BRPI0720478A2 - Sphingosine-1-Phosphate RECEPTOR AGONIST AND ANTAGONIST COMPOUNDS - Google Patents

Description

“Sphingosine-1-Phosphate RECEPTOR AGONISTS AND ANTAGONISTS”

CROSS REFERENCE FOR RELATED APPLICATION

This order claims priority for US Interim Serial Order No.

5 60 / 876,288 filed December 21, 2006 and US Interim Serial Application No. 60 / 876,318 filed December 21, 2006, the contents of which are incorporated herein.

BACKGROUND OF THE INVENTION

Sphingosine-1-phosphate (S1P) is part of the sphingomyelin biosynthetic pathway and is known to affect multiple biological processes. S1P is formed by sphingosine phosphorylation by sphingosine kinases (SK1 and SK2) and is degraded by cleavage by sphingosine lyase to form palmitaldehyde and phosphoethanolamine or by dephosphorylation by phospholipids phosphatases. It is present at high levels (-500 nM) in serum, and is found in most tissues. It can be synthesized in a wide variety of cells in response to various stimuli, including cytokines, growth factors, and G-protein coupled receptor (RPG) ligands. S1P-binding RPGs (commonly known as S1P 1.5 receptors), coupled via pertusis toxin sensitive (Gi) pathways as well as pertusis toxin insensitive pathways to stimulate a variety of processes. Individual receptors of the S1P family are ambis, tissue and specific response and thus attractive as therapeutic targets.

S1P evoke many responses from cells and tissues. In particular, S1P has been shown to be an agonist of all five RPGs, SIP1 (Edg-1), SIP2 (Edg-5), SIP3 (Edg-3), SIP4 (Edg-6) and SIP5 (Edg-8) . The action of S1P on S1P receptors has been linked to resistance to apoptosis, changes in cell morphology, cell migration, growth, differentiation, cell division, angiogenesis and modulation are targets for therapy of, for example, neoplastic diseases. autoimmune disorders and tissue rejection in transplantation. These receptors also share 50-55% amino acid identity with three other structurally related lysophospholipid receptors, LPA1, LPA2, and LPA3.

RPGs are excellent drug targets with numerous examples of commercial drugs.

through multiple disease areas. RPGs are cell surface receptors that bind to hormones on the cell's extracellular surface and transduce a signal across the cell membrane into the cell. The internal signal is amplified by interacting with G proteins which in turn interact with various second messenger copies. This transduction pathway is manifested in cell cascade responses that include cytoskeleton changes, cell motility, proliferation, apoptosis, secretion, and protein expression regulation, to name a few. S1P receptors make good drug targets because individual receptors are expressed in different tissues and signal through different pathways, making individual receptors both tissue and response-specific. Tissue specificity of S1P receptors is desirable because the development of a receptor selective agonist or antagonist localizes the cellular response to tissues containing this receptor, limiting unwanted side effects. Response specificity of S1P receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the specificity of the S1P receptor response may allow for a mimicking of S1P that initiates platelet aggregation without affecting cell morphology.

The physiological implications of stimulating individual S1P receptors are largely unknown, due in part to an absence of selective ligand-type receptors. Isolation and characterization of S1P analogs that have angonist or antagonist activity for S1P receptors has been limited.

S1P1, for example, is widely expressed, and its deficiency causes etiology.

embryonic due to major vascular rupture. Foster cell transfer experiments using lymphocytes from S1P1-deficient mice have shown that S1P1-deficient lymphocytes sequester to secondary lymphoid organs. Conversely, T cells overexpress S1P1 partition preferably in the blood compartment rather than secondary lymphoid organs. These experiments provide evidence that S1P1 is the major sphingosine receptor involved in lymphocyte “migration” and traffic to secondary lymphoid compartments.

Currently, there is a need for novel, potent and selective agents that are individual receptor S1P receptor family agonists or antagonists in order to address unmet medical needs associated with individual receptor S1R receptor family agonism or antagonism.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

Formula I

Wherein D is H, N (R5) 2 or OR6;

X is CH, C (CH 3) or N;

Y is CH 2, O 1 S or NR 3; wherein R3 is hydrogen, or single or branched (C1-C10) alkyl;

A is H, hydroxy, -CH 2 OH, -CH (OH) CH 3, -C (O) -OCH 3, -C (O) (CH 3) 2-, -O (CH 2) t-COOH-,

-C (0) -NR6, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) nO-P (= 0) (0R7) (0R7) optionally substituted, - (CH2) optionally substituted nP (= 0) (O R 7) (R 7), -CH = CH-P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, C 100 R 6 or -R 4 -C 100 H, in wherein R4 is single or branched (C1-C20) alkylene, single or branched (C1-C20) alkylene, single or branched (C1-C20) alkynyl, (C3-C20) cycloalkyl, or optionally substituted azetinyl;

R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, (C1-C20) alkyl, (C1-C20) alkoxy, (C 3-20) cycloalkyl-substituted alkyl, cycloalkyl-substituted alkoxy C 3 -C 20 alkenyl, C 2 -C 20 alkenyl, C 2 -C 20 alkenyl substituted aryl, C 2 -C 20 alkynyl, C 2 -C 20 alkynyl substituted aryl, C 1-4 alkylamino Aryl-substituted C20), heteroaryl-substituted (C2 -C20) alkyl, aryl-substituted alkoxy, heteroaryl-substituted alkoxy, alkyl-substituted aryl, arylalkyl, aryl-substituted arylalkyl, arylalkyl-substituted arylalkyl, CN and -O-indolizinyl;

wherein R1 and R2 may optionally be substituted with one or more substituents independently selected from C1 -C20 alkyl, CF 3, halo, hydroxy, C1 -C20 alkoxy, OCF3, and CN;

wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C20 alkyl group;

wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and

alkynyl at R 1 and R 2 are optionally substituted by oxo or halo;

each R 5 is independently H, optionally substituted (C 1 -C 6 alkyl), or optionally substituted (C 1 -C 10 -C 6 alkyl) phenyl;

each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl;

each R7 is independently H, optionally (C1-C2) alkyl optionally

substituted or optionally substituted phenyl; m is 1 or 2; n is 1, 2 or 3; t is 1, 2 or 3; and u is 0, 1 or 2;

provided that AeD are not both H at the same time; and provided the compound is not wherein X is CH or N;

Y is CH2, NH, N (CH3) 1 is O.

In a second embodiment the invention provides compounds of the preceding embodiment wherein

A is H, -C (O) -OCH 3, -C (O) NR 6, CH 1 C (O) -NHCH 3, COOR 6, -R 4 -COOH, or azetidine.

optionally substituted nila,

wherein R4 is single or branched (C1-C20) alkyl, single or branched (C1-C20) alkylene, single or branched (C1-C20) alkynylene;

R1 and R2 are independently selected from the group consisting of hydrogen, halo, C1 -C10 alkyl, C1 -C10 alkoxy, C3 -C20 cycloalkyl substituted alkyl, C3 -C10 cycloalkyl substituted alkoxy , C 2 -C 10 alkenyl, aryl substituted C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl substituted C 2 -C 10 alkynyl, aryl substituted C 1 -C 10 alkyl, BriIa Heteroaryl-substituted (C1-C10), aryl-substituted (C1-C10) alkoxy, heteroaryl-substituted (C1-C10) alkoxy, C1-C10-alkyl-substituted aryl, aryl-15-aryl and aryl-substituted arylalkyl;

wherein such groups R1 and R2 may be optionally substituted with C1 -C10 alkyl, halo, hydroxy, C1 -C10 alkoxy, or CN;

wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8;

wherein R8 is hydrogen or C1 -C10 alkyl group;

wherein one of R 1 and R 2 is other than hydrogen. and wherein the alkyl, alkenyl and alkynyl groups in R 1 and R 2 are optionally substituted by oxo or halo.

In a third embodiment the invention provides compounds according to any of the preceding embodiments wherein the compound is a formula Ia formula:

Formula Ia

And isomers, stereoisomers, esters, prodrugs, and pharmacologically acceptable salts thereof, wherein; X is CH;

Y is CH 2 or O;

A is -C (O) -OCH 3, -COOH 1 -R 4 -COOH, -C (O) NHCH 3, or optionally substituted azetidinyl;

where R4 is single or branched (C1-C10) alkylene, simple (C1-C10) alkylene

or branched, or single or branched (C1 -C10) alkynylene;

R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 10 alkyl, C 1 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl substituted alkyl, C 3 -C 10 cycloalkyl substituted alkoxy ), C2 -C10 alkenyl, aryl substituted C2 -C10 alkenyl, aryl substituted C2 -C10 alkynyl, aryl substituted C2 -C10 alkynyl, C1 -C10 alkylamino substituted with heteroaryl), aryl substituted (C1-C10) alkoxy, heteroaryl substituted (C1-C10) alkoxy, (C1-C10) substituted alkyl, arylalkyl and aryl substituted arylalkyl;

Where such groups R 1 and R 2 may be optionally substituted with C 1 -C 10 alkyl, CF 3, halo, hydroxy, C 1 -C 10 alkoxy, or CN;

Wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R8 is hydrogen or C1 -C6 alkyl group);

Wherein one of R1 and R2 is other than hydrogen;

Where the alkyl, alkenyl, and alkynyl groups R 2 are optionally substituted by

oxo or halo compounds; and

N is 1 or 2.

In a fourth embodiment the invention provides compounds according to any of the preceding embodiments wherein Y is CH 2;

OH.

A is -CH2-COOH, COOH or

R 1 and R 2 are independently selected from the group consisting of hydrogen substituted C 2 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 SquiniIa and C 1 -C 10 Silyl;

Where such groups R1 and R2 may be optionally substituted with C1 -C6 alkyl

C10) halo, hydroxy, (C1-C10) alkoxy, or CN;

Wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen; wherein one of R1 and R2 is other than hydrogen. In a fifth embodiment the invention provides compounds according to any of the preceding embodiments wherein X is CH;

Y is CH 2;

A is COOH;

R 1 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl;

R2 is H; and m is 1.

In a sixth embodiment the invention provides compounds according to any of the preceding embodiments wherein the compound is

νη2λ

—H-Hi »

In a seventh embodiment the invention provides compounds according to the first

mode in which

Y is CH2, O1, or NR3;

Wherein R3 is hydrogen, or C1 -C10 alkyl;

A is H1 -CH2OH1 -CH2OH1 -C (O) -OCH3, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (O R 7) optionally substituted -CH = CH-O-P (= O) (O R 7) (O R 7) or CN;

R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, single or branched (C 1 -C 10) alkyl, C 1 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl substituted alkoxy, cycloalkyl substituted alkoxy (C 3 -C 10), (C 2 -C 10) alkenyl, aryl substituted C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl substituted C 2 -C 10 alkynyl, aryl. aryl substituted alkyl, heteroaryl substituted C1 -C10 alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, arylalkyl substituted arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and - O-indolizinil;

Where such groups R 1 and R 2 may optionally be substituted with one or more substituents independently selected from single or branched C 1 -C 6 alkyl, halo, hydroxy, C 1 -C 20 alkoxy, OCF 3, and CN;

Wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R 8 is hydrogen or C 1-10 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein the alkyl, alkenyl, and alkynyl groups in R2 are optionally substituted by oxo or halo;

R 6 is independently selected from H or optionally substituted (C 1 -C 2) alkyl;

R7 is independently selected from H or optionally (C1-C2)

replaced; and u is 1 or 2.

In an eighth embodiment the invention provides compounds according to modalities one and seven wherein the compound is a compound of Formula Ib:

Formula Ib

On what;

X is CH or N;

Y is CH 2, O, S or NR 3;

Wherein R3 is hydrogen or C1 -C20 alkyl;

A is optionally substituted -CH 2 -OH, -CH 2 -P (= 0) (0R7) (0R7) or optionally substituted -CH 2 -O-P (= (0) (0R7) (0R7);

R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl substituted alkyl, C 2 -C 20 alkyl substituted alkyl aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl and aryl substituted arylalkyl;

Where such R2 groups may be optionally substituted on R1 or R2 groups may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or (C1 -C20) alkyl group; and

Where R1, C1-6 alkenyl and C1-6 alkyls are optionally substituted by oxo or halo.

In a ninth embodiment the invention provides compounds of any of the one, seven and eight modalities wherein

X is CH;

Y is CH 2;

A is -CH 2 OH, - (CH 2) n -0-P (= 0) (0R 7) (0 R 7) optionally substituted or - (CH 2) n

P (= 0) (0R7) (0R7) optionally substituted; R1 and R2 are independently selected from the group consisting of hydrogen, halo, single or branched (C1 -C10) alkyl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, C1 -C10 alkyl substituted aryl ), arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl;

substituents selected from (C1 -C10) alkyl, halo and (C1 -C10) alkoxy;

Wherein one or more nio atoms; carbon in groups R1 or R2 may be independently substituted with non-peroxide oxygen; wherein one of R1 and R2 is other than hydrogen; and

Wherein the alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo;

Each R 6 is independently selected from H or optionally substituted (C 1 -C 2) alkyl; and u is 1 or 2.

In a tenth embodiment, the invention provides compounds of embodiments one,

te eight nine in which

A is -CH 2 OH or - (CH 2) n -0-P (= 0) (O R 7) (O R 7);

D is NH 2;

R1 and R2 are independently selected from the group consisting of hydrogen, optionally substituted (C1 -C10) alkyl;

In an eleventh embodiment the invention provides compounds of embodiments one, seven, eight, nine and ten wherein the compound is

Where such groups R1 and R2 may be optionally substituted with one or more

Wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen;

25

Wherein one of R1 and R2 is other than hydrogen; m is 1; and u is 1.

In a thirteenth embodiment it provides a pharmaceutical composition comprising a compound of Formula I.

Formula I

On what

D is H1 N (R5) 2i or OR6;

X is CH1 C (CH3) or N;

Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or straight or branched (C1 -C10) alkyl;

A is H, hydroxy, -CH 2 OH 1 -CH (OH) CH 3, -C (O) -OCH 3, -C (OH) (CH 3) 2, -0 (CH 2) t-10 COOH-, -C ( 0) -NR6, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, - (CH2) nP (= 0) (0R7) (R7) optionally substituted, -CH = CH-P (= OXOR7) (OR7), C (O) -NHCH 3, CN1 COOR6 or -R4-COOH1 where R4 is C1-4 alkylene (C20) single or branched, single or branched (C1 -C20) alkenylene, single or branched (C1 -C20) alkylenylene, (C3 -C20) cycloalkyl or optionally substituted azetidinyl;

R1 and R2 are independently selected from the group consisting of hydrogen, CF3, halo, (C1 -C20) alkyl, (C1 -C20) alkoxy, (C3 -C20) cycloalkyl substituted alkyl, (C3 cycloalkyl) substituted alkoxy -C20), C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl substituted alkyl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such groups R 1 and R 2 may optionally be substituted with one or more substituents independently selected from (C 1 -C 20) alkyl, CF 3, halo, hydroxy, (C 1 -C 20) alkoxy, OCF 3, and CN;

Wherein one or more of R1 or R2 group butt atoms may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R8 is hydrogen or C1 -C20 alkyl group;

Wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl and

R 2 alkynyl are optionally substituted by oxo or halo;

Each R5 is independently H, optionally substituted C1 -C3 alkyl, or optionally substituted phenyl (-C (O) -O-C1 -C3 alkyl);

Each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl;

Each R7 is independently optionally substituted H1 (C1 -C2) alkyl or phenyl

optionally substituted;

M is 1 or 2;

N is 1, 2 or 3;

T is 1, 2 or 3; and U is 0, 1 or 2;

Or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier.

In a fourteenth embodiment the invention provides a method of treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of Formula I.

Formula I

D is H, N (R5) 2, or OR6;

X is CH, C (CH 3) or N;

Y is CH 2, O, S or NR 3; wherein R3 is hydrogen, or single or branched C1-C10

stay;

A is H, hydroxy, -CH 2 OH, -CH (OH) CH 3, -C (O) -OCH 3 -1 -C (OH) (CH 3) 2, -0 (CH 2) t -COOH-, -C (O ) -NR6, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, - (CH2) nP ( = 0) (0R7) (R7) optionally substituted, -CH = CH-P (= 0) (0R7) (0R7), C (O) -NHCH 3 CN, COOR6 or -R4-COOH, where R4 single or branched (C1-C20) Alkenyl, single or branched (C1 -C20) alkenylene, single or branched (C1-C20) alkylene-Ho, (C3-C20) cycloalkyl, or optionally substituted azetidinyl;

R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, (C 1 -C 20) alkyl, (C 1 -C 20) cycloalkyl substituted, (C 3 -C 20) cycloalkyl substituted alkoxy ( C3 -C20), C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl substituted alkyl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such groups R1 and R2 may be optionally substituted with one or more substituents independently selected from C1 -C20 alkyl, CF3, halo, hydroxy, C1 -C20 alkoxy, OCF3, and CN;

Wherein one or more of R1 or R2 group butt atoms may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R8 is hydrogen or C1 -C20 alkyl group;

Wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo;

Each R 5 is independently H, optionally substituted (C 1 -C 3) alkyl, or phenyl optionally substituted with -CO 2 -C (C 1 -C 6 alkyl) -;

Each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl;

Each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl;

M is 1 or 2;

N is 1, 2 or 3;

T is 1, 2 or 3; and

U is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.

In a fifteenth embodiment the invention provides a method of claiming

14 wherein the disorder is rheumatoid arthritis, lupus, Crohn's disease, asthma, diabetes, pain or psoriasis.

In a sixteenth embodiment the invention provides a method of treating a central nervous system disorder comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of Formula I.

wherein D is H, N (R5) 2, or OR6;

X is CH1 C (CH3) or N;

Y is CH 21 O 1 S or NR 3; wherein R3 is hydrogen, or single or branched (C1 -C10) alkyl

stay;

A is H, hydroxy, -CH 2 OH 1 -CH (OH) CH 3, -C (O) -OCH 3, -C (OH) (CH 3) 2, -0 (CH 2) t-

COOH-, -C (O) -NR 6, - (CH 2) n P (= O) (O R 7) (O R 7) optionally substituted, - (CH 2 Jn-O-P (= O) (O R 7) (O R 7) optionally substituted, - (CH 2) n P (= 0) (O R 7) (R 7) optionally substituted, -CH = CH-P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, COOR 6 or -R 4 -COOH1 wherein R4 single or branched (C1-C20) alkyl, single or branched (C1-C20) alkenylene, single or branched (C1-C20) alkylene, (C3-C20) cycloalkyl, or optionally substituted azetidinyl - faded;

R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, C 1 -C 20 alkyl, C 1 -C 20 cycloalkyl, C 3 -C 20 cycloalkyl substituted alkyl, cycloalkyl substituted alkoxy (C3 -C20), C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl substituted alkyl aryl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such groups R 1 and R 2 may optionally be substituted with one or more independently selected substituents of (C 1 -C 20) alkyl, CF 3, halo, hydroxy, (C 1 -C 20) alkoxy, OCF 3, and CN;

Wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R8 is hydrogen or C1 -C20 alkyl group;

Wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo;

Each R5 is independently H, optionally substituted C1-3 alkyl, or optionally substituted -C (O) -O-C1-3 alkyl;

Each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl;

Each R7 is independently optionally substituted H1 C1 -C2 alkyl or optionally substituted phenyl;

M is 1 or 2;

N is 1,2 or 3;

T is 1, 2 or 3; and

U is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, and

nantiomer or stereoisomer thereof.

In a seventeenth embodiment the invention provides a method of treating multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of any of the foregoing embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.

In an eighteenth embodiment the invention provides a pharmaceutical package comprising one or more compounds according to Formula I.

Formula I

On what

D is H, N (R5) 2, or OR6;

X is CH1 C (CH3) OR N;

Y is CH 21 O 1 S or NR 3; wherein R3 is hydrogen, or single or branched C1 -C10 alkyl;

A is H 1 hydroxy, -CH 2 OH, -CH (OH) CH 3, -C (O) -OCH 3, -C (OH) (CH 3) 2, -0 (CH 2) t -COOH-, -C (O ) -NR6, - (CH2) nP (= 0) (OR7) (OR7) optionally substituted, - (CH2Jn-O-15 P (= 0) (0R7) (0R7) optionally substituted, - (CH2) nP (= O) (O R 7) (R 7) optionally substituted -CH = CH-P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, COOR 6 or -R 4 -COOH, where R 4 is single or branched (C1-C20) alkylene, single or branched (C1-C20) alkylene, single or branched (C1-C20) alkylene, (C3 -C20) cycloalkyl, or optionally substituted azetidinyl;

R1 and R2 are independently selected from the group consisting of hy-

drogen, CF 3, halo, (C1-C20) alkyl, (C1-C20) alkoxy substituted (C3 -C20) cycloalkyl substituted alkyl, (C3 -C20) cycloalkyl substituted alkoxy, (C2 -C20) alkenyl, alkenyl (C2 -C20) substituted with aryl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, substituted alkoxy 25 with heteroaryl, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such groups R 1 and R 2 may optionally be substituted with one or more independently selected substituents of (C 1 -C 20) alkyl, CF 3, halo, hydroxy, (C 1 -C 20) alkoxy, OCF 3, and CN;

Wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8;

Wherein R8 is hydrogen or (C1 -C20) alkyl group; Wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo;

Each R5 is independently H, optionally substituted (C1 -C3) alkyl, or phenyl optionally substituted with -C (O) -0-C1 -C3 alkyl;

Each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl;

M is 1 or 2;

N is 1,2 or 3;

U is 0, 1 or 2;

Or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and instruments for use.

In a nineteenth embodiment the invention provides the pharmaceutical package according to the eighteen embodiment wherein the compound or compounds are present in a therapeutically effective amount.

In a twentieth embodiment the invention provides a compound of Formula 2.

5th

Each R6 is independently H or optionally substituted C1-6 alkyl;

10

T is 1, 2 or 3; and

Formula 2

In a twenty-first embodiment the invention provides a compound of Formula

3

Formula 3

In a twenty-second embodiment the invention provides a compound of formula

4

In a twenty-third embodiment the invention provides a compound of Formula 5.

Formula 5

In a twenty-fourth embodiment the invention provides a compound of Formula 6.

Formula 6

In a twenty-fifth embodiment the invention provides a compound of Formula 7.

Formula 7

In a twenty-sixth embodiment the invention provides a compound of Formula 8.

NH2

Formula 8

In a twenty-seventh embodiment the invention provides a compound of Formula 9.

Formula 9

In a twenty-eighth embodiment the invention provides a compound of Formula 10.

HO ^ vH O

Formula 10

In a twenty-ninth embodiment the invention provides a compound of Formula 11 Formula 11.

In a thirtieth embodiment the invention provides a compound of Formula 12.

Formula 12

In another embodiment, R 1 or R 2 are independently fluorine or chlorine or alkyl substituted with fluorine or chlorine.

In another embodiment, Z is hydroxy or -OPO 3 H2.

In another embodiment, the α-substituted phosphonate is -CHFPO 3H2, -CF2PO 3H2,

CHOHPO3H2, -C = OPO3H2 or -OPO2SH2.

In a further embodiment, the α-substituted phosphonate is -CHFPO 3H2, -CF2PO 3H2, -CHOHPO3H2, or -C = POP3H2.

In another embodiment, R 1 is hydrogen and R 2 is alkyl, alkenyl, or alkynyl having 5, 6, 7, 8 or 9 carbon atoms.

In another embodiment, R1 is hydrogen and R2 is heptyl, octyl, nonyl, -O-heptyl, -O-octyl, or -O-nonyl.

In another embodiment, R 1 is hydrogen and R 2 is - (CH 2) n -OCH 3, - (CH 2 Jn-OCF 3, -O- (CH 2) n -OCH 3, or -0- (CH 2) n-0CF 3, where n is an integer from 1-20, preferably 5, 6, 7, 8, or 9.

In compounds of Formula I, the group R 2 may be an ortho, meta or para substituent on the phenyl ring, preferably para. The group R 1 may be an ortho, meta or para substituent on the phenyl ring, preferably meta.

Preferred embodiments of the compound according to Formula I exhibit greater specificity for particular S1P receptors or greater potency than previously reported S1P receptor agonist compounds.

In another aspect, the invention provides a pharmaceutical composition comprising one or more compounds according to Formula I, or pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof, and a pharmaceutically acceptable diluent or carrier. In a preferred aspect, the invention provides a pharmaceutical composition wherein the compound or compounds are present in a therapeutically effective amount. In a related aspect, the invention provides a pharmaceutical composition wherein the compound or compounds are present in a prophylactically effective amount.

In yet another aspect, the invention provides a pharmaceutical package comprising one or more compounds according to Formula I or pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof and instructions for use. In one embodiment, the invention provides a pharmaceutical package wherein the compound or compounds are present in a therapeutically effective amount. In another embodiment, the invention provides a pharmaceutical package wherein the compound or compounds are present in a prophylactically effective amount.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds of Formula I:

Formula I

And isomers, stereoisomers, esters, prodrugs, and pharmaceutically acceptable salts thereof, wherein;

X is CH or N;

Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or C1 -C10 alkyl;

Z is hydroxy, phosphate, phosphonate, or α-substituted phosphonate;

R1 is selected from the group consisting of hydrogen, halo, (C1-C20) alkyl, halo-substituted (C1-C20) alkyl, hydroxy, (C1-C20) alkoxy, or CN; and R2 is selected from the group consisting of hydrogen, halo, C1 -C20 alkyl,

C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl substituted alkyl, C 3 -C 20 cycloalkyl substituted alkoxy 1 C 2 -C 20 alkenyl, C 2 -C 20 alkenyl, C 2 alkynyl -C20), aryl substituted (C2 -C20) alkyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl substituted arylalkyl and aryl; wherein such R2 groups may be optionally substituted with (C1 -C20) alkyl, halo, hydroxy, (C1 -C20) alkoxy, or CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR4; wherein R4 is hydrogen or C1 -C20 alkyl; and wherein the alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by 30 oxo or halo. 10

15

20

25

30

35

Exemplary compounds according to the invention include, for example,

R, 3S) -1-amino-3- (4-oct-1-ynyl-phenyl) -cyclopentyl] -methanol; R, 3S) -1-amino-3- (4-oct-1-phenyl) cyclopentyl] methanol; R, 3S) -1-amino-3- (4- (3-phenoxy-propyl) -phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- (4-oct-1-ynyl-phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- (4- (4-phenyl-but-1-ynyl) -phenyl] -cyclopentyl} -methanol;

R, 3R) -1-amino-3- (4-hex-1-ynyl-phenyl) -cyclopentyl] -methanol;

R, 3R) -1-amino-3- (4-hept-1-ynyl-phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- [4- (6-methoxyhex-1-ynyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (3-phenyl-prop-1-ynyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (5-phenyl-pent-1-ynyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- (4-oct-phenyl) cyclopentyl] methanol; R, 3R) -1-amino-3- [4- (4-phenyl-butyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (6-methoxyhexyl) phenyl] cyclopentyl} methanol; R, 3R) -1-amino-3- [4- (3-phenyl-propyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (5-phenyl-pentyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (4-propoxy-butyl) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- (4-octyloxy-phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- [4- (2-m-tolyloxy) phenyl] cyclopentyl} methanol; R, 3R) -1-amino-3- {4- [2- (4-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (2- p -tolyloxy-ethoxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4-heptyloxy-phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- (4-nonyloxy-phenyl) -cyclopentyl] -methanol; R, 3R) -1-amino-3- [4- (2-pentyloxy-ethoxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (2-p-tolyl-ethoxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- {4- [3- (4-methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol; R, 3R) -1-amino-3- {4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; R, 3R) -1-amino-3- {4- [2- (4-ethoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol; R, 3R) -1-amino-3- [4- (4-methanesulfonyl-butoxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (5-methoxy-pentyloxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- [4- (2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; R, 3R) -1-amino-3- {4- [2- (3-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol; R, 3R) -1-amino-3- {4- [3- (3-methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol; R, 3R) -1-amino-3- {4- [3- (3,5-dimethoxy-phenyl) -propoxy] -phenyl} -cyclopentyl} -methanol; R, 3R) -1-amino-3- {4- [2- (4-methoxy-3,5-dimethyl-phenyl) -ethoxy] -phenyl} -cyclopentyl} -

methanol; {(1R, 3R) -1-amino-3- {4- [2- (4-benzyloxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol;

{(1R, 3R) -1-amino-3- [4- (3-phenyl-propoxy) -phenyl] -cyclopentyl} -methanol;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (4-phenyl-butyl) -phenyl] -cyclopentyl} ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3S) -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3S) -1-amino-3- (3-decyl-phenyl) -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- (4-nonyloxy-phenyl) -cyclopentylmethyl} ester;

Mono {{1R, 3R) -1-amino-3- [4- (2-p-tolyloxy = ethoxy) -phenyl-cyclopentylmethyl} ester

phosphoric;

Phosphoric acid mono - {(1 R, 3R) -1-amino-3- {4- [2- (4-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl} ester;

Acid mono - {(1R, 3R) -1-amino-3- [4- (3-phenyl-propyl) -phenyl] -cyclopentylmethyl} ester

phosphoric;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- (4-octyloxy-phenyl) -cyclopentylmethyl] ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (6-methoxyhexyl) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3S) -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl] ester;

Phosphoric acid mono - {(1 R, 3S) -1-amino-3- (4-heptyl-phenyl) -cyclopentylmethyl] ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (2-m-tolyloxy-ethoxy) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (2-p-tolyl-ethoxy) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1 R, 3R) -1-amino-3- [4- (4-phenyl-butyl) -phenyl] -cyclopentyl} ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- (4-heptyloxy-phenyl] -cyclopentylmethyl] ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- {4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -cyclopentylmethyl ester;

Mono - {(1 R, 3R) -1-amino-3- {4- [2- (4-ethoxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl ester of the

phosphoric acid;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (2-phenoxy-ethoxy) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1 R, 3R) -1-amino-3- {4- [2- (3-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl} ester;

Mono - {(1 R, 3R) -1-amino-3- {4- [3- (3-methoxy-phenyl) -propoxy] -phenyl} -cyclopentylmethyl) ester

phosphoric acid;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- {4- [3- (3,5-dimethoxy-phenyl) propoxy] -phenyl} -cyclopentylmethyl ester;

Phosphoric acid mono - {(1 R, 3R) -1-amino-3- {4- [2- (4-hydroxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl ester;

Phosphoric acid mono - {(1R, 3R) -1-amino-3- [4- (3-phenyl-propoxy) -phenyl] -cyclopentylmethyl} ester;

Phosphoric acid mono - {(1R, 3S) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentylmethyl} ester;

Exemplary compounds of Formula I include:

(1R, 3R) -1-Amino-3- (4-oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid;

(1R, 3S) -1-Amino-3- (4-non-1-ynyl-phenyl) -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- (4-nonyl-phenyl) -cyclopentanecarboxylic acid;

(1R, 3S) -1-Amino-3- (4-dec-1-ynyl-phenyl) -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- (4-decyl-phenyl) -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- [4- (7-methoxy-hept-1-ynyl) -phenyl] -cyclopentanecarboxylic acid;

(1R, 3R) -1-Amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- (4-oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- (4-hept-1-ynyl-phenyl) -cyclopentanecarboxylic acid;

(1R1 3S) -1-Amino-3- (4-heptyl-phenyl) -cyclopentanecarboxylic acid;

DEFINITIONS

In this invention, the following definitions apply:

A "therapeutically effective amount" is an amount of a compound of Formula I or a combination of two or more compounds that totally or partially inhibits the progression of the condition or at least partially improves one or more symptoms. of the condition. A therapeutically effective amount may also be a quantity that is prophylactically effective. The amount that is therapeutically effective will depend on the size and gender of the patient, the condition being treated, the severity of the condition, and the outcome sought. For a given patient, a therapeutically effective amount may be determined by methods known to those skilled in the art.

"Physiologically acceptable salts" or "pharmaceutically acceptable salts" refer to those salts which retain the biological effectiveness and properties of these free bases and which are obtained by reaction with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, L-aspartic acid, L-mandelic acid , L-succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (for example, (+) or (-) - tartaric acid or mixtures thereof), amino acids (for example, (+) or (-) - amino acids or mixtures thereof), and the like. Such salts may be prepared by methods known to those skilled in the art.

Certain compounds of Formula I which have acidic substituents may exist as salts with pharmaceutically acceptable bases. This invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. Such salts may be prepared by methods known to those skilled in the art.

Certain compounds of Formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.

Certain compounds of Formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Certain compounds of Formula I may contain one or more chiral centers, and exist in different optically active forms. When compounds of Formula I contain a chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers such as racemic mixtures. Enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example by crystallization; formation of diastereoisomeric or complex derivatives which may be separated, for example by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a chiral ligand attached or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted to another chemical entity by one of the separation procedures described above, an additional step may be used to release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized asymmetrically synthesized using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.

When a compound of Formula I contains more than one chiral center, it may exist in diastereomeric forms. Diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example, chromatography or crystallization and individual stereoisomers may be separated as described above. The present invention includes each diastereomer of compounds of Formula I and mixtures thereof.

Certain compounds of Formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomeric and / or geometric isomer of compounds of Formula I and mixtures thereof.

Certain compounds of Formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example, because the steric obstacle or ring tension may allow the separation of different conformers. The present invention includes each conformational isomer of compounds of Formula I to mixtures thereof.

Certain compounds of Formula I may exist in amphoteric form and the present invention

The invention includes each amphoteric form of compounds of Formula I and mixtures thereof.

As used herein the term "prodrug" or "prodrug" refers to an agent that is converted to the parent drug in vivo by some physiological chemical processes (for example, a prodrug being brought to physiological pH is converted to the desired drug form 10). Prodrugs are always helpful because in some situations they may be easier to administer than the active metabolite. They may, for example, be bioavailable by oral administration although the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions than the active metabolite. An example, without limitation, of a prodrug may be a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate passage through the cell membrane where solubility in Water is not beneficial, but then it is metabolically hydrolyzed to carboxylic acid once inside the cell where water solubility is beneficial.

Prodrugs have many useful properties. For example, a prodrug may be more water soluble than the standard drug, thus facilitating oral administration of the drug. A prodrug may also have a higher level of oral bioavailability than the standard drug. Following administration, the prodrug is enzymatically or chemically cleaved to deliver the standard drug to the blood or tissue.

Exemplary cleavage prodrugs release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include, but are not limited to, carboxylic acid substituents (e.g., - (CH 2) C (O) OH or a moiety thereof. contains a carboxylic acid) in which free hydrogen is substituted by (C1 -C4) alkyl, (C2 -C12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl (C4 -C9) ethyl, 1-methyl-1- (alkanoyloxy) ethyl having from 5 to carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms N- (alkoxycarbonyl) aminoethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-chronolactonyl, gamma-butyrolacton-4 C 1 -C 4 alkylamino, di-N, N-C 1 -C 2 alkylamino (such as β-dimethylaminoatyl), C 1 -C 2 alkylcarbamoyl, N, C 1 -C 2 alkylcarbamoyl C 1 -C 2 alkyl and piperidino, pyrrolidino or C 2 -C 3 morpholinoalkyl.

Other exemplary prodrugs release an alcohol of Formula I wherein the free hydrogen of the substituent hydroxy (e.g., Z contains hydroxy) is substituted by phosphate (PO4), alkanoyloxymethyl (C1 -C6), 1- (alkanoyloxy (CrC6) ethyl). 1-methyl-1- (C 1 -C 6 alkanoyloxy, C 1 -C 6 alkoxycarbonyloxymethyl, N-C 6 -C 6 alkoxycarbonylamino methyl, succinoyl, C 1 -C 6 alkanoyl, C 1 -C 4 aminoalkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-aaminoacyl wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P (O) (OH) 2, -P ( 0) (O (C1 -C6) alkyl or glycosyl (the radical resulting from the detachment of the hemiacetal hydroxy from a carbohydrate).

The terms "heterocyclic" or "heterocyclyl" as used herein include non-aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which may be fully saturated or may contain one or more together - 10 unsaturation levels (to be sure, the degree of unsaturation does not result in an aromatic ring system) and have 3 to 12 atoms including at least one heteroatom such as nitrogen, oxygen or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following examples of heterocyclic rings: azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinesyl, piperazinyl, 15 piperidinyl, pyrrolidinyl, quinicudinyl, thiometrahyretrahydro-tetrahydrophilophenyl thiophyrophenyl .

The term "heteroaryl" as used herein includes aromatic ring systems, including but not limited to monocyclic, bicyclic and tricyclic rings, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen or sulfur. For exemplary purposes, which should not be construed as limiting the purpose of this invention: azaindole, benzo (b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, furans, imidazoles, imidazopyridine, indole, indolin, indole indazoles, isoindolinyl, isoxazoles, isothiazoles, oxadiazoles, oxazoles, purine, pyranes, pyrazines, pyrazines, pyridines, pyrimidines, pyrroles, pyrrol [2,3-d] pyrimidine, pyrazol [3,4-d] pyrimidine, quinolines, nazolines, triazoles, thiazols, thiophenyl, tetrahydroindol, tetrazols, thiadiazoles, thienyl, thiomorpholines, triazoles or tropanil.

When the term "substituted heterocyclic" (or heterocyclyl) or "substituted heteroaryl" is used, it means that the heterocyclic group is substituted with one or more substituents which may be made by one of skill in the art and results in a molecule that is an agonist or antagonist of the sphingosine receptor family. For exemplary purposes, which should not be construed as limiting the scope of this invention, preferred substituents for the heterocycle of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyletherocycloalkoxy, alkyl, alkylcarbonyl, alkylester, alkyl-OC (O) -, alkylheterocyclyl, alkylcycloalkyl, alkylnitrile, 35-starch groups, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylamido, carboxylamide -CF 3, -CN, -C (O) OH, -C (O) H, -C (O) -C (CH 3) 3, -OH, -C (O) 0-alkyl, -C (O) O - cycloalkyl, -C (0) 0-heterocyclyl, -C (0) alkyl, -C (0) cycloalkyl, -C (0) heterocyclyl, cycloalkyl, dialkylaminoalkoxy, dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, halogen, heterocyclyl, a heterocycloalkyl group, heterocycle hydroxy, hydroxy, hydroxyalkyl, nitro, -OCF3, oxo, phenyl, -SO2CH3, -SO2CR3, tetrazolyl, thienylalkoxy, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S (O) p-cycloalkyl -S-heterocyclyl-S, 5 heterocycloalkyl, cycloalkylalkyl, heterocyclothio, cycloalkylthio, -Z105-C (0) N (R) 2, -Z105-N (R) -C (0) -Z200, -Z105-N (R ) -S (0) 2-Z200, -Z105-N (R) -C (0) -N (R) -Z200, -N (R) -C (O) R, -N (R) -C ( O) OR, O-C (O) -hetero-cyclyl-O, Rc and -CH2 Oc;

Wherein R is C1 -C4 alkyl, C3 -C6 cycloalkyl or phenyl;

Where p is 0, 1 or 2;

Where Rc for each occurrence is independently hydrogen, optionally

substituted alkyl, optionally substituted aryl, - (C1-C6) -NrdRe, -E- (CH2) t-NrdRe, -E- (CH2) t-0-alkyl, -E- (CH2) rS-alkyl, or - E- (CH 2) rOH;

Where t is an integer from 1 to 6;

Z105 for each occurrence is independently a covalent, alkyl, alkenyl, or alkynyl bond; and

Z200 for each occurrence is independently selected from an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkylphenyl, alkenylphenyl or alkynylphenyl;

E is a direct bond, O, S, S (O), S (O) 2, or NRf, wherein Rf is H or alkyl and Rd and Re are independently H, alkyl, alkanoyl or SO2-alkyl; or Rd, Re and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring.

A "heterocycloalkyl" group, as used herein, is a heterocyclic group that is attached to a compound by an aliphatic group having from one to eight carbon atoms. For example, a preferred heterocycloalkyl group is a morpholinomethyl group.

As used herein, "aliphatic" or "an aliphatic group" or notations such as "(C1-C20)" include single or branched chain hydrocarbons that are fully saturated or contain one or more unsaturation units, and then include alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double or triple bonds.When the group is a CO it means that the fraction is not present or in other words it is a bond. "alkyl" herein means C1 -C20 and includes single or branched chain hydrocarbons which are fully saturated Preferred alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. up to twenty carbon atoms, and isomers thereof As used herein, "alkenyl" and "alkynyl" means C2 -C20 and include single or branched chain hydrocarbons. They contain one or more unsaturation units, one or more alkenyl double bonds and one or more alkynyl triple bonds. As used herein, aromatic groups (or aryl groups) include aromatic carbocyclic ring systems (e.g. phenyl and cyclopentylienyl) and fused polycyclic aromatic ring systems (e.g. naphthyl, biphenylenyl and 1,2,3,4- tetrahydronaphthyl).

As used herein, "cycloalkyl" means monocyclic or multicyclic C3 -C20 hydrocarbons (e.g., bicyclic, tricyclic etc.) that are fully saturated or have one or more unsaturated bonds, but do not amount to an aromatic group. Preferred examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

As used herein, the term "phosphate" means -R-0-P (= 0) (0H) (0H), the term "phosphonate" means -RP (= 0) (0H) (0H) where R it's not O or S.

As used herein, the term "aryl substituted alkyl" or "aryl substituted alkenyl" means fractions such as methylphenyl, ethylphenyl, methylnaphthyl, ethylnaphthyl, ethylenylphenyl, ethylenylnaphthyl and the like wherein the alkyl moiety of the moiety ranges from 1 to 20. carbons and the alkenyl portion of the fraction ranges from 2 to 20 carbons.

As used herein, the term "heteroaryl substituted alkyl" means fractions

such as methylpyridinyl, ethylpyridinyl, and the like wherein the alkyl portion of the moiety ranges from 1 to 20 carbons and the heteroaryl may be any heteroaryl.

As used herein, many fractions or substituents are referred to as being either "substituted" or "optionally substituted". When a fraction is modified by one of these terms, even if otherwise noted, it denotes that any portion of the fraction that is known to one of skill in the art to be available for substitution may be substituted, which includes one or more substituents, wherein if more than one substituent then each substituent is independently selected. Such means for substitution are well known in the art and / or taught by the present disclosure. For purposes of exemplification, which should not be construed as limiting the scope of this invention, some examples of groups which are substituents are: alkenyl groups, alkoxy group (which alone may be substituted, such as -O-C1 -C6 alkyl). (R 1 -C 6 C 1-6 alkyl) -N (R) 2, and - OCF 3), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl alkoxy, alkyl groups (which may also be substituted by themselves, such as -C 1 -C 6 alkyl, OR, -C1 -C6 -B1C6-N (R) 2, and -CF3), alkylamino, alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, -CF3, -COH, -COOH, -CN, cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl, dialkylaminocarbonylalkoxy, dialkylaminosulfonyl, esters (-C (O) -OR, where R is groups such as alkyl, heterocycloalkyl (which may be substituted), heterocyclyl, etc. which may be substituted), halogen or halo ( F, Cl, Br, I), hydroxy, morpholinoalkoxy, morpholinoalkyl, nitro , oxo, -OCF3, optionally substituted phenyl, -S (O) 2CH3, - (O) 2CF3 and sulfonyl, N-alkylamine or β-dialkylamino (wherein alkyl groups may also be substituted). The compounds according to the invention may be prepared following the synthetic schemes disclosed in detail in the Examples below.

Usage Methods

The present invention provides compounds described by general Formula I which are effective as antagonists or agonists of the G-protein coupled S1P receptor family. These compounds reduce the number of circulating and infiltrating TeB lymphocytes, providing a beneficial immunosuppressive effect.

The present invention also provides compounds that exhibit activity within the S1P receptor family.

In a related aspect the invention provides a method for modulating receivers

of the S1P family in a human patient suffering from a disorder in which modulation of S1P activity is beneficial, comprising administering to a human patient a compound of Formula I such that modulation of S1P activity in the human patient is initiated and treatment is achieved.

In another related aspect the invention provides a method of modulating the activity

sphingosine phosphate 1 receptor (S1P1) comprising contacting the cell with one or more compounds of Formula I.

A compound of Formula I or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount is useful in the treatment of a disorder selected from the group consisting of disorders of the central nervous system, arthritis, rheumatoid arthritis, osteoarthritis, arthritis. juvenile chronic, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-independent diabetes mellitus, thyroiditis, asthma, allergic diseases , psoriasis, scleroderma dermatitis, host versus graft disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, coagulation intravascular disease, Kawasaki disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpura, microscopic kidney vasculitis, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Alzheimer's disease, stroke, primary biliary cirrhosis, haemolytic anemia, malignancies, heart failure, myocardial infarction, Adson's disease, sporadic, type I polyglandular deficiency and type I polyglandular deficiency II, Schmidt's syndrome, adult (acute) respiratory disorder syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitis arthropathy, enteropathic synovitis, chlamydia, arthropathy associated with yersinia and samara, atheromatous disease / arteriosclerosis, atopic allergy, bullous disease autoimmune, penfigus vulgaris, penfigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Real Free Disease, chronic mucocutaneous candidiasis, 5 giant cell rite, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Diseases, Hepatitis B, Hepatitis C, common miscellaneous immunodeficiency (common variable hypogammaglobulinemia), female cardiomyopathy, dilated phalliomyopathy disease, premature ovarian failure, pulmonary fibrotic disease, chronic wound healing, cryptogenic fibrosis alveolitis, postinflammatory interstitial lung disease, interstitial pneumonitis, interstitial lung disease associated with cone tissue disease pulmonary disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, pulmonary disease associated with systemic lupus erythematosus, pulmonary disease associated with dermatitis-15 myositis / polymyositis, pulmonary disease associated with Sjogren's disease, pulmonary disease associated with ankylosing spondylitis, diffuse vasculitic pulmonary disease, hemosiderosis-associated pulmonary disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative pulmonary disease , post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, 20 autoimmune hepatitis type 1 (classical or lupid autoimmune hepatitis), autoimmune hepatitis type 2 (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycaemia age, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute organ disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, type 1 psoriasis, type 2 psoriasis, idiopathic leukopenia 25 ca, autoimmune neutropenia, NOS kidney disease, glomerulonephritis, microscopic kidney vasculitis, Lyme disease, discoid lupus erythematosus, male idiopathic infertility or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, secondary pulmonary hypertension connective tissue disease, Goodpasturer's syndrome, pulmonary manifestation of polyarthritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia , autoimmune thyroid disease, hyperthyroidism, goiter autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phageogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver disease, alcoholic cirrhosis, inducible liver injury. 35 alcohol-related disease, idiosyncratic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, allergy and asthma, group B streptococcal infection (GBS), mental disorders (eg, depression and schizophrenia), Th1-type mediated diseases. and Type Th2, chronic and acute pain (different forms of pain), neuropathic pain and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) , hematopoietic malignancies (leukemia and lymphoma), Abetalipoprotein, Acrocyan if acute and 5 parasitic infectious or parasitic processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adeocarcinoma, air ectopic beats, AIDS , dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allographic rejection, α-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, therapy anti-CD3, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneurysm, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paradoxical), atrial fibrillation, blockade atrioventricular, B cell lymphoma, bone graft rejection bone marrow transplant rejection (BMT), branched beam block, 15 Burkitt lymphoma, Burns, cardiac arrhythmias, cardiac shock syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammatory response, cartilage rejection - gem, cerebellar cortical degeneration, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy-associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease ( COPD), chronic salicylate poisoning, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, negative culture sepsis, cystic fibrosis, cytokine therapy-associated disorder, Box Dementia, Doc demyelinating diseases, dengue haemorrhagic fever, dermatitis, dermatological conditions, diabetes, diabetes mellitus, 25 diabetic atherosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglion disorders, Down syndrome in middle age, drug-induced movement induced by drugs that block dopamine receptors in the CNS, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, lymphoistiocytosis hematophagocytic, rejection of the fetal thymus implant, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, sepsis gram negative, sepsis gram positive, granuloma due to organism intracellular smos, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto thyroiditis, hay fever, rejection of heart transplantation, hemacromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpuca, haemorrhage, hepatitis (A), beam arrhythmia , HIV infection / HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitive reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis assessment, idiopathic Addison's disease, pulmonary fibrosis idiopathic, antibody-mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, aortic inflammation, influenza a, exposure to ionizing radiation, iridocyclitis 5 / uveitis / optic neuritis, ischemic reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, atrophy juvenile spinal muscle, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosis, cortical spinal cord injury, lipedema, liver transplant rejection, lymphoderma, malaria, Malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningoccemia , metabolic / idiopathic, migraine, headache, mitochondrial multisystem disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple system degenerations (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph ), myasthenia gravis, intracellular avium mycobacterium, mycobacterium tuberculosis, myelodiplastic syndrome, myocardial infarction, ischemic myocardial disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, neurodegenerative disease, muscular atrophy I, neutropenic fever non-hodgkins, occlusion of the abdominal aorta and its ramifications, occlusive arterial disorders, orchitis / epididymitis, orchitis / reverse vasectomy procedures, organomegaly, osteoporosis, pancreatic transplant rejection, pancreatic carcinoma, paraneoplastic syndrome / malignant hypercalcemia, parathyroid disease, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, gamopathy mono- and skin change syndrome), post-perfusion syndrome, post-pumping syndrome, post-MI cardiotomic syndrome, preeclampsia, progressive supranucle paralysis, primary pulmonary hypertension, radiation therapy, Raynaud's disease and phenomenon. Raynoud's disease Refsum's disease, regular short QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, senile chorea, Lewy body type dementia, seronegative arthropathy, shock, sickle cell anemia, graft rejection. skin, skin-changing syndrome, small bowel transplant rejection 30, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degeneration, streptococcal myositis, subacute sclerosing panencephalitis, syncope, cardiovascular syphilis, anaphylaxis systemic inflammation, systemic inflammatory response syndrome, youth-initiated systemic rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboanginitis obliterans, thrombocytopenia, toxicity, transplantation, trauma / hemorrhage, type III hypersensitivity reactions, hypersensitivity. type I V, unstable angina, uremia, urosepsis, urticaria, coronary valvular disease, venous varicosis, vasculitis, venous disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis / aseptic meningitis, life-associated haemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenographic rejection of any organ or tissue, and diseases involving inappropriate vascularization, for example, diabetic retinopathy, prematurity retinopathy, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas. in humans. In addition, such compounds may be useful in the treatment of disorders such as edema, ascites, effusions, and exudates, including, for example, macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (sera). proliferative disorders such as restenosis, fibrotic disorders such as liver cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, syndromes of thrombotic microangiopathy, and glomerulopathy, coronary myocardial angiogenesis, collateral myocardial angiogenesis, , limb ischemic angiogenesis, ischemia / reperfusion injury, Helicobacter peptic ulcer-related diseases, virally induced angiogenic disorders, Crow-Fukosa syndrome (POEMS), pre-eclampsia, menometrorrhagia, cat scratch fever , rubeose, neovascu glaucoma and retinopathy such as those associated with diabetic retinopathy, premature retinopathy, age-related macular degeneration, or a central nervous system disorder. In addition, these compounds may be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularitis). ovarian stroma characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and / or metastasis.

Combination Therapy

Compounds of Formula I of the invention may be used alone or in combination with

with another therapeutic agent to treat such diseases. It should be understood that the compounds of the invention may be used alone or in combination with an additional agent, for example a therapeutic agent, said additional agent being selected by one of skill in the art for its intended purpose. For example, the additional agent 30 may be a therapeutic agent recognized in the art and useful for treating the disease or condition being treated by the compound of the present invention. The additional agent may also be an agent that provides a beneficial attribute for the therapeutic composition, for example a people that affects the viscosity of the composition.

It is further to be understood that the combinations that are to be included within this invention are those combinations useful for their intended purpose. The agents disclosed below are illustrative for purposes and not intended to be limited. The combinations, which are part of this invention, may be the compounds of the present invention and at least one additional agent selected from the list below. The combination may also include more than one additional agent, for example, two or three additional agents if the combination is such that the composition formed may be intended to perform its function.

Preferred combination (s) is / are non-steroidal antiinflammatory drug (s) also referred to as NSAIDs which include ibuprofen-like drugs. Other preferred combinations are corticosteroids including prednisolone; The well-known side effects of steroid use may be reduced or even eliminated by decreasing the required steroid dose when treating patients in combination with the S1P receptor agonists or antagonists of this invention. Non-limiting examples of the rheumatoid arthritis therapeutic agents with which a compound of Formula I of the invention may be combined include the following: cytokine suppressive anti-inflammatory drug (s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL- 8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. S / T kinase inhibitors of the invention may be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7 .2), CD90, CTLA or other Ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at different points in the autoimmunity and subsequent inflammatory cascade; Preferred examples include chimeric-type TNF antagonists, humanized or human TNF antibodies; HUMIRA®, (US Patent No. 6,090,382), CA2 (REMICADE®), CDP 571, and soluble p55 or p75 TNF receptors derived therefrom (p75TNFR1gG (ENBREL®) or p55TNFR1G (Leonercept), TNFα-converting enzyme (TACE) inhibitors, similarly IL-1 inhibitors (interleukin-1 converting enzyme inhibitors, IL-1 RA etc.) may be effective for the same reason Other preferred combinations include Interleukin 11. Still other preferred combinations are other key parts of the autoimmune response that may act in parallel with, dependent on or in conjunction with IL-18 function, especially preferred are IL-12 antagonists including antibodies to IL-12 or soluble receptors of IL-12, or IL-12-binding proteins.It has been shown that IL-12 and IL-18 overlap more distinct functions and a combination of antagonists for both may be more effective. Preferred combinations are non-depleting anti-CD4 inhibitors. Still other preferred combinations include CD80 (B7.1) or CD86 (B7.2) costimulatory antagonists including antagonist antibodies, soluble receptors or ligands.

A compound of Formula I of the invention may also be combined with agents such as methotrexate, 6-MP, azathioprine sulfasalazine, mesalazine, olsalazine / hydroxychloroquine chloroquinine, pencilamine, aurothiomalate (intramuscular and oral), azathioprine, coccycin, corticosteroids (oral inhalation and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutanil, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedochronone, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, mycophenolate, rapamycin , leflunimide, NSAIDs for example ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, T cell signaling agents such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors and p75TNFRIgG derivatives (Enbrel® p55TNFRIgG (Lenercept)), slL-1 RI, slL-1 RN, slL-6R), anti-inflammatory cytokines (eg IL-4, IL-10, IL-11, IL-13 and TGFP), celecoxib, folic acid, hydrochlorochine sulfate, rofecoxib, etanorcept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, nepanpropene trapsone acetonide, / apap, folate, nabumethane, diclofenac, piroxicam, etodolac, sodium diclofenac, oxaprozine, oxycodone HCI, hydrocodone / tartrate tartrate, fentanyl, anaquinra, tramasalate sulcindolate, cyanocobalami na / fa / pyridoxine, acetaminophen, sodium alendronate, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine / chondroitin sulfate, amitriptyline HCI, sulfadiazine, oxycodone HCI / acetaminophen, olopadadine HCI misoprostol sodium, napr omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX- 740, Roflumilast, IC-485, CDC-801, and Mesopram. Preferred combinations include methotrexate or ieflunomide and in cases of moderate or severe rheumatoid arthritis, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula I of the invention may be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporine, sulfasalazine; aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL- 16, EMAP-II, GM-CSF, FGF, and PDGF; Cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for example ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents that interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., IRAK, NIK, IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFα-converting enzyme inhibitors; T cell signaling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (for example, soluble TNF p55 or p75 receptors, slL-1RI, slL-1 RH, SIL-6R) and anti-inflammatory cytokines (for example IL-4, IL- 10, IL-11, IL-13 and TGF-β). Preferred examples of Crohn's disease therapeutic agents with which a compound of Formula I may be combined include the following: TNF antagonists, e.g., anti-TNF antibodies, HUMIRA®, US Patent No. 6,090,382 ; CA2 (REMICADE®), CDP 571, TNFR-lg constructs, inhibitors (p75TNFIgG (ENBRELTM) and p55TNFIgG and (Lenercept®)) and PDE4 inhibitors. A compound of Formula I may be combined with corticosteroids, for example budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents that interfere with proinflammatory cytokine synthesis or action such as IL-1, for example inhibitors of the IL-1β and IL-1ra converting enzyme; T cell signaling inhibitors, for example tyrosine kinase 6-mercaptopurines inhibitors; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; sodium methylprednisolone succinate; diphenone / atropine sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; cyprofloxacin / dextrose-water; hydrocodone bitartrate / apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal / boric acid; cholestyramine / sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone H-Cl / acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole / trimethoprim; Celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; disodium balsalazide; codeine phosphate / apap; colesevel HCI; cyanocobalamin; folic acid; Ievofloxacin; methylprednisolone; natalizumab and interferon gamma.

Non-limiting examples of multiple sclerosis therapeutic agents with which a compound of Formula I may be combined including the following: prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-pia (Avonex®; Biogen); interferon-pib (Betaseron®; Chiron / Berlex); interferon an3) (Interferon Sciences / Fujimoto), interferon-a (Alfa Wassermann / J & J), interferon βΙΑ-IF (Serone / lnhale Therapeutics), Peginterferon a2b (Enzon / Schering-Plow), Copolymer 1 (Cop-1; Copaxone®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; Intravenous immunoglobulin; clabribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-12, IL-23 , IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A compound of Formula I may be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or the like. binders. A compound of Formula I may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mofetil microfenolate, leflumide, NSAIDs, for example ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by proinflammatory cytokines such as TNF-α or IL-1 (e.g., IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACE1 inhibitors T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, slL-1 R1, slL-1 R11, slL-6R) and anti-inflammatory cytokines (for example, IL-4, IL-10, IL-13 and TGF-β.

Preferred examples of multiple sclerosis therapeutic agents wherein a

The compound of Formula I may be combined to include interferon-β, for example IFN-βa and IFN-βΙb; copaxone, corticosteroids, caspase inhibitors, for example, caspase-1 inhibitors, IL-1 inhibitors, TNF inhibitors, and binding CD40 and CD80 antibodies.

A compound of Formula I may also be combined with agents such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinabidol, α-immunocin NNS03, ABR-215062, AnergiX. MS, chemokine receptor antagonists, BBR-2778, calagualin, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti antibody -receptor IL-6, neurovax, pirfenidone 25 alotrap 1258 (RDP-1258), sTNF-R1, thalampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonist (eg TR-14035, VLA-4 Ultrahaler, Antegran-ELAN / Biogen), interferon gamma antagonist and IL-4 agonists.

Non-limiting examples of angina therapeutic agents with which a compound of Formula I of the invention may be combined including the following: aspirin, nitroglycerine, isosorbide mononitrate, metoprolol succinate, atenolol, metroprolol tartrate, amlodipine besylate, dithiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, calcium atorvastatin, potassium chloride, furosemide, simvastatin, verapamil HCI, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spirolactone enol, hydroleaprol, nadolactol ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofibrate, ezetimibe, bumetanide, potassium iosartan, isopropyl / hydrochlorothiazide, felodipine, captopril and bisoprolol fumarate.

Non-limiting examples of ankylosing spondylitis therapeutic agents with which a compound of Formula I may be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, methotrexate, minocycline, prednisone, etanercept, and infliximab.

5 Non-limiting examples of asthma therapeutic agents with which a

Formula I can be combined include the following: albuterol, salmetrol / fluticasone, sodium montelukast, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, Ievalbuterol HCI, albuterol / ipratropium sulfate, sodium phosphate nisolone, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, 10 azithromycin, pyrbuterol acetate, prednisolone, anhydrous theophylline, methylprednisolone sodium succinate, clarotromycin, zafirlukast, formoterol influenza fumarate vaccine, formoterin influenza vaccine , flunisolide, allergy injection, sodium cromoline, fexofenadine hydrochloride, flunisolide / menthol, amoxicillin / clavulanate, levofloxacin, inhaled assisted device, guaifenesin, dexamethasone phosphate sodium, moxifloxacin HCI, phenycin guinea oxide -methorphan, p-ephedrine / cod / chlorphenide, gatifloxacin, cetirizine hydrochloride, fur mometasone oate, salmeterol xinafoate, benzonatate, cephalexin, pe / hydrocodone, chlorphenir, cetirizine HCI / pseudoefed, phenylephedrine / cod / promethazine, codeine / promethazine, cefprozil, dexamethasone, guaifenesin / pseorfenephronephedrine, cefalydrone terbutaline sulfate, epinephrine, methylprednisolone and metaproterenol sulfate.

Non-limiting examples of COPD therapeutic agents with which a

Compound of Formula I can be combined include the following: albutrol / ipratropium sulfate, ipratope bromide.salmeterol / fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, sodium theophylline, methylprednisolone sodium succinate, sodium montelukast , budesonide, formoterol fumarate, triamcinolone acetonide, Ievo-25 floxacin, guaifenesin, azithromycin, beclomethasone dipropionate, Ievalbuterol HCI, flunolides, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin / clafiloxacin, zafoxin / menthol, chlorpheniramine / hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine / cod / chlorphenide, pyrbuteol acetate, p-ephedrine / loratadine, terbutaline sulfate, tiotropium bromide, (R, R) -formoterol , TgAAT, 30 cilomilast and roflumilast.

Non-limiting examples of HCV therapeutic agents with which a compound of Formula I may be combined include the following: Interferon-a-2a, Interferon-a-2b, Interferon-a with 1, Interferon-a-n1, interferon pegylated -a-2a, pegylated interferon-a-2b, ribavirin, peginterferon alfa-2b + ribavirin, ursodeoxycholic acid, glycyrizic acid, thimalphacasin, maxamine, VX-497 and any compounds that are used to treat HCV through the intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site). Non-limiting examples of Idiopathic Pulmonary Fibrosis therapeutic agents with which a compound of Formula I may be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, interferon gamma, methyl prednisolone succ sod, lorazepam, furosemide, lisinopril, nitroglycerine, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone taconide acetone trichloride , tacrolimus anhydrous, calcium, interferon-α, methotrexate, mofetil mycophenolate and interferon-gamma-β.

Non-limiting examples of myocardial infarction therapeutic agents with which a compound of Formula I may be combined include the following: aspirin, nitroglycerin, metopropol tartrate, sodium enoxaparin, sodium heparin, clopiodegrel bisulfate, carvedilol, atenolol , morphine sulfate, metoprolol succinate, sodium warfarin, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, Iosartan potassium, quinapril carbamide, Hinapril , enalaprilat, amiodarone hydrochloride, tirofiban HCl hydrochloride, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazoline sodium, atrophosphate, - caproic, spirolactone, interferon, sotalol hydrochloride, potassium chloride, sodium docusate, dobutamine HCI, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe / simvastatin, avasimiba, and cariporide.

Non-limiting examples of psoriasis therapeutic agents with which a compound of Formula I may be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinomide, betamethasone diprop increased, fluocinoletone acetonide, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxin / fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate, fluticasone propionate, azithromycin, acid hydrocortisone, hydrocectisone, folic, desonide, pimecrolimus, charcoal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc / bismuth subgal / znox / resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, antraline, clocortolin pivalate, coal extract, charcoal tar / salicylic acid, charcoal tar / acid s alicylic / sulfur, deoxymethasone, diazepam, emollient, fluocinonide / emollient, mineral oil / castor oil / lact, mineral oil / peanut oil, petroleum, isopropyl myristate, psoralen, salicylic acid, soap / tribromsalan, thimerosal / acid boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, and sulfasalazine.

Nonlimiting examples of psoriatic arthritis therapeutic agents with which a compound of Formula I may be combined include the following: methotrexate, etercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, sulfate hydroxychloroquine, prednisone, sulindac, increased diprop beta-methadone, infliximab, methotrexate, folate, triamcinolone acetonide, dichloro-5-phenacho, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methyl-prednisolone, nabumotene, tolmethoden cyclosporine, sodium diclofenac / misoprostol, fluocinonide, glycosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate / apap. Ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept and efalizumab.

Non-limiting examples of therapeutic agents for restenosis with which a

Compounds of Formula I may be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.

Non-limiting examples of sciatica therapeutic agents with which a compound of Formula I may be combined include the following: hydrocode na / apap bitartrate, rofecoxib, cyclobenzaprine HCI, methylprednisolone, naproxen, ibuprofen, oxycodone HCI / acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine / apap phosphate, tramadol HCI / acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, indole acetaminophen, diazepam, nabumetone, oxycodone H-20 Cl, tizanidine HCI, diclofenac sodium / misoprostol, propoxyphene napsilate / apap, aas / oxycod / oxycodone ter, ibuprofen / hydrocodone bit, tramadol HCI, etodolaco HCl, amitriphenyl HCI, carisoprodol / phosphodine / ala, morphine sulfate, multivitamins, sodium naptoxen, orfenad citrate rina, and temazepam.

Preferred examples of LES (Lupus) therapeutic agents with which a compound of Formula I can be combined include the following: NSAIDs, for example diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example celecoxib, rofecoxib, valdecoxib, anti-malarials, for example hydroxychloroquine; steroids, for example prednisone, prednisolone, budenoside, dexamethasone; cytotoxic, for example azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; PDE4 inhibitors or purine synthesis inhibitors, for example, Cellcept®. A compound of Formula I may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents that interfere with the synthesis, production or action of proinflammatory cytokines such as IL-1, for example. caspase inhibitors like IL-1β and IL-1ra converting enzyme inhibitors. A compound of Formula I may also be used with T cell signaling inhibitors, for example tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. A compound of Formula I may be combined with IL-11 or anti-cytokine antibodies, for example, phono-tolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL receptor antibody. -6 and antibodies to B cell surface molecules. A compound of Formula I may also be used with LJP 394 (abetimus), agents that deplete or inactivate B cells, for example Rituximab (anti-CD20 antibody). ), Iinfostat-B (anti-BlyS antibody), TNF antagonists, for example anti-TNF antibodies, HUMIRA® (US Patent No. 6,090,382), CA2 (REMICADE®), CDP 571, TNFR- 1g, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

In the compositions of the present invention the active compound may, if desired, be associated with other pharmacologically compatible active ingredients. For example, the compounds of this invention may be administered in combination with another therapeutic agent which is known to treat a disease or condition described herein. For example, with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuated intracellular responses to VEGF or angiopoietins, intracellular signal transduction blockage, inhibition of vascular hyperpermeability, reduction of inflammation, or inhibition or prevention of edema or neovascularization. The compounds of the invention may be administered before, subsequent or simultaneously with the additional pharmaceutical agent, whatever the appropriate course of administration. Additional pharmaceutical agents include, but are not limited to, anti-edema steroids, NSAIDs, ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF antagonists, COX-1 inhibitors, COX-inhibitors. 2, NO synthase inhibitors, Akt / PTB inhibitors, IGF-IR inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants. The compounds of the invention and additional pharmaceutical agents act either additively or synergistically. Thus, administration of such a combination of substances that inhibit angiogenesis, vascular hypermeability, and / or inhibit edema formation may provide greater relief from the deleterious effects of a hyperproliferative disorder, angiogenesis, vascular hypermeability, or edema than administration of the disease. substance alone. In the treatment of malignant disorders with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.

One or more compounds of the invention may be administered to a human patient by themselves or in pharmaceutical compositions wherein they are mixed with biologically suitable carriers or excipient (s) in doses to treat or ameliorate a disease or condition as described herein. Mixtures of such compounds may also be administered to the patient as a single mixture or in suitable formulated pharmaceutical compositions. A therapeutically effective dose refers to that amount of compound or compounds sufficient to result in the prevention or alleviation of a disease or condition as described herein. Techniques for formulating and administering the compounds of the present application can be found in well-known references to one of ordinary skill in the art, such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.

Pharmaceutical Compositions and Methods of Administration

Suitable routes of administration may, for example, include oral, eye drops, rectal, transmucosal, topical, or intestinal administration; parenteral distribution, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

Alternatively, one may administer the compound in one location rather than in a systemic manner, for example by injecting the compound directly into an edematous site, always in a sustained release deposition or formulation.

In addition, one may administer the drug in a target drug delivery system, for example, in a liposome coated with endothelial cell specific antibody.

The pharmaceutical compositions of the present invention may be produced in a form which is known per se, for example by means of conventional process mixing, dissolving, granulating, dredging, levitating, emulsifying, encapsulating, entrapping or lyophilizing.

Pharmaceutical compositions for use in accordance with the present invention may then be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of active compounds into preparations which may be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants suitable for the barrier to be permeated are used in the formulation. Such penetrators are generally known in the art.

For oral administration, the compounds may be easily formulated by combining active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, pills, capsules, liquids, gels, syrups, mixtures, suspensions and the like for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use may be obtained by combining the active compound with a solid excipient, optionally comminuting a resulting mixture, and processing the mixture of granules after addition of suitable auxiliaries, if desired, to obtain tablet or core cores. . Such excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone 5 (PVP) . If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dredged cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain 10 gum arabic, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, shellac solutions, and suitable organic solvents or mixtures of solvents. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which may be used orally include soft-fitting capsules made of gelatin as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Soft-fitting capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be at doses suitable for administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, compounds for use in accordance with this

The invention is conveniently distributed in the form of an aerosol spray presentation from pressurized packages or a nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of pressurized aerosol the metering unit 30 may be determined by providing a valve to dispense a metered amount. Capsules and lozenges of, for example, gelatin for use in an inhalant or insufflator may be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as germ oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or solubility enhancing agents of the compounds to allow the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile pyrogen free water, prior to use.

The compounds may also be formulated in rectal compositions such as suppositories or retention of enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations previously described, the compounds may also be formulated as a deposition preparation. Such long term formulations may be administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection). Then, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example as a salt. little soluble.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD co-solvent system. VPD is a 3% w / v benzyl alcohol solution, 8% w / v non-polar polysorbate 80 surfactant, and 65% w / v polyethylene glycol 400, made up to absolute ethanol volume. The VPD co-solvent system (VPD: 5W) consists of 1: 1 diluted VPD with 5% dextrose in aqueous solution. This co-valent system dissolves hydrophobic compounds well, and itself produces low toxicity under systemic administration. Of course, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the co-solvent components may be varied: for example, other low toxic non-polar surfactants may be used instead of polysorbate 80; the size of the polyethylene glycol fraction may be varied; other biocompatible polymers may substitute for polyethylene glycol, for example polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of hydrophobic drug delivery vehicles or carriers. Certain organic solvents such as dimethyl sulfoxide may also be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a controlled release system, such as semipermeable arrays of solid hydrophobic polymers containing the therapeutic agent. Various controlled release materials have been established and are well known to those skilled in the art. Controlled-release capsules may, depending on their chemical nature, release the compounds for a few weeks to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

Pharmaceutical compositions may also comprise vehicles or excipients.

suitable solid phase or gel compounds. Examples of such carriers or excipients include, but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Many of the compounds of the invention may be provided as pharmaceutically compatible counterion salts. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in water or other protonic solvents that correspond to the free base forms.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an effective amount to prevent the development of or to alleviate the existing symptoms of the patient being treated. Determination of effective amounts is well within the capability of those skilled in the art.

Dosage

For any compound used in a method of the present invention, the therapeutically effective dose may be estimated initially from cellular assays. For example, a dose may be formulated in cellular and animal models to achieve a varying circulating concentration that includes the EC50 as determined in the cell assays (i.e., the concentration of the test compound achieving the maximum half inhibition of a given receptor activity). In some cases it is appropriate to determine the EC50 in the presence of 3 to 5% serum albumin as long as such determination approximates the binding effects of plasma protein on the compound. Such information can be used to more accurately determine useful doses in humans. In addition, advantageous compounds for systemic administration effectively modulate S1P family receptors in intact cells at levels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of compound that

results in improvement of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example for determination of the maximum tolerated dose (DMT) and ED50 (effective dose for 50% maximum response). The dose ratio 10 between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between DMT and ED50. Compounds that exhibit high therapeutic indices are preferred. Data obtained from these cell culture assays and enzyme studies can be used to formulate a variety of doses for use in humans. The dosage of such compounds is preferably within a variety of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dose may be chosen by the physician in view of the patient's condition. (See, for example, Fingl et al, 1975, in The Pharmacological Basis of Therapeutics Chap. 1, p. 1). In the treatment of seizures, administration of an acute bolus or an infusion close to DMT may be advantageous for rapid response.

Dosage and intervenale amounts can be individually adjusted to provide plasma levels of the active fraction that are sufficient to modulate S1P family receptors, or minimum effective concentration (CME). The CME will vary for each compound, but can be estimated from in vitro data, for example, the concentration required to achieve 50-90% inhibition of binding of the natural ligand using the assays described here. Doses required to achieve CME will depend on individual characteristics and route of administration. However, HPLC assay or bioassays may be used to determine plasma concentrations.

Dose ranges can also be determined using the CME value.

Compounds should be administered using a regimen that maintains plasma levels above CME for 10-90% of the time, preferably between 30-90% and more preferably between 50-90% until the desired symptom improvement is achieved. In cases of local administration or selective uptake, the effective local drug concentration may not be related to plasma concentration.

The amount of composition administered will, of course, be dependent upon the patient being treated, the weight of the patient, the severity of affliction, the manner of administration and the judgment of the prescribing physician.

The compositions may if desired be present in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister pack. The dispensing package or device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Exemplary Formulations In some formulations it may be beneficial to use the compounds of the present invention.

It can be used in the form of very small particle size, for example as obtained by grinding fluid energy.

The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" refers to any compound of the invention, but particularly any compound which is the end product of one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compound and 140 parts by weight of lactose may be disaggregated and mixed. The mixture may be enclosed in hard gelatin capsules, each capsule containing a single dose or part of a single dose of active compound.

b) Tablets

Tablets may be prepared, for example, from the following ingredients:

Parts by weight Compound

Lactosel 90

Cornstarch22 Starch

Polyvinylpyrrolidonal 0

Magnesium Stearate3

The active compound, lactose and any of the starches may be broken down, mixed

The resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol. The dried granulate may be mixed with the magnesium stearate and the rest of the starch. The mixture is then compressed into a compression machine to give tablets, each containing a unit dose or a portion of a unit dose of active compound.

c) Enteric coated tablets

Tablets may be prepared by the method described in (b) above. The tablets may be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Suppositories

In the preparation of suppositories, for example, 100 parts by weight of the active compound

It may be incorporated into 1300 parts by weight of the triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of the active ingredient.

The present invention also comprises the use of a compound of Formula I as a medicament.

A further aspect of the present invention provides the use of a compound of Formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis dependent disorders, proIiferative diseases and / or mammalian immune system disorders , particularly being human.

The present invention also provides a method of treating vast hyperpermeability.

cell, inappropriate neovascularization, proliferative diseases and / or immune system disorders comprising administering a therapeutically effective amount of a compound of Formula I to a mammal, particularly a human being in need thereof.

The teachings of all references, including magazine articles, patents, and

published patent applications are incorporated herein by reference in their entirety.

EXAMPLES

Compounds of the present invention were synthesized and their activity assayed as described below.

SI P Receiver GTPyS Tests

[35S] GTPyS binding assay was performed using both scintillation proximity assay (EPC) and filtration methods. Both formats are advantageously run in 96-well plates and use membranes from stable CHO humna cell lines or overexpressing S1P1, S1P2, S1P3, S1P4 or S1P5. Stocks of the compound were made at 10 mM using DMSO and serial dilutions were made using 100% DMSO. Compounds were transferred to 96-well plates to produce a final DMSO concentration of 1% for all assay (1 µl for 100 µl assay volume). Frozen membranes were thawed and diluted in assay buffer containing 20 mM HEPES, pH 7.4, 0.1% fatty acid free BSA, 100 mM NaCl, 5 mM MgCl2 and 10 µg GDP. For SPA test membranes they are premixed with WGA-SPA beads to produce a final concentration per well of 5 pg membrane and 500 pg bead. For the filtration assay, membranes are added directly to the plate incubation at 5pg per well. Assays begin by adding 50 μ _ of the membrane or membrane / bead mixture to each well of the assay plate. Then 50 μΙ_ of 0.4 nM [35S] GTPyS is added to each well and incubated for 30 minutes. Non-specific binding is measured using 10 μΜ unlabeled GTPyS. For the SPA 5 assay the plates are centrifuged and then read on Topcount. For the filtration assay the plate is collected on GF-C filtration plates using a Packard 96 plate collector.

[33P] S1 P Link Inhibition to SI P Receivers

Radio ligand binding was performed using membranes from transiently transfected HEK cells by overexpressing S1P1, S1P2, S1P3, S1P4 or S1P5. All 10 compounds are dissolved in DMSO and serial dilutions were made in DMSO prior to addition of assay buffer. Assay DMSO concentrations are 1% (v / v). [33 PJSip] purchased from Perkin Elmer and used at 50 pM in all assays. Frozen membranes are thawed and resuspended in assay buffer containing 50 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 and 0.1% fatty acid free BSA. Mem-

brane is added to give 5-10 µg membrane per well. Non-specific binding is determined in the presence of ice cold S1P 1 μΜ. Incubations are performed at room temperature for 45-60 minutes prior to filtration on GF / C filter plates using a Packard 96-well collector. Plates are dried before adding Microscint to each well, closing and counting in a Topcount.

Abbreviations Acac Acetylacetonate ACN Acetonitrile 9-BBN 9-Borabicyclononane BBr3 Borane Tribromide BINAP 2,2'-Bis (diphenylphosphine) -1,1'-binaphthalene I Ethylene CM Copper Iodide (I) DBAD Si-tert-azodicarboxylate butyl DCC Dicyclohexyl carbodiimide DCM Dichloromethane DIEA N, N-Diisopropylethylamine DMA N1N-Dimethylacetamide DME Dimethoxyethane DMF N1N-DimethylIformamide DMSO Dimethylsulfoxide DMSO-d6 Deuterated DMSO Dppf 1,1'-Bis (diphenylphosphino) ferrocene EDC (3-dimethylamino-propyl) -ethyl-cerbodiimide

Et3N Triethylamine

Et2O Diethyl ether

EtOAc Ethyl Acetate

H2 hydrogen gas

HCI Hydrochloric Acid

HOAc Acetic Acid

HOBt 1-hydroxy-1 H-benzotriazole

HPLC High Performance Liquid Chromatography

K2CO3 Potassium carbonate

LAH Lithium Tetrahydroaluminate

LCMS Mass Spectrometry Liquid Chromatography

LDA Lithium Diisopropylamide

LiHMDS Lithium Hexamethyldisilazide

MgSO4 Magnesium Sulphate

MeOH-d4 Deuterated methanol

MeOH Methanol

NaHCO3 Baking Soda

NaOH Sodium hydroxide

NMO N-methylmorpholine-N-oxide

Pd (PPh3) 2Cl2 Bis (triphenylphosphine) palladium (II) chloride

PPh3 Triphenylphosphine

PS-PPh3 Polyphenyl supported triphenylphosphine

Rh Rhodium

RP Reverse Phase

R, Time hold

(S) -BINAP (S) - (-) - 2,2'-Bis- (diphenylphosphine) -1,1'-binaphthalene

TBAF Tetrabutylammonium Fluoride

TFA Trifluoracetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

ANALYTICAL METHODS

Analytical data are defined either within the general procedures or in tables of the examples. Unless otherwise stated, all 1H or 12 C NMR data were collected on a Varian Mercury Plus 400 MHz instrument or a Bruker DRX 400 MHz instrument; Chemical changes are divided into parts per million (ppm). High Performance Liquid Chromatography (HPLC) analytical data are either detailed within the experiment or referenced in HPLC condition tables. Using one letter method of least case in Table 1.

Table 1. HPLC Method List

Method HPLC Conditions Unless otherwise indicated mobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC grade acetonitrile. at 5-95% B for 3.7 minutes with a 95% B retention for 1 minute (1.3 mL / min flight rate). Waters Zorbaz XDB C18 column 4.6 x 50 mm (5 pm particles). Detection methods are diode network (DAD) and Evaporative Light Dispersion Detection (ELSD) as well as pos / neg electrospray ionization. b 30 to 95% B for 2.0 minutes; 95% B for 3.5 minutes at 1.0 mL / min; UV λ = 190-400 nm; Vydac Genesis C18 column 4.6 x 30 mm (4 pm particles). Detection methods are diode network (DAD) and evaporative light scattering detection (ELSD) as well as electrospray pos / neg ionization. C 5-95% B for 2.7 minutes with a 95% B retention for 1 minute (1.3 mL / min flight rate). Vydac Genesis C18 column 4.6 x 30 mm (4 pm particles). Detection methods are diode network (DAD) recording at 250 nm (8 nm BW) and pos / neg atmospheric pressure chemical ionization (APCI). d 5-95% B for 3.7 minutes with a 95% B retention for 1 minute (1.3 mL / min flight rate). Waters Zorbac XDB C18 column 4.6 x 50 mm (5 pm particles). Detection methods are diode network (DAD) and Evaporative Light Dispersion Detection (ELSD) as well as chemical pos / neg atmospheric pressure ionization (APCI). and 5-60% B for 1.5 minutes then 60-95% B for 2.5 minutes with a 95% B retention for 1.2 minutes (1.3 mL / min flight rate). Vydac Genesis C18 column 4.6 x 30 mm (4 pm particles). Detection methods are diode network (DAD) and evaporative light dispersion detection (ELSD) as well as pos / neg electrospray ionization. f 30-95% B in 2 minutes then retention at 95% B for 5.7 minutes (1 mL / min flight rate). Mobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC grade acetonitrile. The column used for chromatography was a C18 Vydac Genesis Column 4.6 x 30 mm (4 pm particles). Detection methods are diode network (DAD) and evaporative light dispersion detection (ELSD) as well as pos / neg electrospray ionization. g The column used for chromatography is a C8 Vydac Genesis 4.6x30 mm column (4 pm particles). The gradient was 5-60% B at 1.5 min then 60-95% B for 2.5 minutes with a 95% retention for 1.2 min (1.3 mL / minute flight rate). Mobile phase A was water with 0.1% formic acid, mobile phase B was HPLC grade acetonitrile. Detection methods are diode network (DAD) and evaporative light scattering detection (ELSD) as well as pos / neg electrospray ionization.

GENERAL SYNTHETIC DIAGRAMS

The general synthetic schemes that were used to construct most of the compounds disclosed in this application are described below in (Schemes 1-5).

Scheme 1. General synthetic route for ((1R, 3S) -1-amino-3-phenylsubstituted cyclopentyl) methanol (general procedures A, B, C, D, E1 F1 G1 H) (General procedures are noted in parentheses).

J-

"-O ^ v 2 = - -s-

\ '' '' 'NHi W -NHi' NH1

J «H)

r ^ O-OCoh

N — I NHi

General synthetic route to ((1R, 3R) -1-amino-3-phenylsubstituted cyclopentyl) methanol (general procedures A, I, J1 E, F, G1 H) (General procedures are noted in parentheses). General synthetic route to ((1R, 3R) -1-amino-3- (4-substituted oxyphenyl) cyclopentyl) methanol (general procedures A, I, J, Ε, H, L, Μ, N) (General procedures are noted in parentheses).

N

///

Cr0 -a- -0O-O- ^ -0O4;

I

NHa

(J)

NHi '' 'NH2 \ - /' '' NHi

J (K)

'-' H H

| (N)

-OH "NH2

General synthetic route for (1-amino-3-substituted phenylcyclopentyl) methyl dihydrogen phosphate (general procedure O)

(General procedures are noted in parentheses).

(THE)

General synthetic route for 1-amino-3-substituted phenyl cyclopentanecarboxylic acid (general procedure P)

(General procedures are noted in parentheses).

(P)

NH2

Scheme 6. General synthetic route to ((1R, 3R) -1-amino-3-

(phenylsubstituted) cyclopentyl) methanol (general procedures A1 I, J, E, S, T, U, Μ, V, H) (General procedures are noted in parentheses). ο W Br * Vli d)

NHt

(J)

Q „J ^ Ov /

I

Scheme 7. General synthetic route for ((1R, 3S) -1-amino-3-phenylsubstituted cyclopentyl) methanol (general procedures A, B, C1 D1 E, S1 T, U1), V, H)

Boronic acid

Procedure Procedure Procedure Procedure Procedure Procedure General General General General General General

BCDES

Phenol

Procedure Procedure Procedure Procedure Procedure

-o ^ O-OC '

\ _ (Nl

General General General General General \ - / NH2

TUMVH

Scheme 8. General synthetic route for preparation of ethers

Alkylating agent - Pi - OH - ■ - ^ R ^ 0 R9

Procedure nc

AA General

General synthetic route for (3-amino-1-phenyl-substituted-cyclopyrrolidin-3-yl) methanol (general procedures BB, CC1 B1 D, E1 H) H

Bi

Br

General Procedure E

aniline

BB general procedure

General procedure H

CC general procedure

General Procedure B

General Procedure D

NH2

General synthetic route ((1R, 3R) -1-amino-3-phenylsubstituted cyclopentyl) methanol (general procedures A, I, J, Ε, Η, K, F, Μ, N)

Cr0

Boronic Acid - »

General Procedure A

Procedure General General Procedure

I J

General Procedure D

General procedure H

General procedure K

Alkino

Phenol

Procedure Procedure Procedure The general general ρ ^

overall F

M

N

General synthetic route ((1R, 3R) -1-amino-3-phenyl-substituted cyclopentyl) methanol (general procedures A, I, J1 Ε, Η, K, F1 G1 L, M1 N)

Cr0

Boronic acid

Procedure Procedure Procedure Procedure Procedure

general general general general general

A I J H H

Alkino Alcohol -m- -c- --- m-

Procedure Procedure Procedure Procedure Procedure

general general general general general

K F G L Mi

General Procedure N Scheme 12. General synthetic route for 3-amino-5-phenyl-substituted tetrahydro-furan-3-carboxylic acid (general procedure D)

,__ THE

R-y ^ V V-OH

General Procedure D

General synthetic route for substituted 3-phenyl-cyclopentylamines (general procedures A, F1 G, DD)

^ yffiQ Alkaline Boronic Acid °

Procedure Procedure Procedure General procedure General general General

A F G DD

NR '

General synthetic route for (1R, 3S) -1-amino-3- (4-substituted phenyl) -cyclopentanecarboxylic acid methyl ester (general procedures A1 B, C, D, E1 F)

Boronic acid

VJ

General Procedure A

Procedure Procedure Procedure General procedure General general General

B C D E

Alkino

General Procedure F

General synthetic route for (1R, 3S) -1-amino-3-phenyl-substituted cyclopentanecarboxylic acid methyl ester (general procedures A, B1 C, D, E, F, G)

Cr0

Boronic acid

General Procedure A

General Procedure B

General Procedure C

General Procedure D

General Procedure E

Alkino

General Procedure F

General procedure

\ —T NH- GENERAL PROCEDURE LIST

General Procedure A: Adding Micheal to an Unsaturated Alpha-Ketone

General Procedure B: Formation of a hydantoin from a ketone.

General Procedure C: Formation of an N-alkylated hydantoin.

General Procedure D: Hydrolysis of a hydantoin to the corresponding amino acid.

General Procedure E: Formation of an ester from acid.

General Procedure F: Cross coupling to an aryl bromide.

General Procedure G: Reduction of an Alkyne.

General Procedure H: Reduction of an ester to alcohol.

General Procedure I: Formation of an amino nitrile from a ketone.

General Procedure J: Hydrolysis of a nitrile to the corresponding acid.

General Procedure K: Formation of an oxazolidinone from an amino acid

alcohol.

General Procedure L: Unprotection of a methyl ether.

General Procedure M: Alkylation of a hydroxy group.

General Procedure N: Hydrolysis of an oxazolidinone.

General Procedure O: Phosphorylation of an alcohol followed by deprotection.

General Procedure Q: Hydrolysis of an ester to acid.

General Procedure Q: Phenol Alkylation.

General Procedure R: Reduction of carboxylic acid.

General Procedure S: Cbz protection of an amine.

General Procedure T: Cross-coupling an aryl brometer to a boronic acid.

General Procedure U: Hydroboration reaction of an alkene. General Procedure V: Unprotection of a Cbz group from an amine. General Procedure W: Synthesis of an unsaturated alpha-beta ketone. General Procedure X: Addition of an organometallic reagent to an ester. General Procedure Y: Conversion of a tertiary alcohol to an alkane. General Procedure Z: Hydration to an Alkyne. General Procedure AA: Synthesis of an alkylester. General Procedure BB: Synthesis of an N-aryl prolinol. General Procedure CC: Oxidation of an alcohol to ketone. General Procedure DD: Reductive Amination in a Ketone. EXAMPLE OF USE OF GENERAL PROCEDURES

The letter encoded in the General Procedure is a synthetic route to the end product. A worked example of how the route is determined is given below using Example D.2 as a non-limiting illustration. The synthesis of Example D.2 was completed using general procedure H as detailed in Table D, that is,

NH2

O (H)

'NH2

OH

Starting material was prepared using the route (A, Β, I, J1 E, F, G) (as detailed in Table C). This translates to the following sequence, where the ester of the starting material used in the general procedure H is the product of the following procedures A, I, J, E, F and G1 in the given order.

GENERAL PROCEDURES

The following describes the synthetic methods illustrated by the preceding General Procedures schemes and are followed by an example of a compound which has been synthesized by the General Procedure. None of the specific conditions and reagents noted in the following are to be construed as limiting the purposes of the present invention and are provided for illustrative purposes only.

General Procedure A: Adding Micheal to an Unsaturated Alpha-Ketone

A solution of a substituted phenylboronic acid (1-3 equivalents, preferably 1.5 Rh (acac) (C2H4) 2 / (R) -BINAP equivalents) and a rhodium catalyst such as hydroxy [(S) -BINAP] dimer rhodium (I), or (preferably hydroxy [(S) -BINAP] dimer rhodium (I) for product (S), Rh (acac) (C2H4) 2 / (R) -BINAP for product (R) (1-5 mol%, preferably 1.25 mol%) in an organic solvent (such as tetrahydrofuran, or dioxane) (preferably dioxane) and water is degassed with nitrogen 2-cyclopent-1-one is added to the mixture. The reaction mixture is stirred at about 20-100 ° C (preferably about 35 ° C) for a period of 1-24 hours (preferably about 16 hours) under an inert atmosphere, the reaction mixture is concentrated under reduced pressure and The crude product is purified by flash chromatography.

Example of General Procedure A: Preparation of (S) -3- (4-Bromo-phenyl) -cyclopentanone

J <G> Cr0

4-Bromophenylboronic Acid, Hydroxy [(S) -BINAP] Rh (I) Dimer

Br

Dioxane / H2O

"t> °

A 3 L three-neck round bottom flask fitted with a temperature and nitrogen bubbling standard was charged with 4-bromophenylboronic acid (100 g, 498 mmol) and rhodium (I) hydroxy [(S) -BINAP] dimer (6) , 20 g, 4.17 mmol) in dioxane (1667 mL) and water (167 mL) at room temperature. The resulting suspension was degassed with nitrogen and 2-cyclopenten-1-one (27.8 mL, 332 mmol) was added in one portion. The mixture was further degassed for 5 minutes and heated at 35 ° C for about 16 hours. The reaction mixture was cooled to room temperature and concentrated. The brown residue was treated with EtOAc (500 mL), dried over Mgso 4. filtered, and concentrated to provide a dark brown solid. The crude reaction product was purified by silica gel chromatography (1: 9 EtOAc: heptane as eluent). Product containing fractions were combined and concentrated to afford (S) -3- (4-bromo-phenyl) -cyclopentanone (70.4 g, 89%, 95% ee as determined by chiral HPLC) as an ivory solid.

LCMS (Table 1, Method a) Rt = 3.54 min; m / z: poor ionization; 1H NMR (400 MHz, DMSO-Je) δ.

7.47 (d, 2H), 7.27 (d, 2H), 3.35 (m, 1H), 2.55 (m, 1H), 2.25 (m, 4H), 1.85 (m, 1H)

General Procedure B: Formation of a hydantoin from a ketone

To a mixture of ammonium carbonate (1-10 equivalents, preferably 4.5 equivalents) and a cyanide salt (such as potassium cyanide, or sodium cyanide) (1-3 equivalents, preferably 1.1 equivalents). ) in water a ketone (1 equivalent) is added. The reaction mixture is heated at reflux for a period of 2-40 hours (preferably 16 hours). The reaction mixture is cooled to room temperature and the solid collected by filtration, washed with water to give crude product which can be purified by titration with a suitable solvent.

Example of General Procedure B:

Preparation of (S) -7- (4-bromo-phenyl) -1,3-diaza-spiro [4.4] nonane-2,3-dione

To a round-bottom flask charged with ammonium carbonate (268 g, 2.79 mol) and potassium cyanide (44.4 g, 0.681 mol) was added water (1500 mL, 82 mol). The mixture was heated to 80 ° C and a solution of (S) -3- (4-bromo-phenyl) -cyclopentanone (148.09 g, 0.62 mol) in ethanol (1500 mL, 25 mol) was added. added. The reaction mixture was heated at reflux for one night. The reaction mixture was cooled to room temperature. The crude reaction mixture was filtered and washed with water. The solid was triturated with ether (1.5 L), filtered, washed with ether and dried under vacuum to afford (S) -7- (4-bromo-phenyl) -1,3-diaza-spiro [4.4] nonane 2,4-dione (181.29 g, 95%) as a 1: 1 mixture of diastereoisomers.

LCMS (Table 1, Method a) Rf = 2.24 min; m / z: 307 (MH) "; 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.49 (d, 2H), 7.27 (d, 1H), 7.24 (d, 1H), 3.14-3.35 (m, 1H), 2.45 (dd, 0.5H), 1.68-2.27 (m, 5.5H)

General Procedure C: Formation of an N-alkylated hydantoin To a flask containing hydantoin (1 equivalent) is added a base (such as

potassium carbonate, or sodium carbonate) (1-3 equivalents, preferably 1.5 equivalents) and an organic solvent (such as DMF, or DMA) (preferably DMF). The mixture is stirred at room temperature for a period of 10-30 minutes (preferably about 15 minutes), then methyl iodide (1-2 equivalent, preferably 1.1 equivalents) is added. The reaction is stirred at room temperature for a period of 24-72 hours (preferably about 48 hours). The reaction mixture is concentrated, cooled with ice water bath and water is added. The precipitate is collected by filtration to give crude product. The two stereoisomers may be separated by crystallization.

Exemplification of General Procedure C: Preparation of (5R, 7S) -7- (4-bromo-phenyl) -3-methyl-1,3-diaza-spiro [4.4] nonana-2,4-one

diona

8rV ^ 5I O I-K2CO31Mel1DMF V ^ O

X 2. Crystallization

OCr-- uH

h \ H O

Flask containing (S) -7- (4-Bromo-phenyl) -1,3-diaza-spiro [4.4] nonane-2,4-dione (1: 1 mixture of diastereomers, 180.3 g, 0.583 mol) Potassium carbonate (120.9 g, 0.875 mol) was added followed by DMF (1 L). After stirring for 15 minutes at room temperature, methyl iodide (39.9 mL, 0.642 mol) was added in one portion. The reaction was stirred at room temperature for about 48 hours. The reaction mixture was partially concentrated in vacuo at 25 ° C, removing approximately 400 mL of DMF and excess of methyl iodide. The crude mixture was cooled with ice water bath and water (2 L) was added. After stirring for 1 hour the resulting white precipitate was filtered and washed with water (1 L). The filter cake was vacuum dried overnight to give 220 g of crude (S) -7- (4-Bromo-phenyl) -3-methyl-1,3-diaza-spiro [4.4] nonane-2,4- dioneas a mixture of diastereoisomers.

The two diastereoisomers may be separated by crystallization as follows: The material was separated into 2 groups of 110 g each. The crude material (110 g) was suspended in ACN (2.5 L), heated to 70 ° C until near complete dissolution occurred. The material was rapidly filtered at 70 ° C and washed with 70 ° C ACN (2 x 500 mL). The combined filtrates were reheated to about 65 ° C with stirring. After a clear solution was obtained the mixture was allowed to cool slowly to 50 ° C at which point each material began to withdraw the solution. The solution was allowed to slowly cool to 30 ° C with stirring (100 rpm). After aging for 2 hours the solution was filtered and the solid was dried at 65 ° C under vacuum for three hours to give (5R, 7S) -7- (4-bromo-phenyl) -3-methyl-1,3-diaza -spiro [4.4] nonane-2,4-dione (22.2 g, 12%). (Note: During an attempt to recrystallize from acetonitrile, a mixture of N-methylhydantoin enriched in (S, S) -diastereomer (2: 1 (S, S) :( R, S)) - How much (5S, 7S) -7- (4-bromo-phenyl) -3-methyl-1,3-diaza-spiro [4.4] nonane-2,4-dione (40 mg) in pure form was isolated ).

LCMS (Table 1, Method a) Rf = 2.50 min; m / z: 321 (M-H) *; 1H NMR. (400MHz, DMSCMs) δ 8.56 (s, 1H), 7.50 (d, 2H, J = 8.42Hz), 7.27 (d, 2H, J = 8.53Hz), 3.16-3.31 (m, 1H), 2.84 (s, 3H), 2.46 (dd, 1H, J = 13.62, 8.40 Hz), 2.02-2.18 (m, 2H), 1.72-1.95 (m, 3H)

General Procedure D: Hydrolysis of a hydantoin to the corresponding amino acid

To a suspension of N-alkylated (1 equivalent) hydantoin in water is added dioxane and an inorganic base (such as lithium hydroxide, or sodium hydroxide) (5-15 equivalents, preferably about 8-10 equivalents). The mixture is heated at reflux for a period of 16-48 hours (preferably 24 hours). After cooling to room temperature, the reaction mixture is acidified, and filtered. The filter cake is washed with a suitable solvent and dried under vacuum to give the corresponding amino acid. Example of General Procedure D:

Preparation of (1R, 3S) -1-Amino-3- (4-bromo-phenyl) -cyclopentanecarboxylic acid

NaOH "Χ ^,. ^ ΝΟΗ

Dioxane / H8O NHP

To a mixture of (5R, 7S) -7- (4-bromo-phenyl) -3-methyl-1,3-diaza-spiro [4.4] nonane-2,4-dione (79 g, 0.24 mol) in water (1 L) was added 2 M aqueous NaOH (1 L, 2 mol) and dioxane (200 mL). The resulting mixture was cooled to room temperature, diluted with water (2 L) and acidified with concentrated HCl until a precipitate began to form (about pH 7). Acetic acid (about 20 mL) was added, yielding a thick precipitate. The white precipitate was collected and washed with water (2 x 1 L) and EtOAc (1 L). The filter cake was suspended in toluene (1 L) and concentrated in vacuo at 45 ° C. The process was repeated once more. The white precipitate was dried at constant weight under vacuum to give (1R, 3S) -1-amino-3- (4-bromo-phenyl) -cyclopentanecarboxylic acid (65 g, 95%).

LCMS (Table I, Mcthod a) R 1 = 1.56 min; m / v 284/286 (M + H) +; 1H NMR (400 MHz, DMSO-J6)? 7.55 (d, 2H), 7.3 (d, 2H), 3.3 (m, 1H), 2.65 (m, 1H), 2.3 (m, 1H), 2.1-2.2 ( m, 2H), 2.0-2.1 (m, 1H), 1.85 (t, 1H)

General Procedure E: Formation of an ester from an acid

An acid (1 equivalent) suspended in large excess of methanol is cooled in an ice / water bath in thionyl chloride (5-20 equivalents, preferably 8-12 equivalents) is added dropwise. The resulting mixture is heated at reflux for a period of 2-48 hours (preferably 24-36 hours). The reaction mixture is cooled to room temperature, filtered and concentrated to dryness. The residue is triturated with a suitable solvent (such as EtOAc, or ether) and dried under vacuum to give the desired product.

Exemplification of General Procedure E: Preparation of (1R, 3S) -1-Amino-3- (4-bromo-phenyl) -acetic acid methyl ester

cyclopentanecarboxylic acid; hydrochloride

XX THE SOCI2 O—

O ^ oh OCjp H-Cl

(1R, 3S) -1-Amino-3- (4-bromo-phenyl) -cyclopentanecarboxylic acid (79 g, 0.28 mol) suspended in MeOH (1.8 L) was cooled in an ice / water bath and Thionyl chloride (178 mL, 2.44 mol) was added dropwise. Following the addition, the reaction was heated to reflux, resulting in an almost homogeneous solution. After refluxing for about 36 hours, the reaction mixture was cooled to room temperature, filtered, and washed with MeOH (2 x 200 mL). The filtrate was concentrated in vacuo to afford a white solid. The solid white was triturated with EtOAc (1 L), collected by filtration, washed with EtOAc (2 x 500 mL), and dried under vacuum to give (1R, 3S) -1-amino-3-methyl ester ( 4-bromo-phenyl) -cyclopentanecarboxylic acid; hydrochloride as a white solid (79 g, 96%).

1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, 2H), 7.35 (d, 2H), 3.82 (s, 3H), 3.3 (m, 1H), 2.65 (m, 1H), 2.3 (m, 1H), 2.1-2.2 (m, 3H), 1.95-2.05 (t, 1H)

General Procedure F: Cross Coupling to an Aryl Bromide

To a vial charged with aryl bromide (1 equivalent), an alkyne compound (1.1-3 equivalents, preferably 2 equivalents), triphenylphosphine (2-10 mol%, preferably 10 mol%), an organic base (such as as piperidine, diethylamine or triethylamine) (preferably piperidine) (3-8 equivalents, preferably 4-6 equivalents) an organic solvent such as tetrahydrofuran, dioxane or DMF (preferably tetrahydrofuran) is added. The mixture has the gases removed prior to the addition of palladium catalyst (such as tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium (II) chloride (2-10 mol%, preferably 5 mol%) and copper iodide ( I) (2-10 mol%, preferably 5 mol%) The reaction mixture is heated to 45-110 ° C (preferably about 60 ° C) for a period of 4-48 hours (preferably 24-36 hours) under During the reaction, more alkyne compound (1-8 equivalents, preferably 2-4 equivalents) is added portionwise to the reaction mixture to direct the reaction to completion Under reaction completion, the mixture is concentrated to dry, dissolved in a suitable organic solvent (such as EtOAc, or DCM), and washed with saturated aqueous NaHCO3, dried by an appropriate drying reagent (such as MgSO4, or Na2SO4) and concentrated to dryness to give crude product. The crude product is purified by flash chromatography, and may be further purified. It is made by co-crystallization with tartaric acid. Example of General Procedure F:

Preparation of (1R, 3S) -1-Amino-3- (4-prop-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester; compound with (2R, 3R) -2,3-dihydroxy succinic acid

Hi ....

1-1 · Octine1 Pd (PPh3) 2Qa, PPh31 Cul1 piperidine

O-T —--

w NH2O 2. L-tartaric acid

Η-0

To a round bottom flask was added (1R, 3S) -1-amino-3- (4-bromo-phenyl) -cyclopentanecarboxylic acid methyl ester; hydrochloride (3.94 g, 0.0118 mol), 1-octine (3.48 mL, 0.0235 mol), triphenylphosphine (0.309 g, 0.00118 mol), piperidine (6.99 mL, 0.0706 mol) ), and THF (100 mL, 1 mol). The mixture had the gases removed, and Pd (PPh3) 2Cl2 (0.41 g, 0.00059 mol) was added and the mixture was stirred for a few minutes under a nitrogen atmosphere before the addition of copper iodide ( 1) (0.11 g, 0.00059 mol). The reaction was stirred under a nitrogen atmosphere at 60 ° C for 2 hours. Further 1-octine (12 mL, 0.081 mmol) was added in 3 portions. The reaction mixture was heated to 60 ° C for a total of about 36 hours. The solvent was then removed and crude material was partitioned between EtOAc and saturated NaHCO 3. The aqueous layer was reextracted once with EtOAc. Organic layers were combined, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography using EtOAc followed by 2% MeOH in EtOAc to give 3.38 g of crude product as a yellow oil. The crude product was dissolved in minimal amount of MeOH, to which L-tartaric acid (1.69 g) in MeOH was added. Ether was then added dropwise until solution became turbid. The mixture was allowed to crystallize. The solid was collected by filtration, washed with ether to give 3.91 g (72.6%) (1R, 3S) -1-amino-3- (4-prop-1-ynyl-phenyl) -acetic acid methyl ester. cyclopentanecarboxylic acid; compound with (2R, 3R) -2,3-dihydroxy succinic acid. LCMS Tartrate Salt (Table 1, Method b) R1 = 2.17 min; m / z: 328 (M + H) +; 1H NMR (400 MHz, DMSO-d6) δ 7.30 (m, 2H), 7.24 (m, 2H), 4.4 (s, 2H), 3.89 (m, 3H), 3.42 (m, 1H), 2.7 (m 1H), 2.46 (m, 1H), 2.39 (m, 2H), 2.22 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.55 (m, 2H), 1.45 (m, 2H), 1.33 (m, 4H), 0.9 (m, 3H).

Preparation of (1R, 3R) -1-Amino-3- (4-prop-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester; compound with (2R, 3R) -2,3-dihydroxy succinic acid

1 · 1 Octine, Pd (PPh3) 2CIa, PPh3, Cul1 piperidine _THF_

2. L-tartaric acid

Oh

To a three-neck round bottom flask was added (1R, 3R) -1-amino-3- (4-bromo-phenyl) -cyclopentanecarboxylic acid methyl ester; hydrochloride (4.00 g, 12.0 mmol), 1-octin (3.53 mL, 24.0 mmol), triphenylphosphine (314 mg, 1.20 mmol), piperidine (7.13 mL, 72.0 mmol) ), and THF (100 mL). The mixture had the gases removed, and Pd (PPh3) 2Ci2 (421 mg, 0.60 mmol) was added and the mixture was stirred for a few minutes under a nitrogen atmosphere before the addition of copper (I) iodide. (114 mg, 0.60 mmol). The reaction was stirred under a nitrogen atmosphere at 60 ° C for 4 hours. Further 1-octine (5.31 mL, 36.0 mmol) was added in two portions and the reaction mixture was heated to 60 ° C for a total of about 30 hours. The solvent was then removed and the crude material was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was reextracted once with EtOAc. Organic layers were combined, dried over MgSO 4, and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography using EA followed by 2% MeOH in EtOAc to give 3.52 g (90%) of crude product as a yellow oil. A portion of crude product (60.0 mg, 0.126 mmol) was dissolved in minimal amount of MeOH, to which L-tartaric acid (1.69 g) in MeOH was added. Ether was then added dropwise until solution only turned turbid. The mixture was allowed to crystallize. The solid was collected by filtration, washed with ether to give 45.0 mg (60%) (1R, 3R) -1-amino-3- (4-prop-1-ynyl-phenyl) -acetic acid methyl ester. cyclopentanecarboxylic acid; compound with (2R, 3R) -2,3-dihydro succinic acid (tartrate salt). LCMS (Table 1, Method b)

R1 = 2.17 min; m / z: 328 (M + H) +; 1H NMR (400 MHz, DMSOnd6) δ 7.30 (m, 2H), 7.22 (m, 2H), 4.01 (s, 2H), 3.73 (m, 3H), 3.43 (m, 1H), 2.40 (m, 1H ), 2.31 (m, 1H), 2.20 (m, 1H), 2.11 (m, 2H), 1.76 (m, 2H), 1.52 (m, 2H), 1.41 (m, 2H), 1.29 (m, 4H) 0.88 (m, 3H).

General Procedure G: Reduction of an Alkyne To a reaction vessel loaded with carbon palladium hydroxide (10-30 wt%, preferably 20 wt%) is added acetic acid and an alkyne compound (1 equivalent). The reaction mixture is evacuated, refilled with nitrogen followed by two evacuation cycles and refilled with hydrogen gas. The reaction is charged to about 206842.77-413685-55 Pa (30-60 psi) (preferably about 344737.95 Pa (50 psi)) with hydrogen and stirred at room temperature for a period of 0, 5-24 hours (preferably about 1 hour). The crude mixture is filtered, washed with a suitable solvent such as ethanol, concentrated. The residue may be purified by crystallization from ethanol / water to give the desired product.

Example of General Procedure G:

Preparation of (1R, 3S) -1-Amino-3- (4-octylphenyl) cyclopentanecarboxylic acid methyl ester

185 mg of palladium carbon hydroxide (20 wt%) and acetic acid (25 mL, 0.44 mol) were loaded on a Parr shaker. (1R, 3S) -1-Amino-3- (4-oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester; (2R, 3R) -2,3-dihydrox succinic acid (2.49 g, 0.00521 mol) was added and the reaction was evacuated, refilled with nitrogen, followed by two emptying cycles and refilled. with hydrogen gas. The reaction was then pressurized to about 50 psi using hydrogen. The reaction was stirred at room temperature for 50 minutes. The crude product was filtered through Celite® and washed with ethanol. The filtrate was concentrated, and the residue was produced in a small amount of ethanol. Water has been added. The mixture was almost clear. Ethanol was removed under reduced pressure, and the remaining aqueous solution was allowed to stand. After a few minutes, needle-like crystals began to form. More water was added, and the mixture allowed to crystallize. The white solid was collected by filtration, and washed with water three times. The white solid was dried frozen to remove remaining water. 1.9 g (90%) of (1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentanecarboxylic acid methyl ester; compound with 0.5 equivalent of (2R, 3R) -2,3-dihydroxy succinic acid was obtained as a soft white solid.

(1/2 tartrate salt) LCMS (Table 1, Method b) R1 = 2.56 min; m / z: 332 (M + H) +; 1H NMR (400 MHz, DMSO-J6) δ 7.2 (m, 2H), 7.1 (τη, 2H), 4.35 (s, 1H), 3.86 (s, 3H), 3.33 (m, 1H), 2.67 (m, 1H), 2.57 (m, 2H), 2.4 (m, 1H), 2.19 (m, 1H), 2.13 (m, 2H)? 1.95 (m, 1H), 1.59 (m, 2H), 1.3 (m, 10H), 0.9 (m, 3H)

Oh

The OH General Procedure Η: Reduction of an Ester to Alcohol

Substituted 1-amino-cyclopentanecarboxylic acid methyl ester dissolved in a suitable solvent (such as tetrahydrofuran or ether) is cooled below room temperature (about 0-1 ° C, preferably 0 ° C). To this solution is slowly added a reducing reagent such as LAH (1-3 equivalents, preferably 2 equivalents). The reaction mixture is stirred for a period of 0.5-6 hours (preferably 0.5-2 hours). The reaction mixture is worked up by successively adding η mL of water, η mL of 2 M Na-OH solution, and 2n mL of water per η g of LAH used in the reaction. After stirring for a period of 1-24 hours (preferably 2 hours), Na 2 SO 4 is added and the precipitate is filtered off. The product precipitates as hydrochloride by adding HCl to the filtrate.

1-Amino-3- (4-octyl-phenyl) -cyclopentanecarboxylic acid methyl ester; hydrochloride (640 mg, 0.0017 mol) was partitioned between Et 2 O and 2 Na NaOH solution. The organic layer was separated, washed with brine, dried over Na 2 SO 4, filtered and concentrated. The free base was dissolved in Et 2 O (20 mL) and cooled to 0 ° C. To this solution was added LAH (130 mg, 0.0035 mol) slowly. After 30 minutes, water (130 µl) was added followed by 2 M NaOH (130 µl) followed by water (260 µl). After stirring for 2 hours, Na 2 SO 4 was added and the white precipitate was filtered. 1 M HCl in Et 2 O (3.4 mL) was added and the resulting fine precipitate was collected to provide 470 (79%) of [(1 R, 3S) -1-amino-3- (4-octylphenyl) - cyclopentyl] methanol; hydrochloride.

LCMS (Table 1, Method a) Rf = 2.64 min; m / z: 304 (M + H) +; 1 H NMR (400 MHzr CDCl 3) δ 8.26 (bs, 3H), 7.06 (d, 2H), 7.02 (d, 2H), 3.79 (s, 2H), 3.62 (m, 1H), 2.52 (m, 3H), 2.52 (m, 3H), 2.13 (m, 3H), 1.76 (m, 1H), 1.64 (m, 1H), 1.54 (m, 3H), 1.27 (m, 12H), 0.87 (t, 3H)

ammonium chloride (1-4 equivalents, preferably 2 equivalents) and a cyanide salt such as sodium cyanide or potassium cyanide (1-4 equivalents, preferably 2 equivalents). The reaction is capped and stirred at room temperature for a period of 12-72 hours (preferably about 36 hours). The crude reaction mixture is concentrated, partitioned between a suitable solvent (such as EtOAc or DCM) and a saturated aqueous NaHCO3 solution. The organic layers are combined, washed with water, dried over an appropriate drying reagent (such as Na 2 SO 4 or MgSO 4), and concentrated to dryness. The

Example of General Procedure H:

Preparation of [(1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl] methanol

LAH

General Procedure I: Formation of an amino nitrile from a ketone To a cyclopentanone substituted in methanolic ammonia solution is added two stereoisomers may be separated by co-crystallization with tartaric acid in methanol.

Example of General Procedure I:

Preparation of (1R, 3R) -1-amino-3- (4-methoxy-phenyl) -cyclopentanecarbonitrile; composed of (2R, 3R) -2,3-dihydroxy succinic acid

A solution of (R) -3- (4-methoxy-phenyl) -cyclopentane (11.0 g, 57.9 mmol) in 7 M metal ammonia solution was treated with ammonium chloride (6.21 g, 116 mmol). ) and sodium cyanide (5.68 g, 116 mmol). The reaction was stopped and stirred at room temperature for about 48 hours. The reaction was concentrated, treated with saturated NaCO3 solution (80 mL) and extracted with DCM (2x100 mL). The extracts were washed with water (40 mL), dried over MgSO4, and concentrated to an oil to give the product as a mixture of diastereoisomers. The (1R, 3R) - isomer was separated as follows:

The residue was dissolved in methanol (100 mL) and the solution was added to a solution of L-tartaric acid (8.69 g, 57.9 mmol) in methanol (100 mL). The resulting solid was collected and repeatedly triturated with methanol (80 mL) until the most soluble isomer was as indicated by HPLC (50 x 4.6 mm ThermoQuest Hypercarb column, 5 pm, part # 35005-025. The white solid The remaining residue was dried to yield 6.0 g (28%) of (1R, 3R) -1-amino-3- (4-methoxy-phenyl) -cyclopentanecarbonitrile: compound with (2R, 3R) -2,3-dihydroxy acid - succinic.

LCMS <Table 1, Method a) R4 = 2.26 min; m / t Poor ionization; 1H NMR: (400 MHz, DMSO-rfe) δ 7.18 (d, 2H), 6.85 (d, 2H), 4.22 (s, 2H), 3.72 (s, 3H), 3.30-3.41 (m, 1H), 2.10 -2.30 (m, 3H), 1.8-2.0 (m, 2H), 1.6-1.75 (m, 1H).

General Procedure J: Hydrolysis of a nitrile to the corresponding acid A 1-amino-cyclopentanecarbonitrile saturated in 6 M hydrochloric acid and dioxane is heated at 80-110 ° C (preferably at about 100 ° C) for a period of 12-24 hours ( preferably 16 hours). The reaction mixture is melted on ice. The precipitate is collected by filtration and washed with water to give the desired product. Example of General Procedure J:

Preparation of (1R, 3R) -1-Amino-3- (4-methoxy-phenyl) -cyclopentanecarboxylic acid; hydrochloride

1. NH 4 Ct, NaCN, MeOH

2. Tartaric acid, MeOH

THE

6 M HCI

OH

Oh

HO

(1R, 3R) -1-amino-3- (4-methoxy-phenyl) -cyclopentanecarbonitrile suspension; The compound with (2R, 3R) -2,3-dihydroxy succinic acid (5.0 g, 13.66 mmol) in 6 M hydrochloric acid (50 mL) and dioxane (5 mL) was heated at 100 ° C for 16 hours under nitrogen. The reaction was cooled on ice and the product was filtered, washed with water (3x5 mL) and dried to yield 2.72 g (74%) of (1R, 3R) -1-amino-3- (4-methoxy) acid. phenyl) cyclopentanecarboxylic acid; hydrochloride as a white sodium.

LCMS (Table 1, Method a) Rf = 1.43 min; m / z: 236 (M + H) +; 1H NMR (400 MHz, DMSCM6) δ 13.9 (s, 1H), 8.55 (s), 3H), 7.17 (d, 2H), 6.88 (d, 2H), 3.40-3.52 (m, 1H), 2.28-2.40 (m, 2H). 2.13-2.20 (m, 2H), 1.90-1.99 (m, 1H), 1.74-1.85 (m, 1H).

General Procedure K: Formation of an oxazolidinone from an amino acid

alcohol

To a mixture of an amino alcohol in diethyl carbonate (10-20 equivalents,

preferably 15 equivalents) potassium carbonate (1-3 equivalents, preferably 1.15 equivalents) is added. The mixture is heated at reflux for a period of 12-48 hours (preferably about 20 hours). The reaction is concentrated and the residue is partitioned between a suitable organic solvent (such as EtOAc or DMC) and water. The organic layer is dried in an appropriate drying reagent (such as MgSO4 or Na2SO4), filtered and concentrated. The crude product is further purified by flash chromatography.

g, 30.3 mmol) in diethyl carbonate K 2 CO 3 (4.83 g, 35.0 mmol) was added and the mixture was heated at reflux for about 20 hours. The reaction was concentrated, taken up in EtOAc (150 mL), washed with water (75 mL), dried over Na 2 SO 4, filtered and concentrated. The crude product was further purified by flash chromatography with a gradient from 40% to 80% EtOAc in heptane. Pure fractions were combined and concentrated to yield 5.99 (80%) of (5R, 7R) -7- (4-methoxy-phenyl) -3-oxa-1-aza-spiro [4.4] nonan-2-one as a white solid.

Example of General Procedure K:

Preparation of (5R, 7R) -7- (4-methoxy-phenyl) -3-oxa-1-aza-spiro [4.4] nonan-2-one

20

To a suspension of [(1R, 3R) -1-amino-3- (4-methoxyphenyl) cyclopentyl] methanol (6.70 LCMS (Table 1, Method a) Rt = 2.18 min; m / z: 248 (M + Hf; 1H NMR (400 MHz, DMSO-rfe) δ 8.05 (broad) o, 1H), 7.14 (d, 2H), 6.84 (d, 2H), 4.22 (dd, 2H), 3.71 ( s, 3H), 3.17 (m, 1H), 1.98 - 2.15 (m, 3H), 1.7 -1.85 (m, 2H), 1.49 -1.60 (m, 1H)

General Procedure L: Unprotection of a methyl ether

A methyl ether compound in a suitable solvent (such as dichloromethane or dichlorethane) is cooled in an ice bath and BBr3 (1-5 equivalents, preferably 3 equivalents) is added. The reaction mixture is stirred at about 0 ° C for a period of 0.5-2 hours (preferably 0.5 hour). The reaction is quenched with a practical solvent such as methanol or water, warmed to room temperature, and concentrated to dryness. The residue is triturated with water, filtered to give the desired product.

A solution of (5R, 7R) -7- (4-methoxy-phenyl) -3-oxa-1-aza-spiro [4.4] nonan-2-one (3.95 g, 16.0 mmol) in DCM ( 30 mL) was cooled in an ice bath and 1 M BBr 3 in DCM solution (64.0 mL, 64.0 mmol) was added at a rapid drop rate and the reaction allowed to continue stirring at about 0 ° C for about 50 ° C. 0.5 hour. The reaction was quenched by the dropwise addition of methanol (25.0 mL). The reaction was allowed to warm to room temperature and then concentrated. The residue was triturated with water (50 mL), filtered, washed with water (2x50 mL), and dried to yield 3.14 g (84%) of (5R, 7R) -7- (4-hydroxyphenyl ) -3-oxa-1-aza-spiro [4.4] nonan-2-one as a gray solid. LCMS (Table I, Method a) R1 = 1.70 min; m / z: 234 (M + H) +; 1 H NMR (DMSO-d) δ 9.15 (s, 1H), 8.04 (s, 1H), 7.01 (d, 2H), 6.67 (d, 2H). 4.21 (d, d, 2H), 3.11 (m, 1H), 1.97-2.13 (m, 3H), 1.68-1.83 (m, 2H), 1.46-1.58 (m, 1H)

General Procedure M: Alkylation of a hydroxy group

A solution of a phenol, an alcohol (1-3 equivalents, preferably 1.1 equivalents) and triphenylphosphine resin bonding (1-3 equivalents, preferably 2.2 equivalents) in a suitable solvent (such as tetrahydrofuran, dichloromethane) is aphricide at about 0 ° C. An azodicarboxylate (such as diethyl azodicarboxylate, diisopropyl azocarboxylate, or di-tert-butyl azodicarboxylate) (1-3 equivalents, preferably 1.1 equivalents) is added to the mixture. The reaction is warmed to room temperature and stirred for a period of 2-24 hours (preferably 3 hours). The resin is filtered and washed with a suitable solvent (such as tetrahydrofuran, dichloromethane). The filtrate is concentrated to dryness.

10

Example of General Procedure L:

Preparation of (5R, 7R) -7- (4-hydroxy-phenyl) -3-oxa-1-aza-spiro [4.4] nonan-2-one The crude product is further purified by flash chromatography. Example of General Procedure M:

Preparation of (5R, 7R) -7- (4-octyloxy-phenyl) -3-oxo-1-aza-spiro [4.4] nonan-2-one

A solution of (5R, 7R) -7- (4-hydroxy-phenyl) -3-oxo-1-aza-spiro [4.4] nonan-2-one (75 mg, 0.32 mmol), octanol (55, 6 µL, 0.35 mmol) and triphenylphosphine resin binding (343 mg, 2 mmol / g, 0.70 mmol) in THF (4.0 mL) was cooled to about 0 ° C and di-tert-butyl azodicarboxylate (80 ° C). 0.5 mg, 0.35 mmol) was added dropwise. The reaction was allowed to warm to room temperature for about 3 hours, then the resin was filtered and washed with DCM (10 mL). The filtrates were combined and concentrated. The crude product was purified on silica gel using a gradient of 30% to 60% EtOAc in heptane. Pure fractions were combined and concentrated to yield 67.0 mg (61%) of (5R, 7R) -7- (4-octyloxy-phenyl) -3-oxo-1-aza-spiro [4.4] nonan-2-one as a white solid.

LCMS (Table 1, Method a) Rt = 3.76 min; m / z 346 (M + H) +; 1 H nmr (DMSO-δ) δ 8.04 (s (broad, 1H), 7.10 (d, 2H), 6.81 (d. 2H), 4.20 (dd, 2H) (3.89 (t, 2H), 3.15 (m, 1.99-2.13 (m, 3H) 1.61-1.82 (m, 4H), 1.46-1.59 (m, 1H), 1.20-1.44 (m, 10H), 0.84 (t, 3H)

General Procedure N: Hydrolysis of an oxazolidinone

To an oxazolidinone dissolved in a suitable solvent (such as dioxane or tetrahydrofuran) is added water and an inorganic base (such as lithium hydroxide, sodium hydroxide or potassium hydroxide) (10-20 equivalents, preferably 12-15 equivalent). The mixture is heated at reflux for a period of 2-24 hours (preferably about 10 hours). The reaction is concentrated, partitioned between a suitable organic solvent (such as ether, or ethyl acetate) and water. The organic layer is dried in an appropriate drying reagent (such as Na 2 SO 4, MgSO 4), filtered and concentrated. The product may be isolated as an ammonium salt by treating the residue with an inorganic acid (such as HCl).

Example of General Procedure N:

Preparation of [(1R, 3R) -1-amino-3- (4-octyloxy-phenyl) cyclopentyl] -methanol; Dioxane / H2O hydrochloride

H 0

A solution of (5R, 7R) -7- (4-octyloxy-phenyl) -3-oxa-1-aza-spiro [4.4] nonan-2-one (61.0 mg, 0.177 mmol) in diocane (3, 0 mL) was treated with lithium hydroxide, hydrate (100 mg, 2.38 mmol) and water (1.0 mL). The mixture was heated at reflux for about 10 hours. The reaction was concentrated, treated with water (10 mL) and extracted twice with ether (10 mL).

The ether extracts were dried over Na 2 SO 4, filtered and concentrated. The residue was treated with 2M HCl (2.0 mL) to afford a white solid which was collected and dried to yield 33.0 (52%) of [(1R, 3R) -1-amino-3- (4-octyloxy). (phenyl) cyclopentyl] methanol; hydrochloride. LCMS (Table 1, Method a) R 1 = 2.58 min, m / z: 320 (M + H) +; 1H nmr (400 MHz, DMSO? Ze) δ 7.89 (s (broad), 3H), 7.12 (d, 2H), 6.83 (d, 2H), 5.56 (s), LH), 3.90 (t, 2H ), 3.46 (m, 1H), 1.96 - 2.10 (m, 2H), 1.56 - 1.74 (ra, 4H), 1.32-1-42 (m, 2H), 1.18-1.32 (m, 10H), 0.85 (t , 3H)

General Procedure O: Phosphorylation of an alcohol followed by deprotection An alcohol dissolved in a suitable solvent (such as tetrahydrofuran, dioxane)

It is treated with a strong base (such as LiHMDS, NaH) (1-25 equivalents, preferably 1.1 equivalents) for a period of 10-30 minutes (preferably 20 minutes) under inert atmosphere. Tetrabenzyl diphosphate (1-1.5 equivalents, preferably 1.1 equivalents) is added to the mixture and the reaction mixture is stirred at room temperature for a period of 0.5-4 hours (preferably 1 hour). The reaction is filtered and the filtrate is concentrated. The intermediate phosphate ester is dissolved in a suitable solvent (such as acetic acid or ethanol) to which Pearlman's Catalyst (5-20 mol%, preferably 5-10 mol%) is added. The mixture is attached to the hydrogen balloon and stirred at room temperature for a period of 2-24 hours (preferably 14 hours). The crude reaction is filtered, concentrated and purified by trituration with a suitable solvent (such as a small amount of DMSO and water) to give the desired product. Alternatively, the intermediate phosphate ester is taken up in a solution of HBr in acetic acid, stirred at 0-50 ° C (preferably room temperature) for 1-30 minutes (preferably 5 minutes) then concentrated. The residue is triturated with a suitable organic solvent such as ether, ethyl acetate or acetonitrile (preferably acetonitrile), then triturated with dilute, filtered and dried aqueous ammonium acetate solution.

Example of General Procedure O:

Preparation of phosphoric acid mono - [(1R.3S) -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl] ester

^ o

Il

LT5NHf OH

((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) methanol; tartrate salt (0.250 g) was based free by partitioning between ether and saturated NaHCO3 solution, dried over MgSO4, filtered, and concentrated to give ((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl ) methanol (138 mg, 0.455 mmol) in a white powder that was used directly in the reaction. A 200 ml round bottom flask equipped with rubber septum and nitrogen inlet needle was charged with ((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) methanol (0.138 g, 0.455 mmol) and THF (10 ml) to give a colorless solution. 1.1 M solution of LiHMDS in THF (0.459 mL, 0.500 mmol) was added dropwise via syringe. The resulting solution was allowed to stir at room temperature for about 20 minutes. Tetrabenzyl diphosphate (0.269 g, 0.500 mmol) was added in one portion. The resulting solution was stirred at room temperature for 1 hour. 1.25 M solution of HCl in ethanol (0.728 mL, 0.909 mmol) was added in one portion. The resulting solution was concentrated and the residue was dissolved in EtOH (10 mL) and the reaction flask was charged with Pearlman Catalyst (0.016 g, 0.023 mmol). The resulting suspension was attached to a hydrogen balloon and stirred at room temperature for 14 hours. The reaction mixture was filtered through Celite® bed. The filtrate was concentrated and triturated with water to give a white precipitate which was collected by filtrate and washed with DMSO (2x2 mL) followed by water (2x10 mL), and dried under vacuum to give mono - [(1R, 3S) ester Phosphoric acid -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl as white powder (0.147 g, 84%).

LCMSC Table 1, Method d) R 1 = 2.36 min; m / z: 382 (MH) δ; 1 F Rmn (400 MHz, DMSO-ε) δ 7.89 (s, broad, 3H), 7.12 (d, 2H), 6.83 (d, 2H), 5.56 (st broad, 1H ), 3.90 (t, 2H), 3.46 (m, 1H), 1.96 - 2.10 (m, 2H), 1.56 - 1.74 (m, 4H), 1.32-1.42 (m, 2H), 1.18-1.32 (m, 10H ), 0.85 (t, 3H) Example of General Procedure O: Phosphorylation of an alcohol followed by deprotection

An alcohol dissolved in a suitable solvent (such as tetrahydrofuran, dioxane) is treated with a strong base (such as LiHMDS, NaH) (1-25 equivalents, preferably 1.0 equivalents) over a period of 10-30 minutes (preferably 20 minutes) under inert atmosphere. Tetrabenzyl diphosphate (1-1.5 equivalents, preferably 1.0 equivalents) is added to the mixture and the reaction mixture is stirred at room temperature for a period of 0.5-4 hours (preferably 2 hours). The reaction is briefly cooled to about 0 ° C and the precipitated solid is filtered off and the filtrate is concentrated. The residue is taken up in a solution of HBr in acetic acid, stirred at 0-50 ° C preferably at room temperature) for 1-30 minutes (preferably 5 minutes) then concentrated. THE

W NMa

1. UHMDSpTetrabenzylphosphate, _THF_

The residue is triturated with an organic solvent such as ether, ethyl acetate or acetonitrile (preferably acetonitrile), then triturated with dilute, filtered and dried aqueous ammonium acetate solution.

Example of General Procedure O:

A 25 mL round bottom flask equipped with rubber septum and nitrogen inlet needle was charged with {(1R, 3S) -1-amino-3- [3,5-dichloro-4- (2-phenoxyethoxy ) -phenyl] -cyclopentyl} -methanol (50.0 mg, 0.126 mmol) in THF (4 mL) to give a colorless solution. A LiHMDS solution in THF (1.0 M1 0.126 mL, 0.126 mmol) was added dropwise via syringe. The resulting solution was allowed to stir at room temperature for about 20 minutes. Tetrabenzyl diphosphate (67.9 mg, 0.126 mmol) was added in one portion. The resulting solution was stirred at room temperature for 2 hours. Brief cooling to 0 ° C and filtration of solids, wash with THF (1.0 mL). The resulting solution was concentrated and the residue was dissolved in 33% HBr in acetic acid (1.5 mL) and stirred at room temperature for 5 minutes and then concentrated. The residue was triturated with ether (2x5.0 mL) and dilute aqueous ammonium acetate solution (2x5.0 mL) then filtered and dried to yield mono {(1R, 3S) -1-amino-3- [3] acid. , 5-Dichloro-4- (2-phenoxy-ethoxy) -phenyl] -cyclopentylmethyl} -phosphoric (34 mg, 57%) as a cream powder. LCMSC Table 1, Method d) Rf = 2.73 min; m / z: 476/478/480 (M-H) '; 1 F nm (400 MHz, DMSO-d 6 + 3 µL Tfa) δ 8.15 (s, broad, 3H), 7.40 (s, 2H), 7.29 (m, 2H), 6.94 (m, 3H), 4.32 (s, 4H ), 20 3.96 (m, 2H), 3.33 (m, 1H), 2.11 (m, 3H), 1.85 (m, 1H), 1.71 (m, 2H)

Example Procedure General: Phosphorylation of an alcohol followed by deprotection with HBr Preparation of ((1R, 3R) -1-amino-3- (4- (3- (thiophen-2-yl) propoxy) phenyl) cyclopentyl phosphate ) methyldihydrogen

5th

Preparation of phosphoric acid mono {(1R, 3S) -1-amino-3- [3,5-dichloro-4- (2-phenoxy-ethoxy) -phenyl] -cyclopentylmethyl} ester

25

((1R, 3R) -1-amino-3- (4- (3- (thiophenyl-2-yl) propoxy) phenyl) cyclopentyl) methanol (0.05 g, 0.151 mmol) was dissolved in THF (3.02 mL) under nitrogen. Lithium bis (trimethylsilyl) amide (0.151 mL - 0.151 mmol) (Aldrich) was added and the reaction stirred for 30 minutes. Tetrabenzyl diphosphate (0.081 g, 0.151 mmol) (FIuka) was added and the reaction stirred for 16 hours. The resulting solid was removed by vacuum filtration and washed with THF. The filtrate was concentrated and a mixture of acetic acid hydrogen bromide (0.030 mL, 0.151 mmol) (Aldrich) and triidopropylsilane (0.031 mL, 0.151 mmol) (Aldrich) were added. The reaction was stirred for about 30 minutes at which time LCMS showed complete reaction. The reaction was diluted with ether (15 mL), depositing a residue on the sides of the flask, and stirred until the ether was clear. The ether was decanted and the residue washed with ether. 1 mM ammonium acetate buffer (~ 5 mL) was added and the vial sonicated. A precipitated light bronze resulted. The resulting solid was collected by vacuum filtration and washed with water and then acetonitrile to provide ((1R, 3R) -1-amino-3- (4- (3-thiophen-2-yl) propoxy) phosphate dihydrogen phosphate. phenyl) cyclopentyl) methyl (0.024 g, 0.058 mmol, 38.7% yield) as a tan solid on drying: LC / MS (Table 1, Method A) Rf = 2.57 min; MS m / z: 412.35 (M + H) +. General Procedure Q: Hydrolysis of an ester to acid

To an ester dissolved in a suitable solvent (such as tetrahydrofuran, dioxane) is added a suitable inorganic base (such as lithium hydroxide, sodium hydroxide) (5-10 equivalents, preferably 10 equivalents) and water. The mixture is heated to 45-65 ° C (preferably 50 ° C) for a period of 2-24 hours (preferably 4-5 hours). The crude reaction is acidified with acid. The precipitate is collected by filtration, washed with ether and water, dried to give the desired product.

Example of General Procedure Q:

Preparation of phosphoric acid mono - [(1R, 3S) -1-amino-3- (4-octyl-phenyl) -cyclopentylmethyl] ester; hydrochloride

1.757 mmol) in THF (5 mL), sodium hydroxide (0.703 g, 17.57 mmol) dissolved in water (5 mL) was added. The reaction was heated at 60 ° C for 4-5 hours. The reaction mixture was acidified to pH 1-2 with 6 H HCl. The resulting mixture was stirred with 1: 1 water and ether (40 mL). The resulting mixture was filtered. The solid was washed a few times with diethyl ether, water, and air dried to yield 311 mg (48%) of mono - [(1R, 3S) -1-amino-3- (4-octylphenyl) - cyclopentylmethyl] of phosphoric acid; hydrochloride as a bright white solid.

25

To a solution of 1-amino-3- (4- (non-1-ynyl) phenyl) cyclopentane carboxylate (0.600 g, LCMS (Tablei, Métodob) R f = 2.47min; m / Z: 348 (M + H) Δ 1H (400MHzf MeOD - δ) δ7.2 (dd, 4H), 3.48 (m, 1H), 2.73 (m, 1H), 2.51 (m, 1H), 2.39 (m, 1H), 2.26 (m, 1H), 2.13 (m, 1H), 2.03 (m, 1H), 1.85 (m, 1H), 1.59 (m, 2H), 1.47 (m, 2H), 1.33 (m, 6H), 0.99 (t, 3H )

General Procedure Q: Phenol Alkylation

A phenol solution substituted in an organic solvent (such as tetrahydrofuran, DMF or dioxane) (preferably DMF) is added dropwise to a stirred suspension of Sodium Hydride in the same solvent at -10-30 ° C. preferably about 0 ° C under an inert atmosphere. The alkylating agent, for example ethyl bromoacetate, iodomethane, iodoethane or tert-butyl bromoacetate, is added dropwise to the stirred anion and then the reaction is heated to 20-100 hours preferably at room temperature for 1-24 hours. . The reaction is then concentrated under reduced pressure and the crude product taken up in ethyl acetate, washed with water, dried (Na 2 SO 4), filtered, concentrated and further purified by flash chromatography.

Example of General Procedure Q:

Preparation of (3-Fluoro-phenoxy) -acetic acid ethyl ester

F - F

I Ethyl bromoacetate |

Sodium Hydride ^ Wv

iX <x

The

A 50 mL three inlet round bottom flask equipped with temperature and nitrogen bubbling standard was charged with Sodium Hydride (785 mg, 19.6 mmol) and DMF (10.0 mL) and cooled to 0 ° C. A solution of 3-fluorophenol (2.00 g, 17.8 mmol) in DMF (2.0 mL) was added dropwise keeping the reaction temperature below 10 ° C. The mixture was stirred for an additional 15 minutes and then ethyl bromoacetate (2.48 mL, 22.3 mmol) was added dropwise keeping the reaction temperature below 10 ° C. The reaction was stirred at room temperature for 4 hours. The reaction was then concentrated under reduced pressure and the crude product was taken up in ethyl acetate, washed with water, dried (Na 2 SO 4), filtered, concentrated and further purified by flash chromatography using 4: 1 / heptane. : ethyl acetate as eluent. Product containing fractions were combined and concentrated to afford (3-fluorophenoxy) ethyl ester (2.26 g, 69%) as a clear oil.

LCMS (Table Método. Method a) m / z: poor ionization; 1H NMR (400 MHz, DMSO-d6) δ. 7.32 (m, 1H), 6.81 (m, 3H), 4.81 (s, 2H), 4.17 (q, 2H), 1.21 (t, 3H)

Preparation of (3-Ethoxy-phenyl) -acetic acid ethyl ester

Iodoethane Sodium Hydride

DMF

Oh

A nitrogen-bubbling, 100 mL three-neck round bottom flask was charged with Sodium Hydride (2.89 g, 72.3 mmol) and DMF (30.0 mL) and cooled to 0 ° C. . A solution of (3-hydroxy-phenyl) -acetic acid (5.00 g, 32.9 mmol) in DMF (10.0 mL) was added dropwise keeping the reaction temperature below 10 ° C. The mixture was stirred for an additional 15 minutes, and then ethyl iodide (5.84 mL, 72.3 mmol) was added keeping the reaction temperature below 10 ° C. The reaction was stirred at room temperature for one night. The reaction was then concentrated under reduced pressure and the crude product was taken up in ethyl acetate, washed with water, dried (Na 2 SO 4), filtered, concentrated and further purified by flash chromatography using 8: 1 / heptane: ethyl acetate as eluent. . Product containing fractions were combined and concentrated to afford (3-ethoxy-phenyl) -acetic acid ethyl ester (3.48 g, 51%) as a clear oil.

LCMS C Table 1 Method a t) 3.64 min, m / z: poor ionization; 1H NMR (400 MHz, DMSOd6) δ 7.22 (m, 1H), 6.83 (m, 3H), 4.15 (q, 2H), 4.03 (q, 2H), 3.57 (s, 2H), 1.40 (t, 3H) 1.25 (t, 3H)

Preparation of (S) -1-Phenoxy-propan-2-ol

A microwave vessel was charged with (S) -2-methyl-oxirane (0.46 mL, 7.78 mmol), triethylamine (0.33 mL, 2.36 mmol), phenol (222 mg, 2.36 mmol) ) and DMF (2.0 mL). The mixture was heated by microwave for 20 minutes at 150 ° C. The reaction was concentrated and dried under reduced pressure. The crude mixture (approximately 9: 1) was dissolved in DMF (3.0 mL) and treated with imidazole (160 mg, 2.36 mmol) and triisopropylchlorosilane (181 mg, 0.94 mmol) overnight at room temperature under nitrogen. The reaction was concentrated under reduced pressure and the crude product was purified by flash chromatography using 3: 2 / heptane: ethyl acetate as eluent. Product containing fractions were combined and concentrated to afford (S) -1-phenoxy-propan-2-ol (390 mg, 62%) as a clear oil.

(S) -2-methyl oxirane triethylamine

DMF LCMSC Table 1, Method a i) m / z: ροοτ ionization; 1 H nmr (400 MHz, DMS 0-4%) 6. 7.30 (m, 2H), 6.90 (m, 3H), 4.80 (d, 1H), 3.90 (m, 1H), 3.80 (m, 2H), 1.10 (d, 3H) General Procedure R: Reduction of carboxylic acid

A solution of carboxylic acid in an organic solvent (such as tetrahydrofuran or dioxane) (preferably THF) is added dropwise to a stirred solution of borane in THF at 0-50 ° C, preferably about 23 ° C under a inert atmosphere. The reaction is stirred and heated to 20-50 ° C, preferably room temperature for 1-24 hours. The reaction is then quenched by careful addition of methanol at 0-50 ° C, preferably about room temperature. The crude product is concentrated under reduced pressure, taken up in ethyl acetate, washed with water, dried (Na 2 SO 4), filtered and concentrated.

Example of General Procedure R:

Preparation of 2- (3-Methoxy-phenoxy) -ethanol

THE

A 250 ml three-neck round bottom flask equipped with standard temperature and bubbling nitrogen was charged with 1 M Borane / THF solution (60.4 ml, 60.4 mmol) and an acid solution (3-methoxy). -phenoxy) -acetic (5.00 g, 27.4 mmol) in THF (2.0 mL) was added dropwise, keeping reaction temperature below 30 ° C. The reaction was allowed to stir at room temperature for one night. The reaction was quenched by dropwise addition of methanol (20 mL) keeping the reaction temperature below 35 ° C. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to afford 2- (3-methoxy-phenoxy) -ethanol (4.51 g, 98%) as a clear oil which was used without purification. additional.

LCMSC Table 1, Method a) 2.43 min., M / z: 169 (M + H) *; 1 K NMR (400 MHz1 DMSO-Je) δ. 7.15 (m, 1H), 6.48 (m, 3H), 4.81 (t, 1H), 3.94 (t, 2H), 3.71 (s, 3H), 3.68 (m, 2H)

General Procedure S: Cbz Protection of an Amine

The appropriately substituted amine in a suitable organic solvent (preferably acetonitrile) and the aqueous mixture (about 1: 1 to 8: 1 ratio, preferably 4: 1 ratio) is added N- (benzyloxycarbonyloxy) succinimide (preferably 1 equivalently). followed by potassium carbonate (preferably 1 equivalent). The reaction mixture is stirred at room temperature for a period of 1-4 hours (preferably 1 hour). The solvent is then removed and the remaining aqueous mixture is taken up in water and organic solvent (preferably ethyl acetate). The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting crude may be purified by column chromatography to give the desired product. Example of General Procedure S:

Preparation of (1R, 3R) methyl-1- (benzyloxycarbonylamino) -3- (4-

bromophenyl) cyclopentanecarboxylate

CBZ-OSu K2CO3

To (1R, 3R) methyl 1-amino-3- (4-bromophenyl) cyclopentanecarboxylate (1.5 g, 5.03 mmol) in acetonitrile (7.2 mL) and water (1800 mL) was added N- ( Benzyloxycarbonyloxy) succinimide (1.254 g, 5.03 mmol) followed by potassium carbonate (0.695 g, 5.03 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed and the remaining aqueous mixture was taken up in water and ethyl acetate. The organic layer was removed and washed with brine, dried over MgSO 4 and concentrated in vacuo. The crude product was purified by flash chromatography to afford (1R, 3R) methyl 1- (benzyloxycarbonylamino) -3- (4-bromophenyl) cyclopentanecarboxylate (1.4 g, 3.25 mmol, 64.4% yield) as a White gum. LCMS (Table 1, Method b) Tf = 3.01 min; m / z: 433.28 (M + H) +.

General Procedure T: Cross-Coupling Aryl Bromide to Acid

boronic

To a vial charged with aryl bromide (1 equivalent), boronic acid (1-3 equivalents, preferably 1 equivalent) and an inorganic base (cesium carbonate or sodium carbonate) (preferably cesium carbonate) (3-8 equivalents, preferably 3 equivalents) is added an organic solvent (such as 1,2-dimethoxyethane, dioxane or DMF; preferably 1,2-dimethoxyethane) and aqueous mixture (about 10: 1 to 1: 1 ratio; preferably 4: 1 ratio). The mixture has the gases removed earlier by adding a palladium catalyst (such as tetrakis (triphenylphosphine) palladium, 1,1'-bis (diphenylphosphino) ferrocene palladium or bis (triphenylphosphine (palladium (II)) chloride; preferably dichloride; 1,1'-bis (diphenylphosphino) ferrocene palladium) (2-10 mol%, preferably 5 mol%) The reaction mixture is heated to 100-200 ° C (preferably about 120 ° C) for a period of 20-60 minutes (preferably 30 minutes) in a microwave reactor.After completion of the reaction, the mixture is concentrated to dry, dissolved in a suitable organic solvent (such as EtOAc, or DCM), and washed with a saturated aqueous NaHCO3 solution, dried over a suitable drying reagent (such as MgSO 4 or Na 2 SO 4) and concentrated to dry the crude product The crude product is purified by flash chromatography to provide the desired product.

Example of General Procedure T:

Preparation of

vinylphenyl) late cyclopentanocarboxy

(1R, 3R) methyl-1- (benzyloxycarbonylamino (-3- (4-

The

0I

PdCI2 (dppf)

Cs2CO3 Dioxane '/ H2O

To a 60 mL microwave vessel was suspended (1R, 3R) methyl 1- (benzyloxycarbonylamino) -3- (4-bromophenyl) cyclopentanecarboxylate (1.1 g, 2.54 mmol) and 4.4.5.5 -tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.431 g, 2.80 mmol) and Cs3 CO3 (2.487 g, 7.63 mmol) in DME (30 mL) and water (7.50 mL). The reaction vessel was purged with nitrogen for 5 minutes. PdCl 2 (dppf) (0.186 g, 0.254 mmol) was added and the reaction vessel was purged with nitrogen once more. The reaction mixture was heated to 120 ° C in microwave for 30 minutes. ((1R, 3R) -methyl-1- (benzyloxycarbonylamino) -3- (4-vinylphenyl) cyclopentanecarboxylate product (705 mg, 1.858 mmol, 71.0% yield)) was isolated by flash chromatography as a colored oil clear. LCMS (Table 1, Method b) Rt = 2.94 min; m / z: 380.43 (M + H) +.

General Procedure U: Hydrogenation Reaction of an Alkenes To an ice-cold solution of an alkene in an organic solvent (preferably tetrahydrofuran) is added 9-BBN (1-8 equivalents, preferably 4 equivalents) dropwise. The reaction mixture is monitored by TLC to ensure complete conversion to boronate. After the reaction is complete, the ice bath is removed and the reaction is allowed to stir at room temperature for a period of 4-24 hours (preferably 12-20 hours) under an inert atmosphere. The reaction mixture is then cooled to about 0 ° C and diluted with an organic solvent (such as methanol). A sodium hydroxide solution (about 4-12 equivalents, preferably 8 equivalents) and 30% w / v hydrogen peroxide solution (about 4-12 equivalents, preferably 8 equivalents) is then poured into the reaction mixture. Stirring is continued for a period of 1-8 hours (preferably 2 hours). The solvent is removed under atmospheric pressure and the resulting crude product may be purified by flash chromatography to provide the desired product. Exemplification of General Procedure U: Preparation of (1R, 3R) methyl 1- (benzyloxycarbonylamino) -3- (4- (2-

hydroxyethyl) phenyl) cyclopentanecarboxylate 9-η (25 mL, 12.50 mmol) was added dropwise to a stirred and stirred solution of (1 R, 3R) methyl-1- (benzyloxycarbonylamino) -3- (4 vinylphenyl) cyclopentanecarboxylate (0.682 g, 1.797 mmol) in THF (15 mL). The reaction mixture was checked by TLC to ensure complete conversion to boronate. Once complete the ice bath was removed and stirring was continued for one night. The reaction mixture was cooled to 0 ° C and methanol (20 mL) was added. Aqueous NaOH (7.30 mL, 14.59 mmol) in H 2 O 2 (1.522 mL, 14.90 mmol) was poured into a reaction mixture. Agitation was continued for 2 hours. The solvent was removed under reduced pressure and the product purified by TLC to afford (1R, 3R) methyl-1- (benzyloxycarbonylamino) -3- (4- (2-hydroxyethyl) phenyl) cyclopentanecarboxylate (0.507 g, 1.276 mmol 71.0% yield) with colorless oil. LCMS (Table 1, Method b) Rt = 2.53 min; m / z: 398.30 (M + H) +.

General Procedure V: Unprotection of a Cbz Group from an Amine

A Cbz protected amine dissolved in an organic solvent (such as methanol, ethanol or ethyl acetate; preferably ethanol) is added to a mixture of Pearlman's catalyst (2-10 mol%, preferably 5 mol%) in an organic solvent (such as methanol, ethanol or ethyl acetate; preferably ethanol). Hydrogen gas is bubbled through the reaction for about 5 minutes. The reaction is stirred under the hydrogen atmosphere for a period of 1-48 hours (preferably 2-24 hours). The progress of the reaction is monitored through LCMS. The resulting crude reaction mixture is filtered through Celite® and the filtrate is concentrated in vacuo to yield crude product, which can be further purified by column chromatography or used as is for the next step.

Example of General Procedure V:

Preparation (1R, 3R) -methyl 1-amino-3- (4- (2- (3-

methoxyphenoxy) ethyl) phenyl) cyclopentanecarboxylate

Pd (OH) 2

A solution of (1R, 3R) methyl 1- (benzyloxycarbonylamino) -3- (4- (2-3-

methoxyphenoxy) ethyl) phenyl) cyclorpentanecarboxylate (0.266 g, 0.528 mmol) in EtOH (2.0 mL) was added to a mixture of Pearlman Catalyst (0.019 g, 0.026 mmol) in EtOH (5.28 mL). Hydrogen gas was then bubbled through the reaction mixture for 2-3 minutes. The resulting mixture was stirred under the hydrogen atmosphere overnight. The crude mixture was filtered through CeIiteO and the filtrate was concentrated in vacuo to afford (1R, 3R) methyl 1-amino-3- (4- (2- (3-methoxyphenoxy) ethyl) phenyl) cyclopentanecarboxylate (157 mg, 0.425 mmol) as a colorless oil. LCMS (Table 1, Method b) Rt-1.82 min; m / z: 370.40 (M + H) +. General Procedure W: Synthesis of an unsaturated alpha-beta ketone An organometallic reagent (1-3 equivalents preferably 1.1 equivalents) is added a solution of a beta-alkoxy enone in an organic solvent (preferably THF) to about - 78 ° C-room temperature (preferably 0 ° C). Following the addition the reaction mixture is allowed to warm to about room temperature. After 1h, 1N HCl is added until a pH of 1 is obtained. The reaction mixture is taken up by aqueous development and the crude product may be purified by chromatography.

To a suspension of magnesium (1.477 g, 60.8 mmol) in THF (56 mL) was added 1-bromo-4-octylbenzene (15.00 g, 55.7 mmol). After stirring for about 6 hours the reaction mixture was added by filtration to a solution of 3-ethoxycycloex-2-enone (7.10 g, 50.6 mmol) in THF (28.0 mL) at 0 ° C. Following the addition the reaction mixture was allowed to warm to room temperature. After 1h 1N HCl was added until a pH of 1 was obtained. The reaction mixture was diluted with Et 2 O and the organic layer was separated, washed with Na-HOC 3, and brine, dried with Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (EtOAc / Hep) to afford 3- (4-octylphenyl) cyclohex-2-enone (9.5 g, 33.4 mmol, 65.9% yield) as an oil. colorless.

LCMS (Table I, Method a) R1 = 4.53 min; m / z: 285 (M-H) -; 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, 2H), 7.25 (d, 2H), 6.34 (s, 1H), 2.76 (dd, 2H), 2.60 (dd, 2H), 2.40 (dd, 2H), 2.03 (dddd, 2H) δ t.58-1.55 (m, 2H), 1.27-1.24 (m, 10H), 0.85 (t, 3H).

General Procedure X: Addition of an Organometallic Reagent to an Ester

To a solution of an ester in an organic solvent (preferably THF) at about -78 ° C-room temperature (preferably 0 ° C) is added an organometallic reagent (2-10 equivalents, preferably 5 equivalents). After about 2 hours the reaction mixture is quenched with water and the crude product is extracted into a suitable organic solvent (preferably ether). The crude product may be purified by chromatography.

15

Exemplification of General Procedure W: Preparation of 3- (4-octylphenyl) cyclohex-2-enone

Λ

The Example of General Procedure X:

Preparation of 2 - ((1 R, 3R) -1-amino-3- (4-octylphenyl) cyclopentyl) propan-2-ol

To a solution of (1R, 3R) methyl 1-amino-3- (4-octylphenyl) cyclopentanecarboxylate (640 mg, 1.931 mmol) in THF (20 mL) at 0 ° C was added a 3M solution of methylmagnesium iodide (3 , 22 mL, 9.65 mmol) in THF. After 2 hours it was added to the resulting reaction mixture in an emulsion. The reaction mixture was diluted with Et 2 O (100 mL) and water (100 mL). To the emulsion Rochelle salt (approximately 5 g) was added. The resulting emulsion was sonicated for 15 minutes. The organic layer has been removed. The aqueous layer was extracted with sonicated Et 2 O (100 mL) for 15 minutes to break the emulsion. The combined organic layers were dried (Na2 SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g) eluting with DCM: MeOH: HOAc: H2 O (900: 90: 9: 1). The product containing fractions were combined and concentrated in vacuo. The resulting residue was diluted with water and lyophilized to afford 2- ((1R, 3R) -1-amino-3- (4- (octylphenyl) cyclopentyl) propan-2-yl, acetic acid salt (265 mg, 0.677 mmol , 35.1% of production).

LCMS c Table ι. Method a) Rt = 3.28 min; m / z: 333 (M-H) -; 1H (400 MHz, DMSO-d 6) δ 7.15 (d, 2H), 7.08 (d, 2H), 5.30 (bs, 3H), 3.40-3.25 (m, 1H), 2.52-2.50 (m, 2H), 2.20 -2.05 (m, 2H), 1.90-1.78 (m, 4H), 1.70-1.60 (m, 1H), 1.51-1.49 (m, 3H), 1.40-1.30 (m. 1H), 1.30-1.25 (m, 10H), 1.17 (s, 6H), 0.85 (t, 3H).

General Procedure Y: Conversion of a tertiary alcohol to an alkane To a mixture of silica gel and Iewis acid (preferably copper sulfate hydrate) in an organic solvent (preferably toluene) is added a tertiary alcohol. The reaction mixture is heated to about 50-200 ° C (preferably 100 ° C). After about 2 days a dehydrating reagent (preferably Na 2 SO 4) is added. After about 1 day the reaction mixture is filtered. The resulting alkene is added to a mixture of a metal catalyst (preferably palladium carbon dioxide) in an organic solvent (preferably methanol). Hydrogen is bubbled through the solution for about 5 minutes and a hydrogen atmosphere is maintained through the balloon. After 15 hours the reaction mixture is filtered and concentrated in vacuo to afford the alkane.

Example of General Procedure Y:

Preparation of (5R, 7R) -7- (4- (7-methyloctyl) phenyl) -3-oxa-1-azospiro [4.4] nonan-2-one

H

A mixture of silica gel (1g) and copper sulfate hydrate (1g) in toluene (10ml) was added (5R, 7R) -7- (4- (7-hydroxy-7-methyloctyl) phenyl) -3 -oxa-1-azospiro [4.4] nonan-2-one (230 mg, 0.640 mmol). The reaction mixture was heated to 100 ° C. After 2 days Na 2 SO 4 (approximately 500 mg) was added. After an additional 1 day at 100 ° C the reaction mixture was cooled to room temperature and filtered, washing with EtOAc. The resulting alkenene was added to a mixture of palladium carbon dioxide (4.49 mg, 0.032 mmol) in MeOH. (10.00 mL). Hydrogen was bubbled through the solution for 5 minutes and a hydrogen atmosphere was maintained through a balloon. After 15 hours the reaction mixture was filtered and concentrated in vacuo. The crude alkane was purified by silica gel chromatography (EtOAc / Hep) to approve (5R, 7R) -7- (4- (7-methyloctyl) phenyl) -3-oxa-1-azospiro [4.4] nonan-2- (120 mg, 0.349 mmol, 54.6% yield) as a colorless solid.

1H "MN (400 MHz, DMSO-dmft) δ 8.06 (s, 1H), 7.13 (d, 2H), 7.08 (d, 2H), 4.26 (d, 1H), 4.19 (d, 1H), 3.23-3.16 (m, 1H), 2.55-2.50 (m, 2H), 2.16-2.00 (m, 3H), 1.85-1.75 (m, 2H), 1.60-1.45 (m, 4H), 1.3-1.2 (m, 6H) 0.15-1.10 (m, 2H), 0.84 (d, 6H).

General Procedure Z: Hydration of an Alkyne An alkyne is dissolved in formic acid and heated to about 50-120 ° C (preferably

80 ° C). After about 4 hours the reaction mixture is cooled to room temperature and concentrated in vacuo, diluted with water and heated to about 50-120 ° C (preferably 80 ° C). After about 4 hours the reaction mixture is purified by RP HPLC.

Exemplification of General Procedure Z: Preparation of 1- (4 - ((1R, 3R) -3-amino-3- (hydroxymethyl) cyclopentyl) phenyl) -5-phenylpentanyl

1-one, acetic acid salt

((1R, 3R) -1-amino-3- (4- (5-phenylpent-1-ynyl) phenyl) cyclopentyl) methanol (900 mg, 2.70 mmol) was dissolved in formic acid (20 mL) and heated at about 80 ° C. After 4 hours the reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (10 mL) and reheated to about 80 ° C. After 4 hours the reaction mixture was purified by RP HPLC. Concentration of fractions containing the desired product provided 1- (4- ((1R, 3R) -3-amino-3- (hydroxymethyl) cyclopentyl) phenyl) -5-phenylpentan-1-one, acetic acid (320 mg, 0.778 mmol, 28.8% yield) as a cream foam.

LCMSC Table 1, Method a) R 1 = 2.19 min; m / z: 352 (M-H) *; 1 H nmr (400 MHz, DMSO- d d) δ 7.87 (d, 2H), 7.36 (d, 2H), 7.29-7.15 (m, 5H), 3.46-3.35 (m, 1H), 3.32 (dd, 2H) 3.00 (dd, 2H), 2.61 (dd, 2H), 2.13-2.08 (m, 1H), 1.93-1.76 (m, 5H), 1.69-1.60 (m, 6H), 1.51-1.41 (m, 1H) .

General Procedure AA: Synthesis of an Alkylether

To a strong base (preferably sodium hydride) 0.5-2 equivalents (preferably 1 equivalent) in a suitable solvent (preferably DMF) is added a 1-5 equivalent alkylating agent (preferably 1.2 equivalent) followed by a solution of an alcohol. After the reaction is substantially complete the reaction mixture is taken up with an aqueous product and purified by chromatography or distillation.

Methyl iodide (12.29 mL, 197 mmol) followed by a solution of hept-6-yn-1-ol (24.5 g, 197 mmol) in DMF (50 mL). Following the addition the reaction was monitored by TLC. After 2 hours additional methyl iodide (6 mL, 50 mmol) was added followed by portions of sodium hydride (1 g, 25 mmol). At 1 hour intervals additional portions of sodium hydride (1 g, 25 mmol) were added until no alcohol remained as indicated by TLC. Et 2 O (50 mL) and water (100 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed with brine, dried using Na 2 SO 4, filtered and distilled (145-155 ° C) to afford 1-methoxyhept-1-yne (18 g, 121 mmol, 61.7% yield) as an oil. colorless.

1H NMR (400 MHz, DMSO-Je) 5. 3.28 (t, 2H), 3.19 (s, 3H), 2.71 (t, 1H), 2.13 (dddd, 2H), 1.51-1.33 (m, 6H).

To a microwave reaction vessel is added 1,4-dibromobutan-2-ol (0.5-2 equivalents, preferably 1.1 equivalents), an aniline (0.5-2 equivalents, preferably 1.0 equivalents). ), potassium carbonate (0.5-2 equivalents, preferably 1.1 equivalents) and a practical polar solvent (preferably water). The reaction vessel is heated in a microwave at (50-200 watts, preferably 100 watt), (50-200 ° C, preferably 120 ° C, (689475.91-1378951.82 Pa (100-200 psi) preferably 10342113.86 Pa (150 psi)) (decline time 2-10 min., preferably 5 minutes) and (retention time 10-30 minutes, preferably 20 minutes). (preferably EtOAc) is added to the reaction mixture The organic layer is removed and concentrated in vacuo The crude product is purified by silica gel flash chromatography.

Exemplification of General Procedure AA: Preparation of 7-Methoxy-1-yne

To a mixture of sodium hydride (7.86 g, 197 mmol) in DMF (100 mL) was added

20

General Procedure BB: Synthesis of an N-atyl prolinol

Exemplification of General Procedure BB: Preparation of 1- (4-octylphenyl) pyrrolidin-3-ol Br

Br

To 10 microwave wells were added 1,4-dibrobutan-2-ol (0.375 mL, 2.75 mmol), 4-octylaniline (0.572 mL, 2.5 mmol), potassium carbonate (0.390 g, 2.75 mmol). ) and water (3 mL). Each vial was heated in a 100 watt CEM microwave, 120 ° C, 150 psi, decline time 5 minutes and retention time 20 minutes. After cooling to room temperature EtOAc (1 mL) was added to each vial. After completion of mixing the organic layers were removed, combined and concentrated in vacuo. The product was purified by silica gel flash chromatography (eluting with EtOAc / Hep) to afford 1- (4-octylphenyl) pyrrolidin-3-ol (3.7 g, 13.43 mmol, 53.7%). as a white solid that was stored under nitrogen in a sealed vial.

LCMS (Table 1, Method a) Rf = 4.88 min; m / r 276 (MH) "; 1H nmr (400 MHz1 DMSCWtf) δ 6.95 (d, 2H), 6.41 (d, 2H), 4.88 (d, 1H), 4.37 (m, 1H), 3.36 (dd, 1H), 3.3-3.17 (m, 3H), 3.01 (dd, 1H), 2.43 (t, 2H), 2.06-1.98 (m, 1H), 1.89-1.84 (m, 1H), 1.52-1.47 (m, 2H), 1.29-1.24 (m, 10H), 0.85 (t,

General Procedure CC: Oxidation of an alcohol to ketone To a solution of an alcohol in DMSO and an organic solvent (preferably toluene) at -10-100 ° C (preferably 0 ° C) is added a weak organic base (preferably pyridine, 2-5 equivalents, preferably 3.5 equivalents), followed by a carbohydrimide (preferably DCC, 1-3 equivalents, preferably 1.75 equivalents), and an organic acid (preferably TFA, 0.5-2 equivalents). preferably 1 equivalents). Following the addition the reaction mixture is allowed to warm to about room temperature. After about 5 hours saturated NaCHCO3 is added to the reaction mixture and the suspension was filtered. The filtrate is concentrated in vacuo and the resulting dark oil extracted with heptane. The heptane extracts are purified by silica gel chromatography.

To a solution of 1- (4-octylphenyl) pyrrolidin-3-ol (3.7 g, 13.43 mmol) in DMSO (50 mL) and Toluene (50.0 mL) at 0 ° C was added pyridine (3.80 mL, 47.0 mmol), DCC (4.85 g,

3H).

Example of the General Procedure CC: Preparation of 1- (4-octylphenyl) pyrrolidin-3-one 23.51 mmol), and TFA (1.035 mL, 13.43 mmol). Following the addition the reaction mixture was allowed to warm to room temperature. After 5 hours saturated NaCHCO 3 was added to the reaction mixture and the suspension was filtered. The filtrate was concentrated in vacuo and the resulting dark oil extracted with heptane. The heptane extracts were purified by silica gel chromatography eluting with EtOAc / Hep to afford 1- (4-octylphenyl) pyrrolidin-3-one (3.1 g, 11.34 mmol, 84% yield) as a colorless solid.

400 MHz NMR, DMSO-40 δ 7.03 (d, 2H), 6.61 (d, 2H). 3.61 (s, 2H), 3.56 (t, 2H), 2.66 (t, 2H), 2.47 (t, 2H), 1.55-1.48 (m, 2H), 1.30-1.20 (m, 10H), 0.85 (t, 3H).

General Procedure DD: Reductive Amination in a Ketone

To a ketone dissolved in a suitable solvent (such as dichloromethane, methanol, tetrahydrofuran, or dimethylformamide, preferably methanol) is added an amine (1-2 equivalents, preferably 1 equivalent), acetic acid (1-5 equivalents, preferably 3 equivalents) and resin-bound sodium cyanoborohydride (1-5 equivalents, preferably 3 equivalents). The reaction mixture is stirred under an inert atmosphere at room temperature for a period of 12-72 hours (preferably 48 hours). The reaction is then filtered to remove the resin bound borohydride and the resin washed 3x with a suitable solvent (such as dichloromethane, methanol, tetrahydrofuran, or dimethylformamide, preferably methanol). The filtrate is collected, concentrated and chromatographed to give the desired product.

Exemplification of the General Procedure DD: Preparation of methyl [[3- (4-octylphenyl) cyclopentyl] amino} acetic acid

Methylamino acetic acid Acetic acid MP-cyanoborohydride

MeOH

To a 3- (4-octyl-phenyl) -cyclopentanone (0.200 g, 0.734 mmol) dissolved in methanol (4.0 mL) was added methylamino acetic acid (0.065 g, 0.734 mmol), acetic acid (0.125 mL, 2 , 20 mmol) and resin bonded sodium cyanoborohydride (0.941 g, 2.20 mmol, 2m34 mmol / g loading). The reaction mixture was stirred under an inert atmosphere at room temperature for 72 hours. The reaction was then filtered to remove resin bound borohydride and the resin was washed with MeOH (3x10 mL). The filtrate was collected, concentrated and purified by RP-HPLC (A = 50 mM ammonium acetate, B = acetonitrile; 30-80% B for 30 minutes (21.0 mL / min flight rate); column C18 Thermo Hyperprep 21.2x250, 8 pm particles) to give methyl- [3- (4-octylphenyl) -cyclopentyl] -amino} acetic acid as a white solid (0.112 g, 43%).

LCMS (Table 1, Method f) Rt = 1.94 min; m / z = 344 (M-H), m / z: 346 (M + H) +.

TABLES USING GENERAL PROCEDURES

Table A: Exemplis following general procedures A, B, C, D, E, F, H (Scheme 1) Cr0

Boronic acid

General Procedure A

General Procedure B

General Procedure C

General procedure

General Procedure E

Alkino

General Procedure F

General procedure H

EX # Alkino Boronic Acid Product RWnh (method) rrVz A1 4-Bromophenylxyronic Acid OcM-in Quirai Sa * ^ r / - 0 "0'γ 2.44 (a) 300 (MHH) + Product: [(1 R, 3S > 1-amino3 <4Oct-1-riM ferd} dclopentiKiieta ^

Table B: Examples Following General Procedures A1 B, C, D, E1 F, G1 H (Scheme 1)

^ Boronic Acid

Cr0 ----- —- —-

* - 'Procedure Procedure Procedure Procedure

General general general general

A B C D

_ ^ Alkino ^ _ ^ _ (^ f ^

Procedure Procedure Procedure Procedure \ _ / NH2

General general general general

E F G H

Ex # Albino Boronic Acid Product RMnin mte (method) Β.1 B-bcomophenyl Acid Oct-1-ro \ Chiral ^ -OCh. CIH 2.75 (a) 304 (NMH) * Product: [(1 R 3 S) -1 Hc> 4 dWert} ac bpentij-meand; <± 3hydrate B2 4-Brofrenix-oxonium Acid Prop-2-radiabenzene ^^ chiral XPm 2.17 (a) 326 (M + HH Product: {(1 R, 3S) -1 dorhydrate Boronic Acid Alquho Product Rttriin (meth) whole) m / z B.3 3-Ichomethylphenonic acid Deo-1-yo 3.92 (a) 332 (M + H) * Product: ((3S) -1 ^ ho-3 ^ 3 <Jahreni) <± io ^^ dorhydrate B.4 3-Bromopheniboronic acid) Non-1-yno HzN _c, .cTH 3.04 (a) 318 (M + H) f Product: ((3S) -1H-3 (3wTonylphenyl) cidop; dorhydrate B.5 3-bromophenylxxonium acid Oct-1-yne H2N _ 3.32 (a) 304 (IVMH) * Product: ((3S> 1'-irx> -3 ^^ lphenyl) ^^ dorhydrate B.6 3-bromophenibrononium acid Hept-1-yne CT ™ 3.00 (a) 290 (M + H) * Product: ((3S) -1H-2 (4-phenylphenyl)) -hydrochloride B.7 Ar bromopheniboronkx) 6-methoxy-1hex acid -1-ho Hi-OH 2.51 (a) 306 (M + H) + · Product: ((1R, 3S> 1-amino-4,46Tieta) of ^^ dorhydrate B.8 Addo A-bromoferixDroro BuW- nbenzBno çp 3.j 3.19 (a) 324 (Ν / ΗΉ) * Product: ((1 R, 3S) -1-hydrochloride B.9 4-Bromophenphloronic Acid & Ethoxy-1- One (Q) H 1 N Chiral w 2.a 2.67 (a) 320.45 (IYMH) * Product: ((1 R3 S> 1-amyrch3 {4- (6-ethoxyxy) hydrochloride B.10 Addo A- bromoferylxyronic 6-isopropoxyhex-1-yo 2.68 (a) 334 (M + H) f Product: ((1R, 3S} -1-amino-C H4 ^ 6-isopropoxyxy) phenyl) cyclohydrate

Table C: Examples Following General Procedures A, I, J, E, F1 H (Scheme 2) Boronic Acid

Cr0

Procedure Procedure Procedure Procedure

General general general general

The IJE

Ex Addo BonSnioo Alquino Product Rfmin mfz # (method) C.1 Acid A- Oct-1- _ Chiral r 2.37 300 bromopheniboronine Λ - f \ (Zy ^ Y '(a) (IVH-H) CO W> + Product: [(1 I added with acetic acid C 2 Acid 4-bromophenoxyfurium-00 BuW-hl · benzen Chiral 2.24 (a) 320 (IVWH) + Product: {(1 R, 3R) - 1-ariroe {4 <44en UduM 4Tí}% ii]) <± lopeni} - ^^ compound with acetic acid C.3 4-bromophenixyronic acid Hex-1-yo S CHiral <'·' JJ 2.14 ( a) 272 (IVWH) + Product: [(1 R, 3 R> 1 H 3 (4-Hexesulfonic 1-nWeri) dipropoperoxide (2R, 3R) -2,3 <RTI-C 4 4-bromfenphenic acid> Hept-1-yno 2.36 (a) 286 (IVWH) + Product: [(1R, 3R> 1-amino-44Tept-1Hn »phenl) <* ^^ compound with acid (2R , 3R> -213dldroxj-suodenic C.5 4-bromophenylxyroric acid »- 00 6- methoxy-1-hex-1-chiral ► *> 1.86 (a) 302 (IVWH) + Product: [(1 R , 3R) -1H-3-4-β-Dxy-hex-1-rt} phenyl} <3cl ^^ compound with acidic acid C.6 4-bnDmofeniboroni acid - CO Prop-2-ynbenzene 2.16 (a) 306 (IVH-H) + Product: [(1 R, 3 R> 1 H irK) -3- [4 <3-ferhHDrop-1-one] } phenylKx ±) peni ^ compound with acetic acid C.7 4-Bromopheniboronyl-00 Pent-4-ynylbenzene 1Cv,> CM S 334 (M + H) + Product: {(1 R, 3R) - 1-aminoe {4- (54enl · pent-14iyl> phenyl (H, dopenyl} Hthiethyl) as a compound with aethioic acid C.8 4-Bromophenibophonic acid CO Oct-1-yne ^ - \ Chiral ^ f = o 3.02 (a) 314 (M + H) + Product: Acid (1 R 3 R> 1 ^ yno <3 {4 X-14 IIIHerf Compound with Acetic Acid Table D. Examples Following General Procedures A, II J1 E, F, G1 H (Scheme 2) Boronic acid

Cr0

General Procedure A

General Procedure I

General Procedure J

General Procedure E

Alkino

General Procedure F

General procedure G

General procedure H

Ex # Albino Boronic Acid Product Rt / min (method) m / z D.1 4-Bromophenylboronic Acid Oct-1-yo-chiral OH 1.94 (a) 304 (M + H) + Product: [ (1 R, 3R) -1-amino-3- (4-octylphenyl) cyclopentyl] methanol; hydrochloride D.2 4-Bromophenylboronic acid But-3-ynylbenzene Chiral 2.85 (a) 324 (M + H) + {(1R, 3R) -1-amino-3- [4- (4- phenyl butyl) phenyl] cyclopentyl} methanol; compound with acetic acid D.3 4-Bromophenylboronic acid Prop-2-ynyloxybenzene Chiral 2.18 (a) 326 (M + H) + Product: {(1R, 3R) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentyl} -methanol; compound with acetic acid D.4 4-bromophenylboronic acid 6-methoxyhex-1-yo-o-Vv Chiral-o-O-Ch. 2.56 (a) 306 (M + H) + Product: {(1 R, 3R) -1-amino-3- [4- (6-methoxyacetic acid hexyl) phenyl] cyclopentyl} methanol; compound with D.5 4-Bromophenylboronic acid Prop-2-ynylbenzene O'V 2.27 (a) 310 (M + H) + Product: {(1R, 3R) -1-amino-3- [ 4- (3-phenyl-propyl) -phenyl] -cyclopentyl} -methanol; compound with acetic acid D.6 4-Bromophenylboronic acid Pent-4-ynylbenzene S- / Chiral \ - \ VJ OH 2.48 (a) 338 (M + H) + Product: {( 1R, 3R) -1-amino-3- [4- (5-phenyl-pentyl) -phenyl] -cyclopentyl} -methanol; compound with acetic acid D.7 4-bromophenylboronic acid 4-propoxy-1-yne Chiral 2.58 (a) 305 (M + H) + Product: {(1 R, 3R) -1-amino 3- [4- (4-propoxy-butyl) -phenyl] -cyclopentyl} -methanol; hydrochloride D.8 4-Bromophenylboronic acid Hept-1-yo 3.43 (a) 290 (M + H) + Product: {(1 R, 3R) -1-amino-3- (4-heptylphenyl) cyclopentyl) methanol; hydrochloride D.9 4-bromophenylboronic acid Hex-1-yn 3.18 (a) 276 (M + H) + Product: {(1 R, 3R) -1-amino-3- (4-hexylphenyl) cyclopentyl )methanol; hydrochloride D.1 0 4-bromophenylboronic acid 7-methoxyhept-1-yne (Q) OH W chiral f * "A w / Vvvvi # 2.83 (a) 320.42 (M + H) + Product: { (1 R, 3R) -1-amino-3- (4- (7-methoxyethyl) phenyl) cyclopentyl) methanol hydrochloride D.1 1 4-bromophenylboronic acid 6-ethoxyxy-1-yn (Q) • VI chiral (1) 320.41 (M + H) + Product: {(1 R, 3R) -1-amino-3- (4- (6-ethoxyhexyl) phenyl) cyclopentyl) methanol; hydrochloride D.1 2 4-bromophenylboronic acid (prop-2-ynyloxy) benzene [N] 2.69 (a) 326 * M + H) + Product: {(1 R, 3R) -1- amino-3- (4- (3-phenoxypropyl) phenyl) cyclopentyl) methanol; hydrochloride D.1 3 4-Bromophenylboronic acid 5-ethoxypent-1-yn 'NH 2 2.37 (a) 306 (M + H) + Product: ((1 R, 3R) -1-amino-3- ( 4- (5-ethoxyphenyl) phenyl) cyclopentyl) methanol; chloridate D.1 4 4-bromophenylboronic acid 3- (2-methoxyethoxy) prop-1-yn 1.85 (a) 308 (M + H) + Product: ((1 R, 3R) -1 -amino-3- (4- (3- (2-methoxyethoxy) propyl) phenyl) cyclopentyl) methanol; hydrochloride D.1 5 4-bromophenylboronic acid 1- (prop-2-ynyloxy) butane 3.08 (a) 306 (M + H) + Product: ((1 R, 3R) -1-amino-3- (4- (3-butoxypropyl) phenyl) cyclopentyl) methanol; hydrochloride D.1 6 4-bromophenylboronic acid 1-ethynyl-4-methoxybenzene / NH 2 2.58 (a) 326 (M + H) + Product: ((1 R, 3R) -1-amino- 3- (4- (4-methoxyphenethyl) phenyl) cyclopentyl) methanol; hydrochloride D.1 7 4-Bromophenylboronic acid 1-ethynyl-4-propoxybenzene 3.24 (a) 354 (M + H) + Product : (1-amino-3- (4- (4-propoxyphenethyl) phenyl) cyclopentyl) methanol;

Table Ε. Examples following procedures A11, J, Ε, Η, K, L, Μ, N (Scheme 3)

Cr0

Boronic acid

Procedure Procedure Procedure Procedure Procedure

General General General General General

The IJEH

alcohol

Procedure Procedure Procedure Procedure

General general general general

K LMN

Ex # Bo Acid Alcohol Product Rt / min m / z ronic (method) Ε.1 Acid A- Octa n-1 -ol - \ 2.58 320 methoxyphenylborô- '-k CHW Γ (a) (M + single H) + Product: [(1 R, 3R) -1-amino-3- (4-octyloxy-phenyl) -cyclopentyl] -methanol; hydrochloride E.2 A-2- (4- .Y 2,11 380 methoxyphenylborofluoromethylphenoxy (a) (M + single nil) ethanol H) Acid + Product: ((1R, 3R) -1- amino-3- {4- [2- (4-trifluoromethyl-phenyl) -ethoxy] -phenyl} -cyclopentyl) -m; hydrochloride E.3 A-2- (3- [e] V 2.68 380 methoxyphenylborobenzoic acid trifluoromethylphenyl chiral λ-yU- (a) (M + single nyl) -ethanol H) + Product: ((1R, 3R) -1-amino-3- {4- [2- (3-trifluoromethyl-phenyl) (ethoxy] -phenyl} -cyclopentyl) -methyl compound with (2R, 3R) -2,3-dihydroxy succinic acid E.4 A-Methoxyphenylboronic acid 2-m-tolyloxyethanol 2.60 (a) 342 ( M + H) + Product: {(1 R, 3R) -1-amino-3- [4- (2-m-tolyloxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.5 Acid A-4, 4,5,5,5- V 2,07 368 methoxyphenylborobenta-pentafluoro-chiral (a) (M + single pentan-1-ol H) + Product: {(1RI3R) -1-amino-344- (4, 4,5,5,5-entafluoro-pentyloxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.6 Acid 2- (4-methoxy- / 1.91 342 methoxyphenylborophenyl) -ethanol K (a) (M + only (1R, 3R) -1-amino-3- {4- [2- (4-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methanol; hydrochloride Ε.7 A-Methoxyphenylboronic acid 2-p-tolyloxyethanol 2.08 (a) 342 (M + H) + Product: {(1 R, 3R) -1-amino-3- [4- (2-p-tolyloxy -ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.8 A-methoxyphenylboronic acid Heptan-1-olchiral ho - ^ (2) 2.24 (a) 306 (M + H) + Product: [(1 R, 3R) -1-amino -3- (4-heptyloxy-phenyl) -cyclopentyl] -methanol; hydrochloride E.9 A-Methoxyphenylboronic acid Nonan-1-olchiral OM 2.87 (a) 334 (M + H) + Product: [(1 R, 3R) -1-amino-3- (4-nonyloxy (phenyl) cyclopentyl] methanol; hydrochloride E.1 0 A-Methoxyphenylboronic acid 2-pentyl-oxyethanol-2-squaline CM 2.45 (a) 322 (M + H) + Product: {(1 R, 3R) -1-amino-3 - [4- (2-pentyloxy-ethoxy) -phenyl) -cyclopentyl] -methanol; hydrochloride E.1 1 A-Methoxyphenylboronic acid 2-p-tolylethanol ^ OH 2.60 (a) 326 (M + H) + Product: {(1 R, 3R) -1-amino-3- [4 - (2- p -tolyl-ethoxy) -ethoxy) -phenyl) -cyclopentyl] -methanol; hydrochloride E.1 2 A-Methoxyphenylboronic acid 3- (4-methoxyphenyl) propan-1-ol VC-chiral ^^ CM 2.57 (a) 356 (M + H) + Product: ( (1 R, 3 R) -1-amino-3- {4- [3- (4-methoxy-phenyl) propoxy] -phenyl} -cyclopentyl) -methanol; hydrochloride E.1 3 A-Methoxyphenylboronic acid 2- (2-methoxyethoxy) -ethanol \ cw O — P 7 "* \ I MHt 1.90 (a) 310 (M + H) + Product: (( 1R, 3R) -1-amino-3- {4- [2- (2-methoxy-ethoxy) ethoxy] -phenyl} -cyclopentyl) -methanol; hydrochloride Ε.1 4 A-Methoxyphenylboronic acid 2- (4 - ethoxyphenyl) ethanol> chiral hR 2.63 (a) 356 (M + H) + Product: ((1R, 3R) -1-amino-3- {4- [2- (4-ethoxy) phenyl) ethoxy] -phenyl} -cyclopentyl) -methanol; chloric acid E.1 5 4-Methoxyphenylboronic acid 4-methanesulfonyl-butan-1-ol 1.78 (a) 342 (M + H) + Product: {( 1R, 3R) -1-amino-3- [4- (2-methanesulfonyl-butoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.1 6 4-Methoxyphenylboronic acid 5-methoxypenta-1-ol chiral CH 2.13 (a) 308 (M + H) + Product: {(1R, 3R) -1-amino-3- [4- (5-methoxy-pentyloxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.1 7 4-Methoxyphenylboronic acid 2- (3-fluoro-4-methoxy-phenyl) -ethanol-1-hydroxy-1 H-NH 2 Cl 2.41 (a ) 360 (M + H) + Product: ((1R , 3R) -1-amino-344- [2- (3-fluoro-4-methoxy-phenyl) -ethoxy] -phenyl] -cyclopentyl} -methanol; hydrochloride E.1 8 4-Methoxyphenylboronic acid 2-phenoxyethanol 2.59 (a) 328 (M + H) + Product: {(1 R, 3R) -1-amino-3- [4- (2- phenoxy-e1 -oxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.1 9 4-Methoxyphenylboronic acid 2- (3-methoxyethoxy) -ethanol ° (c) 342 (M + H) + Product: ((1R, 3R) -1-Amino-3- {4- [2- (3-methoxy-phenyl) -ethohydrochloride Ε.2 4- 3- (3-methoxy-acid) 2.47 356 Methoxyphenylboronate (a) (M + single 1-ol X = Zx ^ OM H) + Product: ((1R, 3R) -1-amino-3- {4- [3- (3- methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl} -methanol; hydrochloride E.2 4- 3- (3,5- / 2,33 386 1 methoxyphenylboromethoxyphenyl) -chiral (a) (M + single propan-1-ol OH H) + Product: ((1R, 3R) -1-amino-344- [3- (3,5-dimethoxy-phenyl) -propoxy] -phenyl} -cyclopentyl} -methanol hydrochloride E.2 2 4-Methoxyphenylboron-2- (4-methoxy-3,5-dimethyl-4-yl) acid 2.88 (a) 370 (M + single phenyl) -ethanol H) + Product: ((1R, 3R) -1-amino-344- [2- (4-methoxy-3,5-dimethyl-phenyl) -ethoxy] -phenyl} -cyclopen; .2 3 4-Methoxyphenylboronic acid 2- (4-benzyloxy-phenyl) -ethanol 3.28 (a ) 418 (M + H) + Product: ((1 R, 3R) -1-amino-3- {4- [2- (4-benzyloxy-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methanol E. 2 4 Chiral 4-methoxyphenylboron-2- (4-fluorophenoxy) -ethanol 2.41 (a) 346 (M + single H) + Product: ((1 R, 3R) -1-amino-3- {4 - [2- (4-Fluoro-1-Phenoxy) -ethoxy] -phenyl} -cyclopentyl} -methanol; hydrochloride E.2 5 4-Methoxyphenylboronic acid 3-phenyl-propan-1-ol Chiral 2.52 (a) 326 (M + H) + Product: {(1 R, 3R) -1-amino- 3- [4- (3-phenylpropoxy) -phenyl} -cyclopentyl} -methanol; hydrochloride Ε.2 6 4-Methoxyphenylboronic acid (1-methyl-1H-benzoimidazol-2-yl) -methanol αV - 1.99 (a) 352 (M + H) + Product: {(1 R, 3R) - 1-amino-3- [4- (1-methyl compound with -1H-benzoimidazol-2-ylmethoxy) -phenyl] -cyclopentyl} -methanol; E.2 7 4-Methoxyphenylboronic acid 2- (3-fluoro-phenoxy) -ethanol (Q.H) δ. 2.34 (a) 346 (M + H) + Product: ((1 R, 3R) -1-amino-3- {4- [2- (3-fluoro-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; compound with hydrochloric acid CM 11 O 4 -Methoxyphenylboronic acid (3-ethoxy-phenyl) -methanol 2.30 (a) 342 (M + H) + Product: {(1 R, 3R) -1-amino-3-one [4- (3-ethoxy-benzyloxy) -phenyl] -cyclopentyl} -methanol; hydrochloric acid composition E.2 9 4-Methoxyphenylboronic acid 3- (5-methyl-oxazol-2-yl) -propanol-ol V 2.25 (a) 331 (M + H) + Product: ((1 R, 3R) -1-amino-3- {4- [3- (5-methyl-oxazol-2-yl) -propoxy] -phenyl} -cyclopentyl) -methanol; compound with hydrochloric acid E.3 O 2- (2,4-Difluoro-phenoxy) -ethanol A-methoxyphenylboronic acid (Q. H) CH2 O 2.77 (a) 364 (M + H) + Product : ((1R, 3R) -1-amino-3- {4- [2- (2,4-difluoro-phenoxy) ethoxy] -phenyl} -cyclopentyl) -methanol; compound with hydrochloric acid E.3 1 4-Methoxyphenylboronic acid 2- (4-fluoro-2-methylphenoxy) ethanol (Q, H) '-Ox 2.57 (a) 360 (M + H) + Product : ((1R, 3R) -1-amino-3- {4- [2- (4-fluoro-2-methyl-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; hydrochloric acid compound E.3 2 2- (3-Methoxyphenoxy) -ethanol (R) 4'-methoxyphenylboronic acid CM 'hcI 2.60 (a) 358 (M + H) + Product: ((1R , 3R) -1-amino-3- {4- [2- (3-methoxy-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; hydrochloric acid with E.3 3 4-methoxyphenylboronic acid 2- (3-ethoxyphenyl) -ethanol (Q, H) Va 2.70 (a) 356 (M + H) + Product: ((1R, 3R) -1-amino-3- {4- [2- (3-ethoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol; compound with hydrochloric acid E.3 4 4- methoxyphenylboronic acid 2- (3-chloro-4-methoxyphenyl) ethanol (Q1 H) -6 2.60 (a) 376/378 (M + H) + Product : ((1R, 3R) -1-amino-3- {4- [2- (3-chloro-4-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol; composed of hydrochloric acid E.3 5 (4) Methoxyphenylboronic acid (R) -1-phenoxypropan-2-ol (Q) aYOiJ, - 2.71 (a) 342 (M + H) + Product: { (1R, 3R) -1-amino-3- [4 - ((R) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methane compound with hydrochloric acid E.3 6 4-Methoxyphenylborô acid - (S) -1-Phenoxy-propan-2-ol (Q) O - TO 2 - 2.32 (a) 342 (M + H) + Product: {(1R, 3R) -1-amino-3 - [4 - ((S) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methane with hydrochloric acid; compound E.3 7 4-Methoxyphenylboronic acid 2- (4-benzyloxy-phenyl) -ethanol δ 2.49 (a) 418 (M + H) + Product: ((1R, 3R) -1-amino-3-one {4- [2- (4-Benzyloxy-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methane with hydrochloric acid; compound E.3 8 4-Methoxyphenylboronic acid 2-phenoxyethanol Η'σ ^^ \ NH4 2.94 9 (a) 406/408 (M + H) + Product: {(1 R, 3R) -1-amino-3- [3-bromo-4- (2-phenoxy-ethoxy) -phenyl] hydrochloride E.3 9 4-Methoxyphenylboronic acid 2-phenoxyethanol 2.93 (a) 342 (M + H) + Product: {(1 R, 3R) -1-amino-3- [3-methyl-4- (2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride E.4 0 4-Methoxyphenylboronic acid 3- (3-methoxyphenyl) propan-1-Ol ( R) H'a 2.60 (a) 434/436 (M + H) + Product: ((1 R, 3R) -1-amino-3- {3-bromo-4- [3- (3-methoxy) phenyl) -phenyl} -cyclopentyl} -methanol; hydrochloride Ε.4 4- 3- (3-methoxyphenyl) 3.12 370 1 methoxyphenylborophenyl) propan-1- (a) (M + ol (R) H) + Product: ((1R, 3R) -1-amino-3- {4- [3- (3-methyl oxyphenyl) hydrochloride Ε.4 2 4-methoxyphenylboron-2-phenoxyethanol Acid 2.93 (a) 396 / 398nic / 400 (M + H) + Product: ((1r, 3R) -1 -amino-3- [3,5-dichloro-4- (2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride 0 E.4 4-Pentan-1-ol V 3.12 346/3 methoxyphenylboron-X c, "'cl h0V QV'" ^ '[*' nh8 (a) 348nic / 350 (M + H) + Product: ((1 R, 3R) -1-Amino-3- (3,5-dichloro-4-pentyloxy-phenyl) -cyclopentyl} -methanol; hydrochloride E.4 4- 2- (4-Methoxy acid) H 2.84 448/4-methoxyphenylboron-3,5-dimethyl-h (a) 450 single phenyl) -ethanol (M + H) + Product: ((1R, 3R) -1-amino-3- {3-bromo -4- [2- (4-methoxy-3,5-dimethyl-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methanol; hydrochloride E.4 4- (Z) -hept-4-en-2 acid, 83 304 methoxyphenylboronic 1-ol (a) (M + H) + Product: ((1R, 3R) -1-amino-3- (4 - ((Z) -hept-4-enyloxy) phenyl) -cyclopentyl) -methanol E.4 6 4-Methoxyphenylboronic acid 2- (4- (trifluoromethoxy) phenyl) -et 2- (4- (trifluoromethoxy) F ^ F αΗ .OH "ΧΧ ,, ^ Ο-3.03 (a) 396.32 (M + H) + phenyl) ethanol Product: ((1R, 3R) -1-amino-3- {4- [2- (4-trifluoromethoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl hydrochloride LL1 4-methoxyphenylboronic acid 2- (3-methoxy-4-methylphenyl) - and tanol 2.72 (a) 356.42 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3-methoxyH t-methylphenotoxOphenyl ^ cyclopentyl} methanol hi OO Acid 4- methoxyphenylboronic 3- (pyridin-3-ii) propan-1-ol Ctvo 1.47 (a) 327.20 (M + H) + Product: ((1R, 3R) -1-amino-3 - (^ ( 3- (pyridin-3-yl) propoxy) phenyl) cyclopentyl) methanol E.4 9 4-Methoxyphenylboronic acid 3- (4-fluoro-3-methoxyphenyl) propan-1-ol [R] nh2 2.84 (a) 374.38 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3- (4-fluoro-3-methoxyphenyl) propoxy) phenyl) - cyclopentyl) methanol E.5 0 4-Methoxyphenylboronic acid 3- (2-methoxyphenyl) propan-1-ol CKLO nh2 2.92 (a) 356.42 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3- (2-methoxyphenyl) propoxy) phenyl) cyclopentyl) methanol E.5 1 4-methoxyphenylboronium 2- (4-methoxy-3-methylphenyl) ethanol 2.95 (a) 356.42 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (4-methoxy-3-methylphenethoxy) phenyl) cyclopentyl) methanol E.5 4- 3- (thiophen-2-yl) 2,10 332,2 methoxyphenylboronic acid l) propan-1-ol NH2 (a) 21 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3- (thiophen-2-yl) propoxy) phenyl) cyclopentyl ) methanol E.5 Acid 4- 3- (pyridin-4-yl) NHa 1.43 327,3methoxyphenylboronic yl) propan-1-ol (a) 21 (M + H) + Product: ((1 R , 3R) -1-amino-3- (4- (3- (pyridin-1 (MI) propoxy) phenyl) cyclopentyl) methanol

Table F: Examples Following General Procedures O (Scheme 4) The letters in parenthesis below the amino alcohol precursors indicate the General Procedure by which the amino alcohol precursor was made.

- / ° H

RtWOH -

\ / "NHp Procedure

General O

Ex # Amino alcohol Product Rt / min (method) m / z F. 1 {(1R.3R) -1-amino-3- [4- (4-phenyl-butyl) -phenyl] -cyclopentyl} -methanol (A, 111 J, E, F1 G1 H) HO 3 (a) 404 (M + H) + Prochosphate: mono - {(1R, 3R) -1-amino-2) rich ester 1- [4- ( Acid 4-phenyl-butyl) -phenyl] -cyclopentyl] methyl} 2 {(1R.3R) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentyl} -methanol (A, I, J, E, F, G, H) Chiral 2.57 (a) 406 (M + H) + Product phosphate: mono - {(1R, 3R) -1-amino-3-ester > rich; 4- (3R (3R), 3S) -1-amino-3- [4-octylphenyl) -cyclopentyl] -methanol (A, B1 4- (3-phenoxy-propyl) -phenyl] -cyclopentylmethyl} hydrochloride (A) 382 (M + H) + Proce: mono - [(1R, 3S) -1-amino-3 - (1 H -octyl) ester. F) phosphoric acid phenyl) -cyclopentylmethyl> 4 [(1R, 3R) -1-amino-3- (4-octylphenyl) cyclopentyl] methanol (A, J1, E1 F1 G, H); 9 (a) 384 (M + H) + Proc with phosphoric acid mono - [(1R, 3R) -1-amino-3- (4-octylphenyl) -cyclopentylmethyl} ester; phosphoric acid F. 5 [(1R, 3S) -1-amino-3- (3-decyl-phenyl) cyclopentyl] -methanol (A, I, J, E, F, G, H) § 1.67 (a) 412 (M + H) + Phosphoric acid mono - [(1R, 3S) -1-amino-3- (3'-decyl-phenyl) -cyclopentylmethyl} ester. 6 [(1R.3R ) -1-amino-3- [4- (4-nonyloxy-phenyl) -cyclopentyl} -methanol (A, J1, E1 Η, K, L, Μ, N) Chiral> v> Π 2.44 (a ) 330 (M + H) + Protu: phosphoric acid mono - [(1R, 3R) -1-amino-3- (N-t-nonyloxy-phenyl) -cyclopentylmethyl] ester. 7 {( 1R.3R) -1-amino-3- [4- (2-p-tolyloxyethoxy) phenyl] cyclopentyl} methanol (A, I, J 1 E 1 H, K 1 L 1 M, N) chiral JT 4 1 94 (a) 422 (M + H) + Phosphate: mono - [(1R, 3R) -1-amino-3- [4- (2-p-thioxy-ethoxy) -phenyl] -cyclopenyl ester F. 8 {(1R, 3R) -1-Amino-3- {4-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentyl} -methanol (A, J, E, H, K1 L1 M1 N) chiral 1.87 (a) 422 (M + H) + Acid product: mono - [(1R, 3R) -1-amino-3 - {2- (4-methoxy) phosphoric ester F. {{(1R, 3R) -1-Amino-3- [4- (4,4,5,5,5-pentafluor-pentyloxy) -phenyl] -phenyl} -phenyl} -cyclopentylmethyl} cyclopentyl} methanol (A, I, J, E1 H1 K1 L1 M1 N) H / t (4). - JTT2rv FF, 99 (a) 448 (M + H) + Product: mono - [(1 R, 3R) -1-amino-3- [4- (4,4,515,5-pentafluoro-pentyloxy Kenyl]-ester phosphoric acid cyclopentylmethyl}. 10 {(1R, 3R) -1-amino-3- [4- (3-phenylpropyl) -phenyl] -cyclopentyl} -methanol (A, I, J, E1 F1 G Chiral ►v * 8 I> OH 2.03 (a) 388 (M + H) + Pro (phosph (Juto: mono - [(1R, 3R) -1-amino-3- [4- (3 -Artic acid F-phenyl (propyl) -phenyl] -cyclopentylmethyl} 11 [(1R.3R) -1-amino-3- (4-octyloxy-phenyl) -cyclopentyl} -methanol (A, I, J1 Ε, H, K1 L, δ, N) chiral; 2.29 (d) 400 (M + H) + Proce: mono - [(1R, 3R) -1-amino-3- (4 H -tyloxy-phenyl) -cyclopentylmethyl ester } of phosphoric acid F. 12 {(1R, 3R) -1-amino-3- [4- (6-methoxy-exyl) -phenyl] -cyclopentyl} -methanol (A, I, J, E1 F G1 H) chiral 1.83 (a) 386 (M + H) + Prochosphate: mono - {(1R, 3R) -1-amino-3-) rich ester 4- (6-methoxyhexyl) phenyl ] Acid] -cycliopentylmethyl} 13 [(1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl] methanol (A, B1 C1 D, E, F, G1 H) chiral ___ «V 2.36 (d) 382 (M + H) + Product: phosphoric acid mono - [(1R, 3S) -1-amino-3- (4k) ethylphenyl) -cyclopentylethyl] ester. 14 [(1R, 3S) -1-amino-3- (4-heptylphenyl) cyclopentyl] methanol (A, B, C, D, E, F, G 1 H) Jiral-O, cr ^ 2.18 (a) 370 (M + H) + Product: phosphoric acid mono - [(1R, 3S) -1-amino-3- (4'-heptyl-phenyl-cyclopentylmethyl] ester. 15 {(1R.3R) -1-amino-3- [4- (2-pentyloxyethoxy) phenyl] cyclopentyl} methanol (A, I, J1 E1 H1 K1 L1 M1 N) chiral 2.49 (a) 402 (M + H) + Phosphate: F-acid mono - [(1R, 3R) -1-amino-3- [4- (2-pentyloxy-ethoxy) -phenyl) -cyclopenyl] methyl] ester 16 ((1R.3R) -1-amino-3- [4- (2-m-tolyloxyethoxy) phenyl] cyclopentyl} methanol (A, I, J1 E1 H1 K, L1 M1 N) chiral S Von 2.53 (a) 422 (M + H) + Product: phosphoric acid F. - ((1R, 3R) -1-amino-3- [4- (2-m-tolyloxy-ethoxy) -phenyl) -cyclopentylmethyl] ester 17 {( 1R.3R) -1-amino-3- [4- (2-p-tolyl-ethoxy) -phenyl] -cyclopentyl} -methanol (A, J1 E, H1 K1 L1 M1 N) chiral S ν 2.60 (The ) 406 (M + H) + Pro (phosph (uto: ester mono - [(1 R, 3 R) -1-amino-3- [4- (2-p-tolyl-ethoxy) phenyl) cyclopentyl] methyl] F 18 [(1R.3R) -1-amino-3- (4-heptyloxy-phenyl) —cyclopentyl] -methanol (A, I, J, Ε, Η, K, L1 M1 N) chiral acid 2.80 (a) 386 (M + H) + Product: phosphoric acid mono - [(1R, 3R) -1-amino-3 - (4 Hieptyloxy-phenyl-cyclopentylmethyl] ester 19 ((1 R. 3R) -1-amino-3- {4- [3- (4-methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol (A, I, J 1 Ef H, K 1 L 1 Μ, N). chiral how ° 2.51 (a) 436 (M + H) + Acid proc: mono - ((1R, 3R) -1-amino-3- {4- [3- (4-methoxy-phenyl)-ester) propoxy] -phenyl phosphoric acid -cyclopenylmethyl] F. 20 (((1R.3R) -1-amino-3- {4- [2- (2-methoxyethoxy) ethoxy] phenyl} -cyclopentyl) methanol (A, I, J, Ε, Η, K, L1 M1 N) chiral 1.79 (a) 390 (M + H) + Acid yield: mono - ((1R, 3R) -1-amino-2 ester 1- {4- [2- (2-Methoxy-ethoxy) -ethoxy] -phenyl-cyclopenylmethyl] -phosphoric acid F. 21 ((1R, 3R) -1-amino-3- {4- [2- (4 -ethoxyphenyl) ethoxy] -phenyl} -cyclopentyl) -methanol (A, I, J1 Ε, Η, K, L, Μ, N) Chiral v 2.63 (a) 436 (M + H) + Prod Acid: Mono ((1R, 3R) -1-amino-3-) phosphoric 4- [2- (4-ethoxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl] ester of F 22 {(1 R .3R) -1-Amino-3- [4- (2-phenoxy-ethoxy] -phenyl] -cyclopentyl} -methanol (A, I, J1 Ε, Η, K, L1 Μ, N) 0-9 chiral S t- <»2.47 (a) 408 (M + H) + Phosphate: mono ester - ((1 Ρ, 3Ρ) -1-3ίηίηο-3- [4- (2-ίΘηόχί-θίόχίΗβη! ΐ] - αοΙορΘηΙί> rich methyl] of acid F. 2 3 ((1R, 3R) -1-amino-3- {4- [2- (3-fluoro-4-methoxy-phenyl) ethoxy] -phenyl} -cyclopentyl} -methanol (A, I, J1 E, H1 K1 L1 N, N) / chiral SP> -NH1 2.53 (a) 440 (M + H) + Produ ctu: phosphoric-amino-3-mono- ((1R, 3R) -1-pentylmethyl] ester {4- [2- (3-Fluoro-4-methoxy-phenyl) -ethoxy-phenyl} -F. 24 ((1R.3R) -1-amino-3- {4- [2- (3-methoxy) phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol (A, I1 J1 (H, K1 L, M1 N) chiral Λ 2.57 (a) 420 (M-H) - Proc acid: mono- ester (Phosphorus (1R, 3R) -1-amino-3- {4- [2- (3-methoxy-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl] F. 25 {(1R, 3R) -1 -amino-3- {4- [3- (3-methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol (A, J1, E1 H1 K1 L1 (N) \ VC-chiral Ό 2, (A) 436 (M + H) + Acid yield: mono - ((1 R, 3R) -1-amino-3- {4- [3- (3-methoxy-phenyl) -propoxy] -phenyl ester phosphoric acid; 26 ((1R.3R) -1-amino-3- {4- [3- (3,5-dimethoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol hydrochloride (A, I, J, Ε, Η, K, L, Μ, N) ζ chiral f \ ^ oyvJ nOH \ - 'NHe 2.63 (a) 466 (M + H) + Proc cyclo: mono ester ((1 R, 3R) -1-amino-3- {4- [3- (3,5-dimethoxy-phenyl) -propoxy-pentylmethyl] -phenyl} -F-27 ((1R, 3R) -1-amino -3- {4- [2- (4-benzyloxy-phenyl) -ethoxy] -phenyl} -cyclopentyl) -methanol (A, I, J, Ε, H, K1 L1 Μ, N) cIuiral HO XJ XX 'nh 1.61 (b) 408 (M + H) + Product: mono - ((1R, 3R) -1-amino-3- {4- [2- (4-hydroxy-phenyl) -ethoxy] -phenyl} ester -phosphoric acid F-cyclopentyl 1 28 ((1 R 3 R) -1-ammonium-3- [4- (3-phenyl-propoxy) -phenyl] -cyclopentyl} -methanol (A, J, E1 H1 K1 L1 M1 N) qui 2.59 (a) 404 (M-H) - Prochosphate: mono - {(1R, 3R) -1-amino-3-ironic ester 4- (3-phenyl propoxy) -phenyl] F 29 ((R, 3S) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentyl} -methanol (AB1 C1 D1 E1 F1 G1 H) chiral acid cyclopentylmethyl) • V 1.93 (d) 406 (M + H) + Prochosphate: mono - {(1 R, 3S) -1-amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentyl ester; F 30 ((3S) -1-Amino-3- (3-nonylphenyl) cyclopentyl) methanol acid hydrochloride; hydrochloride (A1 B1 D1 E1 F1 G1 H) 2.50 (d) 398 (M + H) + Product: mono ((3S) -1-amino-3- (3-nonylphenyl) cyclopentyl) methyl ester phosphoric F 31 ((3S) -1-amino-3- (3-octylphenyl) cyclopentyl) methanol; hydrochloride (A1 B1 D1 E1 F1 G1 H) TV-Ash 2.30 (d) 384 (M + H) + Product: mono ((3S) -1-amino-3- (3-octylphenyl) cyclopentyl) methyl ester phosphoric acid F 32 ((1 R, 3S) -1-amino-3- (4- (6-phenylmethoxyhexyl) phenyl] cyclopentyl) methanol hydrochloride (A1 B1 C1 D1 E1 F1 G1 H) 2.10 (d) 404 (M + H) + Product: phosphonic acid mono ((1R, 3S) -1-amino-3- (4- (6-methoxyhexyl) feriyl) cyclopentyl) triethyl ester. 32 ((1R, 3S) -1-amino-3- (4- (4-phenylbutyl) phenyl] cyclopentyl) methanol; hydrochloride (A1 B1 C1 D1 E1 F1 G1 H) 1.81 (d) 386 (M + H) + Product: phosphoric acid mono ((1R, 3S) -1-amino-3- (4- (4-phenylbutyl) phenyl) cyclopentyl) methyl ester F 33 ((1R, 3R) -1 -amino-3- (4-heptylphenyl) cyclopentyl) methanol; hydrochloride (A1 I1 J1 E1 F1 G1 H) Cr = 2.16 (d) 370 (M + H) + Product: mono ester ((1R13S) - F-phosphoric acid 1-amino-3- (4- (heptylphenyl) cyclopentyl) methyl 34 ((1 R.3R) -1-amino-3- (4hexylphenyl) cyclopentyl] methanol hydrochloride (A, I, J , E, F1 G, H) Voh 2.04 (d) 356 (M + H) + Prod u to: phosphoric acid mono ((1R, 3R) -1-amino-3- (4- (hexylphenyl) cyclopentyl) methyl ester F.3 5 {(1 R.3R) -1-amino-3- [4- (5-methoxypentyloxy) phenyl] cyclopentyl} methanol; hydrochloride (A, I, J, Ε, Η, K, L1 M1 N) \ OM OM OM 2.13 (a) 404 (M + H) + Product: mono ((1R, 3R) -1-amino ester F.3 Phosphoric acid -3- (4- (5-methoxy-pentyloxy) -phenyl] cyclopentylmethyl ((1R.3R) -1-amino-3- {4- [3- (5-methyl-oxazol-3-yl) 2-yl) -propoxy] -phenyl} -cyclopentyl) -methanol hydrochloride (A, I, J 1 E 1 H 1 K 1 L 1 M, N) S 2 (2) 386 (MH) - Product: mono ester Opentylmethyl phosphoric acid ((1R, 3R) -1-amino-3- {4- (5-methyl-oxazol-2-yl) propoxy] -phenyl} -cic) F.3 7 ((1R.3R) -1-amino-3- {4- [2- (4-fluoro-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; hydrochloride (A, I, J, Ε, H, K, L1 M1 N) R f 2.47 (a) 426 (M + H) + Product: mono ((1R, 3R) -1-amino-3- {4- [2- (4-fluoro-phenoxy) -ethoxy] -phenyl ester phosphoric acid} -cyclopentylmethyl) F (8 ((1R.3R) -1-amino-3- {4- [2- (3-fluoro-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; (A, I, J, E1 H, K, L1 M1 N) δ s, v%% .OH x O-OC2 2.52 (a) 424 (MH) - Product: mono ester ((1 R, 3R) - 1-amino-3- {4- [2- (3-fluoro phosphoric acid R-phenoxy) -ethoxy] -phenyl} -cyclopentylmethyl) F.3 9 (((1R, 3R) -1-amino-3- {4- [2- (2,4-difluorophenoxy) - ethoxy] phenyl} cyclopentyl) methanol; hydrochloride (A, I, J, E, H1 K1 L1 M1 N) -cc S vr 2.54 (a) 442 (MH) - Product: mono ester ((1 R, 3R) -1-amino-3- { Opentylmethyl phosphoric acid 4- [2- (2,4-difluoro-phenoxy) -ethoxy] -phenyl} -cic) IUO F.4 0 ((1R, 3R) -1-amino-3- {4- [2 - (4-Fluoro-2-methyl-phenoxy) -ethoxy] -phenyl} -cyclopentyl-methanol hydrochloride (A, 11 J 1 E, H 1 K, L, M, N) S sr 2.64 (a) 440 ( M + H) + Product: ((1 R, 3R) -1-amino-3- {4- [2- (4-fluoro-2-methyl-phenoxy) -ethoxy] -phenyl} -cyclopentylmethyl) ester of phosphoric acid F.4 1 ((1 R.3R) -1-amino-3- {4- [2- (3-methoxy-phenoxy) -ethoxy] -phenyl} -cyclopentyl) -methanol; hydrochloride (A, I , J1 E1 H1 K1 L1 M, N) at, S 2.60 (a) 438 (M + H) + Product: mono ester ((1 R, 3R) -1-amino-3- {4 Opentylmethyl) phosphoric acid [2- (3-methoxy-phenoxy) -ethoxy] -phenyl} -cic) F.4 2 ((1R, 3R) -1-amino-3- {4- [2- (3 -ethoxyphenyl) ethoxy] -phenyl} -cyclopentyl} -methanol hydrochloride (A, I, J, Ε, H, K 1 L 1 M1 N) 2.65 (a) 436 (M + H) + Product: ester mono ((1R, 3R) -1-amino-3- {4- [2- (3-etho phosphoric acid F4 3 ((1R, 3R) -1-amino-3- {4- [2- (3-chloro-4-methoxy-phenyl) -phenyl} -ethoxy] -phenyl} -cyclopentylmethyl) (ethoxy] phenyl] cyclopentyl) methanol; (A, I, J1 E1 H, K, L1 M, N) \ Vt 2.60 (a) 456/458 (M + H) + Product: acid mono ((1R, 3R) - 'cyclopentylmethyl) ester phosphoric-amino-3- {4- [2- (3-chloro-4-methoxy-phenyl) -ethoxy] -phenyl} -F.4 4 {(1R, 3R) -1-amino-3- [4- ((R) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride (A, I, J1 E, H1 K1 L1 Μ, N) Cx V uTO ^ x T 2.57 (a) ^ 22 (M + H) + Product: mono - ((1 R, 3R) -1-ester opentylmethyl) phosphoric acid amino-3- [4 - ((R) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cic) F.4 5 ((1R, 3R) -1-amino-3- { 3-bromo-4- [3- (3-methoxy-phenyl) -propoxy] -phenyl} -cyclopentyl) -methanol; hydrochloride (A, I, J1 Ε, Η, K, L1 Mt N) 6Sv - 2.76 (a) 514/516 (M + H) + Product: mono - ((1 R, 3R) -1-amino ester 3-4- (3-Bromo-4- [3- (3-methoxy-phenyl) -propoxy] -phenyl} -α-cyclopentylmethyl) phosphoric acid F.4 6 ((1 R.3R) -1-amino -3- {4- [3- (3-methoxy-phenyl) -propoxy] -3-methyl-phenyl} -cyclopentyl) -methanol; hydrochloride (A1 I, J, E1 H, K1 L, M1 N) V 2.74 (a) 450 (M + H) + Product: mono - ((1 R, 3R) -1-amino-3 ester 3-methylphenyl phosphoric acid {4- [3- (3-methoxy-phenyl) -propoxy] -; cyclopentylmethyl} -F.4 7 {(1 R.3R) -1-amino-3- [ 4 - ((S) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride (A, I, J1 Ε, H1 K1 L, Μ, N) α TO0 2.57 (a) 422 (M + H) + Product: mono - {(1R, 3R) -1-amino-3- [4] ester - opentylmethyl phosphoric acid ((S) -1-methyl-2-phenoxy-ethoxy) -phenyl] -cycl) LL OO {(1R.3R) -1-amino-3- [3,5-dichloro-4- (2-phenoxy-ethoxy) -phenyl] -cyclopentyl} -methanol; hydrochloride (A, I, J1, H, K1 L1 M1 N) O, Sv V "2.73 (a) 476/478 (M + H) + Product: mono - {(1 R, 3R) -1-amino ester Opentylmethyl) -phosphoric acid -3- [3,5-dichloro-4- (2-phenoxy-ethoxy) -phenyl] -cic acid CD "Π [(1R.3R) -1-amino-3- [3,5- dichloro-4-pentyloxy-phenyl) -cyclopentyl] -methanol; hydrochloride (A, I1 J1 E1 H1 K1 L1 M1 N) 2.89 (a) 426/428 (M + H) + Product: mono - [(1R, 3R) -1-amino-3- (3,5 phosphoric acid F.5 0 ((1R.3R) -1-amino-3- {3-bromo-4- [2- (4-methoxy-3,5-dichloro-4-pentyloxy-phenyl) -cyclopentylmethyl) -dimethyl-phenyl) ethoxy] -phenyl} -cyclopentyl} -methanol; hydrochloride (A1 I1 J1 E1 H1 K1 L1 M1 N) S bL Vh 2.76 (a) 526/528 (M + H) + Product: mono - ((1 R, 3R) -1-amino-3- {3-bromo-4- [2- (4-methoxy-3,5-dimethyl-phenyl) -ethoxy] -phenyl} -cyclopentylmethyl ester) phosphoric acid F.5 1 ((1R.3R) -1-amino-3- {4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -cyclopentyl-methanol; hydrochloride (A1 I1 J1 E1 H1 K, L1 M1 N) 2.33 (a) 480 (M + H) + Product: benzylester ester ((1 R, 3R) -1-amino-3- {4- [2- (2-methoxy-ethoxy) phosphoric acid cyclopentylmethyl) -ethoxy] phenyl] compound composed of trifluoroacetic acid F.5 2 {(1 R.3S) -1-amino-3- (4- (6-ethoxyhexyl) phenyl) cyclopentyl )} - methanol (A, B, C, D, E 1 F (Q) 1 G 1 H) chiral NH, 2.60 (a) 400.38 (M + H) + Product: mono ester ((1R, 3S) -1-amino-3- (4- (6-ethoxyhexyl) phenyl) -cyclopentyl) methyl) of phosphoric acid F.5 3 {(1R, 3R) -1-amino-3- (4- (7-Methoxyethyl) phenyl) -cyclopentyl)} -methanol (A, I, J 1 E 1 F (Q) 1 G 1 H) chiral 2.62 (a) 400.41 (M + H) + Product: mono- ( (5R, 3R) -1-Amino-C-phosphoric acid J- (4- (7-methoxyethyl) phenyl) -cyclopentyl) methyl) 4 ({1R.3R) -1-amino-3- ( 4 - ((6-ethoxyhexyl) phenyl) cyclopentyl} methanol (A, I, J 1 E 1 F (Q) 1 G, H) chiral 2.62 (a) 400.38 (M + H) + Product: ester phosphonic acid mono - ((1R, 3R) -1-amino-3- (4- (6-ethoxyhexyl) phenyl) cyclopentyl) methyl) F.5 5 {(1R, 3R) -1-amino-3 - (4- (2- (3-methoxyphenoxy) ethyl) phenyl) cyclopentyl} methanol (A1C1 J1 E1 S1 T1 U1 M1 V1H) CH2 2.52 (a) 422.39 (M + H ) + Product: phosphoric acid F - 6 ((1 1) - ((1R, 3R) -1-amino-3- (4- (2- (3-methoxyphenoxy) ethyl) phenyl) cyclopentyl) methyl) ester R, 3R) -1-amino-3- (4- (4-isopropoxyphenethyl) phenyl] cyclopentyl) methanol 2.87 (a) 434 (M + H) + Product: (1R, 3R dihydrogen phosphate; methyl-1-amino-3- (4- (4-isopropoxy-ethyl) phenyl) cyclopentyl) -F.5 7 ((1R, 3S) -1-amino-3- (4- (6-isopropoxyxy) phenyl) - cyclopentyl) methanol δ - 2.68 "(a) 414 (M + H) + Product: ((1R, 3S) -1-amino-3- (4- (6-isopropoxyoxy) cyclopentyl) dihydrogen phosphate methyl F.5 8 ((1R, 3R) -1-amino-3- (4- (7-phenylbumethyloctyl) phenyl] cyclopentyl) methanol 3.34 (a) 398 (M + H) + Product: ((1R, 3R) -1-Amino-3- (4- (7-methyloctyl) phenyl) cyclopentyl) methyl III dihydrogen phosphate F.5 9 1- (4 - ((1R.3R) -3-amino- 3- (hydroxymethyl) cyclopentyl) phenyl) -5-phenylpentan-1-one 2.64 (a) 432 (M + H) + Product: ((1R, 3R) -1-amino-3- (4) dihydrogen phosphate - (5-phenylpentanoyl) cyclopentyl) methyl F.6 0 (1-amino-3- (4-octylphenyl) cyclohexyl) methanol 4.53 (a) 398 (M + H) + Product: (1-amino dihydrogen phosphate -3- (4-octylphenyl) cyclohexyl) methyl F.6 1 (((1R.3R) -1-amino-3- (4- (4-propoxybutyl) phenyl) cyclopentyl) methanol 2.41 (a) 386 (M + H) + Product: ((1R, 3R) -1-Amino-3- (4- (4-propoxybutyl) phenyl) dihydrogen phosphate l) cyclopentyl) methyl F.6 2 ((1R, 3R) -1-amino-3- (4- (5-ethoxypentyl) phenyl) -cyclopentyl) methanol -—CX0Cc 1.79 (a) 386 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (5-ethoxypentyl) cic opentyl) methyl F.6 3 {(1R, 3R) -1-amino-3-hydrogen phosphate - (4- (3-butoxypropyl) phenyl) cyclopentyl) methanol Vjh 2.54 (a) 386 (M + H) + Product: ((1R, 3R) -1-amino-3- (4-) dihydrogen phosphate ((3-Butoxypropyl) phenyl) cyclopentyl) methyl CO LL rt ((1 R.SR 4 I -amino-S - ^^ - methoxyphenethylphenyl-cyclopentylJethanol 2.53 (a) 406 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (4-methoxyphenethyl) 1-phenyl) cyclopentyl) methyl F.6 5 ((1R, 3R) -1-amino-3- (4- (3- (3-Methoxyphenoxy) propyl) phenyl) cyclopentyl) methanol 2.63 (a) 436 (M + H) + Product: (1R, C JR) -1-amino dihydrogen phosphate -3- (4- (3- (3- F.6 6 ((1 R, 3R) -1-amino-3- (4- (2- (3-ethoxyphenoxy) ethyl) phenyl) cyclopentyl) methanol 2 , 65 (a) 436 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (2- (3-et oxyphenoxy) phenyl) cyclopentyl) methyl F.6 7 ((1R.3R) -1-amino-3- (4- (2- (3- (trifluoromethoxy) phenoxy) ethyl) phenyl) cyclopentyl) methanol 2, 84 (a) 476 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (2- (3 (trifluoromethoxy) ethyl) phenyl) cyclopentyl) dihydrogen phosphate methyl F.6 δ ((1 R, 3R) -1-amino-3- (4 - ((R) -3-phenoxybutyl) phenyl) cyclopentyl) methanol 1.97 (a) 420 (M + H) + Product: ((1R, 3R) -1-amino-3- (4 - ((R) -3-phenoxybutyl) phenyl) cyclopentyl) methyl dihydrogen phosphate F.6 9 ((1R, 3R) -1- amino-3- (4- (4-propoxyphenethyl) phenyl) cyclopentyl) methanol 2.07 (a) 434 (M + H) + Product: ((1R, 3R) -1-amino-3- ( 4- (4-propoxyphenethyl) phenyl) cyclopentyl) methyl F.7 0 ((1 R, 3R) -1-amino-3- (4 - ((R) -3-methoxyphenoxy) butyl) cyclopentyl) methanol 2 73 (a) 450 (M + H) + Product: ((1R, 3R) -1-Amino-3- (4 - ((R) -3- (3-methoxyphenoxy) butyl) phenyl) cyclopentyl dihydrogen phosphate ) methyl F.7 1 ((1 R.3R) -1-amino-3- (4 - ((S) -3- (3-methoxyphenoxy-butyl) phenyl) cyclopentyl) methanol 2.73 (a) 450 (M + H) + Product: ((1R, 3R) -1-amino-3- (4 - ((S) -3- (3-methoxyphenoxy) butyl) phenyl) cyclopentyl) methyl dihydrogen phosphate CM (( 1 R.3R) -1-amino-3- (4 - ((S) -3-phenoxybutyl) phenyl) cyclopentyl) methanol 1.97 (a) 420 (M + H) + Product: ((1R 1,3R) -1-amino-3- (4 - ((S) -3-phenoxybutyl) phenyl) cyclopentyl) methyl LL CO (3-amino-1- (4-octylphenyl) pyrrolidin-3-yl) methanol V0 2.30 (a) 385 (M + H) + Product: (3-amino-1- (4-octylphenyl) pyrrolidin-3-yl) methyl dihydrogen phosphate F.7 4 ((1R.3R) -1 -amino-3- (4 - ((Z) -hept-4-enyloxy) phenyl) cyclopentyl) methanol HO-OH 2.32 (a) 384 (M + H) + Product: ((1R, 3R) dihydrogen phosphate ) -1-amino-3- (4-enyloxy) phenyl) cyclopentyl) methyl - ((Z) -hept-4 F.7 5 ((1R.3R) -1-amino-3- (4- (3- (4-Fluoro-3-methoxyphenyl) propoxy) phenyl) cyclopentyl) methanol NH 1 0.85 (a) 454.38 (M + H) + Product: ((1R, 3R) -1-amino-dihydrogen phosphate 3- (4- 3- (4-fluoro-3-10-methoxyphenyl) propoxy) phenyl) cyclopentyl) methyl F.7 6 ((1R, 3R) -1-amino-3- (4- (3- (2-methoxyphenyl) propoxy) phenyl) cyclopentyl) methanol (R) 2.67 (a) 436.35 (M + H) + Product: ((1R.3 methoxyphenyl) propoxy) phenyl) cyclopentyl) methyl »R) dihydrogen phosphate -1-amino-3- (4- (3- (2- F.7 7 ((1R, 3R) -1-amino-3- (4- (4-methoxy-3-methylphenethoxy) phenyl) cyclopentyl) methanol 2.67 (a) 436.42 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (4-methoxy-3-methylphenoxy) phenyl) cyclopentyl) dihydrogen phosphate methyl F.7 8 ((1R, 3R) -1-amino-3- (4- (4-methoxy-3,5-dimethylphenethoxy) phenyl) cyclopentyl) methanol, HCI 1.98 (a) 450.20 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (4-dimethylphenethoxy) phenyl) cyclopentyl) methyl ^ ηηβίόχ'ι-3,5-CO "Π (( 1 R, 3R) -1-amino-3- (4- (4-phenyl butyltrifluoromethoxy) phenyl) cyclopentyl) methanol 19 "2.81 (a) 474.44 (M + H) + Product: phosphate ((1-trifluomethoxy) phenethoxy) phenyl) cyclopentyl) methyl R, 3R) -1-amino-3- (4- (4- F.8 O (3-amino-5-methyl-5- (4-octylphenyl) ) tetrahydrofuran-3-yl) methanol U, OH O · 2.02 (a) 400.29 (M + H) + Product: phosphate ((3S, 5S) -3-Amino-5-methyl-5- (4-octyl) methyl phenyl) tetrahydrofuran-3-F.8 dihydrogen (3-amino-5- (4-octylphenyl) tetrahydrofuran -3-yl) methanol VOM-MT OH-O ^ 3.07 (a) 386.21 (M + H) + Product: (3-amino-5- (4-octylphenyl) tetrahydrofuran-3-yl) dihydrogen phosphate methyl F.8 2 ((1R, 3R) -1-amino-3- (4- (3- (thiophen-2-yl) propoxy) phenyl) cyclopentyl) methanol 2.57 (a) 412.35 (M + H) + Product: ((1R, 3R) -1-Amino-3- (4- (3-thiophen-2-yl) propoxy) phenyl) cyclopentyl) methyl dihydrogen phosphate F.8 3 ((1R (3R) -1-Amino-3- (4- (3-methoxy-4-methylphenoxy) phenyl) cyclopentyl) methanol (A, I, J, E 1 H 1 K 1 L, M, N) 2.69 (a) 436.38 (M + H) + Product: ((1R, 3R) -1-Amino-3- (4- (3-methoxy-4-methylphenoxy) phenyl) cyclopentyl) methyl dihydrogen phosphate F84 ((1R.3R) -1-amino-3- (4- (3- (pyridin-4-yl) propoxy) phenyl) cyclopentyl) methanol (A, I, J, E1 H, K1 L1 M1 N) NM 1.58 (a) 407.23 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3-pyridin-4-yl) propoxy) phenyl) dihydrogen phosphate cycle pentyl) methyl F.8 5 ((1R, 3R) -1-amino-3- (4- (3- (pyridin-3-yl) propoxy) phenyl) cyclopentyl) methanol (A, I, J1 E1 H1 K1 L1 M1 N) ^^^ Os-o ^ 1.98 (a) 407.36 Product: ((1R, 3R) -1-amino-3- (4-yl) propoxy) phenyl) cyclopentyl) methyl - ( 3-pyridin-3-

Table G. Examples Following General Procedures P (Scheme 5) The letters in parentheses below the ester precursors indicate the General Procedure by which the ester was made.

Ex # Ester Product Rt / ml (method) m / z G.1 (1R, 3S) -1-Amino-3- (4-non-1-ynyl-phenyl) -cyclopentanecarboxylic acid (A, B, C, D1 E, F, G) Chiral V O-CM 2.13 (b) 328 (M + H) + Product: (1R, 3S) -1-Amino-3- (4-non-1-yl) acid (phenyl) -cyclopentanecarboxylic acid G.2 (1R, 3S) -1-amino-3- (4-nonyl-phenyl) cyclopentanecarboxylic acid ethyl ester (A, B1 C, D, E, F1 G) which is HMft CM 1 73 (b) 332 (M + H) + Product: (1R, 3S) -1-Amino-3- (4-nonyl-phenyl) -cyclopentanecarboxylic acid; hydrochloride G.3 (1R, 3S) -1-Amino-3- (4-dec-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester (A, B, C, D, E1 F, G) —OCT t R / CH 1.69 (b) 342 (M + H) + Product: (1R, 3S) -1-Amino-3- (4-dec-ynyl-phenyl) -cyclopentanecarboxylic acid; hydrochloride G.4 (1R, 3S) -1-Amino-3- (4-decyl-phenyl) -cyclopentanecarboxylic acid methyl ester (A, B1 C, D, E, F, G) chiral J 2.51 (b ) 346 (M + H) + Product: (1 R, 3S) -1-Amino-3- (4-decyl-phenyl) -cyclopentanecarboxylic acid G.5 (1R, 3S) -1-Amino acid methyl ester 3- [4- (7-Methoxy-hept-1-ynyl) -phenyl] -cyclopentanecarboxylic acid (A, B, C, D, E1 F1 G) ■ qu, chiral ^ —OCrt 2.02 (e) 330 (M + H) + Product: (1R, 3S) -1-Amino-3- [4- (7-methoxy-hept-1-ynyl) -phenyl] -cyclopentanecarboxylic acid; hydrochloride G.6 (1R, 3R) -1-Amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentanecarboxylic acid methyl ester (A, I, J, E, F, G) 2.66 (a) 340 (M + H) + Product: (1R, 3R) -1-Amino-3- [4- (3-phenoxy-propyl) -phenyl] -cyclopentanecarboxylic acid; hydrochloride G .7 (1R, 3S) -1-Amino-3- (4-oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester (A, B, C, D, E1 F) NHfluiral 2, 30 (a) 314 (M + H) + Product: (1 R, 3S) -1-Amino-3- (4- (oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid G.8 (1R acid ethyl ester , 3S) -1-Amino-3- (4-hept-1-ynyl-phenyl) -cyclopentanecarboxylic acid (A, B, C, D, E, F) Î ± 2.14 (b) 298 (M + H) + IO Product: (1R, 3S) -1-Amino-3- (4-hept-1-ynyl-phenyl) -cyclopentanecarboxylic acid G.9 (1R, 3S) -1-Amino acid methyl ester -3- (4-heptylphenyl) cyclopentanecarboxylic (A, B, C, D, E, F, G) H * / iral / s / s / sj 3.02 (a) 304 (M + H) + Product: (1R, 3S) -1-Amino-3- (4-hept-phenyl) -cyclopentanecarboxylic acid G.1 O (3S) -methyl 1-amino-3- (3-decylphenyl) cyclopentanecarboxylate; B, C, D, E1 F1 G) 2,3,6 2 (a) 346 (M + H) + Product: (3S) -1-amino-3- (3-decylphenyl) cyclopentanecarboxylic acid G.1 1 ( 3S) -methyl 1-amino-3- (3-nonylphenyl) cyclopentanecarbox hydrate (A, B1 C1 D1 E1 F1 G) 2.67 (b) 332 (M + H) + Product: (3S) -1-amino-3- (3-nonylphenyl) cyclopentanecarboxylic acid G.1 2 ( 3S) methyl 1-amino-3- (3-octylphenyl) cyclopentanecarboxylate; hydrochloride (A, B1 C1 D1 E1 F1 G) 2.46 (a) 318 (M + H) + Product: (3S) -1-amino-3- (3-octylphenyl) cyclopentanecarboxylic acid G.1 3 (3S) -methyl 1-amino-3- (3- (oct-1-ynyl) phenyl) cyclopentanecarboxylate; hydrochloride (A1 B1 D1 E1 F1 G) 3.06 (a) 314 (M + H) + Product: (3S) -1-amino-3- (3-oct-1-yn) phenyl) cyclopentanecarboxylic acid G.1 4 (3S) -methyl 1-amino-3- (3- (hept-1-ynyl) phenyl) cyclopentanecarboxylate; hydrochloride (A1 B1 D1 E1 F) 2.12 (a) 300 (M + H) + Product: (3S) -1-amino-3- (3-hept-1-ynyl) phenyl) cyclopentanecarboxylic acid G.1 5 (1R, 3S) -methyl 1-amino-3- (4- (3-phenylpropyl) phenyl) cyclopentanecarboxylate; hydrochloride (A, B1 C1 D, E1 F1 G) H2N 2 Ooh OujO 2.91 (a) 338 (M + H) + Product: (1R, 3S) -1-amino-3- (4- (3- phenylpropyl) phenyl) cyclopentanecarboxylic 11 G.1 6 (7R) -7- (4- (benzyloxy) -3-chlorophenyl) -1,3-diazaspiro [4.4] nonane-2,4-dione (A, B) H / 4 § j-Voh 2.12 (C) 346.34 8 (M + H) + Product: (3R) -1-Amino-3- (4- (benzyloxy) -3-chlorophenyl) cyclopentanecarboxylic acid G.1 7 (3S) -1-Amino-3- (3-chloro-4-methoxyphenyl) cyclopentanecarboxylic acid (A, B, D) -V0B1- 3.26 (a) 372 (M + H) + Product: (3S) -1-Amino-3- (3- (dec-1-ynyl) -4-methoxyphenyl) cyclopentanecarboxylic acid

Table Η. Examples following procedures A, I, J, E, F, G, H, K1 L, Μ, N (Scheme 11)

Boronic acid

Cr0

Procedure Procedure Procedure Procedure Procedure General General General General General

The IJEH

alkyne

alcohol

Procedure Procedure Procedure Procedure Procedure General General General General General

K F GLM

General Procedure N

OH

Ex Boronic acid Alcohol Alcohol Product Rt / ml m / z # η (method) H.1 4- 1-Ethinyl-4-Pro- 2.84 355 bromophenylboromethoxybenzene-2- (a) (M) + H) Single ol + I 10 Product: ((1R, 3R) -1-amino-3- (4- (4-isopropoxyphenethyl) phenyl) cyclopentyl) methanol

Table I. Examples following general procedures A, B1 C1 D, E1 S, T1 U1 M1 V1 H (Scheme 7)

Bor Boronic acid

Cr0 ---—- —- - —- —-

Procedure Procedure Procedure Procedure Procedure Procedure

General General General General General General

BCD ES

phenol

R

\ - / Nl

Procedure Procedure Procedure Procedure Procedure ^ j

General General General General General 2

T UMVH

Ex # Boronic acid Phenol Product Rt / min (method) m / z 1.1 4-Bromophenylboronic acid 3-methoxyphenol ncr: a: chiral 2.41 (a) 342.39 (M + H) + Product: ((1 Rl3R) -1-amino-3- (4- (2- (3-methoxyphenoxy) ethyl) phenyl) cyclopentyl) methanol; clordirate I.2 Chiral 4-bromophenylboronic acid 4-methoxyphenol 2.66 (a) 342.39 (M + H) + Product: ((1 R, 3R) -1-amino-3- (4- (2- ( 3-methoxyphenoxy) ethyl) phenyl) cyclopentyl) methanol; clordirate

Table J. Intermediates prepared following the general AA procedure (Scheme

8)

Alkylating agent

R1.OH -m-O.

AA General Procedure

R2

Ex Alcohol Agent Product 1 H NMR (400 MHz1 DMSO-d6) # alkylating I J. J. But-1-in-1-ol 1-iodopropane δ. 3.56 (c, 2H), 3.42 (t, 2H), 2.47 (dl, 2H), 1.98 (δ, 1H), 1.62-1.58 (m. 2H), 0.92 (t, 3H). Product: 4-propoxybut-1-yne J. 2 Prop-2-yn-1-ol-1-iodobutane 6. 4.11 (d, 2H), 3.50 (I, 2H), 2.39 (t, 1H), 1.59-1.53 (m, 2H), 1.41-1.34 (m. 2H), 0.91 (t, 3H). Product: 1- (prop-2-uniloxy) butane J. 3 Pent-4-yn-1-iodoethane 8. 3.53-3.46 (m, 4H), 2.29 (dddd, 2H), 1.94 (ι, 1H), 1.79 (dddd, 2H), 1.20 (t, 3H). Product: 5-ethoxypent-1-yo J. 4 2-methoxyethanol-3-bromo-prop-1-yo-o- δ. 4.23 (d, 2H), 3.71 (ddd, 2H), 3.59 (ddd, 2H), 3.41 (s, 3H), 2.45 (t, 1H). Product: 3- (2-methoxyethoxy) prop-1-yo J.5 Propan-2-ol Hex-5-ynyl-4-methylbenzenesulfonate 6. 3.47 (*> I HX 3.33 (t, 2HX 2.71 (U 1), 2-W (ddd, 2h), 1.54-1.43 (m, 4H) 1.04 (d. 6H) Proc Juto: 4-propoxybut-1-yo

Table Κ. Examples following the general procedures BB1 CC1 B1 D, Ε, H (Figure 9)

aniline

Procedure Procedure Procedure Procedure General BB General CC General B General D

R-vtt-r-OH Procedure Procedure T-oC General And General H Ex # Aniline Product Rt / min (method) m / z IZU K.1 4-octylaniline 3.42 (a) 305 (M + H) + Product: (3-amino-1- (4-octylphenyl) pyrrolidin-3-yl) methanol

Table L. Examples following the general procedures A1 I, J1 Ε, Η, K, F, Μ, N (Scheme 10)

_ Boronic Acid

Cr0

Procedure Procedure Procedure Procedure Procedure General A General I General J General E General H

Phenol Alkyl ^

Procedure Procedure Procedure Procedure General K General F General M General N

/ ^ O0Th

R1 W NH »

Ex # Boronic acid Alkino Phenol Product Rt / ml (method) m / z L.1 A-bromophenylboronic acid ((prop-2-ynyloxy) methyl) benzene 3-methoxyphenol 2.90 ( a) 356 (M + H) + Product: ((1R, 3R) -1-amino-3- (4- (3- (3-methoxyphenoxy) phenyl) cyclopentyl) methanol; hydrochloride salt L.2 Acid 4- bromophenylboronic (S) - ((pent-4-yn-2-yloxy) methyl) benzen O phenol 3.21 (a) 340 (M + H) + Product: ((1 R, 3R) -1- amino-3- (4 - ((R) -3-phenoxy Dutil) phenyl) cyclopentyl) methanol hydrochloride salt L.3 4-bromophenylboronic acid (S) -1-methoxy-3- (pent-4- in-3-yloxy)) benzene 3-methoxyphenol 3.11 (a) 370 (M + H) + Product: ((1 R, 3 R) -1-amino-3- (4 - ((R ) -3- (3-methoxyphenoxy) butyl) phenyl) cyclopentyl) methanol; calcium salt L.4 4-Bromophenylborob- (R) -1-methoxy-3- (pent-4-yn-2-3-methoxyife-α-O-OC) 2.98 (a) 370 ( M + H) \ (Ithioxyoxy) benzene + Product: ((1 R, 3R) -1-amino-3- (4 - ((S) -3- (3-methoxyphenoxy) butyl ) phenyl) cyclopentyl) methanol; calcium salt L.5 4-bromophenylboronic acid (R) -1-methoxy-3- (pent-4-yn-2-yloxy) benzene phenol O4 ycZ 2.84 (a) 340 (M + H) + Product: ((1R, 3R) -1-amino-3- (4 - ((S) -3-phenoxy Duty) phenyl) cyclopentyl) methanol; hydrochloride salt

Table Μ. Examples Following General Procedures D (Scheme 12) The letters in parentheses below the ester precursors indicate the General Procedure by which the ester was made.

j, —- "O-Ar

| v Procedure _ / NHa

I / Zari I W

General D

Ex # Ester Product Rt / min (method) m / z M.1 8- (4-octylphenyl) -7-oxa-1,3-diazaospiro [4.4] nonane-2.4-dione) 3.22 (a) 320.25 ( M + H) + Product: 3-amino-5- (4-octylphenyl) 1 tetraidrofuran-3-carboxylic acid M.2 8-methyl-8- (4-octylphenyl) -7-oxa-1 , 3-diazaospiro [4.4] nonane-2,4-dione) 2.12 (f) 334.26 (M + H) + Product: 3-amino-5-methyl-5- (4-octylphenyl) tetrahydrofuranate 3-carboxylic

Table N. Examples following the general procedures A1 F1 G, D (Scheme 13)

Cr0

Alauino Boronic Acid

Procedure Procedure Procedure Procedure AFGD

-NR '

Ex # Boronic acid Albino Product Rt / min m / z (method) N.1 4-Bromophenylboronic acid Oct-1-yo 1.75 (f) 358.3 (M + H) + Product: acid 1 - [3- (4-octyl-phenyl) -cyclopentyl] azetidine-3-carboxylic N. 2 4-Bromophenylboronic acid Oct-1-ίηο ^^ - CK / "- 1 * · 1.74 (f) 332.2 (M + H ) + Product: [3- (4-Octyl-phenyl) -cyclopentylamino] -acetic acid N.3 4-Bromophenylboronic acid Oct-1-yo 1.91 (a) 346.3 (M + H) + Product: acid 3- [3- (4-octyl-phenyl) -cyclopentylamino] -propionic

Table O. Examples Following General Procedures A, B, C1 D1 E, F (Scheme

14)

Boronic acid

Cr0

Procedure Procedure Procedure Procedure Procedure General A General B General C General D General E

alkyne ^

\ _ / Nl

Procedure lil ι "lilj

General ^ NHS

F

Ex # Boronic acid Alkyne Product Rt / min (method) m / z 0.1 4-bromophenylboronic acid Oct-1- ino hoy ^ Ajh o chiral Q-CrC 2.14 (b) 328.2 (M + H) + Product: (1R, 3S) -1-Amino-3- (4-oct-1-ynyl-phenyl) -cyclopentanecarboxylic acid methyl ester; compound with (2R, 3R) -2,3-dihydroxy succinic acid

Table P. Examples following the general procedures A1 B, C1 D, E, F, G (Figure 15)

Boronic acid

Cr0 ---- —- —- —-

Procedure Procedure Procedure Procedure Procedure

>

GeraIA GeraIB GeraIC GeraID GeraIE Alkine q f

—- —- r ^ O-W "0

Procedure Procedure \ / "'klLJ

General F GeraIG '-' NHj

Ex # Boronic acid Alkyne Product Rt / min (method) m / z P.1 4-Bromophenylboronic Acid Oct-1-yo \ hVtcS ^ —vniral r · ^ ^ OCK. 2.67 (b) 332.3 (M + H) + Product: acid methyl ester (1 compound with (2R, 3R) -2,3-diid R, 3S) -1-amino-3- (4 -octyl-phenyl) -cyclopentanecarboxylic acid; succinic oxy

Table Q. Examples following the general precedents A, I, J, Ε, Η, K, L, Μ, N (Scheme 3)

λ. Bor Boronic acid

Cr0--

Procedure Procedure Procedure Procedure Procedure General General I General J General E General H

alcohol

Procedure Procedure Procedure Procedure - \ t. „

General K General L General M General N '' NH,

Ex # Boronic acid Alcohol Product Rt / min (method) m / z Q.1 6- Methoxynaphthalen-2-ylboronic acid 1- pentanol 3.05 (a) 328 (M + H) + Producer: ((1 R, 3R) -1-amino-3- (6- (pentyloxy) naphthalen-2-yl) cyclopentyl) methanol hydrochloride Q.2 6-methoxynaphthalen-2-ylboronic acid 1-hexanol NHt 3.23 (a) 342 (M + H) + Product: ((1 R, 3R) -1-amino-3- (6- (hexyloxy) naphthalen-2-yl) cyclopentyl) methanol hydrochloride

Table R. Examples Following General Procedures O (Scheme 4) The letters in parentheses below the amino alcohol precursors indicate the General Procedure by which the amino alcohol precursor was made.

oh

Procedure

General The W / ^ \ _pHH2

Ex # Amino alcohol Product Rt / min (method) m / z R.1 (1-Amino-3- (6- (pentyloxy) naphthalen-2-yl) cyclopentyl) methyl dihydrogen phosphate (A, I, J, Ε, Η, K, L, M) 2.91 (a) 408 (M + H) +

PREPARATION OF ADDITIONAL MOLECULES (NOT TABLES) Preparation of 4-Benzyloxy-N-prop-2-ynylbutyramide

Propargylamine

EDC / HOBt

—--

U DMF ^

A solution of 4-benzyloxy butyric acid (1.00 g, 5.15 mmol) and propargylamine

(284 mg, 5.15 mmol) in DMF (10.3 mL) was treated with diisopropylethylamine (0.90 mL, 5.15 mmol), hydroxybenzotriazole (788 mg, 5.15 mmol) in EDC (665 mg, 5 mL). , 15 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction was concentrated under reduced pressure and the crude product was taken up in ethyl acetate, washed with water, dried using Na 2 SO 4, filtered, and concentrated to afford 4-benzyloxy-N-prop-2-ynylbutyramide (1, 02 g, 86%) as a viscous oil. LCMS (Table 1, Method a) min., M / z: (M + H) +; 1H nmr (400 MHzt DMSO-40 δ. 8.24 (broad t, 1H), 7.30 (m, 5H), 4.43 (s, 2H), 3.82 (m, 2H), 3.40 (1.2H), 3.31 (s, 1H), 2.16 (t, 2H), 1.76 (m, 2H)

Preparation of 2- (3-benzyloxypropyl) -5-methyloxazole acetonitrile A solution of 4-benzyloxy-N-prop-2-ynylbutyramide (500 mg, 2.16 mmol) in acetonitrile (22 mL) ) was treated with gold (III) chloride (32.8 mg, 0.108 mmol) at room temperature. The reaction was heated at 50 ° C for 8 hours then allowed to stir at room temperature for one night. The reaction was concentrated under reduced pressure and the residue was purified on silica gel using 1: 1 / heptane: ethyl acetate as eluent. Product containing fractions were combined and concentrated under reduced pressure to afford 2- (3-benzoxyoxy-propyl) -5-methyl-oxazole (405 mg, 81%) as a clear oil.

LCMSC Table 1, Method a) min., M / fc: (M + H) *; Δ nm (400 MHz, DMSCMd) δ. 7.32 (m, 5H), 6.67 s, 1H). 4.45 (s, 2H), 3.47 (1.2H), 2.73 (1.2H), 2.23 (s, 3H), 1.92 (m, 2H) Preparation of 3- (5-methyl-oxazol-2-yl) - propan-1-ol

Pd in C

H,

ethanol

A solution of 2- (3-benzyloxy-propyl) -5-methyl-oxazole (675 mg, 2.92 mmol) in ethanol (15 mL) containing a 10% suspension of Pd in C (63.9 mg, 0 0.06 mmol) was hydrogenated overnight at room temperature. The catalyst was removed by filtration through Celite®, then the filtrate was concentrated and the residue was purified on silica gel using 1: 1 / heptane: ethyl acetate and then ethyl acetate as eluents. Product containing fractions were combined and concentrated under reduced pressure to afford 3- (5-methyl-oxazol-2-yl) -propan-1-ol (242 mg, 59%) as an oil.

LCMS c Table ι. Method a) i.8s min., 142 (M + H) *; 1H Rmn 400 MHz, DMSO-d 6) 6.64 (s, LH), 4.50 (t, 1H), 3.41 (m, 2H), 2.67 (t, 2H), 2.22 (s, 3H), 1.76 (m, 2H )

Preparation of 5-Methoxy-pentan-1-ol

H9 PCWC

To a flask charged with ((5-methoxypentyloxy) methyl) benzene (4.25 g, 0.0204 mol), palladium on carbon (0.5 g) was added ethanol (40 mL). The mixture was stirred at room temperature under hydrogen (flask) for 1 hour. The crude mixture was filtered through a pad of Celite®, concentrated, and dried under vacuum to give 5-methoxy-pentan-1-ol (2.40 g, 100%). 1H NMR 400MHz, DMSO (δ) δ 4.32 (t, 3Η), 3.37 (m, 2H), 3.31 <m. 1H), 3.21 (s, 3H), 1.39-1.59 (m, 4H), 1.25-1.32 (m, 2H)

Preparation of 3- (3-Methoxy-phenyl) -propan-1-ol

THE

A solution of 3- (3-methoxyphenyl) propanoic acid (2.00 g, 11.10 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (24.42 mL). , 24.42 mmol) so that the reaction temperature is kept below 35 ° C. The mixture was allowed to stir at room temperature for one night. Methanol was added dropwise to stir the mixture until the visible reaction had stopped. An additional mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1: 1 / heptane: EtOAc as eluent). Product containing fractions were combined and concentrated to give 3- (3-methoxyphenyl) propan-1-ol as an oil.

1H NMR (400 MHz, DMSCW6) δ 7.17 (m, 1H), 6.74 (m, 3H), 4.44 (t, 1H), 3.72 (s, 3H), 3.40 (m, 2H), 2.S7 (m, 2H), 1.69 (ra, 2H)

Preparation of 3- (3,5-dimethoxy-phenyl) -propan-1-ol

To a solution of 3- (3,5-dimethoxyphenyl) propanoic acid (2.00 g, 9.51 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (20 mL). 93 mL, 20.93 mmol) to maintain reaction temperature below 35 ° C. The mixture was allowed to stir overnight at room temperature. Methanol was added dropwise to stir the mixture until the visible reaction had ceased. An additional 20 mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1: 1 / heptane: EtOAc with eluent). Product containing fractions were combined and concentrated to give 3- (3,5-dimethoxy-phenyl) -propan-1-ol as an oil.

1H NMR 400MHz, DMSCM *) δ 6.34 (d, 2H), 6.29 (t, 1H), 4.43 (t, 1H), 3.71 (s, 6H), 3.40 (m, 2H), 2.57 (m, 2H) 1.69 (m, 2H).

Preparation of 2- (fluoro-phenoxy) -ethanol

O 1. NaH,

^ X - 2. LAH

- Xl

A solution of 4-fluorophenol (2.00 g, 17.84 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH in DMF (2.0 mL) at about 10 ° C. Ethyl bromoacetate (2.483 mL, 22.30 mmol) was added and then the reaction mixture was allowed to warm to room temperature over 4 hours. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and washed 2 times with water, dried over MgSO 4, filtered and concentrated to dry. The crude product was purified on silica gel using (4: 1 heptane: EtOAc as eluent) to make ethyl 2- (4-fluorophenoxy) acetate (3.12 g, 95%). 1H nmr 400 MHz (DMSO-4s) B 7.09 (m, 2H), 6.94 (m, 2H), 4.84 (t, 1H), 3-94 (t, 2H), 3.69 (m. 2H)

Ethyl 2- (4-fluorophenoxy) acetate (3.12 g, 15.74 mmol) was dissolved in diethyl ether (50 mL) and cooled to about 0 ° C. Aluminum lithium hydride (1.792 g, 47.2 mmol) was added portionwise while maintaining the reaction temperature maintained below 35 ° C. The reaction was allowed to stir at room temperature for one hour. The crude reaction was diluted with ether (50 mL then cooled in an ice bath and quenched by dripping water (6.1 mL), then 2 M NaOH (12.2 mL), then water (6.1 mL) The mixture was filtered and concentrated.The crude product was purified on silica gel (4: 1 heptane: EtOAc with eluent) to give 2- (4-fluoro-phenoxy) -ethanol (1.36 g, 55%). .

1H nmr (400 MHz1 DMSO-?)? 7.08-7.13 (m, 2H), 6.92-6.96 (m, 2H), 4.84 (t, 1H), 3.95 (t, 2H), 3.69 (m, 2H).

Preparation of 4- {2- [4 - ((1R, 3R) -3-Amino-3-hydroxymethyl-cyclopentyl) -phenoxy] -ethyl} -phenol

Hj1PdZC

To a solution of ((1R, 3R) -1-amino-3- (4- (4-

(benzyloxy) phenethoxy) phenyl) cyclopentyl) methanol (250 mg, 0.599 mmol) in ethanol (10 mL) was added 10% Pd / C (20 mg, 0.188 mmol). The mixture was flushed with hydrogen and hydrogenate with a flask for about 16 hours. The crude mixture was filtered, concentrated and the residue was triturated with ether. The solid was collected and dried under vacuum at 50 ° C to give 4- (2- (4 - ((1R, 3R) -3-amino-3- (hydroxymethyl) cyclopentyl) phenoxy) ethyl) phenol (169 mg, 86 %) as a white solid. \ R \ f \ IÍ.O

LCMS (Table 1, Method b.) Rt = 1.75 min; m / v 328 (M + H) *; 1 H nmr (400 MHz, DMSO 4) δ 7.10 (m. 4H), 6.81 (dd, 2H). 6.68 (dd, 2H), 4.63 (b, 1H), 4.05 (t, 2H), 3.31 (s, 3H), 2.88 (t, 2H), 1.98-2.07 (m, 1H), 1.77-1.84 (m, 1H), 1.30-1.65 (m, 5H).

Preparation of 4 - ((7S) -3-methyl-2,4-dioxo-1,3-diazaspiro [4.4] nonan-7-yl) benzonitrile

1X Sv

"V10 z" · zntc ^. "M0

The Pd2 (Ciba) il dppf (TV

O nmp y ^

A suspension of (7S) -7- (4-bromophenyl) -3-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione (General Procedures A, B1 C) (0.500 g, 1.547 mmol) in Anhydrous NMP (4.00 mL) had the gases removed by evacuating the reaction from the vessel then refilling it with N2 a few times. To this suspension was added zinc (1.012 mg, 0.015 mmol), dppf (0.027 g, 0.048 mmol), zinc cyanide 0.145 g, 1.238 mmol), and Pd2 (dba) 3 (0.021 g, 0.023 mmol) at room temperature. The resulting mixture was heated to 120 ° C for about 16 hours. The crude material was filtered through Celite®. The filtrate was taken up in water (70 mL) and ethyl acetate (100 mL). The organic phase was washed with water (50 mLx2) and brine (50 mL), dried (MgSO4) and concentrated to afford 4 - ((7S) -3-methyl-2,4-dioxo-1,3-diazaospiro [ 4.4] nonan-7-yl) benzonitrile (0.44 g, 0.20 mmol) as a light brown silyl. LCMSC Table 1, Method a) Rf = 2.04 min; m / z: 270.15 (M + H) 4; 1H nmr 400 MHz, Methanol - d4) δ ppm 3.52-3.39 (m, 1H). 2.10-1.85 (m, 3H), 2.31-2.15 (m, 3H), 7.69-7.64 (m, 2H), 7.50 (t, J = 8.45 Hz, 2H), 2.96 (d. J = 2.91 Hz, 3H) 2.59-2.34 (m, 1H).

Preparation of (Z) -hydroxy-4 - {(7S) -3-methyl-2,4-dioxo-1,3-diazaspiro [4.4] nonan-7-yl} benzimidamide

TV"

jy „νσ

NHt

4 - ((7S) -3-methyl-2,4-dioxo-1,3-diazaspiro [4.4] nonan-7-yl) benzonitrile (0.88 g, 3.27 mmol) was suspended in ethanol (20 mL ). To this was added hydroxylamine (0.240 mL, 3.59 mmol) as a 50 wt% solution in water, and the reaction was heated at 60 ° C under a nitrogen atmosphere for about 20 hours. The reaction mixture was allowed to cool to room temperature. Solvent has been partially removed. The resulting white precipitate was filtered off, washed with ice cold ethanol and vacuum dried to afford (Z) -N'-hydroxy-4 - {(7S) - ΔΛJ>

3-methyl-21-dioxo-1,3-diazaspiro [4.4] nonan-7-yl} benzimidamide as a light brown solid (1.12 g, 3.20 mmol).

LCMS (Table 1, Methoda) R4 = 1.47 min; m / z: 303.33 (M + H) "; 1H nmr (400MHz, Methanol! - d4) δ ppm 2.96 (d, J = I. 16Hz, 3H), 2.43-2.33 (m, 1H), 3.39 (ddd , J = 18.3, 11.00.7.39 Hz, 1H), 7.36-7.30 (m, 2H) 7.58 (d, J = 8.23 Hz 12 H), 2.29-1.87 (m. 6H).

Preparation of (7S) -7- (4- (5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl) phenyl) -3-methyl-1,3-diazaspiro [4.4] nonan-2 4-dione

A solution of 4-isobutylbenzoic acid (0.130 g, 0.728 mmol), EDC (0.139 g, 0.728 mmol) and HOBt hydrate (0.111 g, 0.728 mmol) in DMF (1.0 mL) was stirred at room temperature for 2 hours. 1-1.5 hours. To the mixture was added (Z) -N'-hydroxy-4 - {(7S) -3-methyl-2,4-dioxo-1,3-diazaspiro [4.4 [nonan-7-yl} benzimidamide (0.200 g, 0.662 mmol) as a solution in 1.0 mL DMF at room temperature. The resulting mixture was heated to about 140 ° C for an additional 2 hours. Solvent was removed under vacuum. The crude product was purified on Prep HPLC system using 20-99% 50 mM NH 4 OAc buffer in 81mL / min acetonitrile to provide (7S) -7- (4- (5- (4-isobutylphenyl) -1.2 , 4-oxadiazol-3-yl) phenyl) -3-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione (0.062 g, 0.139 mmol) as a light brown solid. LCMS (Table 1, Method a) R f = 4.48 min; m / v 445.39 (M + H) *; N NMR (400 MHz, Methane '- d4) δ ppm 7.53-7.39 (m, 4H), 8.15-8.06 (m, 4H), 3.52-3.41 (τπ, 1H), 2.98 (d, J = 3.39 Hz, 3H ), 2.61 (d, J = 7.22 Hz, 2H), 2.46-2.37 (m, 1H), 2.35 δ 2.20 (m, 3H), 2.07-1.90 (m, 3H), 0.95 (d, J = 6.621 g Hz, 6H).

Preparation of (3S) -1-amino-3- (5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl) phenyl) -N-methylcyclopentanecarboxamide

(7S) -7- (4- (5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl) phenyl) -3-methyl-1,3-diazaospiro [4.4] nonan-2,4 -dione (0.052 g, 0.117 mmol) was taken up in dioxane (1.0 mL). To this was added sodium hydroxide (1.0 mL, 2,000 mmol) as 2M solution. The resulting suspension was heated to 120 ° C for about 70 hours, during which time the sodium hydroxide solution was added to induce hydrolysis at completion. Heating was stopped and 10 10 the reaction mixture was concentrated in vacuo. The resulting material was brought into 1-2 mL of DMSO and filtered. The filtrate was purified on Prep HPLC using 30-100% acetonitrile in 50 mM NH 4 Oac buffer at 21 mL / min to yield (3S) -1-amino-3- (5- (4-isobutylphenyl) -1 2,4-oxadiazol-3-yl) phenyl) -N-methylcyclopentanecarboxamide (0.017 g, 0.041 mmol) as a cream solid.

LCMS (Table 1, Method 1) R1 = 1.76min; m / v 419.24 (M + H) *; NI (400MHz, CDCl3) δ ppm 8.11 (dd, J = 9.86.8.34 Hz, 4H), 7.44 (d, J = 8.17 Hz, 2H), 7.32 (d, J = 8.16 Hz, 2H), 7.80- 7.71 (m. 1H), 3.56-3.36 (m, 1H), 2.86 (d, J = 4.81 Hz, 3H), 2.65-2.52 (m, 4H), 2.35-2.23 (m, 1H), 2.05-1.86 ( m, 4H), 1.65-1.55 (m, 1H), 0.94 (d, J = 6.61 Hz, 6H), 1.34-1.17 (m, 1H).

Preparation of 2- (1-amino-3- (4-octylphenyl) cyclopentyl) acetic acid

P CH 2 (QOOH) 2 · NH 4 OAc

^^ s ^^ JLJ EtOH / MeOH

3- (4-Octyl-phenyl) -cyclopentanone, malonic acid (0.076 g, 0.734 mmol), ammonium acetate (0.057 g, 0.734 mmol) were suspended in the ethanol mixture (1.50 mL, 25.7 mmol) and methanol (0.50 mL, 12.36 mmol) in a 2-port round bottom flask equipped with a condenser. The heterogeneous mixture was heated and refluxed at 80 ° C for about 24 hours. Heating has been removed. The crude mixture was taken up in dichloromethane / water mixture (20mL / 20mL). The resulting thin suspension was filtered, washed several times with water and dichloromethane, and vacuum dried to yield 2- (1-amino-3- (4-octylphenyl) cyclopentyl) acetic acid (0.020 g, 0.060 mmol) as a solid cream.

LCMS c Table ι. Method b) Rt = 1.70 min; m / z: 332.30 (M + H) +; 1H nmr (400 MHz, DMSfrdty 6 ppm 8.48 (d, J = 18.37 Hz, 3H), 7.17 (d, J = 8.01 Hz, 2H), 7.06 (d, J = 7.89 Hz, 2H), 3.54-3.00 (m , 1H), 2.85 (d, J = 10.82 Hz, 2H), 2.49-2.44 (m, 2H), 2.32-2.17 (m, 1H), 2.11-1.59 (m, 5H), 1.48 (s, 3H), 1.20 (A, J = 11.44 Hz, 10H), 0.80 (t, J = 6.72, 6.72 Hz, 3H)

Preparation of hept-6-yn-1-ol

2 LAH

To a round bottom flask equipped with a stir bar under N 2 was added LAH (3.61 g, 95 mmol) and anhydrous diethyl ether (300 mL). The mixture was cooled to 0 ° C in a dry ice-acetonitrile bath, a solution of hept-6-ynoic acid (6.00 g, 47.6 mmol) in dry diethyl ether (60.1 mL) was added dropwise. with vigorous agitation. The mixture was then allowed to warm to room temperature and stirred for an additional hour. Then 1M HCl solution (159 mL, 159 mmol) was added dropwise and the reaction mixture was stirred at room temperature for one weekend. The layers were then separated. The aqueous layer was extracted back with diethyl ether (150 mL). The combined organic phase was washed with brine (150 mL), dried (MgSO 4) and concentrated to yield 5.89 g of colorless liquid. The crude liquid was purified by Analogix FCC system using Biotage RS 330 g column, with a gradient of 0-50% ether / petroleum ether for 10 minutes at 40 mL / min then maintained at 50% for 50 minutes. . Product containing fractions were combined and concentrated to yield hept-6-yn-1-ol (4.94 g, 44.0 mmol) as a colorless liquid. The title compound was also prepared according to the procedure described by B. W. Gung etal, Tetrahedron: Asymmetry 2005, 16, 3107-3114.

1H NMR

(400 MHz1 DMSO d6) δ ppm 3.66 (t, J = 6.32, 6.32 Hz, 2H), 2.26-2.17 (m, 2H), 1.98-1.92 (m, 1H), 1.66-1.53 (m, 4H), 1.53 -1.45 (m, 2H)

Preparation of 2- (3-Methoxy-4-methylphenyl) ethanol

2- (3-Methoxy-4-methylphenyl) acidic acid (1g, 5.55 mmol) was dissolved in Tetrahydrofuran (27.7 mL). A solution of borane tetrahydrofuran complex (12.21 mL, 12.21 mmol) was slowly added under nitrogen. The reaction was stirred for about 18 hours. Methanol was slowly extinguishing the reaction. The mixture was rotoevaporated. More methanol was added. The mixture was rotoevaporated. This was repeated twice more. The solution was passed through a short silica gel bed eluting with 1: 1 EtOAc / heptane and then rotoevaporated to give 2- (3-methoxy-4-methylphenyl) ethanol (0.800 g, 4.81 mmol, 87% yield). - tion) as a colorless oil:

1H NMR (400 MHz, COCb) δ ppm 7.07 (dd, 1H), 6.73 (dd, 1H), 6.69 (s, 1H), 3.86 (δ, 2H), 3.30 (s, 3H), 2.84 (t, 2H ), 2.14 (s, 3H), 1.41 (s, 1H)

Preparation of 3- (4-Fluoro-3-methoxyphenyl) propan-1-ol

Ethyl 3- (4-fluoro-3-methoxyphenyl) propanoate (1.019 g, 4.50 mmol) was dissolved in THF (22.52 mL) under nitrogen. A solution of lithium aluminum hydride (4.50 mL, 0.01 mmol) was added slowly. TLC shows reaction done after about 10 minutes. Water (0.35 mL) was slowly added and then the mixture was stirred for 30 minutes. 1N NaOH (1.05 mL) was added and the reaction was stirred for 30 minutes. Additional water (0.35 mL) was added and the solution was stirred and then filtered. The mass was washed with ether and then rotoevaporated. Ether has been added. The solution was dried over magnesium sulfate and then filtered and rotoevaporated. The solution was passed through silica gel with methylene chloride then rotoevaporated ethyl acetate to give 3- (4-fluoro-3-methoxyphenyl) propan-1-ol (0.753 g, 4.09 mmol, 91% yield) as a colorless oil:

MHz, CDCl3Sppra 6.98 (dd, 1H), 6.80 (dd, 1H), 6.71 (ddd, 1H), 3.89 (s, 3H), 3.68 (t, 2H), 2.68 (U 2H). 1.94-1.82 (m. 2H), 1.33 (s. 1H)

Preparation of 3- (2-methoxyphenyl) propan-1-ol

mL). A solution of birane tetrahydrofuran complex (12.21 mL, 12.21 mmol) was added slowly. The reaction was stirred for about 4 hours. Methanol was added and the solvents removed. This process was repeated twice. The solution was passed through a short silica gel bed with 1: 1 ethylheptane acetate, and then rotoevaporated to give 3- (2-methoxyphenyl) propan-1-yl (0.946 g, 5.69 mmol, 103% yield). ) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm

7.19 (dt, 1H), 7.15 (dd, 1H), 6.90 (dt, 1H). 6.86 (d, 1H), 3.84 (s, 3H), 3.60 (t, 2H), 2.73 (t, 2H), 1.92-1.79 (m, 2H), 1.76 (s, 1H),

2- (4-Methoxy-3-methylphenyl) acetic acid (1g, 5.55 mmol) was dissolved in Tetrahydrofuran (27.7 mL). A solution of borane tetrahydrofuran complex (12.21 mL, 12.21 mmol) was slowly added under nitrogen. The reaction was stirred for about 18 hours. Methanol was slowly added to quench the reaction. The solution was rotoevaporated. More methanol was added. The solution was rotoevaporated. This was repeated twice. The solution was passed through a short silica gel bed eluting with 1: 1 EtOAc / heptane and then rotoevaporated to give 2- (4-methoxy-3-methylphenyl) ethanol (0.986 g, 5.93 mmol, 107% yield). ) as an incorlor oil:

HRMN 1 (400

THE

3- (2-Methoxyphenyl) propanoic acid (1.0 g, 5.55 mmol) was dissolved in THF (27.7

Preparation of 2- (4-Methoxy-3-methylphenyl) ethanol I 1 H NMR (400 ΜΗζ, CDCl 3) δ ppm 7.05 (m, 1Η), 7.04 (m, 1Η), 6.80 (m, 1Η), 3.85 (s , 3Η), 3.84 (ι, 2Η), 2.81 (t, 2Η), 2.25 (s, 1Η), 1.64 (s, 1Η)

Preparation of 3- (thiophen-2-yl) propan-1-ol

CV ^ i

OH OH

THE

A solution of borane tetrahydrofuran complex (13.03 mL, 13.03 mmol) was added to THF (29.6 mL). 3- (Thiophen-2-yl) propanoic acid (0.100 g, 0.640 mmol) was dissolved in THF (5 mL) and slowly added to the reaction. The solution was stirred for one night. Methanol was added and then the solution was rotoevaporated. More methanol was added and the solution was rotoevaporated. This was repeated once. The solution was passed through a silica gel layer eluting with ether and then ethyl acetate and unevaporated to give 3- (thiophen-2-yl) propan-1-ol (0.820 g, 5.77 mmol, 97% of production) as a light yellow oil.

1H NMR (400 MHz, CDCB) δ ppm 7.12 (m, 1H), 6.92 (dd, 1H). 6.81 (m.

1H), 3.71 (t, 1H), 2.95 (t, 1H), 2.02-1.87 (m, 1H)

Scheme for preparing furan analogs outlined below:

-O1- ^ or — J? —- Jilx-

Preparation of 1- (4-octylphenyl) but-3-en-1-ol

4-Octylbenzaldehyde (10.0 g, 45.8 mmol) (Aldrich) was dissolved in THF (229 mL) under nitrogen. The reaction was cooled to about 0-5 ° C in an ice bath. A solution of allyl magnesium bromide (48.1 mL, 48.1 mmol) (Aldrich) was added slowly and the reaction stirred for about 2 hours. The reaction was quenched by the addition of saturated ammonium chloride followed by the addition of ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to a cream oil. The residue was dissolved in ether and dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to afford (1- (4-octylphenyl) but-3-en-1-ol (11.54 g, 44.3 mmol, 97% yield) as an oil. light yellow: LC / MS (method f) Rf = 2.90 min; MS m / z: 243.21 (M-water) +.

Preparation of tect-butyldimethyl (1- (4-octylphenyl) but-3-enyloxy) silane

1- (4-octylphenyl) but-3-en-1-ol (11.5 g, 44.2 mmol) and imidazole (3.16 g, 46.4 mmol) were

combined in DMF (221 mL). Tert-butyldimethylchlorosilane (6.66 g, 44.2 mmol) was added and the reaction stirred for about 72 hours. The reaction was quenched by the addition of water and ethyl acetate (500 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 10mL). The combined ethyl acetate extracts were washed with 5% LiCl solution (3x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to afford tert-butyldimethyl (1- (4-octylphenyl) but-3-enyloxy) silane (19.108 g, 51.0 mmol, 115% of production) as a colorless oil. LC / MS (method f) Rf = 5.32, 3.89 min; MS m / z: 243.21 (M-OTBDMS) +.

Preparation of 4- (4-octylphenyl) butane-1,2,4-triol

OH OH

Tert-Butyldimethyl (1- (4-octylphenyl) but-3-enyloxy) silane (19.108 g, 51.0 mmol) and NMO

(7.17 g, 61.2 mmol) were combined in acetone (227 mL) and water (28.3 mL). Osmium tethoxide (32.0 mL, 2.55 mmol) was added and the reaction stirred for about 2 hours. TLC in 1: 1 EtOAc / heptane showed complete reaction. Sodium thiosulfate (8.06 g, 51.0 mmol) was added and the reaction stirred for about 3 hours resulting in a rough black precipitate. The solution was poured into 150 mL silica gel and the product washed entirely or the product washed with ethyl acetate until no product was eluted as shown by TLC (-700 mL EtOAc). The resulting 4- (tert-butyldimethylsilyloxy) -4- (4-octylphenyl) butane-1,2-diol (14.68 g, 35.9 mmol) and desiccants (5 g) (Aldrich) were combined in THF (359 mL) under nitrogen. TBAF (35.9 mL, 35.9 mmol) (Aldrich) was added and the reaction stirred for about 16 hours. The mixture was filtered and the solvents evaporated to afford an orange / brown oil. The oil was passed through a silica gel bed (150 mL) and washed through ethyl acetate. Slowly eluted product and almost 2 L of EtOAc taken by all eluted products. The solvents were removed under reduced pressure to afford 4- (4-octylphenyl) butane-1,2,4-triol (12.045 g, 40.9 mmol, 114% yield) as an orange oil: LC / MS (QC of purity) Rf = 3.89, 3.89 min; MS m / z: 294.40, 294.01 (M + H) +. Preparation of 5- (4-octylphenyl) tetrahydrofuran-3-ol

4- (4-Octylphenyl) butane-1,2,4-triol (12 g, 40.6 mmol) was dissolved in 1,2-dichloroethane (815 mL) under nitrogen. Monohydrate p-toulenesulfonic acid (1.55 g, 8.2 mmol) (TCI) was added and the reaction heated at about 50 ° C for about 3 hours. TLC in 1: 1 EtO-Ac / heptane showed complete (PMA visualization) reaction. The solution was washed with saturated sodium bicarbonate and extracted with methylene chloride (2x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to a yellow oil. The resulting oil was column chromatographed 330 g rediseluting eluting with 20% EtOAc in heptane for 10 minutes declining at 50% for 20 minutes and then retaining at 50% until product was off (monitor at 223 nm due to weak chromophore in longer wavelengths). Solvent removed under reduced pressure to afford 5- (4-octylphenyl) tetrahydrofuran-3-ol (7.36 g, 26.6 mmol, 73.3% yield) as a colorless oil: LC / MS (Method A) Rf = 3.76 min; MS m / z: 277.15 (M + H) +.

Preparation of 5- (4-octylphenyl) dihydrofuran-3 (2H) -one

5- (4-octylphenyl) tetrahydrofuran-3-ol (1 g, 3.62 mmol) was dissolved in dichloromethane

(36.2 mL) in a sealed vial. PCC (3.12 g, 14.47 mmol) (Aldrich) was added and the reaction stirred for about 16 hours. The methylene chloride was evaporated and the residue stirred with ethyl acetate. Ethyl acetate was filtered through a silica gel bed (approx. 50 mL of silica) and product eluted with ethyl acetate. This removed was mostly brown in color. Concentrated and then chromatographed on a 40 g redisp column with 20-50% ethyl acetate in heptane. Removal of solvent under reduced pressure to afford 5- (4-octylphenyl) dihydrofuran-3 (2H) -one (0.839 g, 3.06 mmol, 85% yield) as a colorless oil. LC / MS (Method a) Rf = 4.14 min; MS m / z: 275.25 (M + H) +.

8- (4-octylphenyl) -7-oxa-1,3-diazaspiro [4.4] nonane-2,4-dione

5- (4-octylphenyl) dihydrofuran-3 (2H) -one (0.8 g, 2.92 mmol) in ammonium carbonate

(1.037 g, 13.12 mmol) (Aldrich) were combined in ethanol (12.05 mL) and water (12.05 mL). 10

15

20

25

Potassium cyanide (0.209 g, 3.21 mmol) (FIuka) was added and the reaction heated at about 80 ° C for about 16 hours. The reaction was cooled and concentrated HCl was added acidic (careful for formation of HCN gas). The precipitate was collected by vacuum filtration and washed with water. It was suspended in methylene chloride, filtered, and washed with methylene chloride to afford 8- (4-octylphenyl) -7-oxa-1,3-diazaspiro [4.4] nonane-2,4-dione (0.545 g, 1.582 mmol, 54.3% yield) as a white solid: LC / MS (Method A) Rf = 4.29 min; MS m / z: 343.46 (M-H) -;

Preparation of 3-Amino-5- (4-octylphenyl) tetrahydrofuran-3-carboxylic acid

8- (4-octylphenyl) -7-oxa-1,3-diazaspiro [4.4] nonane-2,4-dione (0.5 g, 1.452 mmol) and sodium hydroxide (10.89 mL, 21 mL, 77 mmol) were combined in water (8.54 mL) and equipped with a reflux condenser. The mixture was heated at about 100 ° C for about 72 hours. The reaction was cooled and acidified with concentrated HCl to pH = 4-5. The product was collected by vacuum filtration and vacuum dried. The residue was purified by flash column chromatography (1 x 6 'silica) eluting with 1: 1 EtOAc / (6: 3: 11 CHCl 3 Z MeOH ZNH 4 OH). The product fractions were combined. The solvents were removed under reduced pressure and The resulting solid was collected by vacuum filtration and washed with ether to provide 3-amino-5- (4-octylphenyl) tetrahydrofuran-3-carboxylic acid (0.280 g, 0.877 mmol, 60.4% of ether). yield) as a white solid: LC / MS (Method A) Rf = 3.22 min; MS mZz: 320.25 (M + H) +.

Preparation of (3-amino-5- (4-octylphenyl) tetrahydrofuran-3-yl) methanol

JH

3-Amino-5- (4-octylphenyl) tetrahydrofuran-3-carboxylic acid (0.246 g, 0.770 mmol) was dissolved in THF (15.40 mL). A solution of lithium aluminum hydride (0.770 mL, 1.540 mmol) (Aldrich) was added carefully and the reaction stirred for about 3 hours. The reaction was quenched by the addition of water (60 µl) and stirred for about 30 minutes. 10% NaOH (180 µL) was added and the reaction stirred for about 1 hour. Finally, water (60 pL) was added and the reaction was left overnight. The mixture was filtered through Celite® and the solvents removed under reduced pressure. The residue was purified by flash column chromatography (0.5 "x7" silica) eluting with 10% MeOH in methylene chloride and the combined product fractions. The solvents were removed under reduced pressure to afford (3-amino-5- (4-octylphenyl) tetrahydrofuran-3-yl) methanol (0.1 g, 0.327 mmol, 42.5% yield) as a colorless oil. . LC / MS (Method A) Rf = 3.12 min; MS m / z: 306.42 (M + H) +. Preparation of (3-amino-5-methyl-5- (4-octylphenyl) tetrahydrofuran-3-yl) methanol

swim carefully after THF (17.99 mL) under nitrogen. 3-Amino-5-methyl-5- (4-octylphenyl) tetrahydrofuran-3-carboxylic acid (0.6 g, 1.799 mmol) was added in small portions causing vigorous bubbles. The reaction stirred for about 2 hours. TLC in 10% MeOH in methylene chloride showed complete (Hannessian staining visualization) reaction. The reaction was quenched by the addition of water (200 µl) and the reaction stirred for about 30 minutes. 10% NaOH (0.6 mL) was added and the reaction stirred for about 30 minutes. Finally, water (200 µl) was added and the reaction stirred for about 30 minutes. The resulting solid was collected by vacuum filtration and washed with ether. The filtrate was concentrated to a colorless oil. The residue was purified by flash column chromatography (40 g Redi-Sep) eluting with 10-20% methanol in methylene chloride and the combined product fractions. Solvents were removed under reduced pressure. The residue was redissolved in methylene chloride and filtered through a syringe filter into a vial and washed with methylene chloride. Solvent was removed under reduced pressure to afford (3-amino-5-methyl-5- (4-octylphenyl) tetrahydrofuran-3-yl) methanol (0.192 g, 0.601 mmol, 33.4% yield) as a colorless oil which solidified to a white solid: LCMS (method f) Rf = 2.21 min; MS m / z: 320.50 (M + H) +.

A solution of lithium aluminum hydride (2.70 mL, 5.40 mmol) (Aldrich) was added.

Phosphonate preparation scheme described below: H2 ^ 9 "Bec-t ^ Y * aoc-NH 9

Ο) 3ο ° ί0 f ^ y Da »* - M» itln Γ)

^ 65% (fV ^ ββ * Λ ^ · - ^ /

jd - xy

C1H17- "^ C1H1 CtH1

ClHl r ^^ f

TFA

TMSBl

HlHrW rV

butyl

Preparation of tert-(1R, 3S) -1- (hydroxymethyl) -3- (4-octylphenyl) cyclopentyl carbamate

((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) methanol (4.72 g, 15.55 mmol) and pyridine (1.384 mL, 17.11 mmol) (Aldrich) were combined in THF (15.55 mL) under nitrogen to give a colorless solution. Di-tert-butyl dicarbonate (3.93 mL, 17.11 mmol) (FIuka) was added and the reaction stirred for about 4 hours and a precipitate formed. TLC in 1: 1 EtOAc / heptane showed complete (KMnO4 visualization) reaction. Ethyl acetate (150 mL) and water (50 mL) were added and the layers separated and extracted with ethyl acetate (2x25 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to a cream mildew. The residue was purified by flash column chromatography (120 g Redi-Sep) eluting with ethyl acetate / heptane and the combined product fractions. The solvent was removed under reduced pressure to provide tert-butyl (1R, 3S- 1- (hydroxymethyl) -3- (4-octylphenyl) cyclopentyl carbamate (4.086 g, 10.12 mmol, 65.1% yield) as a solvent. white solid LC / MS (Method f) Rf = 3.44 min; MS m / z: 404.35 (M + H) +.

Preparation of tert-Butyl (1R, 3S) -1-Formyl-3- (4-octylphenyl) cyclopentylcarbamate tert-Butyl (3-R-3S) -1- (hydroxymethyl) -3- (4-octylphenyl) cyclopentylcarbamate 0.9 g, 9.66 mmol) was dissolved in dichloromethane (193 mL) under nitrogen to give an colorless solution. Dess-Martin periodinane (4.51 g, 10.63 mmol) (Aldrich) was added and the reaction stirred for about 3 hours. LC / MS showed complete reaction. Methylene chloride (100 mL) and water (100 mL) were added and the layers separated and extracted with methylene chloride (2x50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to a cream solid. The residue was purified by flash column chromatography (120 g Redi-Sep) eluting with ethyl acetate / heptane and the combined product fractions. Solvents were removed under reduced pressure to provide tert-butyl (1R, 3S) -1-formyl-3- (4-octylphenyl) cyclopentylcarbamate (3.40 g, 88%) as a white solid: LC / MS (Method F). ) Rf = 3.58 minutes; MS m / z: 401.36 (M + H) +.

Preparation of (1R, 3S) -1 - ((E) -2- (diethoxyphosphoryl) vinyl) -3- (4-

octylphenyl) tert-butyl cyclopentyl carbamate

Sodium hydride (0.020 g, 0.498 mmol) (Alcrich) was stirred in THF (3.32 mL) under

nitrogen to give a colorless suspension. Tetraethyl methylenediphosphonate (0.124 mL, 0.498 mmol) (Aldrich) was added and the reaction stirred for about 30 minutes. Tert-Butyl (1R, 3S) -1-formyl-3- (4-octylphenyl) cyclopentyl carbamate (0.2 g, 0.498 mmol) was added portionwise and the reaction stirred for about 16 hours. Solvents were removed under reduced pressure. Ethyl acetate (50 mL) and water (10 mL) were added and the layers separated and extracted with ethyl acetate (2x10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to a yellow oil. The residue was purified by flash column chromatography (40 g redi-Sep) eluting with ethyl acetate / heptane and the combined product fractions. The solvent was removed under reduced pressure to afford tert-butyl (1R, 3S) -1 - ((E) -2- (diethoxyphosphoryl) vinyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.237 g, 0.442 mmol, 89% yield) as an orange oil: LC / MS (method f) Rf = 3.12 min; MS m / z 553.42 (M + H2 O) +.

Preparation of tert-Butyl (1 R, 3S) -1- (2- (diethoxyphosphoryl) ethyl) -3- (4-octylphenyl) cyclopentylcarbamate

10

Tert-Butyl (1 R, 3S) -1 - ((E) -2- (diethoxyphosphoryl) vinyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.237 g, 0.442 mmol) was dissolved in ethanol. Palladium on carbon (0.094 g, 0.088 mmol) was added and the reaction was fluid with hydrogen and hydrogenate at atmospheric pressure for about 72 hours. The solution was filtered through a syringe filter and washed with methanol. Solvent was removed under atmospheric pressure to provide tert-butyl (1R, 3S) -1- (2- (diethoxyphosphoryl) ethyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.236 g, 0.439 mmol, 99% yield) as a colorless oil: LC / MS (method f) Rf = 3.60; MS m / z: 538.53 (M + H) +.

Preparation of 2 - ((1R, 3S) -1-Amino-3- (4-octylphenyl) cyclopentyl) ethylphosphonic acid

^ t ^ OH

HsH Γ xQH

T-Butyl (1 R, 3S) -1- (2- (diethoxyphosphoryl) ethyl) -3- (4-octylphenyl) cyclopentyl carbamate (0.236 g, 0.439 mmol) was dissolved in dichloromethane (4.39 mL) under nitrogen to give a colorless solution. Bromotrimethylsilane (0.569 mL, 4.39 mmol) (Aldrich) was added and the reaction stirred for about 4 hours. Solvents were removed under reduced pressure. Methanol (4 mL) and water (0.2 mL) were added and the solution was stirred for about 16 hours. Solvents were removed under reduced pressure to give a brown oil / solid. Water was added and the solution sonicated while rubbing the sides of the container. The solution was stirred with a stir bar for about 1 hour. The resulting solid was collected by vacuum filtration and washed with water and then pentane to provide 2- ((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) ethylphosphonic acid (-, 150 g, 0.393 mmol 90% yield) as a cream solid under vacuum drying at 60 ° C: LC / MS (method a) Rf = 3.15 min; MS m / z 382.27 (M + H) +.

Preparation of (E) -2 - ((1R, 3S) -1-Amino-3- (4-octylphenyl) cyclopentyl) vinylphosphonic acid (0.2 g, 0.373 mmol) (10035787-0263) was dissolved in dichloromethane ( 3.73 mL) in a sealed vial to give a colorless solution. Bromotrimethylsilane (0.484 mL, 3.73 mmol) (FIuka) was added and the reaction stirred for about 16 hours. Solvents were removed under reduced pressure to a dense oil. Methanol (4 mL) and water (0.2 mL) were added. The solution was stirred for about 4 hours. Added water (5 mL) and more precipitated products. The resulting solid was collected by vacuum filtration, washed with water and then pentane and vacuum dried to provide (E) -2 - ((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) acid vinylphosphonic acid (0.117 g, 0.308 mmol, 83% yield) as a white solid: LCMS (method a) Rf = 3.01 min; MS m / z: 380.21 (M + H) +.

Preparation of diethyl 2 - ((1 R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) ethylphosphonate

Ή *

Tert-Butyl (1R, 3S) -1-2- (diethoxyphosphoryl) ethyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.2 g, 0.372 mmol) was dissolved in dichloromethane (1.860 mL) in a sealed vial. give a colorless solution. TFA (1.860 mL) was added and the reaction stirred for about 1 hour. Solvents were removed under reduced pressure. Methylane chloride (25 mL) and saturated sodium bicarbonate (25 mL) were added and the layers separated and extracted with methylene chloride (2x10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The oil was dissolved in ether (15 mL). 1 M HCl in dioxane (3 mL) was added. Solvents were removed under reduced pressure. The solid was redissolved in water and lyophilized. The resulting white / bronze solid was suspended in ether and the resulting solid was collected by vacuum filtration and washed with ether then heptane to provide 2 - ((1R, 3S) -1-amino-3- (4-octylphenyl) diethyl cyclopentyl) ethylphosphonate (0.0787 g, 0.180 mmol, 48.4% yield) as a white solid under vacuum drying: LCMS (method a) Rf = 3.46 min; MS m / z: 438.48 (M + H) +.

Preparation of tert-Butyl 2- (4- (4-bromophenyl) -1H-1,2,3-triazol-1-yl) acetate

jCr "-X *

NaN3, CuSO4

Ju -O ^ -

air L-Proline, Na2C03

Sodium L-Ascorbate

A 5 mL microwave reaction vessel equipped with a pressure-release septum cap was charged with tert-butyl 2-bromoacetate (0.408 mL, 2.76 mmol) and sodium azide (0.215 g, 3.31 mmol). ) in water (0.552 mL) and DMSO (4.97 mL) at room temperature. The resulting suspension was heated at 65 ° C for 15 hours. The reaction was allowed to cool to room temperature and ice was added in one portion. The resulting solid was removed by filtration to give tert-butyl 2- (4- (4-bromophenyl) -1H-1,2,3-triazol-1-yl) acetate (0.868 g, 2.57 mmol, 93%). LCMS (method c) Rf = 2.35 min; MS m / z 338.340 (M + H) +.

Preparation of tert-Butyl 2- (4- (4- (oct-1-ynyl) phenyl) -1H-1,2,3-triazol-1-yl) acetate

^ κ F1O ^ "

W (MeCN) 10a

JOJ ^^

A 25 mL round bottom flask equipped with a reflux condenser equipped with a nitrogen inlet adapter was charged with 2- (4- (4-bromophenyl) -1H-1,2,3-triazol-1-yl) tert-butyl acetate (0.200 mg, 0.591 mmol), bis-acetonitrile-palladium (II) chloride (0.003 g, 0.012 mmol), dicycloexyl (2 ', 4', 6'-triidopropylbiphenyl-2-yl) phosphine (0.017 g 0.035 mmol), and cesium carbonate (0.674 g, 2.07 mmol). The flask was evacuated and filled with nitrogen and then acetonitrile (12 mL) and 1-octine (0.228 g, 2.07 mmol) were each added dropwise via syringe. The resulting mixture was heated at 100 ° C for 72 hours. The reaction was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography (elution with ethyl acetate in heptane) to afford 2- (4- (4- (oct-1-ynyl) phenyl) -1H-1,2,3-triazole Tert-butyl acetate (0.15 g, 0.304 mmol, 51% yield) as a solid: LCMS (method a) Rf = 3.89 min; MS m / z: 368 (M + H) +. Preparation of tert-Butyl 2- (4- (4- (octylphenyl) -1H-1,2,3-triazol-1-yl) acetate

Jy ^ p «oHfe N == K

N-N1

M ^

(NH4) aCO3

A 50 mL round-bottom flask equipped with a rubber septum outfitted with a hydrogen-filled flask was charged with 2- (4- (4- (oct-1-ynyl) phenyl) -1H-1,2, Tert-Butyl 3-triazol-1-yl) acetate (0.083 g, 0.226 mmol), Pd (OH) 2 (3.17 mg, 0.023 mmol), and ammonium carbonate (0.217 g, 2.259 mmol) in ethanol ( 4.5 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 6 hours. The resulting mixture was filtered through a celite bed with the aid of EtOAc. The filtrate was concentrated to give tert-butyl 2- (4- (4- (octylphenyl) -1H-1,2,3-triazol-1-yl) acetate (0.070 g, 0.175 mmol, 78% yield). ) as a solid: LCMS (method a) Rf = 4.20 min; MS m / z: 372 (M + H) + Preparation of 2- (4- (4- (octylphenyl) -1H-1, 2p3-triazol-1-yl) acetic

TFA

Us ". Λ-ΟΗ

CHtCh

A 50 mL round bottom flask equipped with a nitrogen inlet adapter was charged with tert-butyl 2- (4- (4- (octylphenyl) -1H-1,2,3-triazol-1-yl) acetate (0.042 g, 0.113 mmol) and TFA (0.044 mL, 0.565 mmol) in CH 2 Cl 2 (2.261 mL) at room temperature The reaction mixture was allowed to stir at room temperature for 20 hours An additional portion of TFA (0.50 mL, 6.49 mmol) was added and the resulting mixture was allowed to stir at room temperature for an additional 24 hours.The mixture was concentrated to provide a solid which was purified by reverse phase HPLC (elution with MeCN in water) to give 2- (4- (4- (octylphenyl) -1H-1,2,3-triazol-1-yl) acetic acid (0.025 g, 0.079 mmol, 70% yield) as a solid: LCMS (method a) Rt = 3.41 min; MS m / z: 316 (M + H) +.

Preparation of (5R, 7R) -7- (3-iodo-4-methoxyphenyl) -3-oxa-1-azospiro [4.4] nonan-2-one

ICI

MeCN

A 50 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with (5R, 7R) -7- (4-methoxyphenyl) -3-oxa-1-azaspiro [4.4] nonan-2- (0.504 g, 2.038 mmol) in acetonitrile (10.2 mL) to give a colorless solution. The vial was protected from light with aluminum foil. ICI (0.255 mL, 5.10 mmol) was added dropwise via syringe. The resulting solution was allowed to stir at room temperature for 2 hours. Saturated Na 2 S 2 O 3 solution was added in one portion and the mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic phase was separated and washed with NaHCO3 and saturated NaCl. The organic phase was dried over MgSO 4, filtered, and concentrated to give (5R, 7R) -7- (3-iodo-4-methoxyphenyl) -3-oxa-1-azospiro [4.4] nonan-2-one (0.760 g 2.04 mmol, 100% yield) as a solid: LCMS (method a) Rt = 3.21 min; MS m / z 374 (M + H) +.

Preparation of (5R, 7R) -7- (4-hydroxy-3-iodophenyl) -3-oxa-1-azospiro [4.4] nonan-2-one λ

λ

BBr3

CH2CI2

THE'

Hi

A 25 mL round bottom flask equipped with a rubber septum and nitrogen inlet needle was charged with (5R, 7R) -7- (3-iodo-4-methoxyphenyl) -3-oxa-1-azaspiro [4.4] nonan-2-one (0.209 g, 0.560 mmol) in dichloromethane (5.6 mL) to give a colorless solution. BBr3 solution in DMC (1.57 mL, 1.57 mmol) was added dropwise via syringe at 0 ° C. The resulting solution was allowed to stir at 0 ° C for 1 hour. The sample was treated with 0 ° C MeOH and concentrated. The residue was treated with three additional 20 mL portions of MeOH and concentrated after each addition to provide (5R, 7R) -7- (4-hydroxy-3-iodophenyl) -3-oxa-1-azaspiro [4.4] nonan-2-one (0.198 g, 0.551 mmol, 98% yield) as an oily solid: LCMS (method c) Rt = 1.77 min; MS m / z: 358 (M-H) -.

Preparation of (5R, 7R) -7- (2-phenylbenzofuran-5-yl) -3-oxa-1-azospiro [4.4] nonan-2-one

A 100 mL round bottom flask equipped with rubber septum and nitrogen inlet needle was charged with (5R, 7R) -7- (4-hydroxy-3-iodophenyl) -3-oxa-1-azaspiro [4.4] nonan-2-one (0.198 g, 0.551 mmol), bis (triphenylphosphine) palladium (II) chloride (0.039 g, 0.055 mmol), and copper (I) iodide (0.010 g, 0.055 mmol), evacuated and filled with nitrogen, and then Et 3 N (3.84 mL) was added to give a suspension. Ethinylbenzene (0.073 mL, 0.662 mmol) was added dropwise via syringe and the resulting suspension was allowed to stir at room temperature for 6 hours. The suspension was filtered through a bed of celite and concentrated. The residue was triturated with water and washed with three 30 mL portions of water. The resulting solid was air dried to give a solid which was purified by silica gel chromatography (elution gradient with 50% -100% ethyl acetate in heptane) to afford (5R, 7R) -7- (2- phenylbenzofuran-5-yl) -3-oxa-1-azospiro [4.4] nonan-2-one (0.055 g, 0.165 mmol, 30% yield) as a solid: LCM (method a) Rt = 3.86 min. ; MS m / z 351 (M + H) +. Preparation of ((1R, 3R) -1-amino-3- (2-phenylbenzofuran-5-yl) cyclopentyl) methanol

one UOH

Dioxane / Water

A 100 mL round bottom flask equipped with a reflux condenser equipped with a nitrogen inlet adapter was charged with (5R, 7R) -7- (2-phenylbenzofuran-5-yl) -3-oxa-1-azaspiro [4.4] nonan-2-one (0.055 g, 0.165 mmol) in dioxane (2.6 mL). Lithium hydroxide (0.079 g, 3.30 mmol) was added in one portion as a solution in water (0.660 mL). The reaction mixture was heated at 100 ° C for 16 hours and then approximately 1 mL of 4N HCl in dioxane was added. The solution was concentrated and the resulting solid was triturated with 2 mL water and 2 mL EtOAc. The material was filtered through a sintered glass funnel, washed with EtOAc, and air dried to give a powder which was suspended in acetic acid and stirred for 5 minutes. The resulting suspension was filtered through a sintered glass funnel and the filtrate was concentrated to afford ((1R, 3R) -1-amino-3- (2-phenylbenzofuran-5-yl) cyclopentyl) methanol (0.003 g, 0.009 mmol 0.5% yield) as a solid: LCMS (method a) Rt = 2.73 min; MS m / z: 308 (M + HH) +.

Preparation of diethyl (ethoxy (methyl) phosphoryl) methylphosphonate

Ν ^, Ο O ^ / + CIvCI S-BuLi

Cf \ o'N - r6 ^ vO ^

Reference: J. Organomet. Chem. 2002, 662, 83-97. THF (30.0 mL) was cooled to about -78 ° C in a dry ice / acetone bath

under nitrogen. A solution of sec-butyllithium (9.39 mL, 13.15 mmol) was added in one portion. A solution of diethyl methylphosphonate (1.933 mL, 13.15 mmol) dissolved in THF (15 mL) was added dropwise and the reaction stirred for about 1 hour. A solution of methylphosphonic dichloride (0.534 mL, 5.90 mmol) dissolved in THF (15 mL) was added and the reaction stirred for about 2 hours. Ethanol (0.345 mL, 5.90 mmol) was added and the reaction stirred for about 16 hours. Methylene chloride (50 mL) and water (30 mL) were added and the layers separated. The aqueous layer was extracted with methylane chloride (2x20 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless oil. The residue was purified by flash column chromatography (80 g Redi-Sep) eluting with EtOAc. The solvent was changed to 10% methanol / methylene chloride and the product eluted. The solvents were removed under reduced pressure to provide diethyl (ethoxy) methyl) phosphoryl) methylphosphonate (0.676 g, 2.62 mmol, 19.92% yield) as a colorless oil: 1 H NMR

2Η), 1.70 (d, 3Η), 1.35 (t, 9H).

(400 MHz, CDCl3) h (ppm) 4.25-4.05 (m, 6H), 2.41 (dd,

Preparation octylphenyl) cyclopentyl carbamate

in

(1R, 3S) -1 - ((E) -2- (ethoxy (methyl) phosphoryl) vinyl) -3- (4-

MgBrt (Et1O)

5th

Reference: Tet; Lett; 1993, 34, 1585-1588.

Magnesium diethyl bromide etherate (0.120 g, 0.465 mmol) and (

Diethyl (methyl) phosphoryl) methylphosphonate (0.1 g, 0.387 mmol) was combined in THF (1.174 mL) in a sealed vial to give a white suspension. The mixture was stirred for about 15 minutes. Triethylamine (0.060 mL, 0.434 mmol) was added and the reaction stirred for about 30 minutes. Tert-Butyl (1R, 3S) -1-formyl-3- (4-octylphenyl) cyclopentyl carbamate (0.184 g, 0.457 mmol) was added and the reaction stirred for about 72 hours. The reaction was quenched by the addition of 0.1 N HCl (2 mL). Methylene chloride (15 mL) was added and the layers separated. The aqueous layer was extracted with methylene chloride (2x10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless oil. The residue was purified by flash column chromatography (12 g Redi-Sep) eluting with EtOAc and the combined product fractions. The solvents were removed under reduced pressure to provide (1R, 3S) -1 - ((E) -2- (ethoxy (methyl) phosphoryl) vinyl) -3- (4-octylphenyl) cyclopentyl carbamate (0.037 g, 0.073 mmol, 18 89% yield) as a colorless oil: LCMS (method f) Rf = 2.92 min; MS m / z: 506.42 (M + H) +,

1H NMR (400 MHz, CDCl3) δ (ppm) 7.12 (m, 4H), 6.86 (1.1H), 5.77 (UH), 4.80 (s, 1H), 4.10-3.90 (m, 2H), 3.22 (m , 1H), 2.58 (t, 2H), 2.52-2.42 (m, 1H), 1.60 (m, 3H), 1.53 (d, 3H), 1.43 (s, 9H), 1.36-1.24 (m, 14H), 0.89 (t, 3H).

20

Preparation octylphenyl) cyclopentyl carbamate

in

(1R, 3S) -1- (2- (ethoxy (methyl) phosphoryl) ethyl) -3- (4-

(1R, 3S) -1 - ((E) -2- (ethoxy (methyl) phosphoryl) vinyl) -3- (4-octylphenyl) cyclopentyl carbamate (0.037 g, 0.073 mmol) was dissolved in ethanol (1.463 mL). Palladium on carbon (7.79 mg, 7.32 µmol) was added, the reaction was fluid with hydrogen, and hydrogenated at atmospheric pressure for about 16 hours. The mixture was filtered through syringe filter and washed through methanol. The solvents were removed under reduced pressure to afford (1R, 3S) -1- (2- (ethoxy (methyl) phosphoryl) ethyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.047 g, 0.093 mmol, 127% yield) as a colorless oil: LCMS

(Method f) Rf = 2.62 min; MS m / z: 508.38 (M + H) 1 H NMR (400 MHz 1 CDCl 3) δ (ppm) 7.12 (dd, 4H), 4.60 (s, 1H), 4.09 (m, 2H), 3.12 (m, 1H ), 2.57 (1.2H), 2.30 (m, 1H), 2.20-1.55 (m, 13H), 1.48 (d, 3H), 1.45 (s, 9H), 1.35-1.26 (m, 14H), 0.89 ( t, 3H).

Preparation of 2 - ((1R, 3S) -1-Amino-3- (4-octylphenyl) cyclopentyl) ethyl (methyl) phosphinic acid, acetic acid

Reference: J. Med. Chem. 1995, 38, 3313-3331.

Tert-Butyl (1 R, 3S) -1- (2-ethoxy (methyl) phosphoryl) ethyl) -3- (4-octylphenyl) cyclopentylcarbamate (0.047 g, 0.093 mmol) was dissolved in dichloromethane (0.926 mL) in a sealed vial to give a colorless solution. Bromotrimethylsilane (0.060 mL, 0.463 mmol) was added and the reaction stirred for about 16 hours. The solvents were removed under reduced pressure. Water (1 mL) and methanol (5 mL) were added and the reaction stirred for about 4 hours. The solvents were removed under reduced pressure. Water (5 mL) was added and the pH adjusted with ammonium hydroxide to about pH-5. The mixture formed a clear gel. The mixture was frozen and lyophilized. Water was added to dissolve the product. Semi-HPLC in 1 mM ammonium acetate buffer. Product fractions were lyophilized to a white sticky solid which was vacuum dried at 60 ° C. Redissolved in methanol and transferred to a vial. The solvents were removed under reduced pressure and vacuum dried at 35 ° C to give 2 - ((1R, 3S) -1-amino-3- (4-octylphenyl) cyclopentyl) ethyl (methyl) phosphinic acid, acetic acid salt (0.029 g, 0.066 mmol, 71.3% yield) as a colorless opaque solid; LCMS (method g) Rt = 1.80 min;

MS m / z: 508.38 (M + H) +, 1H NMR 400 MHz, CDCl3) δ (ppm) 7.15 (dd, 4H), 3.03 (m, 1H), 2.54 (1.2H), 2.38-2.02 (m 1.88-1.78 (m, 3H), 1.60-1.53 (m, 2H), 1.38-1.22 (m, 14H), 0.89 (t, 3H).

Preparation of 1- (tert-Butoxycarbonylamino) -3- (4-octylphenoxy) cyclopentanecarboxylate

of ethyl Of0 "

ο

DBAO

Ethyl 4-octylphenol (1.019 g, 4.94 mmol), ethyl 1- (tert-butoxycarbonylamino) -3-hydroxycyclopentanecarboxylate (0.9 g, 3.29 mmol) (Pharmacore), and triphenylphosphine (2.73 g, 8 , 23 mmol) (Argonaut) were combined in THF (32.9 mL) and nitrogen. 4A desiccants (3.29 mmol) were added and the reaction stirred about 30 minutes. Di-tert-butyl azodicarboxylate (1.137 g, 4.94 mmol) was added and the reaction stirred for about 18 hours. The reaction was filtered through celite and washed through with methylene chloride. The solvents were removed under reduced pressure to provide an oil. The residue was chromatographed on a 40 g column redisulated with EtOAc / heptane gradient (10-50%). The solvent was removed under reduced pressure to afford ethyl 1- (tert-butoxycarbonylamino) -3- (4-10-octylphenoxy) cyclopentanecarboxylate (1.175 g, 2.55 mmol, 77% yield) as a colorless oil:

LCMS (method f) R 1 = S-SSniin-JMSmZz: 462.44 (M + H) +, 1H NMR

(400 MHz, CDCl 3) δ (ppm) 7.13 (m, 2H), 6.77 (m, 2H), 5.20-4.82 (2 broad s, cis / iris isomers, 1

2.383 mmol) was dissolved in dichloromethane (11.91 mL) under nitrogen. Trifluoracetic acid (11.91 mL, 155 mmol) was added and the reaction stirred for about 2 hours. Solvents were removed under reduced pressure. 1N NaOH was added and extraction with ethyl acetate (2x). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless oil. Column chromatography was done on 40 g 20 redispersed in 20-50% EtOAc in heptane. The solvent was removed under reduced pressure to afford ethyl 1-amino-3- (4-octylphenoxy) cyclopentanecarboxylate (0.554 g, 1.532 mmol, 64.3% yield) as a colorless oil:

H), 4.20 (q, 1H), 2.72-1.98 (m, 3H), 2.52 (t, 2H), 1.58 (m, 2H), 1.45 (m, 5H), 1.33-1.20 (m, 12H), 0.89 (t, 3H).

Preparation of ethyl 1-amino-3- (4-octylphenoxy) cyclopentanecarboxylate

The

The

Ethyl 1- (tert-butoxycarbonylamino) -3- (4-octylphenoxy) cyclopentanecarboxylate (1.1 g, LCMS (method f) Rv = 2.91.3.15 min; MS m / z: 363.56, 363.49 (M + H) +,

1H Rmn 400 MHz, CDCl 3) δ (ppm) 7.10 (m, 2H), 6.82 (m, 2H), 5.00-4.85 (2 m, cis / trans isomers, 1H), 4.26-4.18 (m, 2H) , 2.65-2.54 (m, 3H), 2.45-1.92 (m, 7H), 1.72-1.56 (m, 2H), 1.37-1.24 (m, 14H), 0.91 (1.3H).

Preparation of (1-amino-3- (4-octylphenoxy) cyclopentyl) methanol (A-1007664.0)

Ethyl 1-amino-3- (4-octylphenoxy) cyclopentanecarboxylate (0.554 g, 1.532 mmol) was dissolved in THF (15.32 mL) exposed to air. A solution of lithium aluminum hydride 5 (1.532 mL, 3.06 mmol) was added carefully and the reaction mixed for about 2 hours. The reaction was quenched with water (0.116 mL) and stirred for about 30 minutes. 1N NaOH (0.350 mL) was added and the reaction mixed for about 30 minutes. An additional amount of water (0.116 mL) was added and the reaction stirred for more than 30 minutes.

The resulting precipitate was removed by syringe filter. The solution was concentrated on a rotavap and then chromatographed on silica gel in 4: 1 EtOAc / (6: 3: 1 CHCl 2 / MeOH / NH 4 OH).

The solvent was removed under reduced pressure to afford (1-amino-3- (4-octylphenoxy) cyclopentyl) methanol (0.335 g, 1.049 mmol, 68.4% yield) as a colorless oil: LCMS

(Method a) R1 = 3.12 min; MS m / z: 321.17 (M + H) +, 1H (400 MHz, CDCl 3) δ (ppm) 7.06 (m, 2H), 6.76 (m, 2H), 4.90-4.75 (2 m, cis / trans isoxners, 1H), 3.56-3.36 (2m, cis / trans isomers, 2H), 2.52 (t, 2H), 2.25-1.66 (m, 9H), 1.61-1.50 (m, 2H), 1.35-1.22 (m, 11H ), 0.89 (t, 3H).

Preparation of (1-Amino-3- (4-octylphenoxy) cyclopentyl) methyl dihydrogen phosphate

(1-Amino-3- (4-octylphenoxy) cyclopentyl) methanol (0.052 g, 0.163 mmol) was dissolved in THF (3.26 mL) in a sealed vial. A solution of lithium bis (trimethylsilyl) amide (0.163 mL, 0.163 mmol) was added carefully and the reaction stirred for about 15 minutes. Tetrabenzyl diphosphate (0.088 g, 0.163 mmol) was added and the reaction stirred for about 20 hours. The white heavy precipitate was removed by vacuum filtration and washed with THF. The filtrate was concentrated and dissolved in acetic acid. Palladium on carbon (0.017 g, 0.016 mmol) was added and the reaction fluid with hydrogen. Hydrogenated at atmospheric pressure for one night. Filtered and concentrated to remove acetic acid. Water is added and sonicated. The resulting solid was collected by vacuum filtration and washed with water to provide (1-amino-3- (4-octylphenoxy) cyclopentyl) methyl dihydrogen phosphate (0.032 g, 0.080 mmol, 49.2% yield) as a bronze solid in vacuum drying at 60 ° C. LCMS

(method a) Rf = 3.10 min; MS m / z: 400.24 (M + H) *, 1H NMR (400 MHz, CDCl3) δ (ppm) 7.2 (d, 2H), 6.83 (d, 2H), 4.98-4.75 <2 m, cis / trans isomers 3.85 (m, 1H), 2.40-1.6 (m, 5H), 1.55 (m, 2H), 1.24 (m, 12H), 0.91 (1.3H).

Claims (22)

1. Formula I <formula> formula see original document page 152 </formula> Formularized by the fact that D is H, N (R5) 2 or OR6; X is CH1 C (CH3) or N; Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or straight or branched (C1 -C10) alkyl; A is H, hydroxy, -CH 2 OH 1 -CH (OH) CH 3, -C (O) -OCH 31 -C (O) (CH 3) 2-, -O (CH 2) t -COOH-, -C (O) -NR 6 , - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, - (CH2) nP (= 0) (O R 7) (O R 7) optionally substituted -CH = CH- P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, COOR 6 or -R 4-COOH 1 where R 4 is (C 1 -C 20) alkylene ) single or branched, single or branched (C1 -C20) alkylene, simple or branched (C1 -C20) alkynylene, (C3 -C20) cycloalkyl, or optionally substituted azetidinyl; R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, C 1 -C 20 alkyl, C 1 -C 2 alkoxy, C 3 -C 20 cycloalkyl substituted alkyl, C 3 cycloalkyl substituted alkoxy -C20), C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, C1 -C20 substituted C1 -C20 alkynyl, aryl, heteroaryl substituted (C2 -C20) alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein R1 and R2 may optionally be substituted with one or more substituents independently selected from (C1 -C20) alkyl, CF3, halo, hydroxy, (C1 -C20) alkoxy, OCF3, and CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C20 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and alkynyl groups in R 1 and R 2 are optionally substituted by oxo or halo; each R 5 is independently H, optionally substituted (C 1 -C 3) alkyl, or phenyl optionally substituted with C 1 -C 10 alkyl (C 1 -C 6); each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl; each R 7 is independently H 1 optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl; m is 1 or 2; n is 1, 2 or 3; t is 1, 2 or 3; and u is 0, 1 or 2; provided that AeD are not both H at the same time; and provided the compound is not <formula> formula see original document page 153 </formula> wherein X is CH or N; Y is CH 2, NH 1 N (CH 3) 1 S or 0. A compound according to claim 1, characterized in that: A is H 1 -C (O) -OCH 3, -C (O) NR 61 CN 1 C (O) -NHCH 3 COOR61-R 4 -COOH 1 or optionally substituted azetidinyl wherein R4 is single or branched (C1 -C20) alkylene, single or branched (C1 -C20) alkylene, single or branched (C1 -C20) alkynylene; R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 10 alkyl, C 1 -C 10 cycloalkyl, C 3 -C 20 cycloalkyl substituted alkyl, C 3 -C 10 cycloalkyl substituted alkoxy, C 2 -C 10 alkenyl, aryl substituted C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl substituted C 2 -C 10 alkynyl, aryl substituted C 1 -C 10 alkyl, Heteroaryl-substituted C1-C10), aryl-substituted (C1-C10) Bcoxy, heteroaryl-substituted (C1-C10) Blcoxy, (C1-C10) alkyl-substituted aryl, aryl-alkyl and aryl-substituted arylalkyl; wherein such groups R1 and R2 may be optionally substituted with C1 -C10 alkyl, halo, hydroxy, C1 -C10 alkoxy, or CN; wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C10 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein the alkyl, alkenyl and alkynyl groups in R 1 and R 2 are optionally substituted by oxo or halo. A compound according to claim 2, characterized in that the compound is a formula of formula Ia: <formula> formula see original document page 154 </formula> Formula Ia and isomers, stereoisomers, esters, prodrugs and pharmaceutically acceptable salts thereof, wherein; X is CH; Y is CH 2 or O; A is -C (O) -OCH 3, -COOH, -R 4 -COOH 1 -C (O) NHCH 3, or optionally substituted azetidinyl; wherein R4 is single or branched (C1-C10) alkylene, single or branched (C1-C10) alkylene, or single or branched (C1-C10) alkylene; R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, (C 1 -C 10) alkylthio (C 1 -C 10) alkylthio (C 3 -C 10) cycloalkyl substituted alkyl, C 3 -C 10 alkoxy substituted alkoxy ) 1 (C 2 -C 10) alkenyl, aryl substituted C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl substituted C 2 -C 10 alkynyl, aryl substituted C 1 -C 10 alkyl (C 1 -C 10) alkyl; ) substituted with heteroaryl, aryl substituted (C1-C10) alkoxy, heteroaryl-substituted (C1 -C10) alkoxy, (C1-C10) substituted alkyl, arylalkyl and aryl-substituted arylalkyl; wherein such groups R1 and R2 may be optionally substituted with C1 -C10 alkyl, CF3, halo, hydroxy, C1 -C10 alkoxy, or CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C10 alkyl group; wherein one of R1 and R2 is other than hydrogen; wherein the alkyl, alkenyl, and alkynyl and R2 groups are optionally substituted with 0x0 or halo; and n is 1 or 2. A compound according to claim 3, characterized in that Y is CH 2; <formula> formula see original document page 155 </formula> A is -CH2-COOH, COOH or R1 and R2 are independently selected from the group consisting of hydrogen, (C1 -C10) alkyl, (C2 -C10) alkenyl ), (C 2 -C 10) alkynyl and aryl substituted (C 1 -C 10) alkyl; wherein such groups R1 and R2 may be optionally substituted with C1-10 alkyl, halo, hydroxy, C1 -C6 alkoxy, or cyano; wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen; wherein one of R1 and R2 is other than hydrogen. A compound according to claim 4, characterized in that X is CH; Y is CH 2; A is COOH; R1 is (C1 -C10) alkyl, (C2 -C10) alkenyl or (C2 -C10) alkynyl; R2 is H; and Compound according to claim 5, characterized in that the compound is <formula> formula see original document page 155 </formula> A compound according to Claim 1, characterized in that Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or C1 -C6 alkyl); A is H, -CH 2 OH, -CH 2 OH 1 -C (O) -OCH 31 - (CH 2) n P (= 0) (0R 7) (0 R 7) optionally substituted, - (CH 2) n-0-P (= 0) (0 R 7) (O R 7) optionally substituted -CH = CH-O-P (= O) (O R 7) (O R 7) or CN; R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, single or branched (C 1 -C 10) alkyl, C 1 -C 10 alkoxy substituted alkyl, C 3 -C 10 cycloalkyl substituted alkyl, C 3 -C 10 cycloalkyl substituted alkoxy, (C 2 -C 10) alkenyl, aryl substituted C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl substituted C 2 -C 10 alkynyl, aryl, aryl substituted C 1 -C 10 alkyl ) substituted with heteroaryl, aryl substituted alkoxy, heteroaryl substituted alkoxy, C 1-10 alkyl-substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, cyano and —O-indolizinyl; wherein such groups R1 and R2 may be optionally substituted with one or more substituents independently selected from single or branched C1 -C10 alkyl, halo, hydroxy, C1 -C20 alkoxy, OCF3, and CN; wherein one or more of the carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C6 alkyl group); wherein one of R1 and R2 is other than hydrogen; and wherein the alkyl, alkenyl, and alkynyl groups in R2 are optionally substituted by oxo or halo; R 6 is independently selected from H or optionally substituted (C 1 -C 2) alkyl; R 7 is independently selected from H or optionally substituted (C 1 -C 2) alkyl; and u is 1 or 2. A compound according to claim 1, characterized in that the compound is a compound of Formula Ib: wherein; X is CH or N; Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or C1 -C20 alkyl; A is -CH2-OH1 -CH2-P (= 0) (0R7) (0R7) optionally substituted or -CH2-O-P (= (0) (0R7) (0R7) optionally substituted R1 and R2 are independently selected from from the group consisting of hydrogen, halo, (C1-C20) alkyl, (C1-C20) alkoxy, (C3-C20) substituted alkylC1-C20-cycloalkyl-substituted (C1-C20) alkyloxy ), aryl substituted C 2 -C 20 alkyl, C 2 -C 20 alkynyl, aryl substituted C 2 -C 20 alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy aryl substituted aryl, arylalkyl and aryl substituted arylalkyl, wherein such groups R 2 may be optionally substituted with C 1 -C 20 alkyl, halo, hydroxy, C 1 -C 20 alkyl or cyano; carbon atoms in groups R1 or R2 may be independently substituted with oxygen no peroxide, sulfur or NR8; wherein R8 is hydrogen or C1 -C20 alkyl group; and wherein alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo. A compound according to claim 7, characterized in that X is CH; Y is CH 2; A is -CH 2 OH, - (CH 2) n -O-P (= 0) (O R 7) (O R 7) optionally substituted or - (CH 2) n - P (= O) (O R 7) (O R 7) optionally substituted; R1 and R2 are independently selected from the group consisting of hydrogen, halo, single or branched (C1-C10) alkyl, aryl substituted alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl (C1-C10), arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl; wherein such groups R 1 and R 2 may be optionally substituted with one or more substituents selected from C 1 -C 10 alkyl, halo and C 1 -C 10 alkoxy; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen; wherein one of R1 and R2 is other than hydrogen; and wherein the alkyl, alkenyl and alkynyl groups in R2 are optionally substituted by oxo or halo; each R 6 is independently selected from H or optionally substituted (C 1 -C 2) alkyl; and u is 1 or 2. A compound according to claim 9, characterized in that A is -CH 2 OH or - (CH 2) n -O-P (= O) (O R 7) (O R 7) optionally substituted; D is NH 2; R1 and R2 are independently selected from the group consisting of hydrogen, optionally substituted (C1 -C10) alkyl; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen; wherein one of R1 and R2 is other than hydrogen; m is 1; and u is 1. Compound according to Claim 10, characterized in that the compound is <formula> formula see original document page 158 </formula> 12. Compound CHARACTERIZED because of the formula <formula> formula see original document page 158 </formula> <formula> formula see original document page 159 </formula> A pharmaceutical composition characterized in that it comprises a compound of Formula I <formula> formula see original document page 159 </formula> each; Wherein D is H1 N (R5) 2 or OR6; X is CH1 C (CH3) or N; Y is CH 2, O, S or NR 3; wherein R3 is hydrogen, or straight or branched (C1 -C10) alkyl A is H, hydroxy, -CH2 OH, -CH (OH) CH3, -C (O) -OCH3, -C (O) (CH3) 2-, -O (CH 2) r COOH-, -C (O) -NR 6, - (CH 2) n P (= 0) (0 R 7) (0 R 7) optionally substituted, - (CH 2) n-0-1 P (= 0) (0 R 7 ) (0R7) optionally substituted, -CH = CH-P (= 0) (0R7) (0R7) optionally substituted, -CH = CH-P (= 0) (0R7) (0R7), C (O) -NHCH3 , CN, COOR6 or -R4-COOH1 wherein R4 is single or branched (C1 -C20) alkylene, single or branched (C1 -C20) alkenylene, single or branched (C1 -C20) alkynylene, (C3 -C20) cycloalkyl, or azetidinyl optionally substituted; R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, (C 1 -C 20) alkyl, (C 1 -C 2) cycloalkyl substituted alkyl (C 3 -C 20) cycloalkyl substituted (C 3 -C 20) alkoxy ), C 2 -C 20 alkenyl, aryl substituted C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl substituted C 2 -C 20 alkynyl, aryl substituted C 2 -C 20 alkyl, heteroaryl substituted alkyl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -0-indolizinyl, wherein such R 1 and R 2 groups may be optionally substituted with one or more substituents independently selected from (C1 -C20) alkyl, CF3, halo, hydroxy, (C1 -C20) alkoxy, OCF3, and CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C20 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and alkynyl and R 2 groups are optionally substituted by oxo or halo; each R5 is independently H, optionally substituted C1-C3 alkyl, or optionally substituted phenyl (-C (O) -O-C1-C3 alkyl); each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl; each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl; m is 1 or 2; n is 1, 2 or 3; t is1,2 or 3, and u is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier. A method of treating a disorder characterized by administering to a patient in need thereof a therapeutically effective amount of one or more compounds of Formula I. D is H, N (R5) 2 or OR6; X is CH, C (CH 3) or N; Y is CH 2, O, S or NR 3; wherein R3 is hydrogen, or single or branched C1 -C10 alkyl; A is H, hydroxy, -CH 2 OH 1 -CH (OH) CH 3, -C (O) -OCH 3, -C (O) (CH 3) 2-, -O (CH 2) t-COOH-, -C (O) - NR6, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, -CH = CH-P (= O) (O R 7) (O R 7) optionally substituted, -CH = CH-P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, COOR 6 or -R 4 -COOH, wherein R 4 is ClioIene ( Single or branched (C1-C20), single or branched (C1-C20) alkylene, single or branched (2-6C) alkynylene (C3 -C20) cycloalkyl, or optionally substituted azetidinyl; R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, (C 1 -C 20) alkyl, C 1 -C 4 alkoxy substituted alkyl, C 3 -C 20 cycloalkyl substituted alkyl, C 3 -C 8 cycloalkyl substituted alkoxy C20) alkenyl, C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl substituted aryl, heteroaryl substituted alkyl , substituted alkyl alkoxy, substituted heteroaryl alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -0-indolizinyl, wherein such groups R 1 and R 2 may optionally be substituted. with one or more substituents independently selected from C1 -C20 alkyl, CF3, hslo, hydroxy, C1 -C20 alkoxy, OCF3, and CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C6 alkyl group); wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and alkynyl groups in R 2 are optionally substituted by oxo or halo; each R5 is independently H, optionally substituted (C1 -C3) alkyl, or optionally substituted -C (O) -O-C1 -C3 alkyl; each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl; each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl; m is 1 or 2; n is 1, 2 or 3; t is 1, 2 or 3; and u is 0, 1 or 2; or a pharmaceutically acceptable solvent, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof. A method according to claim 14, characterized in that the disorder is rheumatoid arthritis, lupus, Crohn's disease, asthma, diabetes, pain or psoriasis. A method of treating a central nervous system disorder. A method of treating a patient in need thereof of a therapeutically effective amount of one or more compounds of Formula I wherein D is H1 N (R®) 2 or OR6; X is CH1 C (CH3) or N; Y is CH 2, O 1 S or NR 3; wherein R3 is hydrogen, or single or branched C1 -C10 alkyl; A is H 1 hydroxy, -CH 2 OH 1 -CH (OH) CH 3 1 -C (O) -OCH 3 1 -C (O) (CH 3) 2-, -O (CH 2) t -COOH-, -C (O) -NR 6, - (CH2) nP (= 0) (0R7) (0R7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, -CH = CH-P (= 0) ( Optionally substituted 0R7 (0R7), -CH = CH-P (= 0) (0R7) (0R7), C (0) -NHCH3, CN1 COOR6 or -R4-COOH1 where R4 is single (C1-C20) alkylene or branched, single or branched (C 1 -C 20) alkylene, single or branched C 1-4 alkynylene (C 3 -C 20) cycloalkyl, or optionally substituted azetidinyl; R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3 halo, (C 1 -C 20) alkyl, C 1 -C 20 cycloalkyl-substituted alkyl, C 3 -C 20 cycloalkyl substituted alkoxy , C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl, aryl substituted alkyl, heteroaryl substituted alkyl , aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl such that R 1 and R 2 groups may optionally be substituted. with one or more substituents independently selected from (C1-C20) alkyl, CF3l halo, hydroxy, (C1-C20) alkoxy, OCF3 and CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R8 is hydrogen or C1 -C20 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and alkynyl groups in R 2 are optionally substituted by oxo or halo; each R5 is independently optionally substituted H1 C1 -C3 alkyl, or phenyl optionally substituted with -C (O) -0-C1 -C3 alkyl; each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl; each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl; m is 1 or 2; n is 1, 2 or 3; t is 1, 2 or 3; and u is O 1 1 or 2; or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof. A method of treating multiple sclerosis. A method comprising treating a patient in need thereof with a therapeutically effective amount of one or more compounds as described in claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof. 18. Pharmaceutical Packing characterized in that it comprises one or more compounds as described in Formula I wherein <formula> formula see original document page 163 </formula> D is H, N (R5) 2 or OR6; X is CH1 C (CH3) or N; Y is CH 2, O, S or NR 3; wherein R3 is hydrogen or straight or branched (C1 -C10) alkyl; AH, hydroxy, -CH 2 OH, -CH (OH) CH 3, -C (O) -OCH 3, -C (O) (CH 3) 2-, -O (CH 2) t -COOH-, -C (O) -NR 6 , - (CH2) nP (= 0) (OR7) (OR7) optionally substituted, - (CH2) n-0-P (= 0) (0R7) (0R7) optionally substituted, -CH = CH-P (= 0 ) (O R 7) (O R 7) optionally substituted, -CH = CH-P (= O) (O R 7) (O R 7), C (O) -NHCH 3, CN, COOR 6 or -R 4 -COOH, wherein R 4 is C 1 -C 6 alkylene) single or branched, single or branched (C 1 -C 20) alkylene, single or branched C 1-4 alkynylene (C 3 -C 20) alkyl, or optionally substituted azetidinyl; R 1 and R 2 are independently selected from the group consisting of hydrogen, CF 3, halo, C 1 -C 20 alkyl, C 1 -C 20 cycloalkyl, C 3 -C 20 cycloalkyl substituted alkyl, C 3 cycloalkyl substituted alkoxy -C20), C2 -C20 alkenyl, aryl substituted C2 -C20 alkenyl, aryl substituted C2 -C20 alkynyl, aryl substituted C2 -C20 alkynyl, aryl substituted alkyl, C4-substituted alkyl heteroaryl, aryl substituted alkoxy, heteroaryl substituted alkoxy, alkyl substituted aryl, arylalkyl, aryl substituted arylalkyl, arylalkyl substituted arylalkyl, CN and -O-indolizinyl. such groups R1 and R2 may optionally be substituted with one or more substituents independently selected from (C1 -C20) alkyl, CF3 halo, hydroxy, C1 -C4 alkoxy, OCF3 and CN; wherein one or more carbon atoms in groups R1 or R2 may be independently substituted with non-peroxide oxygen, sulfur or NR8; wherein R 8 is hydrogen or C 1 -C 20 alkyl group; wherein one of R1 and R2 is other than hydrogen; and wherein alkyl, alkenyl, and alkynyl groups in R 2 are optionally substituted by oxo or halo; each R 5 is independently H 1 optionally substituted (C 1 -C 3) alkyl, or phenyl optionally substituted with -C (O) -Oa (C 1 -C 3) alkyl; each R 6 is independently H or optionally substituted (C 1 -C 2) alkyl; each R 7 is independently H, optionally substituted (C 1 -C 2) alkyl or optionally substituted phenyl; m is 1 or 2; ne 1,2 or 3; t is 1, 2 or 3; and u is O 1 1 or 2; or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof. Pharmaceutical package according to claim 18, characterized in that the compound or compounds are present in a therapeutically effective amount. 20.Composed By the fact that it is of Formula 2, Formula 3 or Formula 4 <formula> formula see original document page 164 </formula> 21. Compound CHARACTERIZED because it is of Formula 5, Formula 6, Formula 7, Formula 8, Formula 9 or Formula 10 <formula> formula see original document page 164 </formula> 22. Compound CHARACTERIZED because it is of Formula 11 or Formula 12 <formula> formula see original document page 165 </formula>