50 (s, 3H), 2.21-2.39 (m, 1H), 1.25-1.35 (m, 1H), 1.02-1.14 (m, 1H), 0.45-0.68 (m, 4H). HRMS ca|c. for CZ5H27N203 (M-H) 403.2016, found 403.2019.
WO 2015/009616 2014/046515 (i)—4-(re/-(2S,4S)—4-ethyl((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoic acid Intermediate 428 0 1H NMR (400 MHz, CD30D) 5 8.13 (d, J=8.07 Hz, 2H), 7.62 (br. d, HO J=7.80 Hz, 2H), 7.31 (d, J=3.06 Hz, 1H), 6.76 (s, 1H), 6.32 (br. s., 1H), 4.50-4.65 (m, 1H), 4.34 (d, J=12.59 Hz, 1H), 4.17 (d, J=12.60 Hz, 1H), 3.76 (s, 3H), .43 (m, 2H), 2.50 (s, 3H), 2.23-2.38 (m, 1H), 1.94-2.17 (m, 2H), 1.84-1.94 (m, 1H), 1.67-1.83 (m, 3H), 1.02 (t, J=7.34 Hz, 3H). HRMS calc. for C25H31N203 (M+H) 407.2329, found 407.2312. reI-(28,48) Example-18: (i)(1-((5,7-Dimethyl-1H-indolyl)methyl)phenylpiperidinyl)acetonitrile (diastereomer— 1) / N H diastereomer-1 A mixture of (i)—ten‘-butyl 4-((4-(cyanomethyl)—2-phenylpiperidinyl)methyl)-5,7-dimethyl- 1H—indolecarboxylate (diastereomer—1), Intermediate 4-1, (95 mg, 0.208 mmol) and Cs2C03 (300 mg, 0.921 mmol) in MeOH (5 mL) was stirred at 60 °C for 2h, and then cooled to room temperature. The on mixture was d with CH2C|2. The mixture was then washed 10 sively with H20 and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography [CH2C|2/(10% MeOH in EtOAc) = 92/8] to afford the title compound. 1H NMR (400 MHz, CD3CN) 5 9.10 (br. s., 1H), 7.52 (d, J=7.30 Hz, 2H), 7.36 (dd, J=7.30, 7.60 Hz, 2H), 7.23 - 7.30 (m, 1H), 7.18 (app.t, J=2.80 Hz, 1H), 6.72 (s, 1H), 6.59 (br. dd, J=2.30, 2.50 Hz, 1H), 3.73 (d, J=12.13 Hz, 1H), 3.41 - 3.48 (m, 1H), 3.37 (d, 15 J=12.13 Hz, 1H), 2.61 (d, J=8.08 Hz, 2H), 2.45 - 2.54 (m, 1H), 2.37 - 2.40 (m, 3H), 2.21 - 2.32 (m, 4H), 2.15 - 2.20 (m, 1H), 2.00 - 2.07 (m, 1H), 1.61 - 1.78 (m, 2H), 1.48 - 1.58 (m, 1H); HRMS calcd. for C24H28N3 (M+H)+ 358.2283, found 358.2278.
WO 2015/009616 PCT/US2014/046515 e-19: (i)(1-((5,7-Dimethyl-1H-indolyl)methyl)phenylpiperidinyl)acetonitrile (diastereomer— 2) \ N N / N H diastereomer-Z The title nd was synthesized from (i)—ten‘-butyl 4-((4-(cyanomethyl) phenylpiperidiny|)methy|)-5,7-dimethy|-1H-indoIecarboxylate (diastereomer—2), Intermediate 4-2, analogously to the ation of Example-18. 1H NMR (400 MHz, CD3CN) 6 9.09 (br. s., 1H), 7.54 (d, J=7.21 Hz, 2H), 7.39 (dd, J=7.21, 8.10 Hz, 2H), 7.27 - 7.33 (m, 1H), 7.17 (dd, J=2.80, 3.15 Hz, 1H), 6.71 (s, 1H), 6.57 (dd, J=2.15, 3.15 Hz, 1H), 3.66 (d, J=12.38 Hz, 1H), 3.16 (d, J=12.38 Hz, 10 2H), 2.65 - 2.71 (m, 1H), 2.38 (s, 3H), 2.31 (dd, J=1.64, 6.44 Hz, 2H), 2.26 (s, 3H), 1.98 - 2.05 (m, 1H), 1.78 - 1.87 (m, 2H), 1.61 - 1.69 (m, 1H), 1.45 - 1.56 (m, 1H), 1.12 - 1.24 (m, 1H); MS (ES|+) m/z 358.3 (M+H).
Example-20: Example-20a; (+)((2S,4R)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin- 15 enzoic acid 0 HOJKQ O O\ / N H A mixture of tert—butyl 5-methoxy(((2S,4R)—2-(4-(methoxycarbonyl)phenyl)—4- methylpiperidiny|)methy|)methyl-1H-indolecarboxylate, Intermediate 5-1b peak-1 (tr = 4.1 min), (600 mg, 1.184 mmol) and LiOH in H20 (4 mL, 4.00 mmol) in THF (3mL)/MeOH (4 mL) was 20 stirred at 80 °C for 6h. The mixture was cooled to room temperature. The reaction mixture was diluted with H20. The mixture was washed twice with . The aqueous layer was then acidified with citric acid by pH= ca. 6. The mixture was then saturated with NaCl. The mixture was then extracted three times with EtOAc/TFE (ca. 9/1). The organic layer was then dried over Na2804, filtered, and then concentrated. The resulting residue was purified by RP-HPLC (HC-B) to WO 2015/009616 PCT/US2014/046515 afford the title compound. 1H NMR (400 MHz, CD30D) 6 8.12 (d, J=8.10 Hz, 2H), 7.59 (d, J=7.83 Hz, 2H), 7.30 (d, J=2.93 Hz, 1H), 6.75 (s, 1H), 6.30 (br. d, J=2.70 Hz, 1H), 4.25 - 4.50 (m, 2H), 3.98 - 4.13 (m, 1H), 3.75 (s, 3H), 3.44 - 3.54 (m, 1H), 3.24 - 3.28 (m, 1H), 2.50 (s, 3H), 2.04 (br. d, J=14.50 Hz,1H), 1.89 - 1.99 (m, 1H), 1.65 - 1.89 (m, 2H), 1.43 - 1.58 (m, 1H), 1.01 (d, J=6.24 Hz, 3H); HRMS calcd. for C24H29N203 (M+H)+ 393.2178, found 393.2190.
Example-20b; (-)((2R,4S)((5-methoxymethyl-1H-indoly|)methyl)methylpiperidin- 2-yl)benzoic acid 10 The title compound was synthesized from tert—butyl 5-methoxy(((2R,4S)—2-(4- (methoxycarbonyl)phenyl)—4-methylpiperidinyl)methyl)—7-methyl-1H-indolecarboxylate, Intermediate 5-1b peak-2 (tr = 5.8 min), analogously to the preparation of Example-20a. Analytical data; same as e-20a.
Example-20c; 4-((2S,4R)((5-methoxymethyl-1H-indoly|)methyl)methylpiperidin 15 yl)benzoic acid phosphate salt H3PO4 To a sion of (+)((2S,4R)—1-((5-methoxymethyl-1H-indolyl)methyl)—4-methylpiperidin- 2-yl)benzoic acid (122 mg, 0,311 mmol) in 1.2 mL of a 1:9 mixture of methanol and acetonitrile was added H3PO4 (35.8 mg, 0.311 mmol, 85% aqueous) in 1.2 mL of 1:9 mixture of methanol and 20 acetonitrile. The mixture was sonicated for 10 min. The mixture was then heated to 55 0C over 15 min and held at that ature for 30 min. The e was cooled to 5 °C over 2 h and allowed to stir at 5 °C for 1 h. The mixture was then heated to 55 °C over 15 min and the process was WO 09616 PCT/US2014/046515 repeated 3 additional times. The mixture was warmed to rt and filtered, washing with 10 mL of a 1:1 mixture of acetonitrile:methyl tert-butyl ether and the solid collected was dried to give the title compound. 1H NMR (400 MHz, Methanol-d4) 5 8.22 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 3.2 Hz, 1H), 6.79 (s, 1H), 6.35 (d, J = 3.2 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.38 (d, J 5 = 12.7 Hz, 1H), 4.16 (d, J =12.7 Hz, 1H), 3.78 (s, 3H), 3.56 (d, J =12.7 Hz, 1H), 3.38 (m, 1H), 2.53 (s, 3H), 2.10 (d, J = 14.9 Hz, 1H), 1.99 (s, 1H), 1.90 (d, J = 14.5 Hz, 1H), 1.78 (q, J = 12.9 Hz,1H), 1.55 (d, J = 13.4 Hz, 1H), 1.05 (d, J = 6.4 Hz, 3H). X—ray powder diffraction: Angle d value Intensity Intensity % 2-Theta ° Angstrom Count % 7.7 11.509 1522 27 9.1 9.677 5560 100 10.9 8.111 4718 85 10 Example-21: Example-21 a; ((2S,4S)methoxy((5-methoxymethyl-1H-indol yl)methyl)piperidinyl)benzoic acid A mixture of tert—butyl 5-methoxy(2S,4S)—(4-methoxy(4- 15 (methoxycarbonyl)phenyl)piperidinyl)methyl)methyl-1H-indolecarboxylate, Intermediate 5- WO 2015/009616 2014/046515 2b peak-2 (tr = 5.5 min), (30 mg, 0.057 mmol) and LiOH in H20 (500 uL, 0.500 mmol) in THF (0.5 mL)/MeOH (0.5 mL) was stirred at 70 °C for 4h, and then cooled to room temperature. The mixture was then acidified with AcOH. The mixture was then partially concentrated. The ing residue was purified by RP-HPLC (HC-B) to afford the title compound. The te stereochemistry was determined by comparoson with enantiopure synthesis in Example-21c. 1H NMR (400 MHz, D20) 6 7.99 (d, J=8.10 Hz, 2H), 7.63 (br. d, J=8.10 Hz, 2H), 7.34 (d, J=3.03 Hz, 1H), 6.80 (s, 1H), 6.30 (d, J=3.03 Hz, 1H), 3.79 - 4.02 (m, 2H), 3.73 - 3.79 (m, 1H), 3.69 (s, 3H), 3.29 - 3.49 (m, 4H), 2.89 (br. d, J=10.90 Hz, 1H), 2.63 - 2.83 (m, 1H), 2.45 (s, 3H), 2.07 - 2.20 (m, 1H), 1.88 - 2.06 (m, 2H), 1.61 - 1.87 (m, 1H); HRMS calcd. for C24H29N204 (M+H)+ 10 409.2127, found 409.2119.
Example-21 b; (+)((2R,4R)methoxy((5-methoxymethyI-1H-indoI y|)methyl)piperidinyl)benzoic acid H0 The title compound was synthesized from tert—butyl 5-methoxy(2R,4R)-(4-methoxy(4- 15 (methoxycarbonyl)phenyl)piperidiny|)methy|)methyl-1H-indolecarboxylate, Intermediate 5- 2b peak-1 (tr = 2.8 min),, analogously to the preparation of Example-21a. ical data; same as Example-21 a.
Example-21c; (-)((2S,4S)methoxy((5-methoxymethyI-1H-indoI y|)methyl)piperidinyl)benzoic acid 0 HO I Uo O\ / N 20 H To a on of tert—butyl 4-formylmethoxymethyl-1H-indolecarboxylate, Intermediate 1-3, (1.5 g, 5.18 mmol) and methyl ((2S,4S)—4-(4-methoxypiperidinyl))benzoate, Intermediate 2-12b, (1 g, 4.01 mmol) in DOE (20 mL) was added NaBH(OAc)3 (3 g, 14.15 mmol).
The mixture was then stirred at room temperature for 3 days. The reaction was then quenched with WO 2015/009616 PCT/US2014/046515 NaBH4 (200 mg), followed by MeOH (5 mL). The mixture was then stirred at room temperature for 0.5h. The reaction mixture was diluted with EtOAc. The mixture was then washed sively with 5% aq. NaHCOs, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was mixed with LiOH in H20 (15 mL, 15 mmol) and THF (10 mL)/MeOH (20 mL) and was stirred at 70 °C for 22h, and then cooled to room temperature. The reaction mixture was with H20, and then acidified with half satd. aq. KHSO4 and citric acid. The e was then saturated with sodium chloride. The mixture was then extracted with CHZCIZ/TFE (c.a. 9/1). The organic layer was then dried over NaZSO4, filtered, and then trated. The resulting residue was purified by RP-HPLC (HC-B) to afford the title compound. ical data; same as Example-21a. 10 Following examples were preparad from the corresponding peak of the omer by the method described above.
Chemical name Exam structure NMR and HRMS Starting al for enantiomer-a Starting material for enantiomer-b (+) and (-)(re/-(28,4S)—4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin- 2-y|)pico|inic acid O 1H NMR (400 MHz, D20) 5 8.81 / (d, J=0.90 Hz, 1H), 8.01 (dd, HO I N\ J=1.80, 8.10 Hz, 1H), 7.94 (d, J=8.10 Hz, 1H), 7.34 (d, J=3.18 Hz, m 1H), 6.77 (s, 1H), 8.35 (d, J=3.06 Hz, 1H), 3.77 - 3.85 (m, 2H), N 3.85 - 3.78 (m, 4H), 3.81 (q, J=7.10 Hz, 2H), 3.34 (d, J=12.80 Hz, 0\ / 1H), 2.84 (br. d, J=11.90 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.42 (s, 3H), N 1.99 - 2.08 (m, 1H), 1.82 - 1.93 (m, 2H), 1.88 - 1.79 (m, 1H), 1.28 H (t, J=7.10 Hz, 3H); HRMS calcd. for CZ4H30N304 (M+H)+ 424.2238, "H2343 found 424.2226. (-)(re/-(2S,4S)—4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin 22-1a yl)picolinic acid was ed from Intermediate 51 b enantiomer-1 (peak-1, tr = 4.9 min). (+)(re/-(2S,4S)—4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin 22-1 b yl)picolinic acid was prepared from Intermediate 51 b enantiomer-2 (peak-2, tr = 6.0 min).
WO 2015/009616 2014/046515 (+) and (-)(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidin y|)benzoic acid O 1H NMR (400 MHz, 00300003) 5 9.94 (br. s., 1H), 8.07 (d, J=8.56 Hz, 2H), 7.73 (br. d, J=7.50 Hz, 2H), 7.23 - 7.23 (m, 1H), HO m 6.70 (s, 1H), 6.67 (dd, , 3.12 Hz, 1H), 3.78 (s, 3H), 3.74 (d, J=11.98 Hz, 1H), 3.46 (dd, J=3.12, 11.43 Hz, 1H), 3.36 (d, N J=11.98 Hz, 1H), 2.67 - 2.74 (m, 1H), 2.45 (s, 3H), 2.23 - 2.33 (m, 0\ / 1H), 1.50 - 1.58 (m, 1H), 1.36 - 1.48 (m, 2H), 1.20 - 1.30 (m, 1H), 3 1.07 (s, 3H), 0.91 (s, 3H); HRMS calcd. for C25H31N203 407.2335, found 407.2344. (+)(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidinyl)benzoic acid was prepared from Intermediate 52b enantiomer—1 (peak-1, tr = 2.4 min). (-)(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidinyl)benzoic acid —was prepared from Intermediate 52b enantiomer—2 (peak-2, tr = 4.4 min).
Example-23: N\\ o\/ N O\ / N H rel-(28,48) Example-23a; (+)(reI-(2S,4S)ethoxy((5-methoxymethyI-1H-indoI yl)methyl)piperidinyl)benzonitrile To a on of tert—butyl 4-(rel-(2S,4S)—(2-(4-cyanophenyl)—4-ethoxypiperidinyl)methyl)— 5-methoxymethyl-1H-indolecarboxylate iomer—1), Intermediate 53b peak-1 (tr = 1.7 min), (25 mg, 0.050 mmol) in CH2C|2 (1 mL) at 0 °C was added TFA (0.5 mL). The e was 10 then stirred at 0 °C for ca. 3h, and then quenched with 5% aq. NaHCOs at the same temperature.
The mixture was then extracted with CH2C|2. The organic phase was then washed successively with H20 and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by RP-HPLC (HC-B) to afford the title compound. 1H NMR (600 MHz, CD3CN) 6 9.06 (br. s., 1H), 7.72 (s, 4H), 7.20 (t, J=2.57 Hz, 1H), 6.70 (s, 1H), 6.52 (dd, J=2.40, 2.60 Hz, 1H), 3.73 (s, 15 3H), 3.60 (d, J=12.01 Hz, 1H), 3.56 - 3.58 (m, 1H), 3.53 (dd, J=2.80, 11.60 Hz, 1H), 3.46 (dq, J=1.56, 6.97 Hz, 2H), 3.25 (d, J=12.10 Hz, 1H), 2.52 (td, J=3.56, 11.76 Hz, 1H), 2.43 (s, 3H), 2.34 - WO 2015/009616 PCT/US2014/046515 2.40 (m, 1H), 1.83 - 1.89 (m, 1H), 1.72 (td, J=2.84, 13.94 Hz, 1H), 1.63 - 1.70 (m, 1H), 1.46 - 1.55 (m, 1H), 1.18 (t, J=6.97 Hz, 3H). HRMS calcd. for C25H30N302 (M+H)+ 38, found 404.2333.
Example-23b; (-)(reI-(2S,4S)ethoxy((5-methoxymethyl-1H-indol yl)methyl)piperidinyl)benzonitrile The title compound was sized from tert—butyl 4-(rel-(28,4S)—(2-(4-cyanophenyl)—4- ethoxypiperidinyl)methyl)methoxymethyl-1H-indolecarboxylate (enantiomer—2), Intermediate 53b peak-2 (tr = 3.4 min), analogously to the preparation of Example-23a.
Analytical data; same as Example-23a.
Example-24: 10 (+)(reI-(2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin zamide H2N / \ H rel-(28,48) The title compound was synthesized tert—butyl 4-(rel-(2S,4S)—(2-(4-cyanophenyl) piperidinyl)methyl)methoxymethyl-1H-indolecarboxylate (enantiomer—1), 15 Intermediate 53b peak-1 (tr = 1.7 min), analogously to the preparation of Example-8. 1H NMR (400 MHz, CD3COCD3) 6 9.83 (br. s., 1H), 7.85 (d, J=8.44 Hz, 2H), 7.57 (br. d, J=7.80 Hz, 2H), 7.28 (br. s., 1H), 7.13 (dd, J=2.60, 2.70 Hz, 1H), 6.58 (s, 1H), 6.53 - 6.56 (m, 1H), 6.39 (br. s., 1H), 3.66 (s, 3H), 3.59 (d, J=11.98 Hz, 1H), 3.50 (br. s., 1H), 3.42 - 3.48 (m, 1H), 3.38 (q, J=6.97 Hz, 2H), 3.22 (d, J=12.00 Hz, 1H), 2.45 - 2.53 (m, 1H), 2.33 (s, 3H), 2.24 - 2.32 (m, 1H), 1.78 - 1.87 (m, 20 1H), 1.55 - 1.73 (m, 2H), 1.36 - 1.53 (m, 1H), 1.09 (t, J=6.97 Hz, 3H); HRMS calcd. for C25H32N302 (M+H)+ 422.2444, found 422.2435.
Example-25: HO WO 2015/009616 2014/046515 Example-25a; (+)(1-((5,7-dimethyI-1H-indoIyl)methyl)piperidinyl)benzoic acid A mixture of methyl 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoate (enantiomer—1), Intermediate 6-1b peak-1 (tr = 2.6 min), (150 mg, 0.398 mmol) and KOH (50 mg, 0.891 mmol) in THF (1 mL) was stirred at room temperature for 1.5h. The mixture was then concentrated. The resulting e was purified by RP-HPLC (HC-B) to afford the title compound. 1H NMR (400 MHz, D20) 6 7.95 (d, J=8.59 Hz, 2H), 7.58 (br. d, J=7.80 Hz, 2H), 7.20 (d, J=3.00 Hz, 1H), 6.71 (s, 1H), 6.08 (br. s., 1H), 4.32 - 4.39 (m, 1H), 4.13 (d, J=13.60 Hz, 1H), 4.06 (d, J=13.60 Hz, 1H), 3.27 (br. d, J=12.40 Hz, 1H), 3.07 - 3.17 (m, 1H), 2.25 (s, 3H), 1.92 - 2.03 (m, 5H), 1.74 - 1.82 (m, 1H), 1.65 - 1.74 (m, 1H), 1.44 - 1.61 (m, 2H); HRMS calcd. for C23H27N202 (M+H)+ 10 73, found 64.
Example-25b; (-)(1-((5,7-dimethyI-1H-indoIyl)methyl)piperidinyl)benzoic acid The title compound was synthesized from corresponding enantiomer, methyl 4-(1-((5,7- yl-1H-indolyl)methyl)piperidinyl)benzoate (enantiomer—2), Intermediate 6-1 peak-2 (tr = 4.1 min), analogously to the preparation of Example-25a. Analytical data; same as Example-25a. 15 Example-26: Example-26a; 4-((2S,4S)-(4-ethoxy((5-methoxymethyI-1H-indoIyl)methyl)piperidin y|))benzoic acid ((+) as TFA salt) A mixture of methyl 4-((2S,4S)—4-ethoxy((5-methoxymethyl-1H-indol 20 yl)methyl)piperidinyl)benzoate, Intermediate 6-2b peak-1 (tr = 1.9 min), (84 mg, 0.192 mmol) and LiOH in H20 (1 mL, 1 mmol) in THF (1 mL)/MeOH (2 mL) was stirred at room temperature for 16h, and then then concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. Absolute stereochemistry was determined by ison with enantiopure synthesis in Example-26c. 1H NMR (TFA salt, 400 MHz, D20) 6 8.12 (d, J=8.19 Hz, 2H), 7.66 (br. 25 d, J=8.20 Hz, 2H), 7.35 (d, J=3.06 Hz, 1H), 6.67 (s, 1H), 6.25 (d, J=3.06 Hz, 1H), 4.65 (dd, J=4.28, 11.49 Hz, 1H), 4.04 (d, J=13.00 Hz, 1H), 3.87 - 3.98 (m, 2H), 3.53 - 3.69 (m, 5H), 3.38 - 3.50 (m, 1H), 3.20 - 3.35 (m, 1H), 2.40 (s, 3H), 2.17 - 2.33 (m, 2H), 2.08 (br. d, J=15.70 Hz,1H), 1.82 - 1.99 (m, 1H), 1.28 (t, J=7.03 Hz, 3H); HRMS calcd. for C25H31N203 (M+H)+ 423.2284, found 423.2263.
WO 2015/009616 2014/046515 Example-26b; 4-((2R,4R)-(4-ethoxy((5-methoxymethyI-1H-indoly|)methyl)piperidin yl))benzoic acid ((-) as TFA salt) 0 HO K .,.o N O\ / N H 4-((2R,4R)—(4-ethoxy—1-((5-methoxymethyl-1H-indolyl)methy|)piperidinyl))benzoic 5 acid ((-) as TFA salt) was synthesized from methyl 4-((2R,4R)—4-ethoxy((5-methoxymethyl- 1H-indolyl)methyl)piperidinyl)benzoate (enantiomer—2), ediate 6-2b peak-2 (tr = 3.4 min), analogously to the preparation of Example-26a. ical data; same as Example-26a.
Example-26c; 4-((2$,4S)-(4-ethoxy((5-methoxymethyI-1H-indoIyl)methyl)piperidin yl))benzoic acid ((+) as TFA salt) 10 H To a solution of tert—butyl ylmethoxymethyl-1H-indolecarboxylate, Intermediate 1-3, (1.5 g, 5.18 mmol) and methyl 4-((28,4S)—4-ethoxypiperidinyl)benzoate, Intermediate 2-13a, (1.185 g, 4.5 mmol) in DOE (20 mL) was added NaBH(OAc)3 (3 g, 14.15 mmol). The mixture was then d at room temperature for 21 .5h. To the mixture was then 15 added additional amount of tert—butyl 4-formylmethoxymethyl-1H-indolecarboxylate (500 mg, 4.50 mmol). The mixture was then stirred at room temperature for r 20h. The reaction mixture was then diluted with EtOAc, and then washed successively with 5% aq. Nchog, H20, and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was mixed with LiOH in H20 (15 mL, 15 mmol) and THF (10 mL)/MeOH (20 mL) and was stirred at 70 0C for 8h, 20 and then cooled to room temperature. The reaction e was then diluted with H20, and then acidified with half satd. aq. KHSO4 and citric acid. The mixture was then saturated with sodium chloride. The mixture was then extracted with CHZCIZ/TFE (c.a. 9/1 ). The organic layer was then dried over NaZSO4, filtered, and then concentrated. The resulting residue was purified by RP-HPLC (HC-B) to afford the title compound. Analytical data; same as Example-26a.
WO 2015/009616 PCT/US2014/046515 Example-26d; ,4S)-(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl))benzoic acid hydrochloride 0 HOJKQ K "CFON HCI To a solution of 4-((2S,4S)—(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin- 5 benzoic acid (620 mg, 1.467 mmol) in HZO/CH3CN (10/3 mL) was added 5M aq. HCI (500 uL, 2.500 mmol). The mixture was then lyophilized. The resulting amorphous compound was then suspended in iPrOH (300 mL). The mixture was heated to 70 °C. The mixture turned to a on after 1.5h. The solution was then cooled to room temperature with stirring for approx. 5h. The resulting solid was collected by filtration. The solid was dried up under high vacuum at 50 °C to 10 afford the title nd as a crystalline solid. 1H NMR (HCI salt, 400 MHz, CD30D) 6 10.73 (br. s., 1H), 8.23 (d, J=8.44 Hz, 2H), 7.74 (d, J=8.44 Hz, 2H), 7.31-7.36 (m, 1H), 6.77 (s, 1H), 6.37 (dd, J=1.77, 3.12 Hz, 1H), 4.33 (d, J=12.72 Hz, 1H), 4.25 (d, J=12.72 Hz, 1H), 3.79-3.85 (m, 1H), 3.76 (s, 3H), 3.51-3.67 (m, 4H), 3.37-3.44 (m, 1H), 2.51 (s, 3H), 2.21-2.29 (m, 2H), 1.90-2.15 (m, 2H), 1.31 (t, J=6.97 Hz, 3H). X—ray powder diffraction: Angle d value Intensity % 2-Theta ° Angstrom Count % 10.0 8.842 41 11.6 7.631 72 15.3 5.783 100 16.5 5.360 71 17.3 5.131 66 20.1 4.418 77 21.0 4.220 95 22.8 3.900 51 23.3 3.815 73 25.3 3.520 52 26.2 3.393 48 31.0 2.887 25 15 WO 2015/009616 PCT/US2014/046515 The following Examples were synthesized from appropriate starting als by applying similar methods described in the examples above: Chemical name Exam structure NMR and HRMS l% Starting material for enantimer—a Starting material for enantimer—b (+) and (-)(rel-(28,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidin y|)benzoic acid 1H NMR (400 MHz, 020) 5 7.81 (d, J=8.08 Hz, 2H), 7.47 (d, J=8.10 Hz, 2H), 7.11 (d, J=3.03 Hz, 1H), 6.60 (s, 1H), 6.06 (br. s., 1H), 3.92 (br. s., 1H), 3.70 (d, J=12.63 Hz, 1H), 3.59 (br. s., 1H), 3.28 — 3.53 (m, 1H), 3.22 (s, 3H), 2.74 (br. s., 2H), 2.19 (s, 3H), 1.94 — 2.10 (m, 2H), 1.88 (s, 3H), 1.70 — 1.84 (m, 1H), 1.40 — 1.69 (m, 1H); HRMS calcd. for CZ4H29N203 (M+H)+ 393.2178, found 8) 393.2179. (+)(re/-(28,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid was prepared from Example-14a enantiomer—1 (peak-1, tr = 2.4 min) (rel-(28,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid was ed from Example-14b enantiomer—2 (peak-2, tr = 3.4 min) 4-(rel-(28,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)—4-ethoxypiperidinyl)benzoic acid ((+)- as TFA saltand (-)- as TFA salt) 0 1H NMR (TFA salt, 600 MHz, D20) 5 8.04 (d, J=7.79 Hz, 2H), 7.73 HO (br. d, J=7.40 Hz, 2H), 7.38 (d, J=2.84 Hz, 1H), 6.89 (s, 1H), 6.29 N7‘N ( 0 (br. s., 1H), 4.64 (br. s., 1H), 4.28 (br. s, 1H), 4.13 (br. s, 1H), 3.97 N (br. s, 1H), 3.65 (q, J=6.94 Hz, 2H), 3.40 (br. s., 1H), 3.22 (br. s., / 1H), 2.45 (s, 3H), 2.34 (br. s., 2H), 2.15 (br. s., 3H), 2.03 - 2.11 (m, 3 1H), 1.90 (br. s., 1H), 1.29 (t, J=7.02 Hz, 3H); HRMS calcd. for rel-(28,48) 025H31N203 (M+H)+ 407.2335, found 407.2332.
WO 2015/009616 PCT/US2014/046515 4-(rel-(2S,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)—4-ethoxypiperidinyl)benzoic acid (+) 27-2a as TFA salt) was prepared from Intermediate 62b enantiomer—1 (peak-1, tr = 1.7 min). "27% -(2S,4S)—1-((5,7-dimethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid ((- ) as TFA salt) was prepared from ediate 62b enantiomer—2 (peak-2, tr = 4.4 min). (+) and (-)(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4- methoxypiperidinyl)benzoic acid 0 1H NMR (400 MHz, D20) 6 7.81 (br. d, J=8.30 Hz, 2H), 7.51 (br. d, HO J=7.80 Hz, 2H), 7.20 (d, J=3.28 Hz, 1H), 6.52 (s, 1H), 6.16 (br. s., 27_ 0\ 1H), 4.15 - 4.46 (m, 2H), 3.97 (br. s., 1H), 3.66 (br. s., 1H), 3.24 (s, N 3H), 2.96 - 3.20 (m, 2H), 2.23 (s, 3H), 2.14 (br. s., 2H), 1.90 (br. d, / J=15.40 Hz, 1H), 1.70 (br. s., 1H), 1.45 (br. s., 1H), 0.66 (br. s., N H 1H), 0.55 (br. s., 1H), 0.14 (br. s., 1H), - 0.11 (br. s., 1H). HRMS rel-(23743) calcd. for C26H31N203 (M+H)+ 419.2335, found 419.2335. "273—" (-)(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4-methoxypiperidin - a y|)benzoic acid was prepared from Intermediate 63b enantiomer—1 (peak-1, tr = 2.0 min) "27% (+)(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4-methoxypiperidin y|)benzoic acid was prepared from Intermediate 63b enantiomer—2 (peak-2, tr = 4.3 min) (+) and (-)(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4- piperidinyl)benzoic acid 1H NMR (600 MHz, D20) 6 8.03 (d, J=8.25 Hz, 2H), 7.71 (br. d, O J=7.80 Hz, 2H), 7.41 (d, J=2.93 Hz, 1H), 6.71 (s, 1H), 6.32 (br. s., HO 1H), 4.63 - 4.73 (m, 1H), 4.52 (d, J=12.30 Hz, 1H), 4.30 (d, 274 J=12.30 Hz, 1H), 3.98 (br. s., 1H), 3.65 (q, J=7.00 Hz, 2H), 3.42 - N 3.56 (m, 1H), 3.34 (br. d, J=11.00 Hz, 1H), 2.43 (s, 3H), 2.26 - / 2.40 (m, 2H), 2.10 N (d, J=15.31 Hz, 1H), 1.92 (br. s., 1H), 1.61 (br.
H s., 1H), 1.29 (t, J=7.00 Hz, 3H), 0.87 (br. s., 1H), 0.76 (br. s., 1H), rel-(28,48) 0.34 (br. s., 1H), 0.08 (br. s., 1H). HRMS calcd. for C27H33N203 (M+H)+ 433.2491, found 433.2482. __________ (+)(rel-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4-ethoxypiperidin 27-4a y|)benzoic acid was prepared from ediate 64b enantiomer—1 and isolated as a TFA salt (peak-1, tr = 1.3 min) WO 09616 PCT/US2014/046515 (-)(re/-(2S,4S)—1-((5-cyclopropylmethyl-1H-indolyl)methyl)—4-ethoxypiperidin 27-4b y|)benzoic acid was prepared from Intermediate 64b enantiomer-2 and isolated as a TFA salt (peak-2, tr = 2.9 min) Example-28: (i)(5-Methoxy((5-methoxymethyl-1H-indoly|)methyl)piperidinyl)benzoic acid (diastereomer—1) O HO N O/ O\ / N H diastereomer-1 A mixture of Ba(OH)2 (200 mg, 0.716 mmol) and n‘-butyl 4-((2-(4-cyanophenyl)—5- methoxypiperidiny|)methyl)methoxymethyl-1H-indolecarboxylate (diastereomer—1), Intermediate 419, (60 mg, 0.154 mmol) in iPrOH/HZO (0.5/2 mL) was stirred at 100 °C for 36h.
The e was cooled to room temperature. The aqueous layer was ied with AcOH. The 10 mixture was filtered through a plug of celite, which was rinsed with HZO/MeOH (ca. 4/1). The aqueous filtrate was purified by RP-HPLC (HC-B) to afford the title nd. 1H NMR (TFA salt, 400 MHz, D20) 6 8.07 (d, J=8.31 Hz, 2H), 7.63 (d, J=8.31 Hz, 2H), 7.36 (d, J=3.06 Hz, 1H), 6.69 (s, 1H), 6.22 (d, J=3.06 Hz, 1H), 4.40 (dd, J=2.81, 12.23 Hz, 1H), 4.12 (d, J=12.80 Hz, 1H), 3.98 (d, J=12.96 Hz, 1H), 3.59-3.71 (m, 4H), 3.52-3.58 (m, 1H), 3.26 (s, 3H), 2.99 (dd, J=11.50, 11.60 Hz, 15 1H), 2.41 (s, 3H), 2.34 (br. d, J=13.60 Hz, 1H), 2.19-2.28 (m, 1H), 2.03-2.17 (m, 1H), 1.54-1.68 (m, 1H); HRMS calcd. for C24H29N204 (M+H)+ 409.2127, found 409.2117.
Example-29: (i)(5-Methoxy((5-methoxymethyl-1H-indoly|)methyl)piperidinyl)benzamide (diastereomer—1) o H2N N O/ 0‘ / N 20 H diastereomer-1 WO 2015/009616 PCT/US2014/046515 The title compound was isolated in the sis of Example-28 as a minor product. 1H NMR (400 MHz, CD30D) 6 10.77 (br. s., 1H), 8.09 (d, J=8.44 Hz, 2H), 7.69 (d, J=8.44 Hz, 2H), 7.33-7.38 (m, 1H), 6.79 (s, 1H), 6.31-6.34 (m, 1H), 4.50 (dd, J=2.87, 12.29 Hz, 1H), 4.38 (d, J=12.59 Hz, 1H), 4.24 (d, 9 Hz, 1H), 3.76 (s, 3H), 3.53-3.64 (m, 2H), 3.28 (s, 3H), 3.03-3.12 (m, 1H), 2.52 (s, 3H), 2.31-2.40 (m, 1H), 2.17-2.25 (m, 1H), 1.99-2.13 (m, 1H), 1.56-1.70 (m, 1H); HRMS calcd. for C24H30N303 (M+H)+ 408.2280, found 408.2287.
The following Examples were synthesized from appropriate starting materials by applying r methods described in the examples above: chemical name Exam p|_e Starting material al StFUCture= NMR and HRMS (i)(5-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid (diastereomer-2) Intermediate 420 0 1H NMR (400 MHz, 020) 6 .99 (m, 2H), 7.60 (br. d, J=7.90 fl HOJkOU Hz, 2H), 7.33 (t, J=2.93 Hz, 1H), 6.71 (br. d, J=7.30 Hz, 1H), 6.18- N 6.24 (m, 1H), 4.46-4.54 (m, J=12.30 Hz, 1H), 4.14-4.24 (m, 1H), 0/ 4.02-4.12 (m, 1H), 3.79 (m, 4H), 3.48-3.56 (m, 1H), 3.33-3.42 (m, N 1H), 3.21 (br. d, J=1.20 Hz, 3H), 2.29-2.43 (m, 4H), 2.15-2.23 (m, H diastereomer-2 1H), 1.99-2.07 (m, 1H), 1.83-1.94 (m, 1H); HRMS calcd. for C24H29N204 (M+H)+ 409.2127, found 409.2119. (i)(5-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid (diastereomer-1) Intermediate 4-5 O 1H NMR (400 MHz, 020) 6 7.99 (br. d, J=8.15 Hz, 2H), 7.63 (br. d, fl HOXQNOMH J=8.15 Hz, 2H), 7.37 (d, J=3.11 Hz, 1H), 6.82 (s, 1H), 6.29 (d, J=3.11 Hz, 1H), 3.93-4.04 (m, 1H), 3.81-3.92 (m, 2H), 3.72 (s, 3H), 68-NH 3.58-3.79 (m, 1H), .31 (m, 1H), 2.47 (s, 3H), 2.44-2.66 (m, 1H), 2.15 (br. d, J=11.50 Hz, 1H), 2.01-2.09 (m, 1H), 1.92 (br. s., 1H), 1.50-1.64 (m, 1H); HRMS calcd. for C23H27N204 (M+H)+ diastereomer-1 WO 2015/009616 2014/046515 395.1953, found 395.1971. (i)(5-hydroxy((5-methoxymethyl-1H-indoly|)methyl)piperidinyl)benzoic acid (diastereomer-2) Intermediate 4-6 1H NMR (400 MHz, 020) 5 7.98 (br. d, J=8.30 Hz, 2H), 7.61 (br. d, HO E J=7.90 Hz, 2H), 7.34 (d, J=3.06 Hz, 1H), 6.81 (s, 1H), 6.28 (d, J=3.06 Hz, 1H), 3.73-3.82 (m, 2H), 3.71 (s, 3H), 3.49 (br. d, OH 0\ J=10.30 Hz, 1H), 3.37 (br. d, J=12.30 Hz, 1H), 3.09-3.18 (m, 1H), / N 2.46 (s, 3H), 2.25 (app. br. t, J=10.90 Hz, 1H), 2.05-2.14 (m, 1H), H diastereomer_2 1.90-1.98 (m, 1H), .85 (m, 1H), 1.41-1.54 (m, 1H); HRMS calcd. for C23H27N204 (M+H)+ 395.1953, found 395.1965.
Example-31 : ((5,7-Dimethyl-1H-indolyl)methyl)-N-methylphenylpiperidinamine-(diastereomer— 1) H diastereomer-1 To a solution of (i)—benzyl (1-((5,7-dimethyltosyl-1H-indolyl)methyl)—2-phenylpiperidin- 4-y|)carbamate ereomer—1), Intermediate 32, (100 mg, 0.161 mmol) in THF (5 mL) was added LiAlH4 (60 mg, 1.581 mmol). The mixture was stirred at 50 °C for 15h. The reaction mixture was cooled to 0 °C. The reaction was then quenched with H20 (60 uL), 15% aq. NaOH (60 uL), 10 and H20 (120 uL). The mixture was then diluted with THF. The mixture was then filtered through a plug of Celite®, which was rinsed with TH F. The filtrate was then concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. 1H NMR (400 MHz, CDgOD) 6 7.53 (d, J=7.30 Hz, 2H), 7.36 (dd, J=7.30, 7.80 Hz, 2H), 7.25 - 7.30 (m, 1H), 7.14 (d, J=3.30 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J=3.28 Hz, 1H), 3.75 (d, J=12.13 Hz, 1H), 3.50 (dd, J=3.16, 11.49 Hz, 15 1H), 3.29 (br. d, 0 Hz, 1H), 2.79 - 2.83 (m, 1H), 2.58 - 2.65 (m, 1H), 2.42 - 2.47 (m, 1H), 2.39 (br. s, 6H), 2.25 (s, 3H), 1.96 - 2.06 (m, 1H), 1.83 - 1.90 (m, 1H), 1.68 - 1.77 (m, 2H); HRMS calcd. for C23H30N3 (M+H)+ 348.2440, found 348.2426.
WO 2015/009616 PCT/US2014/046515 The ing examples were synthesized from the appropriate starting material by applying similar methods described in the examples above: chemical name Exam p|_e Starting material chemical structure NMR and HRMS (i)—1-((5,7-dimethyl-1H-indolyl)methyl)-N-methylphenylpiperidinamine (diastereomer—2) Intermediate 33 rim 1H NMR (400 MHz, CDgOD) 5 7.53 (br. d, J=7.10 Hz, 2H), 7.37 2_1 (dd, J=7.30, 8.10 Hz, 2H), 7.26 - 7.32 (m, 1H), 7.14 (d, J=3.15 Hz, N 1H), 6.67 (s, 1H), 6.51 (d, J=3.15 Hz, 1H), 3.71 (d, J=12.13 Hz, <1 1H), 3.11 - 3.20 (m, 2H), 2.85 (td, J=3.35, 12.00 Hz, 1H), 2.50 - H. 2.60 (m, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.03 - 2.11 d'aStereomer'Z (m, 1H), 1.96 - 2.03 (m, 1H), 1.77 - 1.85 (m, 1H), 1.53 - 1.63 (m, 1H), 1.23 - 1.35 (m, 1H); HRMS calcd. for N3 (M+H)+ 348.2440, found 348.2430. (i)— (4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanamine Intermediate 311 1H NMR (TFA salt, 400 MHz, D20) 5 7.64 (br. d, J=7.94 Hz, 2H), HZNno 7.55 (br. d, J=7.94 HZ, 2H), 7.29 (d, J=3.03 HZ, 1H), 6.81 2-2 (s, 1H), N 6.17 (br. s., 1H), 4.36 - 4.42 (m, 1H), 4.24 (d, 0 HZ, 1H), 4.12 - 4.18 (m, 3H), 3.34 (br. d, J=12.10 Hz, 1H), 3.14 - 3.24 (m, / N 1H), 2.34 (s, 3H), 1.98 - 2.11 (m, 5H), 1.72 - 1.89 (m, 2H), 1.50 - H 1.88 (m, 2H); HRMS calcd. for C23H30N3 (M+H)+ 348.2434, found 348.2434.
WO 2015/009616 PCT/US2014/046515 (4-((2S,4S)—4-methoxy—1-((5-methoxymethyl-1H-indolyl)methyl)piperidin nyl)methanol Example-21b 1H NMR (400 MHz, CDgOD) 5 9.05 (br. s., 1H), 7.79 (br. d, J=8.60 H0 |'.°00 00 I Hz, 2H), 7.63 (br. d, J=7.90 Hz, 2H), 7.19 (app. t, J=2.81 Hz, 1H), 7.02 (br. s., 1H), 6.70 (s, 1H), 6.52 (dd, J=2.08, 3.18 Hz, 1H), 3.73 (s, 3H), 3.62 (d, J=11.92 Hz, 1H), 3.43 - 3.54 (m, 6H), 3.31 (s, / \ 3H), 3.28 (s, 3H), 3.23 (d, J=11.92 Hz, 1H), 2.47 - 2.54 (m, 1H), H (2343) 2.42 (s, 3H), 2.28 - 2.37 (m, 1H), 1.86 - 1.89 (m, 1H), 1.67 - 1.80 (m, 2H), 1.45 - 1.55 (m, 1H); HRMS calcd. for C27H35N304 (M+H)+ 466.2706, found 466.2696.
Example-33: (i)((2-(3-(2H-tetrazolyl)phenyl)piperidiny|)methyl)-5,7-dimethyl-1H-indole A mixture of (i)—ten‘-butyl 4-((2-(3-cyanophenyl)piperidinyl)methyl)—5,7-dimethyl-1H- indole—1-carboxylate, ediate 4-7, (130 mg, 0.293 mmol), NaNs (58 mg, 0.88 mmol) and CdClz (11 mg, 0.06 mmol) in DMF (1.5 mL) was stirred at 100 °C for 6 h, and then cooled to room temperature. The mixture was d with EtOAc. The organic phase was then washed 10 successively with H20 (twice), and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. 1H NMR (HCI salt, 400 MHz, CD30D) 5 8.16 - 8.31 (m, 2H), 7.54 - 7.74 (m, 2H), 7.25 (d, J=2.78 Hz, 1H), 6.80 (s, 1H), 6.34 (br. s., 1H), 4.53 (br. d, J=10.10 Hz, 1H), 4.38 (d, J=13.40 Hz, 1H), 4.30 (d, J=13.40 Hz, 1H), 3.54 (br. d, J=11.90 Hz, 1H), 3.35 - 3.43 (m, 1H), 2.43 (s, 3H), 2.22 - 2.31 (m, 1H), 2.13 - 2.21 (m, 15 J=13.40 Hz, 1H), 2.09 (br. s., 3H), 1.96 - 2.04 (m, 1H), 1.72 - 1.96 (m, 3H); HRMS calcd. for N5 (M+H)+ 385.2141, found 385.2142.
WO 2015/009616 2014/046515 Example-34: (i)(1-((5,7-Dimethyl-1H-indolyl)methyl)piperidinyl)benzamide H2N O N / N H A mixture of thyl 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoate, Intermediate 4-8, (80 mg, 0.212 mmol), CaC|2 (100 mg, 0.901 mmol), and NH4OH (33%, 10 m) in MeOH (10 mL) was stirred at 80 °C for ca. 16h. The reaction mixture was then cooled to room temperature. The mixture was diluted with EtOAc. The organic phase was then washed successively with H20 (twice), and brine, dried over , ed, and concentrated. The resulting residue was purified by silica gel flash column chromatography (HC-A) to afford the title 10 compound. 1H NMR (400 MHz, CD30D) 6 8.03 (s, 1H), 7.80 (d, J=7.80 Hz, 1H), 7.74 (br. d, J=7.60 Hz, 1H), 7.47 (dd, J=7.60, 7.80 Hz, 1H), 7.14 (d, J=3.28 Hz, 1H), 6.66 (s, 1H), 6.49 (d, J=3.20 Hz, 1H), 3.68 (d, J=12.13 Hz, 1H), 3.14 - 3.25 (m, J=11.40 Hz, 2H), 2.87 (d, J=11.62 Hz, 1H), 2.39 (s, 3H), 2.16 - 2.28 (m, 3H), 1.93 - 2.15 (m, 1H), 1.65 - 1.89 (m, 3H), 1.34 - 1.63 (m, 3H); HRMS calcd. for C23H28N30 (M+H)+ 362.2232, found 362.2223. 15 Example-35: (i)-(3-(1-((5,7-Dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol HO N / N H A mixture of (i)—methyl 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoate, ediate 4-8, (230 mg, 0.611 mmol) and NaBH4 (200 mg, 5.29 mmol) in THF/MeOH (10 mL/5 20 mL) was stirred under the reflux condition for 3h. The mixture was partially trated. The resulting residue was then diluted with EtOAc. The mixture was then washed successively with H20 and brine, dried over NaZSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (HC-A) to afford the title compound. 1H NMR (400 MHz, DMSO-ds) 6 10.82 (br. s., 1H), 7.46 (br. s., 1H), 7.37 (br. d, J=7.60 Hz, 1H), 7.32 (dd, J=7.30, 7.60 25 Hz, 1H), 7.22 (br. d, J=7.60 Hz, 1H), 7.20 (br. dd, J=2.80, 3.00 Hz, 1H), 6.63 (s, 1H), 6.50 (dd, J=2.02, 2.80 Hz, 1H), 5.18 (t, J=5.81 Hz, 1H), 4.52 (d, J=5.81 Hz, 2H), 3.59 (d, J=12.13 Hz, 1H), WO 2015/009616 PCT/US2014/046515 3.00 - 3.12 (m, 2H), 2.57 - 2.66 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 1.84 - 1.94 (m, 1H), 1.54 - 1.75 (m, 3H), 1.46 (br. d, J=8.30 Hz, 1H), 1.26 - 1.41 (m, 2H); HRMS calcd. for C23H29N20 (M+H)+ 349.2280, found 76.
Example-36: (i)-(4-(reI-(2S,4S)-(2-(4-(1H-tetrazolyl)phenyl)ethoxypiperidiny|)methyl)methoxy methyl-1H-indole: ,N=N HN\ / N o\/ N O\ / N H rel-(28,48) To a solution of (i)—ten‘-butyl 4-(rel-(28,4S)—(2-(4-cyanophenyl)ethoxypiperidin y|)methyl)methoxymethy|—1H-indoIecarboxylate, Intermediate 53a, (50 mg, 0.099 mmol) 10 in DMF (1 mL) was added NaNs (30 mg, 0.461 mmol), followed by phosphomolybdic acid hydrate (CAS: 514294, 30 mg, 0.099 mmol). The mixture was then stirred at 110 °C for 3 days, and then cooled to room ature. The reaction mixture was diluted with EtOAc. The mixture was then filtered through a plug of silica gel, which was rinsed with EtOAc/MeOH (ca. 4/1 ). The filtrate was then concentrated. The ing residue was purified by C (HC-B) to afford the title 15 compound. 1H NMR (400 MHz, D20) 6 8.11 (br. d, J=7.80 Hz, 2H), 7.68 (br. d, J=8.10 Hz, 2H), 7.36 (br. s., 1H), 6.75 (br. s., 1H), 6.30 (br. s., 1H), 4.51 (br. s., 1H), 4.15 - 4.26 (m, 1H), 3.91 - 4.01 (m, 2H), 3.60 - 3.71 (m, 5H), 3.14 - 3.41 (m, 2H), 2.40 (s, 3H), 2.19 - 2.35 (m, 2H), 1.86 - 2.12 (m, 2H), 1.29 (t, J=6.82 Hz, 3H); HRMS calcd. for C25H31N502 (M+H)+ 447.2508, found 447.2489.
Example-37: 20 (+)((2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N- (methylsulfonyl)benzamide o /o o )3:WC), or U O\ / N H To a solution of 4-((2S,4S)—(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin- 2-yl)benzoic acid, Example-26a, (98 mg, 0.232 mmol) in DMF (1 mL) were added 25 methanesulfonamide (33.1 mg, 0.348 mmol) and HATU (97 mg, 0.255 mmol), followed by Et3N (0.097 mL, 0.696 mmol). The mixture was then d at room temperature for 20h. To the mixture WO 2015/009616 PCT/US2014/046515 was added an additional amount of methanesulfonamide (20 mg, 0.21 mmol), and then the mixture was stirred for 48h. The reaction was quenched with MeOH /H20 (ca. 1/1), which was ed by RP-HPLC (HC-B) to afford the title compound. 1H NMR z, CD30D) 6 8.21 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 7.32 (d, J=2.8 Hz, 1H), 6.77 (s, 1H), 6.33 (d, J=3.2 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.37 - 4.29 (m, 1H), 4.27 - 4.16 (m, 1H), 3.81 (br. s., 1H), 3.77 (s, 3H), 3.70 - 3.65 (m, 1H), 3.64 - 3.54 (m, 3H), 3.16 - 3.10 (m, 5H), 2.51 (s, 3H), 2.29 - 2.20 (m, 2H), 2.11 - 1.92 (m, 2H), 1.31 (t, J=7.0 Hz, 3H); HRMS ca|cd. for C25H34N305S (M+H)+ 500.2219, found 500.2207.
Example-38: 4-((2S,4S)methoxy((5-methoxymethyl-1H-indoly|)methyl)piperidiny|)-N- 10 methylbenzamide To a solution of 4-(4-methoxy(2S,4S—(5-methoxymethyl-1H-indolyl)methyl)piperidin- 2-yl)benzoic acid, Example-21b, (30 mg, 0.073 mmol) and methylamine (in THF, 100 uL, 0.2 mmol) in DMF (0.5 mL) was added a solution of EDC-HCI (20 mg, 0.104 mmol) and HOAt (10 mg, 15 0.073 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 13h. To the mixture was then added additional amount of EDC-HCI (20 mg, 0.104 mmol). The mixture was stirred at room temperature for 2h. The reaction was quenched with H20. The mixture was purified by RP-HPLC (HC-B) to afford the title compound. 1H NMR (400 MHz, CD3CN) 6 9.05 (br. s., 1H), 7.78 (d, J=8.60 Hz, 2H), 7.63 (br. d, J=8.10 Hz, 2H), 7.18 - 7.21 (m, 1H), 6.93 (br. s., 1H), 6.70 (s, 20 1H), 6.52 (dd, J=2.10, 3.10 Hz, 1H), 3.73 (s, 3H), 3.62 (d, J=11.98 Hz, 1H), 3.44 - 3.51 (m, 2H), 3.28 (s, 3H), 3.23 (d, J=11.98 Hz, 1H), 2.85 (d, J=4.77 Hz, 3H), 2.47 - 2.54 (m, 1H), 2.42 (s, 3H), 2.28 - 2.37 (m, 1H), 1.68 - 1.79 (m, 2H), 1.44 - 1.55 (m, 1H) HRMS ca|cd. for C25H32N303 (M+H)+ 422.2444, found 422.2430. 25 The ing examples were synthesized from appropriate starting materials by ng similar methods described in the examples above: WO 2015/009616 PCT/US2014/046515 Chemical name starting material Chemical structure NMR; HRMS 4-((28,4S)—4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N,N- dimethylbenzamide Example-21b and dimethylamine 1H NMR (400 MHz, CDBCN) 5 9.05 (br. s., 1H), 7.60 (br. d, J=7.90 Hz, 2H), 7.39 (br. d, J=8.40 Hz, 2H), 7.19 (dd, J=2.80, 2.90 Hz, 1H), 6.70 (s, 1H), 6.53 (dd, J=2.08, 3.06 Hz, 1H), 3.73 (s, 3H), 3.66 (d, J=12.23 Hz, 1H), 3.42 - 3.50 (m, 2H), 3.29 (s, 3H), 3.25 (d, J=11.40 Hz, 1H), 2.89 - 3.04 (m, 6H), 2.48 - 2.55 (m, 1H), 2.42 (s, 3H), 2.29 - 2.38 (m, 1H), 1.69 - 1.80 (m, 3H), 1.46 - 1.56 (m, 1H); HRMS calcd. for 026H34N303 (M+H)+ 436.2600, found 436.2589. (4-((28,4S)—4-methoxy—1-((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)phenyl)(morpholino)methanone Example-21b and morpholine 1H NMR (400 MHz, CDBCN) 5 9.07 (br. s., 1H), 7.61 (br. d, J=7.80 Hz, 2H), 7.39 (d, J=8.31 Hz, 2H), 7.18 (dd, , 2.93 Hz, 1H), 6.69 (s, 1H), 6.50 - 6.58 (m, 1H), 3.73 (s, 3H), 3.31 - 3.70 (m, 11H), 3.28 (s, 3H), 3.25 (d, J=11.70 Hz, 1H), 2.48 - 2.57 (m, 1H), 2.42 (s, 3H), 2.28 - 2.39 (m, 1H), 1.86 - 1.91 (m, 1H), 1.69 - 1.80 (m, 2H), 1.45 - 1.56 (m, 1H); HRMS calcd. for o4 (M+H)+ 478.2706, found 478.2696.
WO 09616 PCT/US2014/046515 N-(2-hydroxyethyl)((28,4S)—4-methoxy—1-((5-methoxymethyI-1H-indoI y|)methy|)piperidinyl)benzamide Example-21b and 2-ethanolamine 1H NMR (400 MHz, CD3CN) 5 9.06 (br. s., 1H), 7.82 (br. d, J=8.60 Hz, 2H), 7.64 (br. d, J=8.10 Hz, 2H), 7.20 (app. t, J=2.81 Hz, 1H), 7.10 - 7.17 (m, 1H), 6.70 (s, 1H), 6.53 (dd, J=2.10, 3.20 Hz, 1H), 3.74 (s, 3H), 3.59 - 3.66 (m, 3H), 3.41 - 3.52 (m, 4H), 3.28 (s, 3H), 3.24 (d, J=12.00 Hz, 1H), 3.10 - 3.17 (m, 1H), 2.47 - 2.54 (m, 1H), 2.42 (s, 3H), 2.28 - 2.38 (m, 1H), 1.87 - 1.90 (m, 1H), 1.66 - 1.80 (m, 2H), 1.44 - 1.56 (m, 1H); HRMS calcd. for C26H34N304 (M+H)+ 452.2549, found 452.2532. 4-((28,4S)—4-methoxy((5-methoxymethy|—1H-indoIyl)methyl)piperidinyl)—N-(2- methoxyethyl)benzamide Example-21b and 2-methoxyethylamine 1H NMR (400 MHz, CD3CN) 5 9.05 (br. s., 1H), 7.79 (br. d, J=8.60 Hz, 2H), 7.63 (br. d, J=7.90 Hz, 2H), 7.19 (app. t, J=2.81 Hz, 1H), 7.02 (br. s., 1H), 6.70 (s, 1H), 6.52 (dd, J=2.08, 3.18 Hz, 1H), 3.73 (s, 3H), 3.62 (d, J=11.92 Hz, 1H), 3.43 - 3.54 (m, 6H), 3.31 (s, 3H), 3.28 (s, 3H), 3.23 (d, 2 Hz, 1H), 2.47 - 2.54 (m, 1H), 2.42 (s, 3H), 2.28 - 2.37 (m, 1H), 1.86 - 1.89 (m, 1H), 1.67 - 1.80 (m, 2H), 1.45 - 1.55 (m, 1H); HRMS calcd. for C27H36N304 (M+H)+ 466.2706, found 466.2696.
WO 2015/009616 PCT/US2014/046515 e-40: (i)-N-((4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidin yl)phenyl)sulfonyl)acetamide The title compound was synthesized from (i)—ten‘-butyl 4-((2-(4-(N- acetylsulfamoyl)phenyl)piperidinyl)methy|)cyc|opropylmethyl-1H-indolecarboxylate, Intermediate 326, analogously to the ation of Example-22. 1H NMR (400 MHz, CD3COCD3)610.55(br.s., 1H), 9.98 (br. s., 1H), 8.01 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.24 (app. t, J=2.8 Hz, 1H), 6.69 (dd, J=2.0, 3.1 Hz, 1H), 6.55 (s, 1H), 3.84 (d, J=12.1 Hz, 1H), 3.43 10 (d, J=12.1 Hz, 1H), 3.29 (dd, J=3.0, 10.6 Hz, 1H), 2.88 - 2.82 (m, 1H), 2.40 (s, 3H), 2.27 - 2.22 (m, 1H), 2.00 (s, 3H), 1.81 - 1.74 (m, 2H), 1.74 - 1.67 (m, 1H), 1.57 - 1.52 (m, 1H), 1.51 - 1.39 (m, 2H), 0.89 - 0.79 (m, 1H), 0.76 - 0.69 (m, 1H), 0.62 - 0.54 (m, 1H), 0.20 - 0.12 (m, 1H). HRMS calcd. for C25H32N3038 (M+H)+ 466.2159, found 466.2140.
Example-41: 15 Ethyl 4-((2S,4R)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin yl)benzoate /\OJJ\© NO O\ / N H To a solution of EtOH (200 mL) was added AcCl (2.0 mL), and then the mixture was stirred at room temperature for 5 min. To the solution was added (+)((2S,4R)—1-((5-methoxymethyl- 20 1H-indolyl)methyl)methylpiperidinyl)benzoic acid, Example-20a, (300 mg, 0.764 mmol), and then the e was stirred for 12h under the reflux condition. The reaction e was then cooled to room temperature. The mixture was then rendered basic by satd. aq. NaHCO3, and then concentrated to remove EtOH. The mixture was then extracted with EtOAc. The organic phase WO 2015/009616 PCT/US2014/046515 was then washed with brine, dried over NaZSO4, filtered, and concentrated. The ing residue was purified by by silica gel flash column chromatography (heptanes/EtOAc = 100:0 to 40:60) to afford the title compound. 1H NMR (400 MHz, CD30D) 6 8.04 (d, J=8.46 Hz, 2 H) 7.65 (d, J=7.71 Hz, 2 H) 7.19 (d, J=3.03 Hz, 1 H) 6.67 (s, 1 H) 6.40 (d, J=3.16 Hz, 1 H) 4.38 (q, J=7.07 Hz, 2 H) 3.75-3.81 (m, 1 H), 3.74 (s, 3 H) 3.20-3.27 (m, 2 H) 3.21 (d, 0 Hz, 1 H) 3.02 (d, J=12.38 Hz, 1 H) 2.45 (s, 3 H) 2.18 (d, J=8.84 Hz, 1 H) 1.70 (d, J=12.63 Hz, 1 H) 1.49 - 1.63 (m, 2 H) 1.40 (t, J=7.14 Hz, 3 H) 1.26 - 1.36 (m, 1 H) 0.90 (d, J=6.32 Hz, 3 H). HRMS calcd. for C25H33N203 (M+H) 91, found 421.2475.
Example-42: 10 Ethyl 4-((2$,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoate o /\O 0’0V O\ / N H The title compound was synthesized oulsy as described in Example 41 starting from 4- ((28,4S)-(4-ethoxy((5-methoxymethyl-1H-indoly|)methy|)piperidiny|))benzoic acid, 15 Example-26c. 1H NMR (400 MHz, CD30D) 6 ppm 8.05 (d, J=8.46 Hz, 2H), 7.67 (d, J=8.08 Hz, 2H), 7.19 (d, J=3.12 Hz, 1H), 6.67 (s, 1H), 6.40 (d, J=3.12 Hz, 1H), 4.38 (q, J=7.12 Hz, 2H), 3.71- 3.80 (m, 4H), 3.59-3.69 (m, 2H), 3.46-3.58 (m, 2H), 3.20-3.28 (m, 1H), 2.70-2.81 (m, 1H), 2.47-2.60 (m, 1H), 2.45 (s, 3H), .98 (m, 1H), 1.64-1.88 (m, 3H), 1.40 (t, J=7.12 Hz, 3H), 1.26 (t, J=7.01 Hz, 3H). HRMS calcd. for C27H35N204 (M+H)+ 451.2597, found 451.2603. 20 Biological Example 1: Human complement factor B ELISA assay CVF-Bb complex prepared from purified cobra venom factor (1 uM), recombinant human ment factor B (expressed in drosophila cells and purified using standard methods) and human complement factor D (expressed in E. Coli, refolded and purified using standard methods). 25 CVF-Bb complex at 3 nM concentration was incubated with test compound at various concentrations for 1 hour at room temperature in PBS pH 7.4 containing 10 mM MgC|2 and 0.05% (w/v) CHAPS. Human complement C3 substrate purified from plasma was added to a final tration of 1 uM. After 1 hour incubation at room temperature, the enzyme reaction was WO 2015/009616 PCT/US2014/046515 stopped by addition of a cocktail of concentrated pan-protease inhibitors. The product of the reaction, C3a, was quantified by means of an enzyme-linked-immunosorbent assay. |C50 values were calculated from percentage of tion of CVF-Bb activity as a function of test compound tration. 5 Biological Example 2: Human complement factor B TR-FRET assay Biological Example 2.1. (+) or (-)-tert-Butyl 3-(3-hydroxyphenyl)piperazinecarboxylate OH Resolution of the enantiomers of (i)—ten‘-butyl 3-(3-hydroxyphenyl)piperazinecarboxylate (CAS: 8899567) was achieved by chiral HPLC using a CHIRALPAK AD column with 10 heptane/EtOAc/MeOH 90/5/5 + 0.1 diethylamine to give (+) or (-)-ten‘-butyl 3-(3- hydroxyphenyl)piperazinecarboxylate (tr = 9.7 min) and (-) or (+)-tert—butyl 3-(3- hydroxyphenyl)piperazinecarboxylate (tr = 15.7 min).
Biological Example 2.2. (+) or rt-Butyl 3-(3-(2- (((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazinecarboxylate "mic"(j HN K/fo‘: 15 (+) or n‘-butyl 3-(3-hydroxyphenyl)piperazinecarboxylate (tr = 9.7 min) (Biological Example 2.1) (300 mg, 1.078 mmol) and benzyl 2-hydroxyethylcarbamate (210 mg, 1.078 mmol) were dissolved in THF (10 ml). Tributylphosphine (0.404 ml, 1.617 mmol) was added, and after cooling to 0°C, DEAD 40% in toluene (0.640 ml, 1.617 mmol) was added dropwise. The reaction 20 was stirred for 2h at 0 °C, then for ca. 16h at rt. The reaction mixture was diluted with aqueous . The layers were separated and the s layer was extracted with AcOEt. The organic phase dried over M9804 and concentrated in . The resulting residue was purified by WO 2015/009616 PCT/US2014/046515 preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, CH3CN/H20 (0.1% TFA)) to give the title compound. MS (ESI+) m/z 455.2 (M+H).
Biological Example 2.3. (+) or rt-Butyl 4-(4-amino-6,7-dimethoxyquinazolinyl)(3-(2- (((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazinecarboxylate O NH2 O\/\NJJ\o/\[j /Oj:f\N H \o \NLN K/NYO 0t A solution of 2-chloro-6,7-dimethoxyquinazolinamine (CAS: 84-4) (105 mg, 0.439 mmol) and (+) or (-)-ten‘-butyl 3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazine—1- carboxylate (100 mg, 0.220 mmol) in l alcohol (5 ml) was d for 16 hr at 135 °C. After evaporation, the resulting residue was purified by preparative HPLC (Macherey-Nagel Nucleosil® 10 100-10 C18, CHgCN/HZO (0.1% TFA)) to give the title compound. MS (ESI+) m/z 659.2 (M+H).
Biological Example 2.4. (+) or (-)-tert-Butyl ((1R)(4-(4-amino-6,7-dimethoxyquinazolin-Z-yl)- 3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperaziny|)oxo phenylpropyl)carbamate O NH2 O\/\NJJ\O/\© I \o \NAN K/N o HNYO 0% 15 (+) or (-)-ten‘-Butyl mino-6,7-dimethoxyquinazolinyl)—3-(3-(2- (((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazinecarboxylate (60 mg, 0.078 mmol) was dissolved in 4N HCI in dioxane (5 ml) and stirred for 1 hr at rt. The reaction mixture was evaporated. The resulting resdue was dissolved in DMF (3 ml), and ((ten‘- butoxycarbonyl)amino)—3-pheny|propanoic acid (21.0 mg, 0.079 mmol), DIPEA (0.041 ml, 0.238 20 mmol) and HATU (60.2 mg, 0.158 mmol) were added. The solution was stirred for 16 hr at rt. The reaction mixture was filtrated and evaporated in vacuum. The resulting residue was purified by WO 2015/009616 PCT/US2014/046515 preparative HPLC (Waters SunFireT'VI Prep C18 OBD, CH3CN/H20 (0.1% TFA)) to give the title compound. MS (ES|+) m/z 806.2 (M+H).
Biological Example 2.5. (+) or (-)((1E,3E,5E)(1-(6-((2-(3-(1-(4-amino-6,7- dimethoxyquinazoliny|)((R)((tert-butoxycarbonyl)amino) phenylpropanoyl)piperazinyl)phenoxy)ethyl)amino)oxohexyl)-3,3-dimethyl ndolinylidene)penta-1,3-dienyl)ethyl-3,3-dimethylsulfo-3H-indolium 0\ no \S—OH (+) or (-)-ten‘-Butyl ((1R)—3-(4-(4-amino-6,7-dimethoxyquinazolinyl)—3-(3-(2- (((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazinyl)oxopheny|propyl)carbamate (17 10 mg, 0.021 mmol) was ved in EtOH (5 ml), and added Pd/C (2.24 mg, 2.109 umol). The reaction was stirred under H2 for 16 hr at room temperature. The reaction mixture was filtered and evaporated. The resulting residue was dissolved in DMF (2 ml), and 2-((1E,3E,5E)—5-(1-(6-((2,5- dioxopyrrolidiny|)oxy)—6-oxohexyl)—3,3-dimethylsulfoindolinylidene)penta-1,3-dienyl)—1- ethyl-3,3-dimethyl-3H—indoliumsulfonate (Cy-5, CAS: 146368—14-1) (13.32 mg, 0.020 mmol), 15 DIPEA (0.018 ml, 0.101 mmol) and HATU (15.40 mg, 0.040 mmol) were added. The solution stirred for 16 hr at rt. The reaction mixture evaporated in vacuum and purified by preparative HPLC (Macherey—Nagel Nucleosil® 100-10 C18, H20 (0.1% TFA)) to give the title compound. MS (ESI+) m/z 656.1 (M/2).
Biological Example 2.6. (+) or ((1E,3E,5E)(1-(6-((2-(3-(4-((R)amino 20 phenylpropanoyl)—1-(4-amino-6,7-dimethoxyquinazolinyl)piperazin yl)phenoxy)ethyl)amino)oxohexyl)-3,3-dimethylsulfoindolinylidene)penta-1,3-dien y|)ethy|-3,3-dimethylsulfo-3H-indolium WO 2015/009616 PCT/US2014/046515 (+) or (-)((1E,3E,5E)—5-(1-(6-((2-(3-(1-(4-amino-6,7-dimethoxyquinazolinyl)((R)((tert— butoxycarbonyl)amino)pheny|propanoy|)piperazinyl)phenoxy)ethy|)amino)oxohexyl)-3,3- dimethylsulfoindolinylidene)penta-1,3-dieny|)ethyl-3,3-dimethylsulfo-3H-indolium (4 mg, 3.05 umol) was dissolved in 4N HCI in dioxane (3 ml) and stirred for 1 hr at rt. The mixture was purified by ative HPLC (Waters SunfireT'VI C18 OBD, CH3CN/H20 (0.1% TFA)) to give the title compound. Fractions were combined and evaporated to dryness. The residue was dissolved in a minimum amount of CH3CN and 1M aqueous HCI solution (3 ml, 3.00 mmol) was added. Mixture was then evaporated to give the title compound as HCI salt. 1H NMR (HCI salt, 400 MHz, CD30D) 6 10 8.30 (m, 2 H), 7.90 (s, 1 H), 7.89 (d, J = 5.4 Hz, 1 H), 7.86 (d, J = 5.6 Hz, 1H), 7.72 (dd, J = 8.1, 37 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), .47 (m, 5 H), 7.07-7.28 (m, 4 H), 6.86-6.95 (m, 3 H), 6.68 (t, J = 12.5 Hz, 1 H), 6.38 (dd, J = 4.5, 18.4 Hz, 1 H), 6.31 (d, J = 13.9 Hz, 1 H), 5.95 (br. s, 1 H), 4.76-4.84 (m, 1 H), 4.68-4.71 (m, 1 H), 4.46-4.57 (m, 1 H), 4.18-4.31 (m, 3 H), 4.05-4.11 (m, 3 H), 3.80-4.00 (m, 8 H), .60 (m, 3 H), 3.06-3.09 (m, 2 H), 2.84 (dd, J = 3.8, 22.5 Hz, 1 H), 2.12- 15 2.22 (m, 2 H), 1.75-1.86 (m, 2 H), 1.73 (s, 6 H), 1.70 (s, 6 H), 1.59-1.69 (m, 2 H), 1.39 (t, J = 7.3 Hz, 3 H), 1.29-1.37 (m, 2 H). UPLC-MS (ES|+) m/z 606.1 (M/2); Instrument: Waters UPLC Acquity; column: Acquity HSS T3 1.8um 2.1x50mm at 50°C, eluent A: water + 0.05 % HCOOH + 3.75 mM ammonium e, B: CH3CN + 0.04 % HCOOH, Gradient: 5 to 98 % B in 1.4 min, flow: 1.0 ml/min; Retention time: 0.64 min. 20 Biological Example 2.7. Recombinant human factor B (expressed in hila cells and purified using standard methods) labeled with biotin (10 nM), europium-labeled streptavidin (5 nM) and (+) or (-)((1E,3E,5E)—5-(1-(6-((2-(3-(4-((R)aminophenylpropanoyl)—1-(4-amino-6,7- dimethoxyquinazolinyl)piperazinyl)phenoxy)ethy|)amino)oxohexyl)-3,3-dimethyl 25 sulfoindolinylidene)penta-1,3-dieny|)ethyl-3,3-dimethylsulfo-3H-indolium gical Example 2.6, 240 nM activity agaist factor B when tested using the assay of ical Example WO 2015/009616 PCT/US2014/046515 1) (75 nM) were incubated with test compound at various concentrations up to 2 hours at room temperature in 20mM Tris/HCI, pH 7.4, 0.005% (v/v) Tween20.
The time-gated decrease in fluorescence ity related to the competition between labeled and unlabeled factor B ligands was recorded at both 620 nm and 665 nm, 70 us after excitation at 337 nm using a microplate spectrofluorimeter. |C50 values were calculated from percentage of inhibition of complement factor B-(+) or (-)((1E,3E,5E)—5-(1-(6-((2-(3-(4-((R)—3- aminophenylpropanoyl)—1-(4-amino-6,7-dimethoxyquinazolinyl)piperazin yl)phenoxy)ethyl)amino)—6-oxohexyl)-3,3-dimethylsulfoindolinylidene)penta-1,3-dienyl)—1- ethyl-3,3-dimethylsulfo-3H—indolium (Biological Example 2.6, 240 nM ty agaist factor B 10 when tested using the assay of Biological Example 1) cement as a function of test compound concentration.
Compounds of invention are active on factor B inhibition. Data on Table 1 collected using the assay of ical Example 2. 15 Table 1 Example number |C50 (uM) Example number |C50 (uM) Example-1 >100 Example24 0.035 Example-2b (+) >100 Example25 0.045 Example-2b (-) 7.9 Example26 4.6 Example-3 6 e27 >100 Example-4b (+) 67 Example28 0.16 Example-4b (-) 0.72 Example-18 2.8 Example1 7.2 Example-19 >100 Example2 7.9 Example-20a 0.009 Example3 2.6 Example-20b 0.29 e4 0.18 Example-21a 0.019 Example5 3.5 Example-21b 0.65 e6 0.66 Example1a 0.019 WO 2015/009616 PCT/US2014/046515 Example number 1050 (11M) Example number |C50 (HM) Example7 8.3 1.8 Example1 b Example8 24 Example2a 2.2 Example9 7.1 Example2b 0.013 Example10 1.5 Example-23a >100 Example11 1.3 Example-23b 1.8 Example12 0.037 e-24 8.7 Example-6 14 e-25a 15 Example-7 9. 4 Example-25b 0.047 Example-8 0.71 Example-26a 0.01 Example-9—1 Example-26b 1.1 e-9—2 0.64 Example1 a 3.7 Example-10 11 Example1 b 0.022 Example-11 0.23 Example2a 0.015 Example-12 2.3 Example2b 16 Example-13 0.14 Example3a 0.014 Example-14a 1.7 e3b 0.74 Example-15 8.7 Example4a 0.009 Example-16 0.03 Example4b 1.7 Example1 0.019 Example-28 1.5 Example2 0.12 Example-29 33 Example3 0.038 Example1 3.4 e4 0.087 Example2 8.2 Example5 0.03 Example3 1.3 Example6 6.6 Example1 3.4 Example7 4.5 Example2 8.2 WO 2015/009616 PCT/US2014/046515 Example number I050 (HM) Example number |C50 (HM) Example8 0.07 Example3 1.3 Example9 Example-31 6.8 Example10 0.1 Example1 36 Example11 0.015 Example2 36 Example12 0.45 Example3 0.34 Example13 0.063 Example-33 1.2 Example14 1.8 e-34 2.9 Example15 0.023 Example-35 2.7 Example16 1.9 Example-36 0.02 e17 2.1 Example-37 0.022 Example18 0.027 Example-38 0.13 Example19 29 e1 1.7 e20 2.8 Example2 1.8 Example21 0.84 Example3 0.28 Example22 0.1 Example4 0.3 Example23 1.7 Example-40 0.055 Example29 0.011 Example-41 0.165 Example30 0.013 Example-42 0.24 THE REST OF THIS PAGE INTENTIONALLY LEFT BLANK

Claims (25)

What is claimed is
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: (I) n is 0, 1 or 2; R is hydrogen, C1-C4alkyl, or hydroxyC1-C4alkyl; R1 is halogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxy, haloC1- C6alkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C3- C6cycloalkylC1-C6alkoxy, haloC1-C6alkoxy, -S(O)pC1-C6alkyl, -CH2NHC(O)C1-C4alkyl, or - OCH2C(O)R7; p is 0, 1, or 2; R2 is C1-C6alkyl, C1-C6alkoxy, hydroxyC1-C6alkyl or halogen; R3 is hydrogen, halogen, cyano, C1-C4alkyl, haloC1-C4alkyl, O)R7, phenyl or 5- or 6- membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 lkyl groups, and wherein the alkyl and haloalkyl are optionally substituted with 0 or 1 hydroxy; R4 is phenyl, naphthyl or heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, and S, and wherein the phenyl or heteroaryl is optionally substituted by R5 and further substituted by 0 or 1 substituents selected from n, C1-C4alkyl, lkoxy, hydroxy C1-C4alkyl, hydroxy, and cyanomethyl; R5 is -C(O)R8, -CH2C(O)R8, R9, -C(O)NHSO2C1-C4alkyl, C(O)C1-C4alkyl, - SO2N(H)m(C1-C4alkyl)2-m, -SO2C1-C4alkyl, cyano, halogen, hydroxyC1-C4alkyl and 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring sulfur or oxygen atoms; m is 0, 1, or 2; W is O or C(R6)2; each R6 is independently selected from hydrogen, y, amino, mono- and di- C1- C4alkylamino, C1-C4alkyl, hydroxyC1-C4alkyl, cyanoC1-C4alkyl, and C1-C4alkoxy; or C(R6)2, taken in ation, form a spirocyclic carbocycle having 3 to 6 ring atoms; R7 is hydroxy, lkoxy, amino, or mono- and di-C1-C4alkylamino; R8 is hydroxy, lkoxy, amino, or a 5- to 7-membered saturated heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; or R8 is mono- and C4alkylamino, which is unsubstituted or substituted with halogen, hydroxy, or C1-C4alkyl; and R9 is a ered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atoms, which heterocycle is optionally substituted by 0 to 2 lkyl groups.
2. The nd of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.
3. The compound of claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein W is CHR6 or C(CH3)R6.
4. The compound of any one of claims 1 to 3 or a pharmaceutically able salt thereof, n R1 is C1-C4alkyl, C1-C4alkoxy, or cyclopropyl.
5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen, or C1-C4alkyl.
7. The nd of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, according to Formula (IIa) or (IIb): (IIa) or (IIb).
9. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, according to Formula (IIIa) or (IIIb): (IIIa) or (IIIb), wherein X is N or CH.
10. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R4 is pyridinyl, which is substituted para to the piperidine ring with R5.
11. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted para to the piperidine ring with R5 and optionally substituted with fluoro, y, ymethyl, or hydroxy.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted para to the piperidine ring with R5.
13. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, according to Formula (IVa) or (IVb): (IVa) or (IVb).
14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R5 is CO2H, , , or tetrazolyl.
15. The compound of claim 1 selected from: 1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinol; 4-((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole; 5,7-dimethyl((2-phenylpiperidinyl)methyl)-1H-indole; 1-((5,7-dimethyl-1H-indolyl)methyl)phenyl-piperidinyl)methanol; (5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide; 4-((2-(4-fluorophenyl)methoxypiperidinyl)methyl)-5,7-dimethyl-1H-indole; (1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinyl)methanol; (4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol; 5,7-dimethyl((2-(4-(methylsulfonyl)phenyl)piperidinyl)methyl)-1H-indole; 4-((2-(4-(2 azolyl)phenyl)piperidinyl)methyl)-5,7-dimethyl-1H-indole; 1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinamine; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzamide; 4-(1-((5-chloromethyl-1H-indolyl)methyl)piperidinyl)benzamide; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzamide; 4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin yl)benzamide; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)hydroxypiperidinyl)benzoic acid; 4-(1-((5-chloromethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; methyl 4-(1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoate; 4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)fluorobenzoic acid; 4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)pyrrolidinyl)benzoic acid; (5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)picolinic acid; 4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)methoxybenzoic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; oxymethyl((2-(pyridinyl)piperidinyl)methyl)-1H-indole; 5-methoxymethyl((2-(pyridinyl)piperidinyl)methyl)-1H-indole; 3-fluoro(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 4-(4-((5-methoxymethyl-1H-indolyl)methyl)morpholinyl)benzoic acid; 6-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)nicotinic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)propoxypiperidinyl)benzoic acid; 4-(4-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)methylbenzoic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)ethylpiperidinyl)benzoic acid; 2-(4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)phenyl)acetic acid; 2-(3-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)phenyl)acetic acid; 5-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidinyl)picolinic acid; 2-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)thiazolecarboxylic acid; 2-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)methylthiazolecarboxylic acid; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)azepanyl)benzoic acid; 4-((2-(4-(1H-pyrazolyl)phenyl)piperidinyl)methyl)methoxymethyl-1H-indole; 4-((2-(4-(1H-pyrazolyl)phenyl)piperidinyl)methyl)methoxymethyl-1H-indole; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)naphthoic acid; 1-(2,2,2-trifluoro(5-methoxymethyl-1H-indolyl)ethyl)piperidinyl)benzoic acid; 2-methoxy(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 2-(1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinyl)acetonitrile; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid; 4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 5-(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)picolinic acid; 4-(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidinyl)benzoic acid; 4-(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzonitrile; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 4-((4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid; 4-(1-((5,7-dimethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid; 4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid; 4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid; ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzamide; 4-(5-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; 1-((5,7-dimethyl-1H-indolyl)methyl)-N-methylphenylpiperidinamine; (4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanamine; (4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol; 4-((2-(3-(2H-tetrazolyl)phenyl)piperidinyl)methyl)-5,7-dimethyl-1H-indole; 3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzamide; (3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol; (4-((2-(4-(1H-tetrazolyl)phenyl)ethoxypiperidinyl)methyl)methoxymethyl-1H- indole; 4-(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N- (methylsulfonyl)benzamide; 4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N- methylbenzamide; 4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N,N- dimethylbenzamide; (4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)phenyl)(morpholino)methanone; N-(2-hydroxyethyl)(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin zamide; 4-(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N-(2- methoxyethyl)benzamide; N-((4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidin yl)phenyl)sulfonyl)acetamide; 4-(6-((5-methoxymethyl-1H-indolyl)methyl)azaspiro[2.5]octanyl)benzoic acid; 4-ethyl((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; ethyl 4-((2S,4 R)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin yl)benzoate; ethyl 4-((2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoate; (-)((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinol (diastereomer-2); (±)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer-1); (-)((4-methoxyphenylpiperidinyl)methyl)-5,7-dimethyl-1H-indole (diastereomer-2); 7-dimethyl((2-phenylpiperidinyl)methyl)-1H-indole; (±)((5,7-dimethyl-1H-indolyl)methyl)phenyl-piperidinyl)methanol (diastereomer- 1); (±)((5,7-dimethyl-1H-indolyl)methyl)phenyl-piperidinyl)methanol (diastereomer- 2); (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzenesulfonamide; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)-N-methylbenzenesulfonamide; (±)((2-(4-fluorophenyl)methoxypiperidinyl)methyl)-5,7-dimethyl-1H-indole; (±)-(1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinyl)methanol; (4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol; (±)-5,7-dimethyl((2-(4-(methylsulfonyl)phenyl)piperidinyl)methyl)-1H-indole; (±)((2-(4-(2 H-tetrazolyl)phenyl)piperidinyl)methyl)-5,7-dimethyl-1H-indole; (±)((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinamine (diastereomer-1); (±)((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinamine (diastereomer-2); (1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzamide; (±)(1-((5-chloromethyl-1H-indolyl)methyl)piperidinyl)benzamide; (±)(rel -(2 S,4 S)((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidin yl)benzamide; (±)(4-methoxy((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin yl)benzamide (single diastereomer); (±)(rel -(2 S,4 (5,7-dimethyl-1H-indolyl)methyl)hydroxypiperidinyl)benzoic acid; (±)(rel -(2 S,4 R)((5,7-dimethyl-1H-indolyl)methyl)hydroxypiperidinyl)benzoic acid; (±)(1-((5-chloromethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)-methyl 4-(rel -(2 S,4 S)((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidin yl)benzoate; (±)-methyl 4-(rel -(2 S,4 R)((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidin yl)benzoate; (-)-(S)(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)fluorobenzoic acid; (-)-(S)(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)(1-((5-cyclopropylmethyl-1H-indolyl)methyl)pyrrolidinyl)benzoic acid; )(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)picolinic acid; (-)-(S)(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidinyl)methoxybenzoic acid; (-)-(S)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)methoxymethyl((2-(pyridinyl)piperidinyl)methyl)-1H-indole; methoxymethyl((2-(pyridinyl)piperidinyl)methyl)-1H-indole; (+)-(S)fluoro(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (-)-(R)(4-((5-methoxymethyl-1H-indolyl)methyl)morpholinyl)benzoic acid; (-)-(S)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)nicotinic acid; (-)((2 S,4 S)((5-methoxymethyl-1H-indolyl)methyl)propoxypiperidinyl)benzoic acid; (-)((2 S,4 S)hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)methylbenzoic acid; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid e diastereomer); (±)(rel -(2 S,4 R)ethyl((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoic acid; (±)(4-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)phenyl)acetic acid; (±)(3-(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)phenyl)acetic acid; (±)(rel -(2 S,4 S)((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidin olinic acid; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)thiazolecarboxylic acid; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)methylthiazole carboxylic acid; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)azepanyl)benzoic acid; (-)-(S)((2-(4-(1 H-pyrazolyl)phenyl)piperidinyl)methyl)methoxymethyl-1H- indole; (-)-(S)((2-(4-(1 H-pyrazolyl)phenyl)piperidinyl)methyl)methoxymethyl-1H- indole; (±)(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)naphthoic acid; 4-((2 S)(2,2,2-trifluoro(5-methoxymethyl-1H-indolyl)ethyl)piperidinyl)benzoic acid (diastereomer-1); methoxy(1-((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (±)(6-((5-methoxymethyl-1H-indolyl)methyl)azaspiro[2.5]octanyl)benzoic acid; (±)(rel-(2S,4S)ethyl((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoic acid; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)phenylpiperidinyl)acetonitrile (diastereomer-1); (+)((2S,4R)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid; (-)((2R,4S)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidinyl)benzoic acid; (+)((2R,4R)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin zoic acid; (-)((2S,4S)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoic acid; (-)(rel-(2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)picolinic acid; (+)(rel-(2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)picolinic acid; (+)(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidinyl)benzoic acid; (-)(1-((5-methoxymethyl-1H-indolyl)methyl)-4,4-dimethylpiperidinyl)benzoic acid; (-)(rel-(2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzonitrile; (+)(rel-(2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzamide; (+)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (-)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzoic acid; (-)((2R,4R)-(4-ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin nzoic acid; (+)(rel-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid; (-)(rel-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl)methoxypiperidinyl)benzoic acid; (+)(rel-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid (-)(rel-(2S,4S)((5,7-dimethyl-1H-indolyl)methyl)ethoxypiperidinyl)benzoic acid; (-)(rel-(2S,4S)((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidin yl)benzoic acid; (+)(rel-(2S,4S)((5-cyclopropylmethyl-1H-indolyl)methyl)methoxypiperidin yl)benzoic acid; (+)(rel-(2S,4S)((5-cyclopropylmethyl-1H-indolyl)methyl)ethoxypiperidin yl)benzoic acid; (-)(rel -(2 S,4 S)((5-cyclopropylmethyl-1H-indolyl)methyl)ethoxypiperidin yl)benzoic acid; (±)(5-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid (diastereomer-1); (±)(5-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzamide (diastereomer-1); (±)(5-methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid (diastereomer-2); (±)(5-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid (diastereomer-1); (±)(5-hydroxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)benzoic acid ereomer-2); (±)((5,7-dimethyl-1H-indolyl)methyl)-N-methylphenylpiperidinamine- (diastereomer-1); (±)((5,7-dimethyl-1H-indolyl)methyl)-N-methylphenylpiperidinamine (diastereomer-2); (±)-(4-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanamine; (4-((2 S,4 S)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)phenyl)methanol; (±)((2-(3-(2 H-tetrazolyl)phenyl)piperidinyl)methyl)-5,7-dimethyl-1H-indole; (±)(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)benzamide; (±)- (3-(1-((5,7-dimethyl-1H-indolyl)methyl)piperidinyl)phenyl)methanol; (±)-(4-(rel -(2 S,4 S)-(2-(4-(1 H-tetrazolyl)phenyl)ethoxypiperidinyl)methyl)methoxy- 7-methyl-1H-indole; ((2 S,4 S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N- (methylsulfonyl)benzamide; 4-((2 S,4 S)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N- methylbenzamide; 4-((2 S,4 S)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N,N- dimethylbenzamide; (4-((2 S,4 ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)phenyl)(morpholino)methanone; N-(2-hydroxyethyl)((2 S,4 S)methoxy((5-methoxymethyl-1H-indol yl)methyl)piperidinyl)benzamide; 4-((2 S,4 S)methoxy((5-methoxymethyl-1H-indolyl)methyl)piperidinyl)-N-(2- methoxyethyl)benzamide; (±)-N-((4-(1-((5-cyclopropylmethyl-1H-indolyl)methyl)piperidin yl)phenyl)sulfonyl)acetamide; ethyl 4-((2S,4 R)((5-methoxymethyl-1H-indolyl)methyl)methylpiperidin yl)benzoate; and ethyl 4-((2S,4S)ethoxy((5-methoxymethyl-1H-indolyl)methyl)piperidin yl)benzoate.
16. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical combination comprising a therapeutically effective amount of a nd according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a second therapeutically active agent.
18. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating complement alternative pathway activity.
19. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder or a disease mediated by complement activation.
20. The use of claim 19, wherein the disorder or disease is mediated by tion of the complement alternative pathway.
21. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of age-related macular degeneration, phic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada me, imtermediate uveitis, birdshot -chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular gus, 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, alysis complications, hyperacute allograft rejection, xenograft rejection, eukin-2 d toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune es, Crohn's e, adult respiratory distress syndrome, myocarditis, postischemic reperfusion conditions, myocardial infarction, n angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery usion after aortic reconstruction, infectious e or sepsis, immune complex disorders and mune diseases, rheumatoid arthritis, ic lupus matosus (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, enic dust diseases, pulmonary fibrosis, , allergy, bronchoconstriction, ensitivity pneumonitis, parasitic es, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.
22. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a ment for treating age related r degeneration.
23. Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating paroxysmal nocturnal hemoglobinuria (PNH).
24. Use of a compound of any one of claims 1 to 15 or a ceutically acceptable salt thereof in the manufacture of a medicament for treating atypical hemolytic uremic syndrome (aHUS).
25. The compound of claim 1, substantially as herein described with reference to any one of the Examples thereof.
NZ715780A 2013-07-15 2014-07-14 Piperidinyl indole derivatives and their use as complement factor b inhibitors NZ715780B2 (en)

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