AU2013206281A2 - Sulphur-linked compounds for treating ophthalmic diseases and disorders - Google Patents

Abstract

Provided are sulphur-linked compounds, pharmaceutical compositions thereof, and methods of treating ophthalmic diseases and disorders, such as age-related macular degeneration and Stargardt's Disease, using said compounds and compositions.

Description

H:\fmt\Imenoven\NRPortbi\DCC\FMT524123 I _.DOC-I 1/06/2013 SULPHUR-LINKED COMPOUNDS FOR TREATING OPHTHALMIC DISEASES AND DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/094,841, filed on September 5, 2008, and U.S. Provisional Patent Application No. 61/197,065, filed on October 22, 5 2008, both of which are incorporated by reference in their entirety. [0001a] This is a divisional of Australian Patent Application No. 2009288087, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Neurodegenerative diseases, such as glaucoma, macular degeneration, and Alzheimer's disease, 10 affect millions of patients throughout the world. Because the loss of quality of life associated with these diseases is considerable, drug research and development in this area is of great importance. [00031 Macular degeneration affects between ten and fifteen million patients in the United States, and it is the leading cause of blindness in aging populations worldwide. Age-related macular degeneration (AMD) affects central vision and causes the loss of photoreceptor cells in the central part of retina 15 called the macula. Macular degeneration can be classified into two types: dry-type and wet-type. The dry-form is more common than the wet; about 90% of age-related macular degeneration patients are diagnosed with the dry-form. The wet-form of the disease and geographic atrophy, which is the end-stage phenotype of dry AMD, causes the most serious vision loss. All patients who develop wet-form AMD are believed to previously have developed dry-form AMD for a prolonged 20 period of time. The exact causes of age-related macular degeneration are still unknown. The dry form of AMD may result from the senescence and thinning of macular tissues associated with the deposition of pigment in the macular retinal pigment epithelium. In wet AMD, new blood vessels grow beneath the retina, form scar tissue, bleed, and leak fluid. The overlying retina can be severely damaged, creating "blind" areas in the central vision. 25 [0004] For the vast majority of patients who have the dry-form of macular degeneration, no effective treatment is yet available. Because the dry-form precedes development of the wet-form of macular degeneration, therapeutic intervention to prevent or delay disease progression in the dry-form AMD would benefit patients with dry-form AMD and might reduce the incidence of the wet-form. [0005] Decline of vision noticed by the patient or characteristic features detected by an ophthalmologist 30 during a routine eye exam may be the first indicator of age-related macular degeneration. The formation of "drusen," or membranous debris beneath the retinal pigment epithelium of the macula is often the first physical sign that AMD is developing. Late symptoms include the perceived distortion of straight lines and, in advanced cases, a dark, blurry area or area with absent vision appears in the center of vision; and/or there may be color perception changes. 35 [00061 Different forms of genetically-linked macular degenerations may also occur in younger patients. In other maculopathies, factors in the disease are heredity, nutritional, traumatic, infection, or other ecologic factors. [0007] Glaucoma is a broad term used to describe a group of diseases that causes a slowly progressive visual field loss, usually asymptomatically. The lack of symptoms may lead to a delayed diagnosis

I

H:\fmt\Intenvoven\NRonbl\DCC\FMT\5241231_1.DOC-l11/06/2013 of glaucoma until the terminal stages of the disease. The prevalence of glaucoma is estimated to be 2.2 million in the United States, with about 120,000 cases of blindness attributable to the condition. The disease is particularly prevalent in Japan, which has four million reported cases. In many parts of the world, treatment is less accessible than in the United States and Japan, thus glaucoma ranks as 5 a leading cause of blindness worldwide. Even if subjects afflicted with glaucoma do not become blind, their vision is often severely impaired. la WO 2010/028088 PCT/US2009/055785 5 100081 The progressive loss of peripheral visual field in glaucoma is caused by the death of ganglion cells in the retina, Ganglion cells are a specific type of projection neuron that connects the eye to the brain. Glaucoma is usually accompanied by an increase in intraocular pressure. Current treatment includes use of drugs that lower the intraocular pressure; however, contemporary methods to lower the intraocular pressure are often insufficient to completely stop disease progression. Ganglion cells are believed to be susceptible to 10 pressure and may suffer permanent degeneration prior to the lowering of intraocular pressure. An increasing number of cases of normal-tension glaucoma are observed in which ganglion cells degenerate without an observed increase in the intraocular pressure. Current glaucoma drugs only treat intraocular pressure and are ineffective in preventing or reversing the degeneration of ganglion cells. [00091 Recent reports suggest that glaucoma is a neurodegenerative disease, similar to Alzheinr's disease and 15 Parkinson's disease in the brain, except that it specifically affects retinal neurons. The retinal neurons of the eye originate from diencephalon neurons of the brain. Though retinal neurons are often mistakenly thought not to be part of the brain, retinal cells are key components of the central nervous system, interpreting the signals from the light-sensing cells. [0010] Alzheimer's disease (AD) is the most common form of dementia among the elderly. Dementia is a brain 20 disorder that seriously affects a person's ability to carry out daily activities. Alzheimer's is a disease that affects four million people in the United States alone. It is characterized by a loss of nerve cells in areas of the brain that are vital to memory and other mental functions. Currently available drugs can ameliorate AD symptoms for a relatively period of time, but no drugs are available that treat the disease or completely stop the progressive decline in mental function. Recent research suggests that glial cells that support the 25 neurons or nerve cells may have defects in AD sufferers, but the cause of AD remains unknown. Individuals with AD seem to have a higher incidence of glaucoma and age-related macular degeneration, indicating that similar pathogenesis may underlie these neurodegenerative diseases of the eye and brain. (See Giasson et al., Free Radic. Biot. Med. 32:1264-75 (2002); Johnson et al., Proc. Nati. Acad. Scl. USA 99:11830-35 (2002); Dentchev et al., Mol. Vis. 9:184-90 (2003)). 30 [00111 Neuronal cell death underlies the pathology of these diseases. Unfortunately, very few compositions and methods that enhance retinal neuronal cell survival, particularly photoreceptor cell survival, have been discovered. A need therefore exists to identify and develop compositions that that can be used for treatment and prophylaxis of a number of retinal diseases and disorders that have neuronal cell death as a primary, or associated, element in their pathogenesis. 35 [0012] In vertebrate photoreceptor cells, the irradiance of a photon causes isomerization of 11 -cis-retinylidene chromophore to all-trans-retinylidene and uncoupling from the visual opsin receptors. This photoisomerization triggers conformational changes of opsins, which, in turn, initiate the biochemical chain of reactions termed phototransduction (Filipek et al., Annu. Rev. Physiol. 65:851-79 (2003)), Regeneration of the visual pigments requires that the chromophore be converted back to the 1 1-cis-configuration in the 40 processes collectively called the retinoid (visual) cycle (see, e.g., McBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). First, the chromophore is released from the opsin and reduced in the photoreceptor by retinol dehydrogenases. The product, all-trans-retinol, is trapped in the adjacent retinal pigment epithelium (RPE) in the form of insoluble fatty acid esters in subcellular structures known as retinosomes (Imanishi et al., J. Cell Bio. 164:373-87 (2004)). 45 [00131 In Stargardt's disease (Allikmets et al., Nat Genet. 15:236-46 (1997)), a disease associated with mutations in the ABCR transporter that acts as a flippase, the accumulation of all-trans-retinal may be responsible for 2 WO 2010/028088 PCT/US2009/055785 5 the formation of a lipofuscin pigment, A2E, which is toxic towards retinal pigment epithelial cells and causes progressive retinal degeneration and, consequently, loss of vision (Mata et al., Proc. Natl. Acad. Sci. USA 97:7154-59 (2000); Weng et al., Cell 98:13-23 (1999)). Treating patients with an inhibitor of retinol dehydrogenases, 13-cis-RA (Isotretinoin, Accutane@, Roche), has been considered as a therapy that might prevent or slow the formation of A2E and might have protective properties to maintain normal vision 10 (Radu et al., Proc. NatL Acad. Sci. USA 100:4742-47 (2003)). 13-cis-RA has been used to slow the synthesis of 1 1-cis-retinal by inhibiting 1 1-cis-RDH (Law et al., Biochem. Biophys. Res. Commun. 161:825-9 (1989)), but its use can also be associated with significant night blindness. Others have proposed that 13-cis-RA works to prevent chromophore regeneration by binding RPE65, a protein essential for the isomerization process in the eye (Gollapalli et al., Proc. Nat. Acad. Sci. USA 101:10030-35 (2004)). 15 Gollapalli et al. reported that 13-cis-RA blocked the formation of A2E and suggested that this treatment may inhibit lipofuscin accumulation and, thus, delay either the onset of visual loss in Stargardt's disease or age-related macular degeneration, which are both associated with retinal pigment-associated lipofuscin accumulation. However, blocking the retinoid cycle and forming unliganded opsin may result in more severe consequences and worsening of the patient's prognosis (see, e.g., Van Hooser et al., J. Biol. Chem. 20 277:19173-82 (2002); Woodruff et al., Nat. Genet. 35:158-164 (2003)). Failure of the chromophore to form may lead to progressive retinal degeneration and may produce a phenotype similar to Leber Congenital Amaurosis (LCA), is a very rare genetic condition affecting children shortly after birth. SUMMARY OF THE INVENTION 100141 A need exists in the art for an effective treatment for treating ophthalmic diseases or disorders resulting in 25 ophthalmic disfunction including those described above. In particular, there exists a pressing need for compositions and methods for treating Stargardt's disease and age-related macular degeneration (AMD) without causing further unwanted side effects such as progressive retinal degeneration, LCA-like conditions, night blindness, or systemic vitamin A deficiency. A need also exists in the art for effective treatments for other ophthalmic diseases and disorders that adversely affect the retina. 30 [00151 In one embodiment is a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R-33)" Rk.Y Z N R12

R

1 Formula (I) wherein, Z is a bond, -C(R')(R 2 )-, -C(R)(R' 0

)-C(R')(R

2 )-, -X-C(R 3 )(R)-, -C(R)(R'")-C(R')(R 2

)-C(R)(R

7 )-, 35 X-C(R )(R 32 )-C(R')(R)- or -C(R")(R)-X-C(R')(R1)-; Y is -SO 2

NR*

0 -, -S-C(R 4 )(R"s)-, -S(=O)-C(R 4

)(R'

5 )-, or -S(=0)rC(R M(R")-; R1 and R 2 are each independently selected from hydrogen, halogen, C 1

-C

5 alkyl, fluoroalkyl, -OR 6 or NRR 0 ; or R' and R 2 together form an oxo;

R

3 1 , R 3 , R 3 and R" are each independently selected from hydrogen, C 1

-C

5 alkyl, or fluoroalkyl; 40 R" is selected from hydrogen, alkyl, alkonyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached hotorocyclyl; or R* and R, together with the nitrogen atom to which they are attached, form a heterocycle; 3 WO 2010/028088 PCT/US2009/055785 5 each R'" and R" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R1" together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, Rs and either one R14 or R' 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; R36 and R 37 are each independently selected from hydrogen, halogen, C-C5 alkyl, fluoroalkyl, -OR 6 or 10 NR 7

R

5 ; or R' and R' together form an oxo; or optionally, R3 6 and R' together form a direct bond to provide a double bond, or optionally, R 6 and R' together form a direct bond, and R 7 and R2 together form a direct bond to provide a triple bond; R' and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R3 and R 4 together with the carbon atom to which they are 15 attached, form a carbocyclyl or heterocyclyl; or RW and R 4 together form an imino;

R

5 is C-Cls alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R' and R are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R", SOR", COR1" or SO2NR 4 "; or R' and R together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 20 X is -0-, -8-, -S(--O)-, -S(=O)-, -N(R'0)-, -C(O)-, -C(=CH2)-, -C(=N-NR")-, or -C(=N-O0)-;

R

9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR'R! or carbocyclyl; or R 9 and R' form an oxo; or optionally, R? and R' together form a direct bond to provide a double bond; or optionally, R! and R' together form a direct bond, and R" and R 2 together form a direct bond to provide a triple bond; 25 R'" and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R1, SO 2 R", C0211" or SONR' 4 R"; or R" and R12, together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R1 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 , R"0, R and R0 is independently hydrogen or alkyl; 30 each RM and R25 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R3" is independently selected from halogen, OR 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 100161 In another embodiment is the compound of Formula (la); (R 33 )n Xl RkY Z N12

R

11 Formula (la) 35 wherein, Z is -C(R 9 )(R'")-C(R')(R2)- or -O-C(RM) Y is -SO 2

NR

40 -, -S-C(R14)(R 5 )-, -S(=O)-C(R'4)(R")-, or -S(=0)rC(R'4)(R )-; R' and R2 are each independently selected from hydrogen, halogen, CI-C, alkyl, fluoroalkyl, -OR 6 or NR7R8; or RI' and R2 together form an oxo; 40 R3 and R3" are each independently selected from hydrogen, CI-C5 alkyl, or fluoroalkyl; R3 and R" are each independently selected from hydrogen or alkyl; or RW and R4 together form an imino; R5 is C-Cis alkyl or carbocyclyalkyl; 4 WO 2010/028088 PCT/US2009/055785 5 R 7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R"; or R 7 and RW, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; Ro and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR 7 R or carbocyclyl; or R? and R 10 together form an oxo; R1 and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R; or R" and 10 R1 2 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 and R 4 are independently hydrogen or alkyl; each R 33 is independently selected from halogen, -0R, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 15 [0017] In another embodiment is the compound of Formula (lb): (R 33)n R17 1 R 1

R

2

R

11

R

18 Y '9 4%R R10R 3

R

4 Formula (Ib) wherein, Y is -S-C(R 4 )(R")-, -S(=O)-C(R')(R")-, or -3(=O)rC(R1)(R")-; R' and R 2 are each independently selected from hydrogen, halogen, CI-C, alkyl, fluoroalkyl, -OR 6 or 20 NR 7 R'; or R' and R 2 together form an oxo; R3 and R 4 are each independently selected from hydrogen or alkyl; or R and R4 together form an imino;

R

7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R; or R7 and R', together with the nitrogen atom to which they are attached, form an N-heterocyclyl; R9 and R1' are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR7R' or 25 carbocyclyl; or R9 and R10 together form an oxo; R" and R 2 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R"; or R" and R 2, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R' 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each Re and R3 4 are independently hydrogen or alkyl; 30 R1 4 and R" are each independently selected from hydrogen or alkyl;

R'

6 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R'1, together with the carbon to which they are attached form a carbocyclyl, or a heterocyclyl; R" is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 3 is independently selected from halogen, -OR, alkyl, or fluoroalkyl; and 35 n is 0, 1, 2, 3, or 4. [0018] In a further embodiment is the compound wherein n is 0 and each of R" and R' 2 is hydrogen. In a further embodiment is the compound wherein each of R3, R 4 , R 4 and R" is hydrogen. 10019] In a further embodiment is the compound wherein, R' and R2 are each independently selected from hydrogen, halogen, CI-CS alkyl, -OR 6 ; 40 R! and R10 are each independently selected from hydrogen, halogen, alkyl, -OR 6 ; or R? and R1' together form an oxo; each R 6 is independently hydrogen or alkyl;

R

6 and R", together with the carbon to which they are attached, form a carbocyclyl; and 5 WO 2010/028088 PCT/US2009/055785 5 R" is selected from a hydrogen, alkoxy or hydroxy. [00201 In a further embodiment is the compound wherein R' 6 and R", together with the carbon to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R' is hydrogen or hydroxy. [0021] In another embodiment is the compound wherein R" is hydrogen and R' 2 is -C(=O)R' 3 , wherein R1 3 is 10 alkyl. 10022] In a further embodiment is the compound wherein, R' and R 2 are each independently selected from hydrogen, halogen, C 1

-C

5 alkyl, or -OR 6 ; R! and R1 0 are each independently selected from hydrogen, halogen, alkyl, or -OR 6 ; or R' and R1 0 together form an oxo; 15 each R 6 is independently selected from hydrogen or alkyl;

R

6 and R", together with the carbon atom to which they are attached, form a carbocyclyl; and R'8 is hydrogen, hydroxy or alkoxy. [00231 In a further embodiment is the compound wherein n is 0; R' and R", together with the carbon atom to which they are attached, form an optionally substituted 20 cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R'8 is hydrogen or hydroxy. [0024] In a further embodiment is the compound wherein, R' and R 2 are each independently selected from hydrogen, halogen, C-C 5 alkyl or -OR; R! and R' 0 are each independently selected from hydrogen, halogen, alkyl, or -OR; or R 9 and R' 0 together 25 form an oxo; each RW is independently hydrogen or alkyl;

R'

6 and R1 7 are each independently alkyl; and R" is hydrogen, hydroxy or alkoxy. [0025] In another embodiment is the compound having the structure of Formula (Ic): (R Y R R12 30

R

3

R

4 Formula (Ic) wherein, Y is -S-C(R 4 )(R)-, -S(=0)-C(R')(R)-, or -S(=O)2-C(R'4)(R")-; R1 and R 32 are each independently selected from hydrogen, C-C 5 alkyl, or fluoroalkyl;

R

3 and R 4 are each independently selected from hydrogen or alkyl; or R 3 and R 4 together form an imino; 35 R" and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl, or -C(=O)R1 3 ; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl;

R

3 is selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; R1 4 and R" are each independently selected from hydrogen or alkyl; R 6 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R16 and R 1 , 40 together with the carbon atom to which they are attached, form a carbocyclyl, or heterocyclyt; R 'a is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyt; each R 3 3 is independently selected from halogen, -OR 3 4 , alkyl, or fluoroalkyt;

R

34 is hydrogen or alkyl; and 6 WO 2010/028088 PCT/US2009/055785 5 n is 0, 1, 2,3, or4. [0026] In another embodiment is the compound wherein n is 0 and each R'" and R' 2 is hydrogen. [0027] In another embodiment is the compound wherein each R 3 , 4 , R1 4 and R' 5 is hydrogen. [00281 In another embodiment is the compound wherein,

R

3 1 and R 32 are each independently hydrogen, or C-C 5 alkyl; 10 R' and R , together with the carbon atom to which they are attached, form a carbocyclyl; and

R

1 8 is hydrogen, hydroxy, or alkoxy. [0029] In another embodiment is the compound wherein R' and R, together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R" is hydrogen or hydroxy. 15 [0030] In another embodiment is the compound wherein, R' and R 2 are each independently selected from hydrogen, or C-C 5 alkyl; and R is hydrogen, hydroxy or alkoxy. [0031] In another embodiment is the compound having the structure of Formula (Id): (RI)n R 1 6 R 3 2 RI1

R

18 Y X ( 'R12

R

3

R

4 Formula (Id) wherein, 20 Y is -S-C(R 1 4 )(R")-, -S(=0)-C(R 4

)(R

3 )-, or -S(=0)rC(R")(R")-; X is -S-, -S(=O)-, -S(=O)-, -N(R 30 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR 3 5 )-, or -C(=N-OR)-; R and R32 are each independently selected from hydrogen, C 1 -C, alkyl, or fluoroalkyl;

R

3 and R 4 are each independently selected from hydrogen or alkyl; or R 3 and R 4 together form an imino; R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, or -C(=0)R; or R" and 25 R2, together with the nitrogen atom to which they are attached, form an N-heteroyclyl;

R

3 is selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;

R

4 and R' 5 are each independently selected from hydrogen or alkyl; R 16 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R", together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; 30 R'8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 3 is independently selected from halogen, -OR 34 , alkyl, or fluoroalkyl; It 3 , R3 and Rs are each independently hydrogen or alkyl; and n is 0, 1, 2, 3, or 4. [0032] In another embodiment is the compound wherein n is 0 and each R 1 and R 2 is hydrogen, In a further 35 embodiment is the compound wherein each R 3 , R4, R1 4 and R1 5 is hydrogen. [00331 In another embodiment is the compound wherein, R3' and R 32 are each independently hydrogen, or C 1 -C5 alkyl;

R

6 and R 7 , together with the carbon atom to which they are attached, form a carbocyclyl; and R is hydrogen, hydroxy, or alkoxy. 40 [0034] In a further embodiment is the compound wherein R1 6 and R 7 , together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and

R

8 is hydrogen or hydroxy. 7 WO 2010/028088 PCTIUS2009/055785 5 [0035] In a further embodiment is the compound wherein, R 3 1 and R 3 2 are each independently selected from hydrogen, or C 3 -CS alkyl; and R8 is hydrogen, hydroxy or alkoxy. 10036] In a further embodiment is the compound having the structure of Formula (Ie): (R33.

R

4 0 -O 3

R

4 R R 1 6 Na X- 1 R1a 0 0 R 1 Formula (le) wherein, 10 Z is -C(R 9

)(R'

0 )-C(R')(R)- or -O-C(R3)(R3)-; R' and R2 are each independently selected from hydrogen, halogen, Ci-C 5 alkyl, fluoroalkyl, -OR6 or NRR 8 ; or R' and R2 together form an oxo; R3 and R4 are each independently selected from hydrogen or alkyl; or R3 and R4 together form an imino; R? and R8 are each independently selected from hydrogen, alkyl, carbocyclyl or -Cq-0)R; or R and R 8 , 15 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; R! and R0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NRR' or carbocyclyl; or R9 and R10 form an oxo; or optionally, R? and R' together form a direct bond to provide a double bond; or optionally, R9 and R' together form a direct bond, and R10 and R2 together form a direct bond to provide a triple bond; 20 R and R32 are each independently selected from hydrogen, C3-Cs alkyl, or fluoroalkyl; R" and R12 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R"; or R" and R1 2 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R"13 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R( and R4 are independently hydrogen or alkyl; 25 R16 and R1" are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or 1R36 and R"7, together with the carbon to which they are attached form a carbocyclyl, or a heterocycly; or optionally, R40 and either one of R,16 or R", form a heterocycle; R's is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R3 is independently selected from halogen, -OR34, alkyl, or fluoroalkyl; 30 R(4 is selected from hydrogen or alkyl; or optionally, R40 and either one of R 6 or R', form a heterocycle; and n is 0, 1, 2, 3, or 4. (0037] In a further embodiment is the compound having the structure of Formula (If): (R3)n R1

NH

2

R

18 0 R 9

R

10 Formula (f) 35 wherein, R9 and R10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NRR or carbocyclyl; or R9 and R10 together form an oxo; RW and R' are each independently selected from hydrogen, alkyl, carbocyclyl or -CQ=O)R 13 ; or R7 and R, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 8 WO 2010/028088 PCT/US2009/055785 5 each R and R 4 are independently hydrogen or alkyl; R" and R' 5 are each independently selected from hydrogen or alkyl;

R'

6 and R", together with the carbon to which they are attached form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; R1 8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; 10 each R 3 is independently selected from halogen, -OR , alkyl, or fluoroalkyl; and n is 0, 1, or 2. 10038] Tn a specific embodiment is a compound selected from: N H2NH co

NH

2

NH

2 , HNH2

SNH

2

~

3 N ~NH 2 c0 S

NH

2 5S S NH 2 NH2 OH

NH

2

NH

2

NH

2

~NH

2 N H 2 '

N

2 0 00 H K N Q N, -' NH 2 2000 N~ H2 N H 2 O H OH NH 0 OH HK#~ H 9 WO 2010/028088 PCT/US2009/055785 5-C NH 2

->NH

2 si NH 2 NH 2 OH Io : H OH I9, NH OH

NH

2 - H K)OH 0) ii 9H N H 2 10

CH

3 OH NHDc BrNH2

NH

2 1 )OH OHl 0 H O osl CH OH

NH

2 ~ 0..-' ,

NH

2 OH Q~J6 OH ~ OH 3 ~ OH

NH

2

NH

2

NI-ILN

2 C~r S I NH 2 1OH OH N

CF

3 OF -8~ NH 2 s ~ NH 2 0 COH NH 150 WO 2010/028088 PCTJUS2009/055785 s H 110

NH

2 (N:~

NH

2 ii D NH 5 OHD K OH D NH 2 0NH 2 OH 0 OH" D DD s NH 2 D DDDO NH D WN 0 JOYNN H D D LDD0 D D D D )D D D DD NNH 03,, -0 OH OOH OHH ii NH 2 N 10 C o-

N

2 NH2 N H 2 -~~-'~S .- - NH 2 00 rj l_ NH 2 ..-

NH

2 0' N N H oH O\ 1NH 2 11 C- , NH 2 N 15 H 0 .- NH 2 N H 0SI 0 11 WO 2010/028088 PCT/US2009/055785 loo NH.- N 5 0 NH N - NH 2 . -- 9,C:1,IO NH 2 ) OH SO NH 2 c~~ 'O H S 0 0 NH I o1 NH 2 S H 2 -.--. NH 2 10 0r HO OH N' NH N" N NH 2 J H 9j , NH 2 '. II 0 9I NH 2 NH 0 (r8 OH I.- NH 2 (::N' :)y -,NH 2 15 0K0i0 0 ~N 8

N'NH

2 0 i~ NH 2 K-OH k! 0 OH 0 OH 12 WO 2010/028088 PCT/US2009/055785 9i0 N NH 2 0 i NH2 OH 0- OHO O H O I NH 2 OH I NH 2

CH

3 OH ONI NH 2 sN 2 8I OH NH NH 2 0 OH 0 01 N NH 2

NNH

2 O 0 0 s

NH

2 NNH 10OH 0 OH 100

'INH

2

NH

2 F F 01

NH-

2 11NH N.' 0 OH OHF HO N' NH 2 N"N' S,,NH 2 -: s S0 II FOF 0 OH 1 WO 2010/028088 PCT/US2009/055785 OH9 0 OH I NH S-r ' O -- NHz SJ:: 5 0 OH 0 OH9 NH 2 OH s NH 2 OH 0 OHI NH 2 OHO I N , H 2 8 OH 0 OH OHs I TH OHo ,H, OH O y NH 2 S S It 0 0 0 OH IOHO 0

,_NH

2 11(: ,,T..... NH 2 K0 OH 0 OH OH OH9 0 H 10 rt~s~NH 2 11NH 2 NH s

H

2 sNH 2 P O 0 0H

N

0 N o 0 NH,",C::),,, NH 2 ~-0 OH OH

NH

2 0NH 2 OH 0 OH 15 Cr ~OH oK'OH sNH 2 0NH 2 C OH 0 OH 14 WO 2010/028088 PCTIUS2009/055785 F F No N

SNH

2 11NH 2 OH 0 OH 5 NF

OHNH

2 S0 OH 2 OH C o OH 11 N N, N I NH 2 S S 11 11 0 OH 0 OH N DH OH 2 D DO HNH D N oNH 2 j(:

NH-

2 0IS OH OH

NH

2 Nil 2 10 C o OH OH NH2 T- NH 2 0 0 OH )T00 OH NH2 NH 2 NHOH 00 O 0 N

NH

2 NH 2 00 OH 0 O OH 0 0 N

NH

2 NH 2 - 0 OH 0 O is WO 2010/028088 PCT/US2009/055785

NH

2 -N H 5 OH 0 OH 0I NO NH2 NH 2 0 0 Nan %lC) O [0039] In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically 10 acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R). R3 Y Zr N,

R

11 Formula (1) wherein, Z is a bond, -C(R')(R 2 )-, -C(R 9

)(R

1 )-C(R')(R)-, -X-C(R 31 )(R')-, -C(R 9

)(R'

0

)-C(R')(R

2

)-C(R)(R

7 )-, X-C(R")(R")-C(R')(R2)- or -C(R")(R)-X-C(RM)(R")-; 15 Y is -SO 2 NRO-, -S-C(R 4 )(R)-, -S(=O)-C(R' 4 )(R")-, or -S(=0)r C(R'4)(R')-; R' and R 2 are each independently selected from hydrogen, halogen, C-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7

R

8 ; or R' and R 2 together form an oxo;

R

3 , R 3 , R 3 8 and R are each independently selected from hydrogen, C-C 5 alkyl, or fluoroalkyl;

R

4 0 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached 20 heterocyclyl; or R" and R3, together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R" is independently selected from hydrogen, alkyl, alkenyL, alkynyL, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R'4 and R" together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R14 or R's, together with the carbon atom to which they are attached, form a carbocycle or heterocycle; 25 R3 6 and R 3 7 are each independently selected from hydrogen, halogen, C-C, alkyl, fluoroalkyl, -OR 6 or NR 7 R'; or R6 and R" together form an oxo; or optionally, R 6 and R' together form a direct bond to provide a double bond; or optionally, R 6 and R' together form a direct bond, and R 3 7 and R2 together form a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 30 carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is C 2 -Cs alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R 7 and R 8 are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=0)R 3 ,

SO

2

R'

3 , CO 2 R or SO 2

NR

2 4

R

5 ; or R' and R' together with the nitrogen atom to which they are attached, 35 form an N-heterocyclyl; X is -O, -S-, -S(=O)-, -S(=0)-, -N(R 3 )-, -C(=0)-, -C(=CH 2 )-, -C(=N-NRs)-, or -C(=N-OR')-; 16 WO 2010/028088 PCT/US2009/055785 5 R! and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NR 7 R or carbocyclyl; or R and R' 0 form an oxo; or optionally, R 9 and R 1 together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond;

R'

1 and R 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R, SO 2 R', CO2R" 10 or S0 1

NR

24

R

2 ; or R" and R' 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R' 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, hoteroaryl or heterocyclyl; each R, R', R' and R" 5 is independently hydrogen or alkyl; each R 24 and R is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 15 carbocyclyl or heterocyclyl; each R 3 3 is independently selected from halogen, ORE, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [00401 In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a 20 pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R 33)r Rq. Y L ZR 'R 12

R

11 Formula (I) wherein, Z is a bond, -C(R')(R 2 )-, -C(R 9

)(R'

0

)-C(R')(R

2 )-, -X-C(Rl)(Rz)-, -C(R)(R')-C(R')(R 2 )-C(R)(R)-, X-C(R')(R)-C(R')(R 2 )- or -C(R 3 e)(R")-X-C(R 3 )(R')-; 25 Y is -SO 2 NR4-, -S-C(R'4)(R'')-, -S(=O)-C(R1 4 )(R)-, or -S(=0)rC(R")(R")-; R' and R 2 are each independently selected from hydrogen, halogen, C 1 -Cs alkyl, fluoroalkyl, -OR 6 or NR 7

R

8 ; or R' and R 2 together form an oxo;

R

3 , R 3 , R 8 and R" are each independently selected from hydrogen, C-C, alkyl, or fluoroalkyl;

R

4 is selected from hydrogen, alkyl, alkenyt, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached 30 heterocyclyl; or R 4 0 and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R' and R' 5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R 1 4 and R 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R and either one R' 4 or R 15 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; 35 R 36 and R 7 are each independently selected from hydrogen, halogen, C 1

-C

5 alkyl, fluoroalkyl, -OR 6 or NRR'; or R and R together form an oxo; or optionally, R" and R' together form a direct bond to provide a double bond; or optionally, R 36 and R' together form a direct bond, and R 37 and R2 together form a direct bond to provide a triple bond; R3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroary], 40 carbocyclyl or C-attached heterocyclyl; or R 3 and R4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or RW and R 4 together form an imino;

R

5 is C-C, 5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 17 WO 2010/028088 PCTIUS2009/055785 5 each R 7 and R 8 are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R,

SO

2

R

3 ", CO 2 R" or SO 2

NR

24 R"; or R' and R' together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -O-, -S-, -S(=O)-, -S(=O)r, -N(R 30 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR)-, or -C(=N-OR 35 )-;

R

9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR'R' or 10 carbocyclyl; or R? and R' 0 form an oxo; or optionally, R 9 and RI together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and RI 0 and R 2 together form a direct bond to provide a triple bond; R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R", SO2R, COzR 3 or SO 2

NNR

2 s; or R" and R', together with the nitrogen atom to which they are attached, form an N 15 heterocyclyl; each R 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each RW, R3 0 , R3 4 and R" is independently hydrogen or alkyl; each R 24 and t 25 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 20 each R 33 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [00411 In a further embodiment is the method wherein the ophthalmic disease or disorder is a retinal disease or disorder. In an additional embodiment is the method wherein the retinal disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. In an additional embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, 25 retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, and a retinal disorder associated with AIDS. In an additional 30 embodiment is the method wherein the ophthalmic disease or disorder is selected from diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury. [00421 In an additional embodiment is the method of inhibiting at least one visual cycle trans-cis isomerase in a cell comprising contacting the cell with a compound of Formula (I) as described herein, thereby inhibiting 35 the at least one visual cycle trans-cis isomerase. In a further embodiment is the method wherein the cell is a retinal pigment epithelial (RPE) cell. [00431 In a further embodiment is the method of inhibiting at least one visual cycle trans-cis isomerase in a subject comprising administering to the subject the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a 40 pharmaceutically acceptable solvate, hydrate, salt N-oxide or prodrug thereof: (R 33).,I Rq. xa V ,AKR1 Y Z i

R

11 Formula (1) wherein, 18 WO 2010/028088 PCT/US2009/055785 5 Z is a bond, -C(R')(R 2 )-, -C(R)(R'"-C(R')(R 2 )-, -X-C(R)(R 32 )-, -C(R 9

)(R'

0

)-C(R')(R

2

)-C(R

3 6 )(R)-, X-C(R)(R 3

)-C(R')(R

2 )- or -C(R")(R1)-X-C(Re)(R2)-; Y is -SO 2

NR

4 0 -, -S-C(R)(R)-, -S(=O)-C(R)(R' 5 )-, or -S(=0)2-C(R1)(R')-; R' and R2 are each independently selected from hydrogen, halogen, CI-Cs alkyl, fluoroalkyl, -OR 6 or NR 7 R ; or R' and R 2 together form an oxo; 10 R 1 , R 2 , R 8 and R" are each independently selected from hydrogen, CI-Cs alkyl, or fluoroalkyl; R40 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R40 and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and RIS is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R' 5 together with the carbon atom to which 15 they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R14 or R 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle;

R

3 6 and W are each independently selected from hydrogen, halogen, C-Cs alkyl, fluoroalkyl, -OR 6 or NR 7 Re; or R' and R 3 together form an oxo; or optionally, R's and R' together form a direct bond to provide a double bond; or optionally, R 3 6 and R' together form a direct bond, and R 37 and RW together form 20 a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R and R 4 together form an imino;

R

5 is C2-Cis alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 25 each R 7 and R' are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R 3 ,

SO

2 R', CO2R" or SO 2

NKR

25 ; or R 7 and R' together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=O)-, -N(R 3 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR 3 )-, or -C=N-OR"); R! and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR7RS or 30 carbocyclyl; or R! and W form an oxo; or optionally, R? and R' together form a direct bond to provide a double bond; or optionally, R! and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R" and R' 2 are each independently selected from hydrogen, alkyl, carbocycly], -C(=O)R", SOzR", CO2R' 3 or SO 2

NRR

2 s; or R" and R' 2 , together with the nitrogen atom to which they are attached, form an N 35 heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 , R 30 , R 3 and R 35 is independently hydrogen or alkyl; each R 24 and R is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 40 each R 3 3 is independently selected from halogen, OR, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 100441 In a further embodiment is the method wherein the subject is human. In a further embodiment is the method wherein accumulation of lipofuscin pigment is inhibited in an eye of the subject. In a further embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In a further embodiment is the method wherein degeneration of a retinal cell is inhibited. In a further 45 embodiment is the method wherein the retinal cell is a retinal neuronal cell. In a further embodiment is the method wherein the retinal neuronal coil is a photoreceptor cell, an amacrine cell, a horizontal cell, a 19 WO 2010/028088 PCT/US2009/055785 5 ganglion cell, or a bipolar cell, In a further embodiment is the method wherein the retinal cell is a retinal pigment epithelial (RPE) cell. [0045} In an additional embodiment is a compound that inhibits I 1-cis-retinol production with an IC 50 of about 1 M or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at 10 room temperature. In an additional embodiment, the compound is a non-retinoid compound. In a further embodiment is the compound, wherein the compound inhibits 1 1-cis-retinol production with an IC50 of about 0.1 pM or less. In a further embodiment is the compound, wherein the compound inhibits 1 I-cis retinol production with an IC 50 of about 0.01 pM or less. [0046] In an additional embodiment is a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase 15 reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED5 0 value of I mg/kg or less when administered to a subject. In a further embodiment is the non-retinoid compound wherein the EDs 0 value is measured after administering a single dose of the compound to said subject for about 2 hours or longer. [00471 In a further embodiment is the non-retinoid compound wherein the structure of the non-retinoid compound 20 corresponds to Formula (1) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof (R 33)r X1_ Rk R 5 R 12 Y Z N,

R"

1 Formula (1) wherein, Z is a bond, -C(R')(R2)-, -C(R 9 )(RI")-C(R')(R2)-, -X-C(R")(R)-, -C(R 9

)(R'")-C(R')(R

2

)-C(R')(R

7 )-, 25 X-C(R")(RI)-C(R')(R2)- or -C(R")(R")-X-C(RM)(R2)-; Y is -SO 2 NR4-, -S-C(R4)(R'")-, -S(=O)-C(R')(R")-, or -S(=0)r(R14)(RM) R' and R2 are each independently selected from hydrogen, halogen, C-C5 alkyl, fluoroalkyl, -OR 6 or NR 7 R'; or R' and R' together form an oxo; R, RI, R and RI 9 are each independently selected from hydrogen, C,-CS alkyl, or fluoroalkyl; 30 R 40 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, beteroaryl or C-attached heterocyclyl; or R 40 and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R1 4 and RIs is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or RI' 4 and R' 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R' and either one R1 4 or RI", together 35 with the carbon atom to which they are attached, form a carbocycle or heterocycle;

RI'

6 and R"3 7 are each independently selected from hydrogen, halogen, C-Cs alkyl, fluoroalkyl, -OR or NR 7 R; or R' and R 7 together form an oxo; or optionally, R 36 and R' together form a direct bond to provide a double bond; or optionally, R" and RI' together form a direct bond, and RI3 7 and R2 together form a direct bond to provide a triple bond; 40 R3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R and R 4 together form an imino; R' is C-C,, alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 20 WO 2010/028088 PCTfUS2009/055785 5 each R' and R' are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R' 3 , SO2R, CO2R or SO 2

NR

24 R; or R 7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocycyl; X is -0-, -S-, -S(=O)-, -S(-0)-, -N(R 0 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR')-, or -C(=N-OR 3 s)-; R? and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR', -NR 7 R' or 10 carbocyclyl; or R 9 and R1 0 form an oxo; or optionally, R! and R' together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R, S0 2 R, CO 2 R ' or S0 2

NR

2 4

R

2 5 ; or R" and R1 2 , together with the nitrogen atom to which they are attached, form an N 15 heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each Re, R 30 , R 4 and R is independently hydrogen or alkyl; each R4 and R 2 5 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 20 each R3 is independently selected from halogen, OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 100481 In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits 1 1-cis-retinol production with an ICso of about 1 pM or less when assayed In vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room 25 temperature. In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 50 value of 1 mg/kg or less when administered to a subject. [0049] In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising 30 introducing into a subject a compound of Formula (1) as described herein. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. In another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In yet another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl ethanolamine (A2E). 35 100501 In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a compound that inhibits I 1-cis-retinol production as described herein. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. In another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N retinyl-ethanolamine (A2E). In yet another embodiment is the method wherein the lipofuscin pigment is N 40 retinylidene-N-retinyl-ethanolamine (A2E). [00511 In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a non-retinoid compound that inhibits an I 1-cis-retinol producing isomerase reaction as described herein. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. In another embodiment is the method wherein the lipofuscin 45 pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In yet another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). 21 WO 2010/028088 PCT/US2009/055785 5 [0052] In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits I1 -cis-retinol production with an IC5 0 of about 1 sM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room 10 temperature. In a further embodiment is the method wherein the ophthalmic disease or disorder is age related macular degeneration or Stargardt's macular dystrophy. In a further embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy,optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of 15 prematurity, or ischemia reperfusion related retinal Injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, myopia, and a retinal disorder associated with AIDS. In a further 20 embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. [0053] In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase 25 reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED, 0 value of 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. In a further embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, 30 optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with 35 viral infection, a retinal disorder related to light overexposure, myopia, and a retinal disorder associated with AIDS. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. 100541 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with a compound of Formula (I) as described herein. 40 [00551 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with a compound that inhibits 1 1-cis-retinol production as described herein. [00561 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with a non-retinoid compound that inhibits an 1 -cis-retinol producing 45 isomerase reaction as described herein. [0057] In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of 22 WO 2010/028088 PCT/US2009/055785 5 the retina comprising contacting the retina with a compound of Formula (I) as described herein. [00581 In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of the retina comprising contacting the retina with a compound that inhibits 1 1-cis-retinol production as described herein. 100591 In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of 10 the retina comprising contacting the retina with a non-retinoid compound that inhibits an 11-cis-retinol producing isomerase reaction as described herein. [0060] In a further embodiment is a method of reducing ischernia in an eye of a subject comprising administering to the subject the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable 15 solvate, hydrate, salt, N-oxide or prodrug thereof: (R33), Ri R3 4 R Rk za VN- 1 Y Z

R

1 Formula (1) wherein, Z is a bond, -C(R')(R 2 )-, -C(R')(R')-C(R')(R 2 )-, -X-C(R 3 )(R)-, -C(R 9

)(R'

0

)-C(R')(R

2

)-C(R)(R

7 )-, X-C(R31)(R2)- C(R')(R2)- or -C(R0)(R")-X-C(RW')(R2)-; 20 Y is -SO 2 NR"-, -S-C(R)(R")-, -S(=O)-C(R')(R)-, or -S(=0)-C(R )(R")-; R' and R 2 are each independently selected from hydrogen, halogen, CI-Cs alkyl, fluoroalkyl, -OR 6 or NRR 8 ; or R' and R 2 together form an oxo;

R

1 , R 32 , R and R are each independently selected from hydrogen, C-C 5 alkyl, or fluoroalkyl;

R

4 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, hetcroaryl or C-attached 25 heterocyclyl; or R and RW, together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R's is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R' 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R' 4 or R' 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; 30 R 36 and R 7 are each independently selected from hydrogen, halogen, Cr Cs alkyl, fluoroalkyl, -OR 6 or NR 7 R'; or R 3 and R 37 together form an oxo; or optionally, R 36 and R' together form a direct bond to provide a double bond; or optionally, R 16 and R' together form a direct bond, and R" and R together form a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 35 carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is C-Cis alkyl, carbocyclyalkyl, arylalkyl, heteroaylalkyl or heterocyclylalkyl; each R 7 and R are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R' 3 ,

SO

2 R", CO 2 R" or SO 2 NR4R 5 ; or R 7 and R8 together with the nitrogen atom to which they are attached, 40 form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=0)2-, -N(R 3 )-, -C(=O)-, -C(-CH 2 )-, -C(=N-NRM)-, or -C(=N-OR 35 );

R

9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR 7 RO or carbocyclyl; or R 9 and R1 0 form an oxo; or optionally, R 9 and R' together form a direct bond to provide a 23 WO 2010/028088 PCT/US2009/055785 5 double bond; or optionally, R 9 and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R' and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R", SO 2 R", C0 2

R

1 or SO2NR 4

R

5 ; or R" and R 1 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; 10 each R1 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, beteroaryl or heterocyclyl; each R, R, R 34 and R is independently hydrogen or alkyl; each R 2 4 and R is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R 3 3 is independently selected from halogen, OR1 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 15 [00611 In another embodiment is a method of reducing ischemia in an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits 1 1-cis-etinol production with an IC 50 of about 1 pM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In a further 20 embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby reducing ischemia in the eye. [00621 In another embodiment is a method of reducing ischemia in an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non retinoid compound that inhibits an I 1-cis-retinol producing isomerase reaction, wherein said isomerase 25 reaction occurs in RPE, and wherein said compound has an ED 5 0 value of 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby reducing ischemia in the eye. [00631 In another embodiment is a method of inhibiting neovascularization in the retina of an eye of a subject 30 comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits I 1-cis-retinol production with an IC 5 o of about 1 pM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In a further embodiment is the method wherein the pharmaceutical composition is 35 administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby inhibiting neovascularization in the retina. 100641 In another embodiment is a method of inhibiting neovascularization in the retina of an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase 40 reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 50 value of 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby inhibiting neovascularization in the retina, [00651 In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising 45 contacting the retina with the compound of Formula (I) as described herein. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell. In yet another embodiment is the method wherein 24 WO 2010/028088 PCT/US2009/055785 5 the retinal neuronal cell is a photoreceptor cell. [0066] In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with a compound that inhibits I 1-cis-retinol production with an 1C 5 0 of about 1 gM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room 10 temperature. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell. In yet another embodiment is the method wherein the retinal neuronal cell is a photoreceptor cell. [00671 In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with a non-retinoid compound that inhibits an 11 -cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED5e value of 15 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell. In yet another embodiment is the method wherein the retinal neuronal cell is a photoreceptor cell, [0068] In a further embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically 20 acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: >i~ R 3

$

4 R R12 Y Z N, '

R

1 1 Formula (I) wherein, Z is a bond, -C(R')(R 2 )-, -C(R)(R'*)-C(R')(R 2 )-, -X-C(R)(R 2 )-, -C(R)(R')-C(R)(R 2

)-C(R')(R"

1 )-, 25 X-C(R 3

)(R

3

)-C(R)(R

2 )- or -C(R")(R")-X-C(RM)(R)-; Y is -SO 2 NR*-, -S-C(R'4)(R' 5 )-, -S(=O)-C(R' 4 )(R")-, or -S(=O)-C(R' 4

)(R)

R1 and R 2 are each independently selected from hydrogen, halogen, CrC 5 alkyl, fluoroalkyl, -OR 6 or NRR'; or R' and R 2 together form an oxo;

R

3 , R, R 3 and R are each independently selected from hydrogen, C-C, alkyl, or fluoroalkyl; 30 R 40 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R4 and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R1 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R1 4 or R 1, together 35 with the carbon atom to which they are attached, form a carbocycle or heterocycle; R" and R" are each independently selected from hydrogen, halogen, C,-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7

R

8 ; or R 36 and R 7 together form an oxo; or optionally, R 3 6 and R' together form a direct bond to provide a double bond; or optionally, R 36 and R' together form a direct bond, and R3 7 and R 2 together form a direct bond to provide a triple bond; 40 R 3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is Cr Cis alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 25 WO 2010/028088 PCT/US2009/055785 5 each Rt 7 and R' are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R 3 ,

SO

2 R", CO 2 R" or SONRR 2 ; or R and RW together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -O-, -S-, -S(nO)-, -S(=O)-, -N(R 3 0 )-, -C(=Q)-, -C(=CH 2 )-, -C(=N-NR 3 5 )-, or -C=N-OR") R? and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR7R" or 10 carbocyclyl; or R! and R' 0 form an oxo; or optionally, R? and R 1 together form a direct bond to provide a double bond; or optionally, R and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R" and R 12 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=0)R, SQ 2 R, C0 2

R

1 " or SO 2

NR

2 Re; or R" and R)2, together with the nitrogen atom to which they are attached, form an N 15 heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R6, R 3 0 , R and R 3 1 is independently hydrogen or alkyl; each R 2 and R 25 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 20 each R 33 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. In a further embodiment is the method wherein the lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E). [00691 In another embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically 25 acceptable carrier and a compound that inhibits 1 1-cis-retinol production with an ICso of about 1 iM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In a further embodiment is the method wherein the lipofuscin is N-retinylidene-N-retinyl ethanolamine (A2E). 30 [0070] In another embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an I 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 50 value of 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the 35 lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E). INCORPORATION BY REFERENCE [00711 All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [00721 The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0073] Figure 1 depicts dose-dependent inhibition of 11 -cis-retinol production (as assayed by a human in vitro 26 WO 2010/028088 PCT/US2009/055785 isomerase assay) by the compound of Example 5. 10074) Figure 2 depicts dose-dependent inhibition oft 1-cis-retinol production (as assayed by a human in vitro isomerase assay) by the compound of Example 11. [00751 Figure 3 depicts dose-dependent inhibition of I 1-cis-retinol production (as assayed by a human in vitro isomerase assay) by the compound of Example 14. 100761 Figure 4 depicts dose-dependent inhibition of 1 1-cis-retinol production (as assayed by a human in vitro isomerase assay) by the compound of Example 17. 5 DETAILED DESCRIPTION OF THE INVENTION [0077) Sulphur-linked compounds are described herein that inhibit an isomerization step of the retinoid cycle. These compounds and compositions comprising these compounds are useful for inhibiting degeneration of retinal cells or for enhancing retinal cell survival. The compounds described herein are, therefore, useful 10 for treating ophthalmic diseases and disorders, including retinal diseases or disorders, such as age related macular degeneration and Stargardt's disease. Sulphur-Linked Compounds [0078) In one embodiment is a compound of Formula (1) or tautomer, stercoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (RM) Rq.IfI1 5K 'R 1 2 Y Z$ N 15 R" 1 Formula () wherein, Z is a bond, -C(R')(R2)-, -C(R)(R' 0

)-C(R')(R

2 )-, -X-C(R)(R)-, -C(R)(R'%)-C(R)(R 2

)-C(R

36

)(R

7 )-, X-C(R")(RM)-C(RI)(R2)- or -C(R")(R")-X-CR")(R") Y is -SO 2 NR-, -S-C(R')(R")-, -S(=O)-C(R)(R" 5 )-, or -S(=0)rC(R")(R")-; 20 R' and R2 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7

R

8 ; or R' and R2 together form an oxo;

R

31 , R 2 , R' and R 9 are each independently selected from hydrogen, C-C, alkyl, or fluoroalkyl;

R

0 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R and RW, together with the nitrogen atom to which they are attached, form a heterocycle; 25 each R and R" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R1 4 and R1 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R5 and either one R14 or R", together with the carbon atom to which they are attached, form a carbocycle or heterocycle;

R

6 and R3 7 are each independently selected from hydrogen, halogen, CrC5 alkyl, fluoroalkyl, -OR 6 or 30 NR 7 R; or R" and R 7 together form an oxo; or optionally, RM and R' together form a direct bond to provide a double bond; or optionally, R36 and R' together form a direct bond, and R3 7 and R2 together form a direct bond to provide a triple bond; R) and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R3 and R4 together with the carbon atom to which they are 35 attached, form a carbocyclyl or heterocyclyl; or RW and RW together form an imino; 27 WO 2010/028088 PCT/US2009/055785 5 R5 is CrC 5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R7 and Ro are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R,

SO

2 R", CO 2

R

3 or SO2NR 4

R

2 s; or R7 and R together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=0)-, -N(R 3 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NRM)-, or -C(=N-OR35 10 R 9 and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR', -NR' or carbocyclyl; or RW and R'" form an oxo; or optionally, R! and R 1 together form a direct bond to provide a double bond; or optionally, R9 and R together form a direct bond, and R 0 and R2 together form a direct bond to provide a triple bond; R)" and R 12 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(-O)R, SO 2

R'

3 , CO 2

R

3 15 or SO 2

NR

2 RW; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R', R", R 4 and R is independently hydrogen or alkyl; each R 2 4 and R 25 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 20 carbocyclyl or heterocyclyl; each R 33 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [00791 In another embodiment is the compound of Formula (la):

(R

33 )n R r >t R R1

R

11 Formula (Ia) wherein, 25 Z is -C(R 9 )(R')-C(Rt')(R)- or -O-C( 3

')(R

32 )-; Y is -SO 2 NR4-, -S-C(R 4 )(R")-, -S(=0)-C(R 4 )(R")-, or -S(=0)2-C(R')(R") R1 and R2 are each independently selected from hydrogen, halogen, C-C 5 alkyl, fluoroalkyl, -OR' or NR 7 R'; or R and R 2 together form an oxo; R1 and R 32 are each independently selected from hydrogen, Cr C 5 alkyl, or fluoroalkyl; 30 R 3 and R 4 are each independently selected from hydrogen or alkyl; or Rt and R 4 together form an imino;

R

5 is C 2

-C

15 alkyl or carbocyclyalkyl;

R

7 and R8 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R"; or R 7 and Ra, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; R9 and R 1 ' are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NR 7 R' or 35 carbocyclyl; or R 9 and R 1 0 together form an oxo; R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R 3 ; or R" and

R'

2 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, beteroaryl or heterocyclyl; each R 6 and R 34 are independently hydrogen or alkyl; 40 each R 3 3 is independently selected from halogen, -OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [0080 In another embodiment is the compound of Formula (Ib): 28 WO 2010/028088 PCT/US2009/055785 (R33). R 17RW6 R 1

R

2

R

11 R. Y N,R12 R 18 X Rt 5 R 1 0R 3

R

4 Formula (Ib) wherein, Y is -S-C(R 14 )(R")-, -S(=O)-C(R)(R 15 )-, or -S(=0)rC(R4)(R1)-; R' and R 2 are each independently selected from hydrogen, halogen, C-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7

R

t ; or R' and R 2 together form an oxo; 10 R 3 and R 4 are each independently selected from hydrogen or alkyl; or RW and R4 together form an imino; R7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl or -CQO)R1 3 ; or R' and R, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; R? and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NRR 8 or carbocyclyl; or R and R' together form an oxo; 15 R" and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=O)R; or R" and RD, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 and R 34 are independently hydrogen or alkyl; R 4 and R' 5 are each independently selected from hydrogen or alkyl; 20 R 16 and R' 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R", together with the carbon to which they are attached form a carbocyclyl, or a heterocyclyl;

R

1 a is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R3 is independently selected from halogen, -OR , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 25 [00811 In a further embodiment is the compound wherein n is 0 and each of R1" and R 2 is hydrogen. In a further embodiment is the compound wherein each of R3, R 4 , R 1 4 and R" is hydrogen. [00821 In a further embodiment is the compound wherein, R' and R 2 are each independently selected from hydrogen, halogen, CrC 5 alkyl, -OR 6 ; R? and R1 are each independently selected from hydrogen, halogen, alkyl, -OR; or R? and R1 0 together 30 form an oxo; each R 6 is independently hydrogen or alkyl;

R

6 and R , together with the carbon to which they are attached, form a carbocyclyl; and R" is selected from a hydrogen, alkoxy or hydroxy. [0083] In a further embodiment is the compound wherein R 6 and R', together with the carbon to which they are 35 attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R1t is hydrogen or hydroxy. [0084] In another embodiment is the compound wherein R" is hydrogen and R 2 is -C(=O)R", wherein R" is alkyl. [0085] In a further embodiment is the compound wherein, 40 R' and R2 are each independently selected from hydrogen, halogen, C-C 5 alkyl, or -ORW; R and R' 0 are each independently selected from hydrogen, halogen, alkyl, or -OR 6 ; or R and R' 0 together form an oxo; each R 6 is independently selected from hydrogen or alkyl; 29 WO 2010/028088 PCT/US2009/055785 5 R" and R", together with the carbon atom to which they are attached, form a carbocyclyl; and

R'

8 is hydrogen, hydroxy or alkoxy. [00861 In a further embodiment is the compound wherein n is 0;

R'

6 and R' 7 , together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R' 8 is 10 hydrogen or hydroxy. [0087] In a further embodiment is the compound wherein, R' and R2 are each independently selected from hydrogen, halogen, C-Cs alkyl or -OR 6 ; R! and R' 0 are each independently selected from hydrogen, halogen, alkyl, or -OR; or R! and R' 0 together form an oxo; 15 each R 6 is independently hydrogen or alkyl;

R'

6 and R 7 are each independently alkyl; and R is hydrogen, hydroxy or alkoxy. [0088] In another embodiment is the compound having the structure of Formula (Ic): (Ray

R

1 7 D6i ~R31 R32 RI I

R

3

R

4 Formula (Ic) 20 wherein, Y is -S-C(R' 4

)(R'

5 )-, -S(=O)-C(R)(Rs)-, or -S(=0)rC(R")(RS)-; R and R 32 are each independently selected from hydrogen, C-Cs alkyl, or fluoroalkyl; R' and R 4 are each independently selected from hydrogen or alkyl; or R 3 and R 4 together form an imino; R11 and R' 3 are each independently selected from hydrogen, alkyl, carbocyclyl, or -C(=O)R1 3 ; or R" and 25 R' 2 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl;

R

3 is selected from alkyl, alkeny), aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; R1 4 and R's are each independently selected from hydrogen or alkyl;

RI

6 and R 1 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R1 6 and R", together with the carbon atom to which they are attached, form a carbocyclyl, or heterocyclyl; 30 R" is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 33 is independently selected from halogen, -OR 34 , alkyl, or fluoroalkyl;

R

4 is hydrogen or alkyl; and n is 0, 1, 2,3, or 4. 100891 In another embodiment is the compound wherein n is 0 and each R"' and R1 is hydrogen. 35 [0090] In another embodiment is the compound wherein each RW, R 4 , R' 4 and R" is hydrogen. [00911 In another embodiment is the compound wherein, R and R2 are each independently hydrogen, or C-C, alkyl;

R'

6 and R", together with the carbon atom to which they are attached, form a carbocyclyl; and R'8 is hydrogen, hydroxy, or alkoxy. 40 [00921 In another embodiment is the compound wherein R' and R", together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R" is hydrogen or hydroxy. [0093] In another embodiment is the compound wherein, R 3 ' and R 3 2 are each independently selected from 30 WO 2010/028088 PCT/US2009/055785 5 hydrogen, or C-C 5 alkyl; and R1 is hydrogen, hydroxy or alkoxy. [0094] In another embodiment is the compound having the structure of Formula (Id): (R33. R1y 16 aj"tR3 32 1

R

18 Y X 'R12

R

3 4 Formula (Id) wherein, Y is -S-C(R 14 )(R')-, -S(=O)-C(R' 4 )(R)-, or -S(=0)rC(R')(R) 10 X is -S-, -S(=O)-, -S(=O)-, -N(R 3 )-, -C(=O)-, -C(=CH2)-, -C(=N-NR")-, or -C(=N-OR)-;

R

1 and R 2 are each independently selected from hydrogen, C-C 5 alkyl, or fluoroatkyl;

R

3 and R 4 are each independently selected from hydrogen or alkyl; or R 3 and R 4 together form an imino; R" and R' 2 are each independently selected from hydrogen, alkyl, carbocyclyl, or -C(=0)R"; or R" and R1, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 15 R 13 is selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocycLyl; R14 and R' 5 are each independently selected from hydrogen or alkyl;

R'

6 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R' 7 , together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl;

R

18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; 20 each R 3 3 is independently selected from halogen, -ORM, alkyl, or fluoroalkyl; W, R 3 4 and R 3 are each independently hydrogen or alkyl; and n is 0, 1, 2, 3, or 4. 100951 In another embodiment is the compound wherein n is 0 and each R" and R 12 is hydrogen. In a further embodiment is the compound wherein each R, R 4 , R" and R 15 is hydrogen. 25 100961 In another embodiment is the compound wherein, R and R 2 are each independently hydrogen, or C-Cs alkyl;

R

16 and R 17 , together with the carbon atom to which they are attached, form a carbocyclyl; and R' 8 is hydrogen, hydroxy, or alkoxy. [0097] In a further embodiment is the compound wherein R and R 1 , together with the carbon atom to which they 30 are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and Ra is hydrogen or hydroxy. [00981 In a further embodiment is the compound wherein, R 1 and R 32 are each independently selected from hydrogen, or C-C 5 alkyl; and R18 is hydrogen, hydroxy or alkoxy. 35 [0099] In a further embodiment is the compound having the structure of Formula (Ie): (R33 )n

R

40 A Rft R I, R7 ,R R16 NR 1 ' R Z1N R18O O R 1 Formula (Te) wherein, Z is -C(R)(R)-C(R)(R 2 )- or -O-C(R3)(R3) 31 WO 2010/028088 PCT/US2009/055785 5 R' and R2 are each independently selected from hydrogen, halogen, C-C5 alkyl, fluoroalkyl, -OR 6 or NR'R; or R' and R 2 together form an oxo;

R

3 and R 4 are each independently selected from hydrogen or alkyl; or R3 and R 4 together form an imino;

R

7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=0)R"; or R 7 and R 8 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 10 R! and K' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NK 7 R or carbocyclyl; or R 9 and K' 0 form an oxo; or optionally, R 9 and R' together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and R 0 and R 2 together form a direct bond to provide a triple bond; R?' and R 32 are each independently selected from hydrogen, C,-C 5 alkyl, or fluoroalkyl; 15 R" and 1 1 2 are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=0)R 3 ; or R" and R2, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R' 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R and R 4 are independently hydrogen or alkyl; R1 6 and R1 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R 6 and R', 20 together with the carbon to which they are attached form a carbocyclyl, or a heterocyclyl; or optionally, R 40 and either one of R 16 or R", form a heterocycle;

R

18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R is independently selected from halogen, -OR 3 , alkyl, or fluoroalkyl;

R

4 is selected from hydrogen or alkyl; or optionally, K 4 and either one of R' or R4, form a heterocycle; 25 and n is0, 1, 2, 3, or 4. (00100] In a further embodiment is the compound having the structure of Formula (If: (R33 )

R

1 4

R

15 R NH2

R

18 O O R 9 RIO Formula (If) wherein, 30 R 9 and R 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NRR 8 or carbocyclyl; or R 9 and R 0 together form an oxo;

R

1 and R' are each independently selected from hydrogen, alkyl, carbocyclyl or -C(=0)R' 3 ; or R 7 and R1, together with the nitrogen atom to which they are attached, form an N-heterocyclyl; each R 6 and R 34 are independently hydrogen or alkyl; 35 R 4 and R' 5 are each independently selected from hydrogen or alkyl; R' and R", together with the carbon to which they are attached form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; R1 8 is selected from a hydrogen, alkyl, aikoxy, hydroxy, halo or fluoroalkyl; each R? 3 is independently selected from halogen, -OR, alkyl, or fluoroalkyl; and 40 n is 0, 1, or 2. [00101] In another embodiment, the compound of Formula (1) has one, more than one or all of the non exchangeable 'H atoms replaced with 2 H atoms. 100102] Another embodiment provides a compound selected from the group consisting of: 32 WO 2010/028088 PCT/US2009/055785 5 NH2 NH2 cz. NH 2 , :1

NH

2 0 NH2 sN H2 N N A

NH

2

NH

2 IN N SJ~ s NH NH 2 , NNN A NH 2 N H12 OH NH2 NH2 O OH n 1A OH

NH

2 c rA

NH

2 C S NH2 NH 2 10 A NH0 N N. OH A > NH2 NA NH 2 NN33 OH OH N. NH 2

NH

2 OH OHso " H N3 WO 2010/028088 PCT/US2009/055785 OH NH 2 - NH 2 5 Ors OH 0)

NH

2 s

NH

2 0r CH 3 OH NHAc Br OH NH 2 OH OH N~ ~

CH

3 N 13 s NH 2 S1 NH 2 OH Qi~N~ OH S

NH

2

NH

2 Or 0 0 Oll S

NH

2 N

NH

2 10 DOH OH 'N H ' OH S

DNH

2

NH

2 15 - NH 2

$NH

2 OH NH

OCF

3

OCF

3

NH

2 NH2 LCr3 OH 0 OH N OC

NH

2 (: ol N

NH

2 OHD0 OHD D

NNH

2

NH

2 15 OH OH

DDNH

2

NNH

2 OH C OH 34 WO 2010/028088 PCT/US2009/055785 D D DD NH 2 NH 2 DD DD ix c o 5 D D D 3 H NH D bNH 2 0 D D D u Ila N NH 2 OH OH criNH 2 NH 0 1 HNH 2 sN NH2 NH2 10 N H 2 7 - s A A N H 2 0 S H2NH

NH

2 _ NH 2 0 NH2

NH

2 10 0

NH

2

NH

2 N flbSN

H

0 0 15o NH2NH N H s

NH

2 x x '-NH 2

H

0 0 NHO

NH

2

NH

2 O 0 3 35 WO 2010/028088 PCTIUS2009/055785

NH

2 .jo iiN r,- NH 2 50 0 OH N N~lxN N 2 0 0

OH

2 N"~- .- NH 2

NH

2 II S oo 0 H OH a %JNH 2 .- NH 2 0

NH

2

NH

2 0 1

NH

2 11 NH 2 SS OH (ro OH

NH

2 Cr ,(:) NH 2 OO 01 ii NH 2 sNNH 2 S, 0I OH 15 0r OH N0 O OHO ~* , NH 2 HNH

CH

3 OH qo l, I

NI-

2 N.o NH(r OH 36 WO 2010/028088 PCTIUS2009/055785 I NH2NH 2 5 0 OH 0

NH

2 0 NH 2 0 0 0 0 so- NH 2

NH

2 OH 0 O 010 ii NH 2 s NN 2 0 8

NH

2 0'

NH

2 OH 4:0 H 10FNH 2 F N lNH 2 0 O F 7C 0 8 H F0 F $ N' NH 2 9,(NH 2 ,C- H 1,

OHNH

2 OHNH OH 0O NH 2 11 NH 2 OH N' NH 2 OH NH 2 OH 0HOH OH~I NH 2 OH N NH 2 S 8 a 0OH 0 OH Sii NH 2 S N N7 WO 2010/028088 PCTIUS2009/055785 OH I NH 2 OHQ ~ NH 2 5 LIrii0N0 OH I OO NH 2 N H2 VN2 sNH 2 NH. 0 $ 0 00 N l, NH 2 sNNH 10I 0 N H ot NH 2 OH 0 0H 00

NH

2 oNH 2 S O H 0 O H NH o NH 2 Sb l" SI CrOH 0 OH F F o I1 NH2 INH 2 s NH 2 OH 0 OH (:rF NH

NH

2 0 0 H 0 IDH 38 WO 2010/028088 PCT/US2009/055785 D D O INH 2 N H D DD O H 2 S OH NH 2 D SNH2 NH2

NH

2 NH 2 O NH OH

NH

2 NH 2 cr6 OH OH

NH

2 adNH 2 00 OH 0 OH NH2

NH

2 7NH 2 K-2 00o OH 7 NH2

NH

2 10 00 OH 0 0 OH KY Z N - ~ NH 2 - ~ NH 2 0OH 00 OH 11 . NH 2

NH

2 Sb 00 OH 0 OH 0 I NH 2 0%NH 2 0 0 ,and b1' OH 15 (00103] In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (1) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt N-oxide or prodnig thereof: R~ 7 2(R 12 RkY zl - Z IN

R

11 Formula (I) wherein, 39 WO 2010/028088 PCT/US2009/055785 5 Z is a bond, -C(R')(R2)-, -C(R')(R'")-C(R)(R 2 )-, -X-C(R 3 1

)(R'

2 )-, -C(R 9

)(RI

1

)-C(R)(R

2

)-C(R

6

)(R

7 )-, X-C(RM)(RE)-C(R')(R2)- or -C(R3')(R")-X-C(RE)(R2)-; Y is -SO 2 NR*-, -S-C(R' 4 )(R)-, -S(=O)-C(R")(R')-, or -S(=O)rC(R' (R )-; R' and R2 are each independently selected from hydrogen, halogen, CI-Cs alkyl, fluoroalkyl, -OR 6 or NR 7

R

1 ; or R' and R 2 together form an oxo; 10 R, R 2 , R 3 and R 9 are each independently selected from hydrogen, C-Cs alkyl, or fluoroalkyl;

R

4 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R" and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R'" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R'" together with the carbon atom to which 15 they are attached, form a carbocyclyl or heterocyclyl; or optionally, R5 and either one R' 4 or R 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle;

R

3 and R 3 are each independently selected from hydrogen, halogen, C-C 5 alkyl, fluoroalkyl, -OR' or NRR'; or R 3 and R 7 together form an oxo; or optionally, R" and R' together form a direct bond to provide a double bond; or optionally, R 6 and R1 together form a direct bond, and RP and R 2 together form 20 a direct bond to provide a triple bond; RW and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino; R is C 2

-C

15 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 25 each R 7 and R 8 are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R' 3 , S0 2 R, CO 2 R" or S 2

NR

4 R1 5 ; or R' and R 8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -O-, -S-, -S(=O)-, -S(=O),-, -N(R)-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR")-, or -C(=N-OR358

R

9 and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NRR or 30 carbocyclyl; or R! and R 10 form an oxo; or optionally, R! and R' together form a direct bond to provide a double bond; or optionally, R9 and R' together form a direct bond, and R 0 and R 2 together form a direct bond to provide a triple bond; R and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R 3 , S0 2 R 3 , CO2R 3 or SOzNR 2 4 R; or R" and R 12 , together with the nitrogen atom to which they are attached, form an N 35 heterocyclyl; each R 1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 , R 3 ', R 34 and R 35 is independently hydrogen or alkyl; each R 24 and R 25 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 40 each R 3 3 is independently selected from halogen, OR, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [00104] In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof; 40 WO 2010/028088 PCT/US2009/055785 R '3, R 3 4.R RY Z N 4' 1 5 R 1 Formula (1) wherein, Z is a bond, -C(R')(R 2 )-, -C(R')(R')-C(R')(R 2 )-, -X-C(R)(R 3 )-, -C(R)(R' 0

)-C(R')(R)-C(R

3 )(R")-, X-C(R3')(R")-C(R')(R2)- or -C(R")(R")-X-C(RW')(R:2)-; Y is -SO 2

NR

4 -, -S-C(R 14 )(R')-, -S(=O)-C(R 4 )(Rs)-, or -S(-O)rC(R'4)(R)-; 10 R' and R 2 are each independently selected from hydrogen, halogen, C,-CS alkyl, fluoroalkyl, -OR 6 or NRR'; or R' and R 2 together form an oxo; W, R, R and R" are each independently selected from hydrogen, CI-Cs alkyl, or fluoroalkyl; R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R44 and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; 15 each R' 4 and R's is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R 4 and R" together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R' 4 or R", together with the carbon atom to which they are attached, form a carbocycle or heterocycle;

R

36 and R are each independently selected from hydrogen, halogen, C,-C 5 alkyl, fluoroalkyl, -OR 6 or 20 NR 7 R; or R 6 and R 7 together form an oxo; or optionally, R 36 and R' together form a direct bond to provide a double bond; or optionally, W 6 and R' together form a direct bond, and R 37 and R 2 together form a direct bond to provide a triple bond; RW and R! are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R and R 4 together with the carbon atom to which they are 25 attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino; R5 is C 2 -Cs alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R 7 and R' are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R",

SO

2

R

3 , CO 2 R" or SO 2

NR

24 "e; or R 7 and R' together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 30 X is -0-, -S-, -S(=O)-, -S(=O) 2 -, -N(R)-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR 3 5 )-, or -C(=N-OR )-; R' and R'" are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -ORO, -NR'R 8 or carbocyclyl; or R and R 0 form an oxo; or optionally, R and R' together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and R 0 and R2 together form a direct bond to provide a triple bond; 35 R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(-O)R 13 , SO 2 R', CO 2

R'

3 or S0 2

NR

2 4

R

5 ; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R', R", R 34 and R is independently hydrogen or alkyl; 40 each RM and R 2 5 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each K3 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [001051 In a further embodiment is the method wherein the ophthalmic disease or disorder is a retinal disease or 41 WO 2010/028088 PCT/US2009/055785 5 disorder. In an additional embodiment is the method wherein the retinal disease or disorder Is age-related macular degeneration or Stargardt's macular dystrophy, In an additional embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal 10 disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, and a retinal disorder associated with AIDS. In an additional embodiment is the method wherein the ophthalmic disease or disorder is selected from diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion 15 related retinal injury. [001061 In an additional embodiment is the method of inhibiting at least one visual cycle trans-cis isomerase in a cell comprising contacting the cell with a compound of Formula (1) as described herein, thereby inhibiting the at least one visual cycle trans-cis isomerase. In a further embodiment is the method wherein the cell is a retinal pigment epithelial (RPE) cell. 20 D00107] In a further embodiment is the method of inhibiting at least one visual cycle trans-cis isomerase in a subject comprising administering to the subject the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R3r, RN. R3 4 R R Y Z NtR12

R

11 Formula (I) 25 wherein, Z is a bond, -C(R')(R 2 )-, -C(R)(R 0

)-C(R')(R

2 )-, -X-C(R)(R 2 )-, -C(R)(R'%)-C(R')(R3)-C(R")(R 3 )-, X..C(RM)(RE)-C(R')(R2)- or -C(R3)(R1)-X-C(R1)(R2)-; Y is -S0 2

NR

4 -, -S-C(R 4 )(R1')-, -S(=O)-C(R't)(R)-, or -S(=0)rC(RM)(R")-; R' and R 2 are each independently selected from hydrogen, halogen, CCs alkyl, fluoroalkyl, -OR 6 or 30 NR'R; or R1 and R 2 together form an oxo; R", R', R and R" are each independently selected from hydrogen, C-C 5 alkyl, or fluoroalkyl;

R

4 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R 4 and R5, together with the nitrogen atom to which they are attached, form a heterocycle; each R1 4 and R1 5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, 35 carbocyclyl, heteroaryl or C-attached heterocyclyl; or R14 and R 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyt; or optionally, R5 and either one R'4 or R'", together with the carbon atom to which they are attached, form a carbocycle or heterocycle; R36 and R 37 are each independently selected from hydrogen, halogen, C 1

-C

5 alkyl, fluoroalkyl, -OR 6 or NR'R; or R 6 and R7 together form an oxo; or optionally, R 3 6 and R' together form a direct bond to 40 provide a double bond; or optionally, R 6 and R' together form a direct bond, and R 37 and R 2 together form a direct bond to provide a triple bond; 42 WO 2010/028088 PCTIUS2009/055785 5 R 3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is C-C 5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R7 and R 8 are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=)R', 10 SO 2 R", CO2R 3 or SOCNR 4

R

2 ; or R 7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=O) 2 -, -N(R 3 0 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR 3 )-, or -C(=N-OR&)-; R and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR, -NR 1 R' or carbocyclyl; or R 9 and R 0 form an oxo; or optionally, R! and R' together form a direct bond to provide a 15 double bond; or optionally, R! and R together form a direct bond, and R 10 and R 2 together form a direct bond to provide a triple bond; R and R 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R, SO 2 R", CO 2 R or SO 2

NR

4

R

5 ; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; 20 each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 , R 3 , R 3 and R 3 5 is independently hydrogen or alkyl; each R 4 and R is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R is independently selected from halogen, OR, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 25 (00108] In a further embodiment is the method wherein the subject is human. In a further embodiment is the method wherein accumulation of lipofuscin pigment is inhibited in an eye of the subject. In a further embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In a further embodiment is the method wherein degeneration of a retinal cell is inhibited. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell. In a further embodiment is the 30 method wherein the retinal neuronal coil is a photoreceptor cell, an amacrine cell, a horizontal cell, a ganglion cell, or a bipolar cell. In a further embodiment is the method wherein the retinal cell is a retinal pigment epithelial (RPE) cell. [001091 In an additional embodiment is a compound that inhibits I 1-cis-retinol production with an IC 50 of about 1 piM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the 35 extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room temperature. In an addtional embodiment, the compound is a non-retinoid compound. In a further embodiment is the compound, wherein the compound inhibits 11 -cis-retinol production with an ]C5s of about 0.1 pM or less. In a further embodiment is the compound, wherein the compound inhibits 11 -cis retinol production with an IC 50 of about 0.01 pM or less. 40 [00110] In an additional embodiment is a non-retinoid compound that inhibits an I 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED5 0 value of 1 mg/kg or less when administered to a subject. In a further embodiment is the non-retinoid compound wherein the ED 50 value is measured after administering a single dose of the compound to said subject for about 2 hours or longer. 45 [00111J In a further embodiment is the non-retinoid compound wherein the structure of the non-retinoid compound corresponds to Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable 43 WO 2010/028088 PCT/US2009/055785 5 solvate, hydrate, salt, N-oxide or prodrug thereof: (R33 n Rk : R 12 Y tI Z N.

R

11 Formula (I) wherein, Z is a bond, -C(R1)(R)-, -C(R')(R")-C(R)(R 2 )-, -X-C(R 3

')(R

3 )-, -C(R)(R")-C(R')(R)-C(R)(R 37 )-, X-C(RI')(RI2)-C(R')(R3)- or -C(RMl)(R39)-X-C(RM)(R2)-; 10 Y is SO 2 NR-, -S-C(R' 4

)(R

5 )-, -S(=0)-C(R 4 )(R')-, or -S(=0)2-C(R')(R')-; R' and R 2 are each independently selected from hydrogen, halogen, C 1

-C

5 alkyl, fluoroalkyl, -OR 6 or NR 7 R!; or R' and R 2 together form an oxa;

R

3 1 , R 32 , R3" and R 9 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl; R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached 15 heterocyclyl; or R and R, together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R's is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' and R' 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R 4 or R1 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; 20 RW 6 and R" are each independently selected from hydrogen, halogen, CI-Cs alkyl, fluoroalkyl, -OR or NR'R; or R 36 and R' together form an oxo; or optionally, R 36 and R' together form a direct bond to provide a double bond; or optionally, R 36 and R' together form a direct bond, and R 3 ' and R together form a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 25 carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is C2-C,5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R' and R are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R",

SO

2 R, CO 2 R" or SO 2

NR"R

2 s; or R' and R together with the nitrogen atom to which they are attached, 30 form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=O) 2 -, -N(R 3 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR)-, or -C(=N-OR3)-;

R

9 and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR'R or carbocyclyl; or R 9 and R' 0 form an oxo; or optionally, Re and R' together form a direct bond to provide a double bond; or optionally, R 9 and R' together form a direct bond, and R' 0 and R 2 together form a direct 35 bond to provide a triple bond, R" and R 1 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R", SO 2 R, CO 2 R" or SO 2

NR

4 R; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R" is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; 40 each R 6 , R", R 34 and R" is independently hydrogen or alkyl; each Re and R15 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R is independently selected from halogen, ORe, alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 44 WO 2010/028088 PCT/US2009/055785 5 (001121 In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits 1 1-cis-retinol production with an IC5o of about 1 pM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In an additional embodiment is a pharmaceutical composition comprising a pharmaceutically 10 acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 50 value of I mg/kg or less when administered to a subject. [00113] In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a compound of Formula (1) as described herein. In a further embodiment is the 15 method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. In another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In yet another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl ethanolamine (A2E). 1001141 In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising 20 introducing into a subject a compound that inhibits 1 1-cis-retinol production as described herein. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject In another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N retinyl-ethanolamine (A2E). In yet another embodiment is the method wherein the lipofuscin pigment is N retinylidene-N-retinyl-ethanolanilne (A2E). 25 [00115] In an additional embodiment is a method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a non-retinoid compound that inhibits an 11-cis-retinol producing isomerase reaction as described herein. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. In another embodiment is the method wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In yet another embodiment is the method 30 wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). [001161 In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits I 1-cis-retinol production with an IC50 of about 1 sM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further 35 comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In a further embodiment is the method wherein the ophthalmic disease or disorder is age related macular degeneration or Stargardt's macular dystrophy. In a further embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy,optic neuropathy, inflammatory retinal 40 disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischenia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder 45 related to light overexposure, myopia, and a retinal disorder associated with AIDS. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the 45 WO 2010/028088 PCTIUS2009/055785 5 subject. 1001171 In an additional embodiment is a method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an EDso value of 10 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. In a further embodiment is the method wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood 15 vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, myopia, and a retinal disorder associated 20 with AIDS. In a further embodiment is the method resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. [001181 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with a compound of Formula (1) as described herein. {001191 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina 25 comprising contacting the retina with a compound that inhibits 1 1-cis-retinol production as described herein. 1001201 In a further embodiment is a method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction as described herein. 30 [00121] In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of the retina comprising contacting the retina with a compound of Formula (I) as described herein. [00122) In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of the retina comprising contacting the retina with a compound that inhibits I 1-cis-retinol production as described herein, 35 [001231 In a further embodiment is a method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of the retina comprising contacting the retina with a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction as described herein. [00124] In a further embodiment is a method of reducing ischemia in an eye of a subject comprising administering to the subject the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a 40 compound of Formula (1) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R3)n RK 5R 12 Y Z N

R

11 Formula (1) wherein, 46 WO 2010/028088 PCT/US2009/055785 5 Z is a bond, -C(R)(R 2 )-, -C(R 9

)(R'")-C(R)(R

2 )-, -X-C(R 1

)(R

2 )-, -C(R)(R")-C(R')(R 2 )-C(R)(R)-, X-C(R')(R')-C(R')(R 2 )- or -C(R 3 )(R)-X-C(R')(R)-; Y is -SO2NR"-, -S-C(R')(Ri 5 )-, -S(=O)-C(R' 4 )(R")-, or -S(=0)2C(R'')(R11N R' and R2 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7 Ra; or R' and R 2 together form an oxo; 10 R 3 , R, R" and R 3 9 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl;

R

4 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R and R 5 , together with the nitrogen atom to which they are attached, form a heterocycle; each R' 4 and R"5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyi; or R' 4 and R 5 together with the carbon atom to which 15 they are attached, form a carbocyclyi or heterocyclyl; or optionally, R5 and either one R4 or R1 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; R and R" are each independently selected from hydrogen, halogen, CI-C 5 alkyl, fluoroalkyl, -OR 6 or NR'; or R 3 6 and R 3 together form an oxo; or optionally, R3 6 and R' together form a direct bond to provide a double bond; or optionally, R 3 6 and R' together form a direct bond, and R and R 2 together form 20 a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino; R' is 0 2

-C

5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; 25 each R 7 and Ke are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R", SO2R", COMR" or SO 2

NR

2 s 2 ; or R7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; X is -0-, -S-, -S(=O)-, -S(=0) 2 -, -N(R)-, -C(=O)-, -C(=CH2)-, -C(=N-NR 3 5 )-, or -C(=N-OR3)-; R! and R1 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR 7 R' or 30 carbocyclyl; or k 9 and R' 0 form an oxo; or optionally, R? and R' together form a direct bond to provide a double bond; or optionally, R and R1 together form a direct bond, and R'" and R 2 together form a direct bond to provide a triple bond; R and R 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R 3 , SO2R 3 , CO2R1 3 or S0 2

NR

2 4

R

2 5 ; or R" and R1 2 , together with the nitrogen atom to which they are attached, form an N 35 heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R 6 , R 3 0 , R 4 and R 3 $ is independently hydrogen or alkyl; each R 24 and R 2 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 40 each R3 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. [001251 In another embodiment is a method of reducing ischemia in an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits 1 1-cis-retinol production with an IC 50 of about 1 FLM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, 45 wherein the compound is stable in solution for at least about I week at room temperature. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at 47 WO 2010/028088 PCT/US2009/055785 5 a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby reducing ischemia in the eye. [001261 In another embodiment is a method of reducing ischemia in an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non retinoid compound that inhibits an 11-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 50 value of 1 mg/kg or less when 10 administered to a subject. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby reducing ischemia in the eye. [00127] In another embodiment is a method of inhibiting neovascularization in the retina of an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically 15 acceptable carrier and a compound that inhibits 1 1-cis-retinol production with an IC5 0 of about 1 pM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room temperature. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, 20 thereby inhibiting neovascularization in the retina. [00128] In another embodiment is a method of inhibiting neovascularization in the retina of an eye of a subject comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 11 -cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 5 0 value of 25 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the pharmaceutical composition is administered under conditions and at a time sufficient to inhibit dark adaptation of a rod photoreceptor cell, thereby inhibiting neovascularization in the retina. [001291 In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with the compound of Formula (I) as described herein. In a further embodiment is the 30 method wherein the retinal cell is a retinal neuronal cell. In yet another embodiment is the method wherein the retinal neuronal cell is a photoreceptor cell. [00130] In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with a compound that inhibits I 1-cis-retinol production with an ICS 0 of about 1 pM or less when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract 35 further comprises CRALBP, wherein the compound is stable in solution for at least about 1 week at room temperature. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell, In yet another embodiment is the method wherein the retinal neuronal cell is a photoreceptor cell. [00131] In another embodiment is a method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with a non-retinoid compound that inhibits an I 1-cis-retinol producing isomerase 40 reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED 5 o value of 1 mg/kg or less when administered to a subject. In a further embodiment is the method wherein the retinal cell is a retinal neuronal cell. In yet another embodiment is the method wherein the retinal neuronal cell is a photoreceptor cell. [00132j In another embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina 45 comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (1) or tautomer, sterecisomer, geometric isomer or a 48 WO 2010/028088 PCT/US2009/055785 5 pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (R33), R !5 R ,R12 Y Z N,

R

1 ' Formula (1) wherein, Z is a bond, -C(R')(R 2 )-, -C(R 9

)(R'

0

)-C(R')(R

2 )-, -X-C(R )(R2)-, -C(R)(R4)-C(R)(R 2 )-C(R)(R)-, X-C(R')(R 2

)-C(R')(R

2 )- or -C(R")(R")-X-C(R')(R2)-; 10 Y is -SO 2

NR

4 -, -S-C(R' 4

)(R

5 )-, -S('O)-C(R"4)(R)-, or -S(=O)rC(R 4 )(R')-; R' and R2 are each independently selected from hydrogen, halogen, CI-CS alkyl, fluoroalkyl, -OR 6 or NRR 8 ; or R' and R 2 together form an oxo; R 3 , R' 2 , R and R" are each independently selected from hydrogen, CI-CS alkyl, or fluoroalkyl;

R

40 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached 15 heterocyclyl; or R 40 and Rs, together with the nitrogen atom to which they are attached, form a heterocycle; each R1 4 and R's is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R1 4 and R' 5 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or optionally, R 5 and either one R' 4 or R' 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; 20 R3 and R 37 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, fluoroalkyl, -OR 6 or NRR 8 ; or R 3 and R" together form an oxo; or optionally, W 6 and R' together form a direct bond to provide a double bond; or optionally, R 36 and R' together form a direct bond, and R 37 and R 2 together form a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, 25 carbocyclyl or C-attached heterocyclyl; or R3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

3 is Q-C alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R 7 and R! are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)R, SO3R", CO 2 R' or SO 2

NRR

2 s; or R 7 and R together with the nitrogen atom to which they are attached, 30 form an N-heterocyclyl; X is -O-, -S-, -S(=0)-, -S("o)r, -N(R 3 )-, -C(=O)-, -C(=CH 2 )-, -C(=N-NR 5 )-, or -C(N-OR3)N R? and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR 6 , -NR 7

R

8 or carbocyclyl; or R 9 and R' 0 form an oxo; or optionally, R? and R' together form a direct bond to provide a double bond; or optionally, R9 and R' together form a direct bond, and R.1 0 and R2 together form a direct 35 bond to provide a triple bond; R" and R1 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R, SOaR', COR" or SO 2

NR

4 R; or R'" and R1 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; 40 each R6, R 3 0 , R 34 and R 35 is independently hydrogen or alkyl; each R 2 4 and R 3 5 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R 3 3 is independently selected from halogen, OR 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2,3, or 4. 49 WO 2010/028088 PCT/US2009/055785 5 In a further embodiment is the method wherein the lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E). 1001331 In another embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound that inhibits 11-cis-retinol production with an IC 50 of about 1 FM or less 10 when assayed in vitro, utilizing extract of cells that express RPE65 and LRAT, wherein the extract further comprises CRALBP, wherein the compound is stable in solution for at least about I week at room temperature. In a further embodiment is the method wherein the lipofuscin is N-retinylidene-N-retinyl ethanolamine (A2B). 1001341 In another embodiment is a method of reducing lipofuscin pigment accumulated in a subject's retina 15 comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a non-retinoid compound that inhibits an 1 1-cis-retinol producing isomerase reaction, wherein said isomerase reaction occurs in RPE, and wherein said compound has an ED5 0 value of I mg/kg or less when administered to a subject. In a further embodiment is the method wherein the lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E). 20 [00135] In certain specific embodiments, the compounds of Formula (1) have the structures shown in Table 1. TABLE I Example Number Structure Name I S 3-(3-(Cyclohexylmethylthio)phenyl)prop-2-yn-1

NH

2 amine 3-(3-(Cyclohexylmethylsulfinyl)phenyl)prop-2 2 - NH2 yn-1-amine 0 3 3-(3-(Cyclohexylmethylsulfonyl)phenyl)prop-2 3J S NH 2 yn-l-amine

NH

2 3-(3-(Cyclohexylmethylthio)phenyl)propan- 1 4nun amine 50 ,NH 2 3-(3-(Cyclohexylmethylsulfonyl)phenyl)propan-1 O amine 6 S

NH

2 3-(3-(2-Ethylbutylthio)phenyl)prop-2-yn- 1-amine 50 WO 2010/028088 PCU1US2009/055785 Example Number Structure Name 7 s N 2 3-(3-(2-Ethylbutylthio)phenyl)propan- I1-amino 8 8 N14 2 3-Amino-1-(3 OH (cyrlohexyhiiethylthio)phenyl)propan-1 -ol OH 10 ~NH 2 3-A i3h~Ihl -n 1110sNH (E)3((yclohexylmethyltio)phenyl)prop- K.FJ c--Aminc-3 120H 2(3-Cyclohexylmthyltion)phenoyl)rtanamI ne 13~ ~ 0Q 0 .-~H -3 11 s 1) 0 NH 2 (,3-(3-(Cyclohexylmthyllfo)phenyl)prop-2 14 en-I-amine 00 N H 2 23-Cyclohexylzneslomienoychnmn 16 N0 _ NH2 23-Amnrp1)N (Cyclohxylezenesulfonyamidenxetami, 14 s .,!O H2 3(3-Cyclohxylmethylonyl)palp- 1 _______ ~ ~ ~ ~ on OH -amino __________ H 3-(-Amioprcp1-ynI)51 WO 2010/028088 PCTIUS2009/055785 Example Number Structure Name 18 'NN 2 (R)-3- Amino- 1-(3-(butylthio)phonyI)prapan.1I-ol ~ ~ ~ NH 2 (R)-3-Amino-l-(3-(butylsulfonyl)phenyl)propan 19o O H 20 s 3-(3-(Cyclopentylmcthylthio)phenyl)prop-2-yn-1

NH

2 amine 21 sN 2 3-(3-(Cycioheptylmcthylthiio)phenylprop-2-yn-1 Cr __NH2amino 22 ~s - > H 2 3-(3-(2-Propylpentylthio)phenyl)prop-2-yn-

I

22 N H 2amine 23 'N SNH 2 3-(3-(Benzylthio)phenyl)prop-2-yn-1I-amino 3-(3-(2-Etbylbutylsulfonyl)pbenyl)prop-2-yn- I1 24

NH-

2 amine 0 OH 'N s ~ .- ' NH 2 (E)-3-((3-(3-Aminoprop-I 25 enyl)phenylthio)methylpentan-3-oI 'NH OH I H 3-((3-(3-Aminopropy)phenylthio)niethyl)peftan 26 S3-ol 27 s

NH

2 .((3-(3-Amino- C rOH hydroxypropyl)phenylthio)methyl)cyclohexalo 28 N~N s

NH

2 3-Aniino-1-(3 28 (oyciohexylmethylthio)phenyl)propan-1 -one 52 WO 2010/028088 PCT/US2009/055785 Example Number Structure Name 0H mn 29

NH

2 3-(3-(Cyclohexylmethylsulfonyl)phenyl)butan- 1 30 NH 2 4-Amizio-2-(3 OH1 - (cyclohexylmethylthio)phemyl)butan-1-oI 31 OHsJ I- -NHAc N-(3-(3-(Cyclohexylmethylthio)pheny]) Or0H hydroxybutyl)acetainide 3 r - C NH 2 3-Amino- 1-(3-(3.-bromobcnzylthio)phcnyl)propan 33 s :) NH 2 3-Amino- -(3-(cyclohexylmethylthio)phcnyl)-2 c rOH tnethylpropan-l-oI (:r I I OH 3

NH

2 3-Anino --(3-(cyclohcxylmethylsulfonyI)phenyl) 0 OH 2-rnethylpropan-l-oI 35s : , N H 2 3-Amino- 1-(3-(oyclohexylmethylthio)phenyl) K.)0 mothylpropan-l-one C O 0 2-metbylpropan-l-one 37 sNH 2 3-Amino-1-(3-(QycIohcx-2 OH enylmethylthio)phenyl)propan-l1-ol 38 N23-Amino.1.(3-(phcnethylthio)phenyl)propan- 1-oI OH 53 WO 2010/028088 PCTJUS2009/055785 Example Number Structure Name I-- OH 39S 14 NH 2 4-Amino-l-(3-(2-propylpentylthio)phenyl)butan. 39 2-ol N~OH 40 S H I-Ainino-3-C3-(2-propylpentylthio)phcnyl)propan 2-ol 41 - - Ni- 2 (E)-3-(3-(Cyclohcxylmethylthio)-S 41 s trifluoromethyl)phenyI)prop-2-en- 1-amine 42 s NH 2 3-(3-(Cyclohcxylniethylthio)phenyl)-3 OH NH hydroxypropanimidamide

OCF

3 43 I(3-Amino-1-(3-(cyclohexylmthylthio)-5 OH b NH, (trifluoromiethoxy)phenyl)propan-1-ol 0N 2 3-Amino-i -C3-(eyvlohexylmethylsulfonyl)-5 S",i (trifluoromethoxy)phenyl)propan-1-oI 01 OH 45

NI-

2 3-Amino- 1-(3-cyclohcxylmethylthio)phenyl)-3,3 CrO"' D D dideuteropropan-l-ol 46 0,NH 2 * 3-Amino-l-(3-(cyclohexymthythio)phenl)-3,3 ~ 6 D ~ dideuteropropan- I1-ol D D 47 s k NH 2 3-Amino-1-(3-(cyelobexylmethylthio)phenyl)-2,2 K) OH dideuteropropan- 1-ol 48 sNH 2 3-Amino-1-(3-(v yclohexyimethylthio)phenyl)-l CirD deuteropropan- 1-ol D D ( XNH2 3-Amino-1-(3 49 (N.Xs N (cyclohexyldideuteramethylthio)phcnyl)propan-1 K>OH 01 54 WO 2010/028088 PCTIUS2009/055785 Example Number Structure Name D D 0 NH 3-Araino-l-(3 50 < '. N 2 (cyclohexyldideuteromethylsulfonyl)phenyl)propa K> 0 OH n-l-oI 51 ((perdeuterocyclohexyl)methylthio)phenyl)propan D D 0 52 DD(Uupn--n D Di1~i? OH((perdeuterocyclohexyl)methylsulok)phnyl)pro DOD D o DD t 3-Amino-1-(3-(ylhymehlufnlpny) 53 D S~~~~~aNH (2,2-ddeuterooa4-oIy~ehlho~hnipoa D~qD OH 54 s H -m--(cyclohexyhne thylsulfony)phen yl) 56 ~-'- NH (ycoE).x3(ylthiosulhenyl)pro-en- amn

~'NH

2 (3-(3-(Butylthio)pheny)prop-n- -anine NN 58 1--1''s ~- - N 2 (E)-3-(3-(ButylsulfinyI)phenyl)but-2-en-l-atnine 59 s--. "0 1_, NH21 3-(3-(Butylthio)phenyl)propan- I-amine 0 60 NH 2 3-(3-(Cyclopentylinethylthio)phenyl)propan-1 amine 55 WO 2010/028088 PCTIUS2009/055785 Example Number Structure Name 61 0j-" N 2 3-(3-(Cyclopentylmethylsulfinyl)phenyl)propan 1-amine 62 .- - N 2 (E)-3-(3-(2-Propylpentylsulfonyl)phenyl)prop-2 00 en-i-amine 63 \ - NH 2 (E)-3-(3-Aminoprop-4-enyl)-N-propyl N ' benzenesulfonamide

H

0 64 0NH 2 3-(3-An-inapropyl)-N-propylbcnzenesulfonamide N

H

0 65 - NH 2 (E).3-(3-Aminoprop-1-eny)-N 65 1 0"s NH2 cyclopentylbenzenesulfonamide 66 ' NH 2 3-(3-(Butylsulfanyl)phenyl)propan- 1-amine 0 I 1X NH 2 (E)-3-(3-(2-Propylpentyisulfinyl)phenyl)prop-2 67 : S, en-I1- aminer 0 68 a ol 9 ' NH 2 3-(3-Aminopropyl)-N-(heptan-4 R yI)bcnzenesulfonarrnde 69 S~ - NH 2 (E)-3-(3.(cyclahexylmethylsulfinyl)phenyl)prop ii 2-en-I-amine 70 .- NHZ (E)-3-(3-(phenethylthio)phenyi)prop-2-en-1-amine 71

NH

2 3-Amino-1-(3-(3 Hphenylpropylthio)phenyl)propan-1 -ol 01 56 WO 2010/028088 PCT/US2009/055785 Example Number Structure Name --. ..- NH 2 (E)-3-(3-(Cyclopentylmcthylthio)phenyl)prop-2 73f S2 en-I-amine 74 s

NH

2 3-Amino-l-(3 74 (cyclopentylmetliylthio)phenyl)propan-1-o V-i OH 75 -. NH 2 3-Amino-l-(3 jo _ (cyclopentylmethytI~o)phenyl)propan- I -one 1 0 76 'N S4 ' - NH 2 (E)-3-(3-(Phethylslfonyl)phenyl)prop-2-en- 1 SI amine 0 77 'NNNH, 2 3-(3-(Phenethylthio)phenyl)propan-l-amine OH . .- NH 2 (E-1-((3-(3-Aminoprop-1 78 Sr e nyl)phenylthia)methyl)cyclohexanoI N 11 110- NH 2 (E)-3-(3-Arninoprop- I-eny)-N-(heptan-4 79 S yl)benzenesulfonamide 80 0 ,, NH- 2 3-(3-(Cyclohexylmethylslfinyl)peyl])ptopan- 1 Cro amine 8 Is NH 2 3-(3-Amino-2-hydroxypropyl)-N il cyciohexylbenzenesulfonamide 82 -. O NH 2 (E)-3-(3-(2-Propylpentylthio)phenyl)prop-2-en-l 82 2 amine 83 s 'N NH 2 3-(3-(2-Propylpcntylthio)phrnyl)propan- I -amino 84 S'O.. NH 2 3-(3-(2-Propylpentylsulfinyl)phenyl)prapan-l S amine 57 WO 2010/028088 PCTJUS2009/055785 Example Number Structure Name 0o 1,1 I I -11NH 2 3-(3-(2-Propylpcntylsulfonyl)phenyl)propan-l 85 " S aine 11amne 0 86 ~-. ,- NH 2 (E)-3-(3-(Cyclopentylmethylsulfinyl)phenyl)prop 87 1210 NH 2 3-(3-Aminopropyl)-N. cyclopentylbenzenesulfonamide 88

NH

2 3-Amino-1-(3 88 (cyclopentylmethylsulfinyl)phenyl)propanl- ol \-~-' 0OH 89

NH

2 3-Amino-l-(3 o 0 (cyolopentylmethylsulfinyl)phenyl)propan-I -one 0 0 90 S .NH 2 3-Amino-l-(3 Cr o 0(cyclohexylmethylsulflnyl)phenyl)propafl- 1 -one 91 s a T, s NH 2 3-Aniino- 1.(3-(benzylthio)phenyl)propan-l-oI OH 02 NH 2 3-Aiino-1-(3-(bonzylsulfonyl)phcnyl)propan--o1 C' 0 OH 93 N 0 NH 2 3-(3-(Phenethylsulfonyl)phenyl)propan-l-amile S' 11 0 94

NH

2 3-An-dno-I-(3-(3 Hcyclohexylpropylthio)phenyl)propan- 1-ol o0 H -mio1(-3 IS, cyclohexylpropylsulfonyl)pheny1)propan- I -ol 96 0 , iy NH, 3-Amino-1-(3-(3 N O phenylpropylsulfonyl)phenyl)propan- I -ol 58 WO 2010/028088 PCT[US2009/055785 Example Number Structure Name OH97NH (-1-((3-(3-Aminoprop-1 6 enyl)phenylsulfonyl)methyl)cyclohexano OH NH 1-((3-(3 98 C r sN2 Anminopropyl)phenylthio)methyl)cyclohexanoI 99 ----~" N H 2 I-((3-(3-Aminopropyl)phenylsulfonyl)methyl) 9__)H______ jr2 cyclohexanol

CH

3 100 3-Amino-l-(3-(cyclohexylmethylthio)-5 NSO NH 2 methylphenyflpropan- I -ol 101 -~ ~s< ). NH 2 3-Amino- 1-(3-(butylsulfinyl)phenylpropan- I-ol 102 ~ ~ s ~NH 2 3-Amino-I-(3-(butythio)pheryI)propon-I -one 0 103 , NH 2 3-Amino-I -(3-(butylsulfinyl)pheny!)propan- I-one 11 013 iiN 2 3-Amino- I -(3-(butyl sul fon yl) phenyl)propan- 1 -one 0 0 105 s NNH 2 3-Aiiiino- I -(3 -(2-propylpentyl thi o)phcn yl) propan S~a 1-01 O H 106

NH

2 3-Amino-l-(3-(2 Sa propylpentylsulfinyl)phcnyl)propan- 1-al O OH 107 " NH 2 3-Atnino-1-(3-(2 ISo y propylpentylsulfonyl)phenyl)propan- 1 -ol o OH 108 ~NH 2 3 -Amino-l1- (3-(2-propylpcntylthio)phenyl)propan s 1-one 59 WO 2010/028088 PCT/US2009/055785 Example Number Structure Name 109

NH

2 3-Amino-1-(3-(2 6 0 propylpentylsulfinyl)phenyl)propan-1-one 0) 110 N NH 2 3-Amino-1-(3-(2 IS propylpentylsulfonyl)phenyl)propan- I-one 3 0 0 S NH 2 3-Amino-1-(3-((4,4 F OH difluorocyclohexyl)methylthio)phenyl)propan-1-ol F 112

NH

2 3-Amino-i-(3-((4,4-difluorocyclohexyl) FOH methylsulfonyl)phenyl)propan-1-ol F

NH

2 3-Amino-1-(3-((4,4 113 N difluorocyclohexyl)methylthio)phenyl)propan-l F0 one F 01 114 N NH 2 3-Anino-1-(3-((4,4-difluorocyclohexyl) F 0 0 methyisulfonyl)phenyl)propan-1-one F 115

NH

2 (-(5-Methoxypentylthio)phenyl)propan-1 9j: amine 116 0 NH 2 3-(3.(5-Methoxypentylsulfonyl)phenyl)propan-1 016 amine A 117 Ho 'NH 2 5-(3-(3-Aminopropyl)phenylthio)pentan- 1-ol 119 0 ,INH 2 5-(3-(3-Aminopropyl)ph-ny-sulfonyl)pentan-1-ol 112 OH NH2 4-((3-(3-Amino-1 1219 OH NH- 2 4-((3-(3-Amiino-1 hydroxypropyl)phenylthio)mcthyl)heptan-4-ol OH OH 120 OH N NHI 2 4-((3-(3-Amino-1 Shydroxypropyl)phenysulfnyl)methyl)hcptan4-o o OH 121 OH ,,(::I -,_NH 2 4-((3-(3-Ainino-1 , r s'.'bydroxypropyl)pbenylsulfanyl)methyl)heptan-4-oI 0 OHI 122 Nkr" Nt- 2 3-Amino-1-(3-(2-hydroxy-2 S propylpc-ntylthio)phenyl)prop an- 1 -one 00 WO 2010/028088 PCTIUS2009/055785 Exaimple Number Structure Name 13OH 0,0 y NH 2 3-Arnino-1-(3-(2-bydroxy-2 123 $ propylpcntylsulfonyl)phenyl)propan-1I-one 0 0 124 hydroxypropyl)phcnylthio)inethyl)cyclopentanoI OH 15 OH N 2 1-((3-(3-Amino-l-hydroxypropyl)phenylsulflnyl) 125NH methyl)cyclopentanol 0 OH 126 0rH t _ NH 2 1-((3-(3-Axnino- I -hydroxypropyl)phenylsulfonyl) S methyl)cyclopentanol 8 OH OH NH 2 3-Amino-l-(3-((1-hydroxycyclopentyl) 127 NH mnethy1thio)pheny1)propan- I1-one 0 OH 3-Axnino-1-(3-((1 128 11 NH 2 hydroxycyclopentyl)methylsulfoflyl)phenylpropa I I n-i-one 19OH INH 2 1,((3-(3-Amnino-l-hydroxypropylphenylsu~finyl) 129S methyl)cyclohexanol 0 OH 130 OH 0 NH 2 1-((3-(3-Arnino-l-hydroxypropyl) N phenylsulfonyl)methyl)cyclohcxano OHO 131 OHr NC r NH 2 3-Amino-1-(3-((1-hydroxycyclohexyl) s methylthio)phenyl)propan- 1-one 0 OH 0 N 2 3-Amino-1-(3-((1-hydroxycyelohexyl) I32 mnethylsulfony1)phcnyl)propan-1I-one 0 0 133 N NH 3-(3-(2-Ethylbutylsulfonyl)phenyl)propan- 1 -amnine 0 0 134

NH

2 3-Armino-1-(3-(2 ethylbyutylsulflnyl)pheny))propan- 1-ol 0 OH 135

NI-

2 3-Amino-1-(3-(2-ethylbutylthio)phenyl)propan.

I

s one 61 WO 2010/028088 PCTIUS2009/055785 Example Number Structure Name 136IIN.NH 3-Amino-l-(3-(2 11ethylbutylsulfonyl)phenyl)propan- -n 137 -. I-I 2 3-(3-(2-Metboxybenzylthio)phenyl)propan- I 137 0 - NH2 amine 1389 N-I 3-(3-(2-Methoxybenzylsulfonyl)phenyl)propan-l 138 a ". NH2 amnine - 0 139 -3-(3-(4-(Benzyloxy)butylthio)phenyl)propan-1 140 0 -""9,(:) NI-14 2 3-(3-(4-(Bcnzyloxy)butylsulfonyl)phenyl)propan 140 I -an-dne OH 141 3-(3-Ammno-1-hydroxypropyl)-5 sb --

NI-

2 (cyclohexyhnethylthio)phenol OH 142 o 3-(3-Amio-1-hydroxypropyl)-5 It NH 2 (cyclohexylmethylsult'onyl)phenoI C o OH OH OH 14

NH

2 2-(3-Ainino-1-hydroxypropyl)-4 S (cyclohexylmethylsulfonyl)phenoI F 145 3-Amino-l-(3-(cyclohexylmethylthio)-5 sb y ---- NH 2 fluaraphenYl)Propan-1-ol F 146 o I3-Amina-l.(3-(cyclohexylmothylsulfonyD)-5 'I . NH 2 fluorophenyl)propan-1-ol s ______6 OH_________ _____ 147

NH

2 3-Amino- 1-(5-(cyclohexylmnethylthia)-2 S~c fluorrophcriyl)propan- 1-ol 62 WO 2010/028088 PCTIUS2009/055785 Example Number Structure Nm 148 0r ~ NH 2 3-Amino-1-(5-(cyclohexylmclhylsulfonyl)-2 8~J~~ OH 01 H 149 N.I I 1-(3-(Cyclohexylmethylsulfonyl)phenyl)-3 11 (rnethylamino)propan-l-ol 0 O OH 15a 9i ID NH 2 3-Amino- 1-(3-(cyclohexyimethylsulfonyi)phenyl) 11S1-deuteropropan-1 -ol cro ~OH P 0 D

NH

2 3-Amino- l-(3-((perdeuterocyclohexy) 151 D - 1 D D0 OH methylsulfonyI)phenyI)propan- 1-ol D DDD D 152 3-Amino-l-(3-(cyclohexylmethylthio)-5 0 ""' b __

NH

2 deutrophenyl)propan- -ol D 153 03-Amino -1-(3-(cyclohcxylmetiylsulfonyl)-5 153 .- _ NH 2 deuterophe inyl)propan- I-ol 0 OH 154

NH

2 3-Amino-1-(5-(cyclohexylmethylthio)-2 S deuterophenyl)propan-1 -ol OH 155 9 IK NH 2 3-Amino- 1-(5-(cyclohexylmethylsulfonyl)-2 S deuterophemyl)propan-l1-ol 0 OH 156

NH

2 3-Amino- 1-(3-(2-cthylbutylthio)phenyl)propan-

I

S O H__ 0_______________ 157

NH

2 3-Aniino-1-(3-(2 C ethylbutylsulfonyl)phenyl)propan- I -ol 0 0 OH 158 ,.--- NH 2 3-Amino-l-(3 158___ OH 2 (cyclopcntylmethytsulfonyl)phenyl)propan-1-oi 159 NH 2 3-Amtino-1-(3 159___ IV NH2 (cyclopcntylmethylsulfonyl)phenyipropan- 1 -one 63 WO 2010/028088 PCT/US2009/055785 Example Number Structure Name 160

NH

2 3-Amino-1-(3-(2 ethylpentylsulfonyl)phenyl)propan-l.-ol 0 0 OH 161

NH

2 (R)-3-Amino-1-(3-((R)-2 ethylpentylsulfonyl)phenyl)propan-1-ol 0 0 OH 162

NH

2 3-Amino-1-(3-(2 1 Oethylhexylsulfonyl)phenyl)propan-1-ol 163

NH

2 (R)-3-Anino-1-(3-((S)-2 ethylhexylsulfonyl)phenyl)propan-1-ol 00 OH 164

NIH

2 3-Amino-l-(3-(2 hO OH propylhexylsulfonyl)phenyl)propan-1-o 00 OH 165 ~NH 2 (R)-3-Amino-1-(3-((S)-2 propylhexylsulfonyl)phenyl)propan-t-ol -0 OH 166 0 3-Amino-1-(3-(cyclohexylmethylsulfonyl)-5 N66 NH 2 methylphenyl)propan-1-ol O OH 167 O 3-Amino-1-(3-(cyclohexylmethylsulfonyl)-5 17 N NH 2 methylphenyl)propan-1-one S O 0 168 1 NH 2 3-(3-Amino- 1 -hydroxypropyl)-N O N cyclohexylbenzenesulfonamide H OH 5 [001361 As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are 10 used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated 15 number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an 64 WO 2010/028088 PCT/US2009/055785 5 embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features. "Sulfanyl" refers to the -S- radical. "Sulfinyl" refers to the -S(=O)- radical. "Sulfonyl" refers to the -S(=0) 2 - radical. 10 "Amino" refers to the -NH 2 radical. "Cyano" refers to the -CN radical. "Nitro" refers to the -NO 2 radical. "Oxa" refers to the -0- radical. "Oxo" refers to the =O radical. 15 "lmino" refers to the =NH radical. "Thioxo" refers to the =S radical. [001371 "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1

-C

15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., CI-C 13 alkyl). In certain 20 embodiments, an alkyl comprises one to eight carbon atoms (e.g., CI-Cs alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5

-C,

5 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5

-C

8 alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise 25 specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SR!, -OC(O)-R", -N(R 8

)

2 , -C(O)R", -C(O)ORa, -C(O)N(R") 2 , -N(Ra)C(O)ORS, -N(Ra)C(O)R", -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2) and -S(O)N(R")2 (where I is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or 30 heteroarylalkyl. 1001381 "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, 35 for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-l-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR', -SR, -OC(0)-Ra, -N(Ra)2, -C(O)R", -C(O)OR", -C(O)N(R")2 -N(R")C(O)OR", -N(R")C(O)Ra, -N(Ra)S(O),Ra (where t is 1 or 2), -S(O) 1 OR' (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is 40 independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. [001391 "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two 45 to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the 65 WO 2010/028088 PCT/US2009/055785 5 specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SR", -OC(O)-R", -N(Ra) 2 , -C(O)Ra, -C(O)OR, -C(O)N(Ra) 2 , -N(R)C(O)ORa, -N(R")C(O)Ra, -N(Ra)S(O),Ra (where t is 1 or 2), -S(OOR' (where t is 1 or 2) and -S(ON(Ra) 2 (where t is 1 or 2) where each R' is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. 10 [00140J "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and 15 to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR, -SR", -OC(O)-R, -N(R 8

)

2 , -C(O)R, -C(O)OR, -C(O)N(R*) 2 , -N(Ra)C(O)ORa, -N(R')C(O)R', -N(Ra)S(O),Ra (where t is 1 or 2), -S(O)tORa (where t is I or 2) and 20 -S(O),N(Ra) (where t is 1 or 2) where each R! is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. [00141J "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, 25 n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, 30 aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR", -SR, -OC(O)-Ra, -N(R") 2 , -C(O)Ra -C(O)ORa, -C(O)N(R)2, -N(R")C(0)0R", -N(R")C(O)Ra, -N(Ra)S(O)Ra (where t is 1 or 2), -S(O)ORa (where t is 1 or 2) and -S(O),N(R)2 (where t is 1 or 2) where each R" is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above 35 substituents is unsubstituted unless otherwise indicated. [001421 "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) it-electron system 40 in accordance with the Hckel theory. Aryl groups include, but are not limited to, groups such as phenyl, fluorenyl, and naphthyl. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted 45 aralkynyl, optionally substituted carbooyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally 66 WO 2010/028088 PCT/US2009/055785 5 substituted heteroarylalkyl, -Rb-OR", -R-OC(O)-R, -R-N(R), -Rb-C(O)R, -Rb-C(O)OR",

-R-C(O)N(R")

2 , -Rb-O-R"-C(O)N(R) 2 , -R.-N(Rt)C(O)OR8, .Rb-N(Ra)C(O)R, -R-N(R)S(O),R2 (where t is 1 or 2), -Rb-S(O)ORa (where t is 1 or 2) and -R-S(O)N(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is 10 independently a direct bond or a straight or branched alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [001431 "Aralkyl" refers to a radical of the formula -R-aryl where R4 is an alkylene chain as defined above, for example, benzyl, diphenylmethyl and the like. The alkylene chain part of the aralkyl radical is optionally 15 substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group. [00144] "Aralkenyl" refers to a radical of the formula -Ri-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene 20 group. [001451 "Aralkynyl" refers to a radical of the formula -R'-aryl, where R' is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain. 25 [001461 "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is optionally saturated, (i.e., containing single C-C bonds 30 only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, 35 adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally 40 substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -RbORa, -Re-SRa, -Re-OC(O)-Ra, -Rb-N(R') 2 , -Rb-C(O)Ra, -R-C(O)ORa, -RbC(O)N(R1 2 , -R-O-R*-C(O)N(Ra) 2 , -R-N(Ra)C(O)OR!, -RbN(R)C(O)R", -RbN(R")S(O)Ra (where t is I or 2), -Re-S(O),OR' (where t is 1 or 2) and -RbS(O),N(R) 2 (where t is 1 or 45 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a 67 WO 2010/028088 PCT/US2009/055785 5 straight or branched alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [00147] "Carbocyclylalkyl" refers to a radical of the formula -R-carbocyclyl where RC is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [00148] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents. 10 [00149] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group. (00150] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve 15 carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and includes fused or bridged ring systems. The heteroatom(s) in the heterocyclyl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule 20 through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyt, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 25 thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyt, optionally substituted aralkynyl, optionally substituted carbocycly), optionally 30 substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-N(R) 2 , -R-C(O)Ra, -R-C(O)OR", -R-C(O)N(Ra)2, -R-O--R*-C(O)N(R"), -Rb-N(Ra)C(O)ORa -Rb-N(Ra)C(O)Rn, -R'-N(R")S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is I or 2) and -R-S(O),N(Ra) 2 (where t is I or 2), where each R" is independently hydrogen, alkyl, fluoroalkyl, 35 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [00151] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heteracyclyl radical as defined above containing 40 at least one nitrogen and where the point of attachment of the heterocycly) radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocycly) radicals. Examples of such N-heterocyciyl radicals include, but are not limited to, I-morpholinyl, 1-piperidinyl, 1-piperazinyl, I -pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. 45 (00152] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroaton and where the point of attachment of the heterocyclyl radical to the rest of the 68 WO 2010/028088 PCT/US2009/055785 5 molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like. [00153] "Heterocyclylalkyl" refers to a radical of the formula -R*-heterocyclyl where R is an alkylene chain as 10 defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group. [001541 "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two 15 to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) n electron system in accordance with the Hfickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, 20 are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4jdioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl 25 (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazoly, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta(d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 30 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[djpyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, l-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, 35 pyrazolyl, pyrazolo{3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,S]thieno[2,3-dpyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydmpyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-dpyrimidinyl, 40 thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally 45 substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Re-SRa, -R-OC(O)-R, 69 WO 2010/028088 PCT/US2009/055785 5 -Rb-N(Ra) 2 , -R-C(O)R, -Rb-C(O)OR, -R-C(O)N(Ra), -R-O-R"-C(O)N(R) 2 , -R-N(R*)C(O)ORa, -Re-N(Ra)C(0)R*, -R-N(Ra)S(O),R (where t is 1 or 2), -Rb-S(O)ORa (where t is 1 or 2) and -R-S(O)N(Ra)2 (where t is 1 or 2), where each R' is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R is a 10 straight or branched alkylone or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [001551 "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl 15 radicals. (001561 "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C heteroaryl radical is optionally substituted as described above for heteroaryl radicals, (00157] "Heteroarylalkyl" refers to a radical of the formula -R 0 -heteroaryl, where Rc is an alkylene chain as defined 20 above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group. (001581 The compounds, or their pharmaceutically acceptable salts may contain one or more asymmetric centers 25 and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all 30 tautomeric forms are also intended to be included. 1001591 "Stereoisomers" are compounds that have the same sequence of covalent bonds and differ in the relative disposition of their atoms in space. "Enantiomers" refers to two stereoisomers that are nonsuperimposeable mirror images of one another. 100160] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only 35 in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by t- or ' 4 C-enriched carbon are within the scope of this invention. [00161) The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, 40 such as for example, deuterium ( 2 f), tritium (H), iodine-125 (1251) or carbon-14 ('C). Isotopic substitution with 2 11, 11 C, 1C, 14C, 5 C, 1 2 N, "N, 1 N, 16N, 6O, "Q, 1F, 5 F, 1 6 F, 1 p s, s, s, 36s, 35,C "C , 'Br, "Br, 1 h1 are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [001621 In certain embodiments, the compounds disclosed herein have some or all of the 'H atoms replaced with 2H 45 atoms. The methods of synthesis for deuterium-containing sulphur-linked amine derivative compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. 70 WO 2010/028088 PCT/US2009/055785 5 1001631 Deuterated starting materials, such as acid i and acid i, are readily available and are subjected to the synthetic methods described herein for the synthesis of sulphur-linked amine derivative compounds. C02H DQC02H DD DD I [00164] Other deuterated starting materials are also employed in the synthesis of deuterium-containing sulphur linked amine derivative compounds as shown, in a non-limiting example, in the scheme below. Large numbers of deuterium-containing reagents and building blocks are available commerically from chemical vendors, such as Aldrich Chemical Co. KOBu-t CH0

CD

3 CN OH 1001651 Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAID 4 ), are employed to transfer 10 deuterium under reducing conditions to the reaction substrate. The use of UAID 4 is illustrated, by way of example only, in the reaction schemes below. R O 2 H LAD 4 D R 00HROH CN L 4 NH 2 OH OH D D I LiAID 4 D.f R R' - ROH [00166] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the 15 reaction schemes below. PR - R"D R"EtOAc D D H ELOAc H D D2 D Brr R" R Pd-C EtOAc [001671 In one embodiments, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contains two deuterium atoms. In another embodiment, the compounds disclosed herein contains three deuterium atoms. In another embodiment, the compounds 20 disclosed herein contains four deuterium atoms. In another embodiment, the compounds disclosed herein contains five deuterium atoms. In another embodiment, the compounds disclosed herein contains six deuterium atoms. In another embodiment, the compounds disclosed herein contains more than six 71 WO 2010/028088 PCT/US2009/055785 5 deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and contains no non-exchangeable 'H hydrogen atoms. In one embodiment, the level of deuterium incorportion is determined by synthetic methods in which a per-deuterated synthetic building block is used as a starting material. In one embodiment, acid 1i Is incorporated in the compounds disclosed herein to provide a compound with eleven deuterium atoms such as, by way of example only, compound 10 li. D N~ D OH D D jj [001681 Another embodiment provides the compound of Formula (I) wherein one, more than one or all of the non exchangeable 'H atoms are replaced with 2 H atoms. [00169] Another embodiment provides the deuterated compound of Formula (I) selected from the group consisting of: 1DNH2 _OD NH2 ' , ) NH2 S . NH 2 <r r 'NH- 2

NH

2 15 OH D DO ODDD D OH DND DD D D D NH2 H2 NH D OD S NH 2 O NH 2 NH 2 OH OH 0 OH DD D 0' NH 2

D~

0 9 0 0 NH, D D uIJ Y _ DI1 o ID D OH A DD D A DD D DH ol D D i 11" NH 2 11NH 2 D DI o OH 0OH D D

NH

2 11NH 2

NH

2 CrOH 0 OH OH 11

NH

2 20 and C oc [00170] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. [n bonding arrangements where tautomerization is possible, a chemical equilibrium of the 25 tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include: 72 WO 2010/028088 PCTIUS2009/055785 H H H H

NH

2 4c JNH2 \-NH NN\ .. H N H N N'N H N NaN 5 [00171] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. 10 1001721 "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the sulphur-linked compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. 15 [001731 "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic 20 acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fuimaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfate,% sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, 25 dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tarates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for 30 example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar. 100174] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and 35 properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, 73 WO 2010/028088 PCT/US2009/055785 5 magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylanine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaininoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, 10 procaine, NN-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. 1001751 Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present 15 structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 3C_ or 1 4 C-enriched carbon are within the scope of this invention, [001761 The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (H), iodine-125 (1251) or carbon-14 (1 4 C). All isotopic 20 variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [00177] "Non-retinoid compound" refers to any compound that is not a retinoid. A retinoid is a compound that has a diterpene skeleton possessing a trimethylcyclohexenyl ring and a polyene chain that terminates in a polar end group. Examples of retinoids include retinaldehyde and derived imine/hydrazide/oxime, retinol and 25 any derived ester, retinyl amine and any derived amide, retinoic acid and any derived ester or amide. A non-retinoid compound can comprise though not require an internal cyclic group (eg., aromatic group). A non-retinoi d compound can contain though not require a sulphur-linked group. [00178] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to 30 therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated, Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a 35 patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. 100179] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be 40 inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). [00180] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. 45 Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference 74 WO 2010/028088 PCTIUS2009/055785 5 herein. [00181] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject, Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present In the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the 10 parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, format and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and 15 the like, [00182] The compounds of the Invention are synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art, [001831 The discussion below is offered to illustrate how, in principle, to gain access to the compounds claimed 20 under this invention and to give details on certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define or limit the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention. The compounds of this invention may be made by the procedures and techniques disclosed in the Examples section below, as well as by known organic synthesis techniques. Preparation of Sulphur-linked compounds 25 [001841 In general, the compounds used in the reactions described herein may be made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich Chemical ('%ilwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado 30 Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K),Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), LCN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. 35 (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc, (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA). [001851 Methods known to one of ordinary skill in the art may be identified through various reference books and 40 databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sander et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. 0. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L Gilchrist, "Heterocyclic Chemistry", 45 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, ,. 75 WO 2010/028088 PCT/US2009/055785 5 Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An 10 Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of 15 Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Quin, L.D. et al. "A Guide to Organophosphorus Chemistry" (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) 20 John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. [001861 Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., 25 may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the sulphur-linked compounds described herein is P, H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. 30 [00187] The term "protecting group" refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. 35 Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid moieties 40 may be blocked with base labile groups such as, without limitation, methyl, or ethyl, and hydroxy reactive moieties may be blocked with base labile groups such as acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. 1001881 Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable 45 protective groups such as the benzyl group, while amine groups may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective 76 WO 2010/028088 PCT/US2009/055785 5 groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates. [00189j Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts, For example, an allyl-blocked cearboxylic acid can be deprotected with a palladium(0)-catalyzed reaction in the presence of acid labile t 10 butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. [001901 Typical blocking/protecting groups are known in the art and include, but are not limited to the following 15 moieties: CH30

H

3 Aly Bn PMB TBDMS Me O HAH 3 HaC

OH

3 0 0 Alce Cbz TEOC BOO H3 Ph\ H3C CH Ph 0 tpun tyl cdtyl acetyl FMOC [001911 Compounds disclosed herein are prepared in a stepwise manner involving a sulphur-linkage formation and a nitrogen-containing side chain formation, both attached to a phenyl ring. Some compounds are prepared by oxidation of a sulphide to a sulphoxide or sulphone. By way of example only, sulphide formation can 20 take place by either alkylation of a thiophenol or by coupling of a thiol with an aryl halide. [001921 In certain embodiments, the compounds disclosed herein are prepared by first preparing a sulphur-linked phenyl core structure. A nitrogen-containing side chain moiety is then attached to the sulphur-linked core structure. This compound is the desired final product, or optionally, this sulphur-linked core structure is further transformed into the desired final product. An optional oxidation of the sulphide to a sulphoxide or 25 sulphone is accomplished either before or after attachement of the nitrogen-containg side chain moiety. [001931 In other embodiments, the compounds disclosed herein are prepared by first preparing a phenyl intermediate having an appropriate nitrogen-containing side chain, followed by sulphur-linkage formation to provide the sulphur-linked core structure, This sulphur-linked core structure is the desired final product, or optionally, this sulphur-linked core structure is further transformed into the desired final product. 30 [001941 The following methods illustrate various synthetic pathways for preparing sulphu-linked intermediates and the side chain moieties. One skilled in the art will recognize that a method for sulphide formation can be combined with a method for side chain formation and a method for sulphur oxidation to provide the compounds disclosed herein. For example, any one of Methods A-C can be combined with any of Methods D-H, or any of Methods 1-J. They can be further combined with any of Methods K-S to modify the linkage 35 and/or the terminal nitrogen-containing moiety. In the following methods Ar is defined as an optionally 77 WO 2010/028088 PCT/US2009/055785 5 substituted phenyl group. Methods for Sulphide Formation [00195] Methods A-C below describe various approaches to sulphide formation. [00196] Method A illustrates the construction of a sulphide intermediate (A-3) through alkylation of a thiophenol (A-2). The alkylating agent (A-1) comprises a moiety (X) reactive to the nucleophilic thiol. This reactive moiety can be, for example, halogen, mesylate, tosylate, triflate and the like. As shown, the alkylation 10 process eliminates a molecule of HX. 100197) A base can be used to facilitate the deprotonation of the thiophenol, Suitable bases are typically mild bases such as alkali carbonates (e.g., K 2

CO

3 ). Method A R+ HS >-R' Base HS, 0SIl (A-1) (A-2) (A-3) 15 [001981 Method B shows the construction of a sulphide intermediate (A-5) through the ring-opening of an epoxide (A-4). Method B 0 Base K .'4A + H !!t'K$ R (A-4) (A-2) (A-5) 20 [001991 Method C shows the construction of a sulphide intermediate (A-3) through Pd-catalysed coupling of a thiol (A-6) with an aryl halide, mesylate, triflate or the like. Method C Palladium -SH -' -AtR' R X Rsc , (A-6) (A-7) (A-3) Methods for Sulphide Oxidation 25 (00200] Methods D and E describe the oxidation of sulphides to sulphoxides and sulphones. Suitable oxidizing agents include meta-chloroperbenzoic acid, hydrogen peroxide and ammonium molybdate, periodic acid and iron (III) Chloride, peroxyacetic acid, OXONE etc. 78 WO 2010/028088 PCT/US2009/055785 5 Method D Oxidation 0 R'''R' R' S' R' Method E Oxidation j P R''R' R 'sR' Side chain formation and modification [002011 Methods F-T describe methods for side chain formation and modifications. [00202] Generally, a suitably substituted phenyl derivative can be coupled to a diverse range of side chains, which 10 is further modified to provide the final linkages and the nitrogen-containing moieties of the compounds disclosed herein. [00203] Methods F-I illustrate pathways to form propylene linkages of the compounds disclosed herein. [00204] Method F illustrates an aryl halide coupling with an allyl alcohol in the presence of a palladium(0) catalyst. The terminal alcohol group of allyl alcohol has been simultaneously oxidized to an aldehyde group, which 15 is further transformed to an amine via a reductive amination. Method F OH reductive examination Pd 0 catalyst [00205) Method G illustrates a condensation between an aryl aldehyde or aryl ketone and a nitrile having at least one a-hydrogen. The resulting intermediate is further reduced to an amine. 20 Method G R'\ Ar R " CN Ar R' R" Ar R' R" H Ar R RA CN Ar NH 2 o Base R OH R OH R = H, Me, CF 3 [002061 Method H is an acylation reaction to form a ketone-based linkage. One skilled in the art will recognize that the R' group may comprise functional groups that can be further modified. Method H 0 Base or Metal Ar-X Ar R' 25 X= Br, I [00207) Method I is an ring-opening reaction of an epoxide to form a hydroxy-substituted propylene side chain 79 WO 2010/028088 PCT/US2009/055785 linkage. 5 Method I Base OH Ar ,X Ar R' X=Hal [002081 Method J is an attachment of side chain moieties via an oxygen atom. More specifically, a side chain precursor (R'OH) can be condensed with an aryl derivative by eliminating a molecule of H20. R' may comprise functional groups that can be further modified to prepare linkages and nitrogen-containing 10 moieties of compounds disclosed herein. Method J HO-R' Ar.,OH aOR Ars , 'R' PPh 3 , DIAD [002091 Method K is a condensation reaction that provides an oxygen linking atom. Here, a molecule of HX is eliminated as the result of the condensation, 15 Method K HO-R' Ar, N Ar, R' Xis Halo 1002101 After attachment, the side chain moiety is optionally further modified to provide the final linkage and the terminal nitrogen-containing moiety for the compounds disclosed herein. The following methods illustrate a variety of synthetic pathways to modify the side chain moiety by reduction, oxidation, substitution, 20 fluorination, acylation and the like. Through application of these methods, one of skill in the art recognizes that a diverse group of linkages can be synthesized. [00211] Method L illustrates an amination process in which carboxylic acid is converted to an amine. Typically, the carboxylic acid (or ester) can be first reduced to primary alcohol, which can then be converted to an amine via mesylate, halide, azide, phthalimide, or Mitsunobu reaction and the like. Suitable reducing 25 agents include, for example, lithium aluminum hydride (LiAIH4) and the like. As shown, the resulting amine can be further functionalized, by known methods in the art. Method L R' Ar&,,^'yO IAr -NH 2 AR OH [00212) Additional or alternative modifications can be carried out according to the methods illustrated below. 80 WO 2010/028088 PCT/US2009/055785 5 Method M OH Oxidation O R R' R R' Method N O R"MgBr or R"Li R" OH R R R R' 10 Method 0 O DAST (Et 2 NSF3) R R' R R Method P OH DAST (Et 2

NSF

3 ) F 15 R R' R R' Method Q o Lithium diisopropylamide (LDA) RA ,R' "' R kR' RPhS(O) 2 ]2NF F 20 Method R 0 Lithium diisopropylamide (LDA) R R ejyR' IN R't r F [PhS(O) 2

]

2 NF F F Method S base R'X Ar R Ar R R'= alkcyl X=Halo 25 81 WO 2010/028088 PCT/US2009/055785 5 Method T reduction R-CN b R-CH 2

NH

2 [00213] As a non-limiting example only, Scheme A illustrates a complete synthetic sequence for preparing a compound disclosed herein. Scheme A Br BSNHBoo [ S Br Gi dIP 3 ) HS Br K2C03, acetone Cul, PdCl2(PhaP)2 Et 3 N, DMF 1. HCI/EtOH S - r j NH 2 10 NH Boc 2. NaHCO 3 100214] In Scheme A, the sulphide intermediate is formed via alkylation of a thiophenol. The amine-containing side chain is introduced through a palladium-mediated cross-coupling reaction. Deprotection of the amine gives the target compound. [00215] In addition to the generic reaction schemes and methods discussed above, other exemplary reaction 15 schemes are also provided to illustrate methods for preparing compounds described herein or any of its subgenus structures. Treatment of Ophthalmic Diseases and Disorders [00216] Sulphur-linked compounds as described herein, including compounds having the structure as set forth in Formula (1) and substructures thereof, are useful for treating an ophthalmic disease or disorder by inhibiting 20 one or more steps in the visual cycle. In some embodiments, the compounds disclosed herein function by inhibiting or blocking the activity of a visual cycle trans-cis isomerase. The compounds described herein, may inhibit, block, or in some manner interfere with the isomerization step in the visual cycle. In a particular embodiment, the compound inhibits isomerization of an all-trans-retinyl ester; in certain embodiments, the all-trans-retinyl ester is a fatty acid ester of all-trans-retinol, and the compound inhibits 25 isomerization of all-trans-retinol to I 1-cis-retinol. The compound may bind to, or in some manner interact with, and inhibit the isomerase activity of at least one visual cycle isomerase, which may also be referred to herein and in the art as a retinal isomerase or an isomerohydrolase. The compound may block or inhibit binding of an all-trans-retinyl ester substrate to an isomerase. Alternatively, or in addition, the compound may bind to the catalytic site or region of the isomerase, thereby inhibiting the capability of the enzyme to 30 catalyze isomerization of an all-trans-retinyl ester substrate. On the basis of scientific data to date, an at least one isonerase that catalyzes the isomerization of all-trans-retinyl esters is believed to be located in the cytoplasm of RPE cells. As discussed herein, each step, enzyme, substrate, intermediate, and product of the visual cycle is not yet elucidated (see, e.g., Moiseyev et al., Proc. Natd. A cad. Sci. USA 102:12413-18 (2004); Chen et al., Invest. Ophthalmol. Vis. &c. 47:1177-84 (2006); Lamb et al. supra). [00217] A method for determining the effect of a compound on isomerase activity may be performed in vitro as described herein and in the art (Stecher et al., J Biol Chem 274:8577-85 (1999); see also Golczak et al., 82 WO 2010/028088 PCT/US2009/055785 Proc. Natl. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium (RPE) microsome membranes isolated from an animal (such as bovine, porcine, human, for example) may serve as the source of the isomerase. The capability of the sulphur-linked compounds to inhibit isomerase may also be determined by an in vivo murine isomerase assay. Brief exposure of the eye to intense light ("photobleaching" of the visual pigment or simply "bleaching") is known to photo-isomerize almost all 11 cis-retinal in the retina. The recovery of 1 1-cIs-retinal after bleaching can be used to estimate the activity of isomerase in vivo (see, e.g., Maeda et al., J. Neurochein 85:944-956 (2003); Van Hooser et al., J Biol Chem 277:19173-82, 2002). Electroretinographic (ERG) recording may be performed as previously described (Haeseleer et al., Nat. Neurosci. 7:1079-87 (2004); Sugitomo et al,, J. Toxicol. Sci. 22 Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica 100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971 (1989); Gollapalli et al., Biochim Biophys Acta. 1651: 93-101 (2003); Parish, pt al., Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu, et al., Proc Nal Acad Sct USA 101: 5928-33 (2004)). In certain embodiments, compounds that are useful for treating a subject who has or who is at risk of developing any one of the ophthalmic and retinal diseases or disorders described herein have IC 5 o levels (compound concentration at which 50% of isomerase activity is inhibited) as measured in the isomerase assays described herein or known in the art that is less than about 1 pM; in other embodiments, the determined IC5 0 level is less than about 10 nM; in other embodiments, the determined IC5 0 level is less than about 50 nM; in certain other embodiments, the determined IC5 0 level is less than about 100 nM; in other certain embodiments, the determined IC5 0 level is less than about 10 pLM; in other embodiments, the determined IC 50 level is less than about 50 pM; in other certain embodiments, the determined ICs 0 level is less than about 100 pM or about 500 pM; in other embodiments, the determined ICso level is between about I pM and 10 pM; in other embodiments, the determined IC 0 level is between about 1 nM and 10 nM. When adminstered into a subject, one or more compounds of the present invention exhibits an EDs 0 value of about 5 mg/kg, 5 mg/kg or less as ascertained by inhibition of an isomerase reaction that results in production of 11-cis retinol. In some embodiments, the compounds of the present invention have EDo values of about 1 mg/kg when administered into a subject. In other embodiments, the compounds of the present invention have EDsO values of about 0.1 mg/kg when administered into a subject. The ED 0 values can be measured after about 2 hours, 4 hours, 6 hours, 8 hours or longer upon administering a subject compound or a pharmaceutical composition thereof. 5 1002181 The compounds described herein may be useful for treating a subject who has an ophthalmic disease or disorder, particularly a retinal disease or disorder such as age-related macular degeneration or Stargardt's macular dystrophy. In one embodiment, the compounds described herein may inhibit (i.e., prevent, reduce, slow, abrogate, or minimize) accumulation of lipofuscin pigments and lipofuscin-related and/or associated molecules in the eye. In another embodiment, the compounds may inhibit (i.e., prevent, reduce, slow, 10 abrogate, or minimize) N-retinylidene-N-retinylethanolamine (A2E) accumulation in the eye. The ophthalmic disease may result, at least in part, from lipofuscin pigments accumulation and/or from accumulation of A2E in the eye. Accordingly, in certain embodiments, methods are provided for inhibiting or preventing accumulation of lipofuscin pigments and/or A2E in the eye of a subject. These methods comprise administering to the subject a composition comprising a pharmaceutically acceptable or suitable 15 excipient (i.e. pharmaceutically acceptable or suitable carrier) and a sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (I) and substructures thereof, and the specific sulphur-linked compounds described herein. 83 WO 2010/028088 PCT/US2009/055785 5 [002191 Accumulation of lipofuscin pigments in retinal pigment epithelium (RPE) cells has been linked to progression of retinal diseases that result in blindness, including age-related macular degeneration (De Laey et al., Retina 15:399-406 (1995)). Lipofuscin granules are autofluorescent lysosomal residual bodies (also called age pigments). The major fluorescent species of lipofuscin is A2E (an orange-emitting fluorophore), which is a positively charged Schiff-base condensation-product formed by all-trans 10 retinaldebyde with phosphatidyletbanolamine (2:1 ratio) (see, e.g., Eldred et al., Nature 361:724-6 (1993); see also, Sparrow, Proc. Nail. Acad. Sci. USA 100:4353-54 (2003)). Much of the indigestible lipofuscin pigment is believed to originate in photoreceptor cells; deposition in the RPE occurs because the RPE internalize membranous debris that is discarded daily by the photoreceptor cells. Formation of this compound is not believed to occur by catalysis by any enzyme, but rather A2E forms by a spontaneous 15 cyclization reaction. In addition, A2E has a pyridinium bisretinoid structure that once formed may not be enzymatically degraded. Lipofuscin, and thus A2E, accumulate with aging of the human eye and also accumulate in a juvenile form of macular degeneration called Stargardt's disease, and in several other congenital retinal dystrophies. [00220J A2E may induce damage to the retina via several different mechanisms. At low concentrations, A2E 20 inhibits normal proteolysis in lysosomes (Holz et al., Invest. Ophthalmol. Vs. Sc 40:737-43 (1999)). At higher, sufficient concentrations, A2E may act as a positively charged lysosomotropic detergent, dissolving cellular membranes, and may alter lysosomal function, release proapoptotic proteins from mitochondria, and ultimately kill the RPE cell (see, e.g., Eldred et al., supra; Sparrow et al., Invest. Ophthalmol. Vis. Sci. 40:2988-95 (1999); Holz et al., supra; Finneman et al., Proc. Natl. Acad. &i. USA 99:3842-347 (2002); 25 Suter et al., J. Riol. Chem. 275:39625-30 (2000)). A2E is phototoxic and initiates blue light-induced apoptosis in RPE cells (see, e.g., Sparrow et al., Invest. Ophthalmol. Vis. Sci. 43:1222-27 (2002)). Upon exposure to blue light, photooxidative products of A2E are formed (e.g., epoxides) that damage cellular macromolecules, including DNA (Sparrow et al., . Biol. Chem. 278(20):18207-13 (2003)). A2E self generates singlet oxygen that reacts with A2E to generate epoxides at carbon-carbon double bonds 30 (Sparrow et al., supra). Generation of oxygen reactive species upon photoexcitation of A2E causes oxidative damage to the cell, often resulting in cell death. An indirect method of blocking formation of A2E by inhibiting biosynthesis of the direct precursor of A2E, all-trans-retinal, has been described (see U.S. Patent Application Publication No. 2003/0032078). However, the usefulness of the method described therein is limited because generation of all-trans retinal is an important component of the visual cycle. 35 Other therapies described include neutralizing damage caused by oxidative radical species by using superoxide-dismutase mimetics (see, e.g., U.S. Patent Application Publication No. 2004/0116403) and inhibiting A2E-induced cytochrome C oxidase in retinal cells with negatively charged phospholipids (see, e.g., U.S. Patent Application Publication No. 2003/0050283). [002211 The sulphur-linked compounds described herein may be useful for preventing, reducing, inhibiting, or 40 decreasing accumulation (iLe., deposition) of A2E and A2E-related and/or derived molecules in the RPE. Without wishing to be bound by theory, because the RPE is critical for the maintenance of the integrity of photoreceptor cells, preventing, reducing, or inhibiting damage to the RPE may inhibit degeneration (i.e., enhance the survival or increase or prolong cell viability) of retinal neuronal cells, particularly, photoreceptor cells. Compounds that bind specifically to or interact with A2E A2E-related and/or derived 45 molecules or that affect A2E formation or accumulation may also reduce, inhibit, prevent, or decrease one or more toxic effects of A2E or of A2E-related and/or derived molecules that result in retinal neuronal cell 84 WO 2010/028088 PCT/US2009/055785 5 (including a photoreceptor cell) damage, loss, or neurodegeneration, or in some manner decrease retinal neuronal cell viability. Such toxic effects include induction of apoptosis, self-generation of singlet oxygen and generation of oxygen reactive species; self-generation of singlet oxygen to form A2E-poxides that induce DNA lesions, thus damaging cellular DNA and inducing cellular damage; dissolving cellular membranes; altering lysosomal function; and effecting release of proapoptotic proteins from mitochondria, 10 [002221 In other embodiments, the compounds described herein may be used for treating other ophthalmic diseases or disorders, for example, glaucoma, cone-rod dystrophy, retinal detachment, hemorrhagic or hypertensive retinopathy, retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, proliferative vitreoretinopathy, genetic retinal dystrophies, traumatic injury to the optic nerve (such as by physical injury, excessive light exposure, or laser light), hereditary optic neuropathy, neuropathy due to a toxic agent 15 or caused by adverse drug reactions or vitamin deficiency, Sorsby's fundus dystrophy, uveitis, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis; a retinal disorder associated with viral infection (cytomegalovirus or herpes simplex virus), a retinal disorder associated with Parkinson's disease, a retinal disorder associated with AIDS, or other forms of progressive retinal atrophy or degeneration. In another specific embodiment, the disease or disorder results from 20 mechanical injury, chemical or drug-induced injury, thermal injury, radiation injury, light injury, laser injury. The subject compounds are useful for treating both hereditary and non-hereditary retinal dystrophy. These methods are also useful for preventing ophthalmic injury from environmental factors such as light induced oxidative retinal damage, laser-induced retinal damage, "flash bomb injury," or "light dazzle", refractive errors including but not limited to myopia (see, e.g., Quinn GE et al. Nature 1999;399: 113-114; 25 Zadnik K et al. Nature 2000;404:143-144; Gwiazda J et al. Nature 2000;404: 144), etc. [00223) In other embodiments, methods are provided herein for inhibiting neovascularization (including but not limited to neovascular glycoma) in the retina using any one or more of the sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (I) and substructures thereof, and the specific sulphur-linked compounds described herein. In certain other 30 embodiments, methods are provided for reducing hypoxia in the retina using the compounds described herein. These methods comprise administering to a subject, in need thereof, a composition comprising a pharmaceutically acceptable or suitable excipient (i.e., pharmaceutically acceptable or suitable carrier) and a sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (I) and substructures thereof, and the specific sulphur-linked compounds described herein. 35 [002241 Merely by way of explanation and without being bound by any theory, and as discussed in further detail herein, dark-adapted rod photoreceptors engender a very high metabolic demand (i.e., expenditure of energy (ATP consumption) and consumption of oxygen). The resultant hypoxia may cause and/or exacerbate retinal degeneration, which is likely exaggerated under conditions in which the retinal vasculature is already compromised, including, but not limited to, such conditions as diabetic retinopathy, 40 macular edema, diabetic maculopathy, retinal blood vessel occlusion (which includes retinal venous occlusion and retinal arterial occlusion), retinopathy of prematurity, ischemia reperfusion related retinal injury, as well as in the wet form of age-related macular degeneration (AMD). Furthermore, retinal degeneration and hypoxia may lead to neovascularization, which in turn may worsen the extent of retinal degeneration. The sulphur-linked compounds described herein that modulate the visual cycle can be 45 administered to prevent, inhibit, and/or delay dark adaptation of rod photoreceptor cells, and may therefore reduce metabolic demand, thereby reducing hypoxia and inhibiting neovascularization. 85 WO 2010/028088 PCT/US2009/055785 5 [002251 By way of background, oxygen is a critical molecule for preservation of retinal function in mammals, and retinal hypoxia may be a factor in many retinal diseases and disorders that have ischemia as a component. In most mammals (including humans) with dual vascular supply to the retina, oxygenation of the inner retina is achieved through the intraretinal microvasculature, which is sparse compared to the choriocapillaris that supplies oxygen to the RPE and photoreceptors. The different vascular supply 10 networks create an uneven oxygen tension across the thickness of the retina (Cringle et al., Invest. Ophthalmo/. Vis. Sci. 43:1922-27 (2002)). Oxygen fluctuation across the retinal layers is related to both the differing capillary densities and disparity in oxygen consumption by various retinal neurons and glia. [00226] Local oxygen tension can significantly affect the retina and its microvasculature by regulation of an array of vasoactive agents, including, for example, vascular endothelial growth factor (VEGF). (See, e.g., 15 Werdich et al., Exp. Eye Res. 79:623 (2004); Arden et al., Br. J. OphthalmoL 89:764 (2005)), Rod photoreceptors are believed to have the highest metabolic rate of any cell in the body (see, e.g., Arden et al., supra). During dark adaptation, the rod photoreceptors recover their high cytoplasmic calcium levels via cGMP-gated calcium channels with concomitant extrusion of sodium ions and water. The efflux of sodium from the cell is an ATP-dependent process, such that the retinal neurons consume up to an 20 estimated five times more oxygen under scotopic (i.e., dark adapted), compared with photopic (i.e., light adapted) conditions. Thus, during characteristic dark adaptation of photoreceptors, the high metabolic demand leads to significant local reduction of oxygen levels in the dark-adapted retina (Ahmed et al, Invest. Ophthalmol. Vis. Sci. 34:516 (1993)). [002271 Without being bound by any one theory, retinal hypoxia may be further increased in the retina of subjects 25 who have diseases or conditions such as, for example, central retinal vein occlusion in which the retinal vasculature is already compromised. Increasing hypoxia may increase susceptibility to sight-threatening, retinal neovascularization. Neovascularization is the formation of new, functional microvascular networks with red blood cell perfusion, and is a characteristic of retinal degenerative disorders, including, but not limited to, diabetic retinopathy, retinopathy of prematurity, wet AMD and central retinal vein occlusions. 30 Preventing or inhibiting dark adaptation of rod photoreceptor cells, thereby decreasing expenditure of energy and consumption of oxygen (i.e., reducing metabolic demand), may inhibit or slow retinal degeneration, and/or may promote regeneration of retinal cells, including rod photoreceptor cells and retinal pigment epithelial (RPE) cells, and may reduce hypoxia and may inhibit neovascularization. [00228] Methods are described herein for inhibiting (i.e., reducing, preventing, slowing or retarding, in a 35 biologically or statistically significant manner) degeneration of retinal cells (including retinal neuronal cells as described herein and RPE cells) and/or for reducing (i.e., preventing or slowing, inhibiting, abrogating in a biologically or statistically significant manner) retinal iscbemia. Methods are also provided for inhibiting (i.e., reducing, preventing, slowing or retarding, in a biologically or statistically significant manner) neovascularization in the eye, particularly in the retina. Such methods comprise contacting the retina, and 40 thus, contacting retinal cells (including retinal neuronal cells such as rod photoreceptor cells, and RPE cells) with at least one of the sulphur-linked compounds described herein that inhibits at least one visual cycle trans-cis isomerase (which may include inhibition of isomerization of an all-trans-retinyl ester), under conditions and at a time that may prevent, inhibit, or delay dark adaptation of a rod photoreceptor cell in the retina. As described in further detail herein, in particular embodiments, the compound that 45 contacts the retina interacts with an isomerase enzyme or enzymatic complex in a RPE cell in the retina and inhibits, blocks, or in some manner interferes with the catalytic activity of the isomerase. Thus, 86 WO 2010/028088 PCT/US2009/055785 5 isomerization of an all-trans-retinyl ester is inhibited or reduced. The sulphur-linked compounds described herein or compositions comprising said compounds may be administered to a subject who has developed and manifested an ophthalmic disease or disorder or who is at risk of developing an ophthalmic disease or disorder, or to a subject who presents or who is at risk of presenting a condition such as retinal neovascularization or retinal ischemia. 10 [00229] By way of background, the visual cycle (also called retinoid cycle) refers to the series of enzyme and light mediated conversions between the 11 -cis and all-trans forms of retinol/retinal that occur in the photoreceptor and retinal pigment epithelial (RPE) cells of the eye. In vertebrate photoreceptor cells, a photon causes isomerization of the 11-cis-retinylidene chromophore to all-trans-retinylidene coupled to the visual opsin receptors. This photoisomerization triggers conformational changes of opsins, which, in turn, 15 initiate the biochemical chain of reactions termed phototransduction (Filipek et al., Annu. Rev. PhysioL 65 851-79 (2003)). After absorption of light and photoisomerization of 11-cis-retinal to all-trans retinal, regeneration of the visual chromophore is a critical step in restoring photoreceptors to their dark-adapted state. Regeneration of the visual pigment requires that the chromophore be converted back to the 11 -cis configuration (reviewed in McBee et al., Prog. Retin. Eye Res. 20:469-52 (2001)). The chromophore is 20 released from the opsin and reduced in the photoreceptor by retinol dehydrogenases. The product, all trans-retinol, is trapped in the adjacent retinal pigment epithelium (RPE) in the form of insoluble fatty acid esters in subcellular structures known as retinosomes (Imanishi et al., . Cell Biol. 164:373-78 (2004)). 1002301 During the visual cycle in rod receptor cells, the 1 1-cis retinal chromophore within the visual pigment molecule, which is called rhodopsin, absorbs a photon of light and is isomerized to the all-trans 25 configuration, thereby activating the phototransduction cascade. Rhodopsin is a 0-protein coupled receptor (GPCR) that consists of seven membrane-spanning helices that are interconnected by extracellular and cytoplasmic loops. When the all-trans form of the retinoid is still covalently bound to the pigment molecule, the pigment is referred to as metarhodopsin, which exists in different forms (e.g., metarhodopsin I and metarhodopsin 1l). The all-trans retinoid is then hydrolyzed and the visual pigment is in the form of 30 the apoprotein, opsin, which is also called apo-rhodopsin in the art and herein. This all-trans retinoid is transported or chaperoned out of the photoreceptor cell and across the extracellular space to the RPE cells, where the retinoid is converted to the I 1-cis isomer. The movement of the retinoids between the RPE and photoreceptors cells is believed to be accomplished by different chaperone polypeptides in each of the cell types. See Lamb et al., Progress in Retinal and Eye Research 23:307-80 (2004). 35 [002311 Under light conditions, rhodopsin continually transitions through the three forms, rhodopsin, metarhodopsin, and apo-rhodopsin. When most of the visual pigment is in the rhodopsin form (i.e., bound with 1 -cis retinal), the rod photoreceptor cell is in a "dark-adapted" state. When the visual pigment is predominantly in the metarhodopsin form (La. bound with all-trans-retinal), the state of the photoreceptor cell is referred to as a "light-adapted," and when the visual pigment is apo-rhodopsin (or opsin) and no 40 longer has bound chromophore, the state of the photoreceptor cell is referred to as "rhodopsin-depleted." Each of the three states of the photoreceptor cell has different energy requirements, and differing levels of ATP and oxygen are consumed. In the dark-adapted state, rhodopsin has no regulatory effect on cation channels, which are open, resulting in an influx of cations (Nat / K* and Ca 2 *). To maintain the proper level of these cations in the cell during the dark state, the photoreceptor cells actively transport the cations 45 out of the cell via ATP-dependent pumps. Thus maintenance of this "dark current" requires a large amount of energy, resulting in high metabolic demand. In the light-adapted state, metarhodopsin triggers an 87 WO 2010/028088 PCTIUS2009/055785 5 enzymatic cascade process that results in hydrolysis of GMP, which in turn, closes cation-specific channels in the photoreceptor cell membrane. In the rhodopsin-depleted state, the chromophore is hydrolyzed from metarhodopsin to form the apoprotein, opsin (apo-rhodopsin), which partially regulates the cation channels such that the rod photoreceptor cells exhibit an attenuated current compared with the photoreceptor in the dark-adapted state, resulting in a moderate metabolic demand. 10 (00232] Under normal light conditions, the incidence of rod photoreceptors in the dark adapted state is small, in general, 2% or less, and the cells are primarily in the light-adapted or rhodopsin-depleted states, which overall results in a relatively low metabolic demand compared with cells in the dark-adapted state. At night, however, the relative incidence of the dark-adapted photoreceptor state increases profoundly, due to the absence of light adaptation and to the continued operation of the "dark" visual cycle in RPE cells, 15 which replenishes the rod photoreceptor cells with 1 1-cis-retinal. This shift to dark adaptation of the rod photoreceptor causes an increase in metabolic demand (that is, increased ATP and oxygen consumption), leading ultimately to retinal hypoxia and subsequent initiation of angiogenesis. Most ischaemic insults to the retina therefore occur in the dark, for example, at night during sleep. 1002331 Without being bound by any theory, therapeutic intervention during the "dark" visual cycle may prevent 20 retinal hypoxia and neovascularization that are caused by high metabolic activity in the dark-adapted rod photoreceptor cell. Merely by way of one example, altering the "dark" visual cycle by administering any one of the compounds described herein, which is an isomerase inhibitor, rhodopsin (i.e., I 1-cis retinal bound) may be reduced or depleted, preventing or inhibiting dark adaptation of rod photoreceptors, This in turn may reduce retinal metabolic demand, attenuating the nighttime risk of retinal ischemia and 25 neovascularizati on, and thereby inhibiting or slowing retinal degeneration. [00234] In one embodiment, at least one of the compounds described herein (i.e., a sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (1) and substructures thereof, and the specific sulphur-Linked compounds described herein) that, for example, blocks, reduces, inhibits, or in some manner attenuates the catalytic activity of a visual cycle isomerase in a 30 statistically or biologically significant manner, may prevent, inhibit, or delay dark adaptation of a rod photoreceptor cell, thereby inhibiting (i.e., reducing, abrogating, preventing, slowing the progression of, or decreasing in a statistically or biologically significant manner) degeneration of retinal cells (or enhancing survival of retinal cells) of the retina of an eye. In another embodiment, the sulphur-linked compounds may prevent or inhibit dark adaptation of a rod photoreceptor cell, thereby reducing ischemia (I.e., decreasing, 35 preventing, inhibiting, slowing the progression of ischemia in a statistically or biologically significant manner). In yet another embodiment, any one of the sulphur-linked compounds described herein may prevent dark adaptation of a rod photoreceptor cell, thereby inhibiting neovascularization in the retina of an eye. Accordingly, methods are provided herein for inhibiting retinal cell degeneration, for inhibiting neovascularization in the retina of an eye of a subject, and for reducing ischemia in an eye of a subject 40 wherein the methods comprise administering at least one sulphur-linked compound described herein, under conditions and at a time sufficient to prevent, inhibit, or delay dark adaptation of a rod photoreceptor cell. These methods and compositions are therefore useful for treating an ophthalmic disease or disorder including, but not limited to, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury. 45 1002351 The sulphur-linked compounds described herein (i.e., a sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (I), and substructures thereof, and 88 WO 2010/028088 PCT/US2009/055785 5 the specific sulphur-linked compounds described herein) may prevent (ie,, delay, slow, inhibit, or decrease) recovery of the visual pigment chromophore, which may prevent or inhibit or retard the formation of retinals and may increase the level of retinyl esters, which perturbs the visual cycle, inhibiting regeneration of rhodopsin, and which prevents, slows, delays or inhibits dark adaptation of a rod photoreceptor cell. In certain embodiments, when dark adaptation of rod photoreceptor cells is prevented 10 in the presence of the compound, dark adaptation is substantially prevented, and the number or percent of rod photoreceptor cells that are rhodopsin-depleted or light adapted is increased compared with the number or percent of cells that are rhodopsin-depleted or light-adapted in the absence of the agent. Thus, in certain embodiments when dark adaptation of rod photoreceptor cells is prevented (i.e., substantially prevented), only at least 2% of rod photoreceptor cells are dark-adapted, similar to the percent or number of cells that 15 are in a dark-adapted state during normal, light conditions. In other embodiments, at least 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, or 60-70% of rod photoreceptor cells are dark-adapted after administration of an agent. In other embodiments, the compound acts to delay dark adaptation, and in the presence of the compound dark adaptation of rod photoreceptor cells may be del ayed 30 minutes, one hour, two hours, three hours, or four hours compared to dark adaptation of rod photoreceptors in the absence of 20 the compound. By contrast, when a sulphur-linked compound is administered such that the compound effectively inhibits isomerization of substrate during light-adapted conditions, the compound is administered in such a manner to minimize the percent of rod photoreceptor cells that are dark-adapted, for example, only 2%, 5%, 10%, 20%, or 25% of rod photoreceptors are dark-adapted (see e.g., U.S. Patent Application Publication No. 2006/0069078; Patent Application No. PCT/US2007/002330). 25 [00236] In the retina in the presence of at least one sulphur-linked compound, regeneration of rhodopsin in a rod photoreceptor cell may be inhibited or the rate of regeneration may be reduced (I e., inhibited, reduced, or decreased in a statistically or biologically significant manner), at least in part, by preventing the formation of retinals, reducing the level of retinals, and/or increasing the level of retinyl enters. To determine the level of regeneration of rhodopsin in a rod photoreceptor cell, the level of regeneration of rhodopsin (which 30 may be called a first level) may be determined prior to permitting contact between the compound and the retina (i.e., prior to administration of the agent). After a time sufficient for the compound and the retina and cells of the retina to interact, (i.e., after administration of the compound), the level of regeneration of rhodopsin (which may be called a second level) may be determined. A decrease in the second level compared with the first level indicates that the compound inhibits regeneration of rhodopsin. The level of 35 rhodopsin generation may be determined after each dose, or after any number of doses, and ongoing throughout the therapeutic regimen to characterize the effect of the agent on regeneration of rhodopsin. [00237] In certain embodiments, the subject in need of the treatments described herein, may have a disease or disorder that results in or causes impairment of the capability of rod photoreceptors to regenerate rhodopsin in the retina. By way of example, inhibition of rhodopsin regeneration (or reduction of the rate of 40 rhodopsin regeneration) may be symptomatic in patients with diabetes, In addition to determining the level of regeneration of rhodopsin in the subject who has diabetes before and after administration of a sulphur linked compound described herein, the effect of the compound may also be characterized by comparing inhibition of rhodopsin regeneration in a first subject (or a first group or plurality of subjects) to whom the compound is administered, to a second subject (or second group or plurality of subjects) who has diabetes 45 but who does not receive the agent. [002381 In another embodiment, a method is provided for preventing or inhibiting dark adaptation of a rod 89 WO 2010/028088 PCT/US2009/055785 5 photoreceptor cell (or a plurality of rod photoreceptor cells) in a retina comprising contacting the retina and at least one of the sulphur-linked compounds described herein (i.e., a compound as described in detail herein, including a compound having the structure as set forth in Formula (I), and substructures thereof, and the specific sulphur-linked compounds described herein), under conditions and at a time sufficient to permit interaction between the agent and an isomerase present in a retinal cell (such as an RPE cell). A first level 10 of I1 -cis-retinal in a rod photoreceptor cell in the presence of the compound may be determined and compared to a second level of 11-cis-retinal in a rod photoreceptor cell in the absence of the compound. Prevention or inhibition of dark adaptation of the rod photoreceptor cell is indicated when the first level of 11-cis-retinal is less than the second level of 11-cis-retinal. [00239] Inhibiting regeneration of rhodopsin may also include increasing the level of 1 1-cis-retinyl esters present in 15 the RPE cell in the presence of the compound compared with the level of 1 1-cis-retinyl esters present in the RPE cell in the absence of the compound (I.e., prior to administration of the agent). A two-photon imaging technique may be used to view and analyze retinosome structures in the RPE, which structures are believed to store retinyl esters (see, e.g., Imanishi et al., J. Cell Blol. 164:373-83 (2004), Epub 2004 January 26.). A first level of retinyl esters may be determined prior to administration of the compound, and a second level 20 of retinyl esters may be determined after administration of a first dose or any subsequent dose, wherein an increase in the second level compared to the first level indicates that the compound inhibits regeneration of rhodopsin. [002401 Retinyl esters may be analyzed by gradient HPLC according to methods practiced in the art (see, for example, Mata et al., Neuron 36:69-80 (2002); Trevino et al. J. Exp. Blol. 208:4151-57 (2005)). To 25 measure 11-cis and all-transretinals, retinoids may be extracted by a formaldehyde method (see, e.g., Suzuki et al., Vis. Res. 28:1061-70 (1988); Okajima and Pepperberg, Exp. Eye Res. 65:331-40 (1997)) or by a hydroxylamine method (see, e.g., Groenendijk et al., Biochim. Blophys. Acta. 617:430-38 (1980)) before being analyzed on isocratic HPLC (see, e.g., Trevino et al., supra). The retinoids maybe monitored spectrophotometrically (see, e.g., Maeda et al., J. Neurochem. 85:944-956 (2003); Van Hooser et al., J. 30 Biol. Chem. 277:19173-82 (2002)). 100241] In another embodiment of the methods described herein for treating an ophthalmic disease or disorder, for inhibiting retinal cell degeneration (or enhancing retinal cell survival), for inhibiting neovascularization, and for reducing ischemia in the retina, preventing or inhibiting dark adaptation of a rod photoreceptor cell in the retina comprises increasing the level of apo-rhodopsin (also called opsin) in the photoreceptor cell. 35 The total level of the visual pigment approximates the sum of rhodopsin and apo-rhodopsin and the total level remains constant. Therefore, preventing, delaying, or inhibiting dark adaptation of the rod photoreceptor cell may alter the ratio of apo-rhodopsin to rhodopsin. In particular embodiments, preventing, delaying, or inhibiting dark adaptation by administering a sulphur-linked compound described herein may increase the ratio of the level of apo-rhodopsin to the level of rhodopsin compared to the ratio 40 in the absence of the agent (for example, prior to administration of the agent). An increase in the ratio (i.e., a statistically or biologically significant increase) of apo-rhodopsin to rhodopsin indicates that the percent or number of rod photoreceptor cells that are rhodopsin-depleted is increased and that the percent or number of rod photoreceptor cells that are dark-adapted is decreased. The ratio of apo-rhodopsin to rhodopsin may be determined throughout the course of therapy to monitor the effect of the agent. 45 [00242] Determining or characterizing the capability of compound to prevent, delay, or inhibit dark adaptation of a rod photoreceptor cell may be determined in animal model studies. The level of rhodopsin and the ratio of 90 WO 2010/028088 PCT/US2009/055785 5 apo-rhodopsin to rhodopsin may be determined prior to administration (which may be called a first level or first ratio, respectively) of the agent and then after administration of a first or any subsequent dose of the agent (which may be called a second level or second ratio, respectively) to determine and to demonstrate that the level of apo-rhodopsin is greater than the level of apo-rhodopsin in the retina of animals that did not receive the agent. The level of rhodopsin in rod photoreceptor cells may be performed according to 10 methods practiced in the art and provided herein (see, e.g., Yan et al. J. Blot Chem. 279:48189-96 (2004)). [002431 A subject in need of such treatment may be a human or may be a non-human primate or other animal (i.e., veterinary use) who has developed symptoms of an ophthalmic disease or disorder or who is at risk for developing an ophthalmic disease or disorder. Examples of non-human primates and other animals include but are not limited to farm animals, pets, and zoo animals (e.g., horses, cows, buffalo, llamas, goats, 15 rabbits, cats, dogs, chimpanzees, orangutans, gorillas, monkeys, elephants, bears, large cats, etc.). [002441 Also provided herein are methods for inhibiting (reducing, slowing, preventing) degeneration and enhancing retinal neuronal cell survival (or prolonging cell viability) comprising administering to a subject a composition comprising a pharmaceutically acceptable carrier and a sulphur-linked compound described in detail herein, including a compound having any one of the structures set forth in Formula (I) and 20 substructures thereof, and specific sulphur-linked compounds recited herein. Retinal neuronal cells include photoreceptor cells, bipolar cells, horizontal cells, ganglion cells, and amacrine cells. In another embodiment, methods are provided for enhancing survival or inhibiting degeneration of a mature retinal cell such as a RPE cell or a MOller glial cell. In other embodiments, a method for preventing or inhibiting photoreceptor degeneration in an eye of a subject are provided. A method that prevents or inhibits 25 photoreceptor degeneration may include a method for restoring photoreceptor function in an eye of a subject. Such methods comprise administering to the subject a composition comprising a sulphur-linked compound as described herein and a pharmaceutically or acceptable carrier (i.e., excipient or vehicle). More specifically, these methods comprise administering to a subject a pharmaceutically acceptable excipient and a sulphur-linked compound described herein, including a compound having any one of the 30 structures set forth in Formula (I) or substructures thereof described herein. Without wishing to be bound by theory, the compounds described herein may inhibit an isomerization step of the retinoid cycle (i.e., visual cycle) and/or may slow chromophore flux in a retinoid cycle in the eye. 1002451 The ophthalmic disease may result, at least in part, from lipofuscin pigment(s) accumulation and/or from accumulation of N-retinylidene-N-retinylethanolamine (A2E) in the eye. Accordingly, in certain 35 embodiments, methods are provided for inhibiting or preventing accumulation of lipofuscin pigment(s) and/or A2E in the eye of a subject. These methods comprise administering to the subject a composition comprising a pharmaceutically acceptable carrier and a sulphur-linked compound as described in detail herein, including a compound having the structure as set forth in Formula (I) or substructures thereof. [002461 A sulphur-linked compound can be administered to a subject who has an excess of a retinoid in an eye 40 (e.g., an excess of 11-cis-retinol or 11-cis-retinal), an excess of retinoid waste products or intermediates in the recycling of all-trans-retinal, or the like. Methods described herein and practiced in the art may be used to determine whether the level of one or more endogenous retinoids in a subject are altered (increased or decreased in a statistically significant or biologically significant manner) during or after administration of any one of the compounds described herein. Rhodopsin, which is composed of the protein opsin and retinal 45 (a vitamin A form), is located in the membrane of the photoreceptor cell in the retina of the eye and catalyzes the only light-sensitive step in vision. The 1 1-cis-retinal chromophore lies in a pocket of the 91 WO 2010/028088 PCT/US2009/055785 5 protein and is isomerized to all-trans retinal when light is absorbed. The isomerization of retinal leads to a change of the shape of rhodopsin, which triggers a cascade of reactions that lead to a nerve impulse that is transmitted to the brain by the optic nerve. [00247] Methods of determining endogenous retinoid levels in a vertebrate eye, and an excess or deficiency of such retinoids, are disclosed in, for example, U.S. Patent Application Publication No: 2005/0159662 (the 10 disclosure of which is incorporated by reference herein in its entirety). Other methods of determining endogenous retinoid levels in a subject, which is useful for determining whether levels of such retinoids are above the normal range, and include for example, analysis by high pressure liquid chromatography (HP LC) of retinoids in a biological sample from a subject. For example, retinoid levels can be determined in a biological sample that is a blood sample (which includes serum or plasma) from a subject. A biological 15 sample may also include vitreous fluid, aqueous humor, intraocular fluid, subretinal fluid, or tears. 100248] For example, a blood sample can be obtained from a subject, and different retinoid compounds and levels of one or more of the retinoid compounds in the sample can be separated and analyzed by normal phase high pressure liquid chromatography (HPLC) (e.g., with a HPl 100 HPLC and a Beckman, Ultrasphere-Si, 4.6 mm x 250 mm column using 10% ethyl acetate/90% hexane at a flow rate of 1.4 ml/minute). The 20 retinoids can be detected by, for example, detection at 325 nm using a diode-array detector and HP Chemstation A.03.03 software. An excess in retinoids can be determined, for example, by comparison of the profile of retinoids (i.e., qualitative, e.g., identity of specific compounds, and quantitative, e.g., the level of each specific compound) in the sample with a sample from a normal subject. Persons skilled in the art who are familiar with such assays and techniques and will readily understand that appropriate controls are 25 included. [00249] As used herein, increased or excessive levels of endogenous retinoid, such as I 1-cis-retinol or 1 1-cis retinal, refer to levels of endogenous retinoid higher than those found in a healthy eye of a young vertebrate of the same species. Administration of a sulphur-linked compound and reduce or eliminate the requirement for endogenous retinoid. In certain embodiments, the level of endogenous retinoid may be compared before 30 and after any one or more doses of a sulphur-linked compound is administered to a subject to determine the effect of the compound on the level of endogenous retinoids in the subject. 100250] In another embodiment, the methods described herein for treating an ophthalmic disease or disorder, for inhibiting neovascularization, and for reducing ischemia in the retina comprise administering at least one of the sulphur-linked compounds described herein, thereby effecting a decrease in metabolic demand, which 35 includes effecting a reduction in ATP consumption and in oxygen consumption in rod photoreceptor cells. As described herein, consumption of ATP and oxygen in a dark-adapted rod photoreceptor cell is greater than in rod photoreceptor cells that are light-adapted or rhodopsin-depleted; thus, use of the compounds in the methods described herein may reduce the consumption of ATP in the rod photoreceptor cells that are prevented, inhibited, or delayed from dark adaptation compared with rod photoreceptor cells that are dark 40 adapted (such as the cells prior to administration or contact with the compound or cells that are never exposed to the compound). 1002511 The methods described herein that may prevent or inhibit dark adaptation of a rod photoreceptor cell may therefore reduce hypoxia (i.e., reduce in a statistically or biologically significant manner) in the retina. For example, the level of hypoxia (a first level) may be determined prior to initiation of the treatment regimen, 45 that is, prior to the first dosing of the compound (or a composition, as described herein, comprising the compound). The level of hypoxia (for example, a second level) may be determined after the first dosing, 92 WO 2010/028088 PCTIUS2009/055785 5 and/or after any second or subsequent dosing to monitor and characterize hypoxia throughout the treatment regimen. A decrease (reduction) in the second (or any subsequent) level of hypoxia compared to the level of hypoxia prior to initial administration indicates that the compound and the treatment regiment prevent dark adaptation of the rod photoreceptor cells and may be used fbr treating ophthalmic diseases and disorders. Consumption of oxygen, oxygenation of the retina, and/or hypoxia in the retina may be 10 determined using methods practiced in the art. For example, oxygenation of the retina may be determined by measuring the fluorescence of flavoproteins in the retina (see, e.g., U.S. Patent No. 4,569,354). Another exemplary method is retinal oximetry that measures blood oxygen saturation in the large vessels of the retina near the optic disc. Such methods may be used to identify and determine the extent of retinal hypoxia before changes in retinal vessel architecture can be detected. 15 (00252] A biological sample may be a blood sample (from which serum or plasma may be prepared), biopsy specimen, body fluids (e.g., vitreous fluid, aqueous humor, intraocular fluid, subretinal fluid, or tears), tissue explant, organ culture, or any other tissue or cell preparation from a subject or a biological source. A sample may further refer to a tissue or cell preparation in which the morphological integrity or physical state has been disrupted, for example, by dissection, dissociation, solubilization, fractionation, 20 homogenization, biochemical or chemical extraction, pulverization, lyophilization, sonication, or any other means for processing a sample derived from a subject or biological source. The subject or biological source may be a human or non-human animal, a primary cell culture (e.g., a retinal cell culture), or culture adapted cell line, including but not limited to, genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or 25 immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiatable cell lines, transformed cell lines, and the like. Mature retinal cells, including retinal neuronal cells, RPE cells, and MUller glial cells, may be present in or isolated from a biological sample as described herein. For example, the mature retinal cell may be obtained from a primary or long-term cell culture or may be present in or isolated from a biological sample obtained from a subject (human or non-human animal). Retinal Cells 30 [002531 The retina Is a thin layer of nervous tissue located between the vitreous body and choroid in the eye. Major landmarks in the retina are the fovea, the macula, and the optic disc. The retina is thickest near the posterior sections and becomes thinner near the periphery. The macula is located in the posterior retina and contains the fbvea and foveola. The foveola contains the area of maximal cone density and, thus, imparts the highest visual acuity in the retina. The foveola is contained within the fovea, which is contained within 35 the macula. 1002541 The peripheral portion of the retina increases the field of vision. The peripheral retina extends anterior to the ciliary body and is divided into four regions: the near periphery (most posterior), the mid-periphery, the far periphery, and the or serrata (most anterior). The ora serrata denotes the termination of the retina. 100255] The term neuron (or nerve cell) as understood in the art and used herein denotes a cell that arises from 40 neuroepithelial cell precursors. Mature neurons (i.e. fully differentiated cells) display several specific antigenic markers. Neurons may be classified functionally into three groups: (1) afferent neurons (or sensory neurons) that transmit information into the brain for conscious perception and motor coordination; (2) motor neurons that transmit commands to muscles and glands; and (3) intemeurons that are responsible for local circuitry; and (4) projection interneurons that relay information from one region of the brain to 45 another region and therefore have long axons. Intemeurons process information within specific subregions 93 WO 2010/028088 PCT/US2009/055785 5 of the brain and have relatively shorter axons. A neuron typically has four defined regions: the cell body (or soma); an axon; dendrites; and presynaptic terminals. The dendrites serve as the primary input of information from other neural cells. The axon carries the electrical signals that are initiated in the cell body to other neurons or to effector organs. At the presynaptic terminals, the neuron transmits information to another cell (the postsynaptic cell), which may be another neuron, a muscle cell, or a secretory cell. 10 1002561 The retina is composed of several types of neuronal cells. As described herein, the types of retinal neuronal cells that may be cultured in vitro by this method include photoreceptor cells, ganglion cells, and interneurons such as bipolar cells, horizontal cells, and amacrine cells. Photoreceptors are specialized light-reactive neural cells and comprise two major classes, rods and cones. Rods are involved in scotopic or dim light vision, whereas photopic or bright light vision originates in the cones. Many 15 neurodegenerative diseases, such as AMD, that result in blindness affect photoreceptors. [00257] Extending from their cell bodies, the photoreceptors have two morphologically distinct regions, the inner and outer segments. The outer segment lies furthermost from the photoreceptor cell body and contains disks that convert incoming light energy into electrical impulses (phototransduction). The outer segment is attached to the inner segment with a very small and fragile cilium. The size and shape of the outer 20 segments vary between rods and cones and are dependent upon position within the retina. See Hogan, "Retina" in Histology of the Human Eye: an Atlas and Tex Book (Hogan et al. (eds). WB Saunders; Philadelphia, PA (1971)); Eye and Orbit, 8* Ed., Bron et al,, (Chapman and Hall, 1997). [002581 Ganglion cells are output neurons that convey information from the retinal interneurons (including horizontal cells, bipolar cells, amacrine cells) to the brain. Bipolar cells are named according to their 25 morphology, and receive input from the photoreceptors, connect with anacrine cells, and send output radially to the ganglion cells. Amacrine cells have processes parallel to the plane of the retina and have typically inhibitory output to ganglion cells. Amacrine cells are often subclassified by neurotransmitter or neuromodulator or peptide (such as calretinin or calbindin) and interact with each other, with bipolar cells, and with photoreceptors. Bipolar cells are retinal interneurons that are named according to their 30 morphology; bipolar cells receive input from the photoreceptors and sent the input to the ganglion cells. Horizontal cells modulate and transform visual information from large numbers of photoreceptors and have horizontal integration (whereas bipolar cells relay information radially through the retina). [002591 Other retinal cells that may be present in the retinal cell cultures described herein include glial cells, such as Miller glial cells, and retinal pigment epithelial cells (RPE). Glial cells surround nerve cell bodies and 35 axons. The glial cells do not carry electrical impulses but contribute to maintenance of normal brain function. Miller glia, the predominant type of glial celi within the retina, provide structural support of the retina and are involved in the metabolism of the retina (e.g., contribute to regulation of ionic concentrations, degradation of neurotransmitters, and remove certain metabolites (see, e.g., KIjavin et al., J Neurosci. 11:2985 (1991)). Miller's fibers (also known as sustentacular fibers of retina) are sustentacular 40 neuroglial cells of the retina that run through the thickness of the retina from the internal limiting membrane to the bases of the rods and cones where they form a row of junctional complexes. 1002601 Retinal pigment epithelial (RPE) cells form the outermost layer of the retina, separated from the blood vessel-enriched choroids by Bruch's membrane. RPE cells are a type of phagocytic epithelial cell, with some functions that are macrophage-like, which lies immediately below the retinal photoreceptors. The 45 dorsal surface of the RPE cell is closely apposed to the ends of the rods, and as discs are shed from the rod outer segment they are internalized and digested by RPE cells. Similar process occurs with the disc of the 94 WO 2010/028088 PCTIUS2009/055785 5 cones. RPE cells also produce, store, and transport a variety of factors that contribute to the normal function and survival of photoreceptors. Another function of RPE cells is to recycle vitamin A as it moves between photoreceptors and the RPE during light and dark adaptation in the process known as the visual cycle. [002611 Described herein is an exemplary long-term in vitro cell culture system permits and promotes the survival 10 in culture of mature retinal cells, including retinal neurons, for at least 2-4 weeks, over 2 months, or for as long as 6 months. The cell culture system may be used for identifying and characterizing the sulphur linked compounds that are useful in the methods described herein for treating and/or preventing an ophthalmic disease or disorder or for preventing or inhibiting accumulation in the eye of lipofuscin(s) and/or A2E. Retinal cells are isolated from non-embryonic, non-tuniorigenic tissue and have not been 15 immortalized by any method such as, for example, transformation or infection with an oncogenic virus. The cell culture system comprises all the major retinal neuronal cell types (photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells), and also may include other mature retinal cells such as retinal pigment epithelial cells and MUller glial cells. [00262] For example, a blood sample can be obtained from a subject, and different retinoid compounds and levels 20 of one or more of the retinoid compounds in the sample can be separated and analyzed by normal phase high pressure liquid chromatography (HPLC (e.g., with a HPI 100 HPLC and a Beckman, Ultrasphere-Si, 4.6 mm x 250 mm column using 10% ethyl acetate/90% hexane at a flow rate of 1.4 ml/minute). The retinoids can be detected by, for example, detection at 325 nm using a diode-array detector and HP Chemstation A.03.03 software. An excess in retinoids can be determined, for example, by comparison of 25 the profile of retinoids (i.e., qualitative, e.g., identity of specific compounds, and quantitative, e.g., the level of each specific compound) in the sample with a sample from a normal subject, Persons skilled in the art who are familiar with such assays and techniques and will readily understand that appropriate controls are included. [00263] As used herein, increased or excessive levels of endogenous retinoid, such as 1 1-cis-retinol or 11 -cis 30 retinal, refer to levels of endogenous retinoid higher than those found in a healthy eye of a young vertebrate of the same species. Administration of a sulphur-linked compound and reduce or eliminate the requirement for endogenous retinoid. In Vivo and In Vitro Methods for Determining Therapeutic Effectiveness of Compounds [00264] In one embodiment, methods are provided for using the compounds described herein for enhancing or prolonging retinal cell survival, including retinal neuronal cell survival and RPE cell survival. Also 35 provided herein are methods for inhibiting or preventing degeneration of a retinal cell, including a retinal neuronal cell (e.g., a photoreceptor cell, an amacrine cell, a horizontal cell, a bipolar cell, and a ganglion cell) and other mature retinal cells such as retinal pigment epithelial cells and Mller glial cells using the compounds described herein. Such methods comprise, in certain embodiments, administration of a sulphur-linked compound as described herein. Such a compound is useful for enhancing retinal cell 40 survival, including photoreceptor cell survival and retinal pigment epithelia survival, inhibiting or slowing degeneration of a retinal cell, and thus increasing retinal cell viability, which can result in slowing or halting the progression of an ophthalmic disease or disorder or retinal injury, which are described herein. [00265] The effect of a sulphur-linked compound on retinal cell survival (and/or retinal cell degeneration) may be determined by using cell culture models, animal models, and other methods that are described herein and 45 practiced by persons skilled in the art, By way of example, and not limitation, such methods and assays 95 WO 2010/028088 PCT/US2009/055785 5 include those described in Oglivie et al., Exp. Neuro. 161:675-856 (2000); U.S. Patent No. 6,406,840; WO 01/81551; WO 98/12303; U.S. Patent Application No. 2002/0009713; WO 00/40699; U.S. Patent No. 6,117,675; U.S. Patent No. 5,736,516; WO 99/29279; WO 01/83714; WO 01/42784; U.S. Patent No. 6,183,735; U.S. Patent No. 6,090,624; WO 01/09327; U.S. Patent No. 5,641,750; U.S. Patent Application Publication No. 2004/0147019; and U.S. Patent Application Publication No. 2005/0059148. 10 [00266] Compounds described herein that may be useful for treating an ophthalmic disease or disorder (including a retinal disease or disorder) may inhibit, block, impair, or in some manner interfere with one or more steps in the visual cycle (also called the retincid cycle herein and in the art). Without wishing to be bound by a particular theory, a sulphur-linked compound may inhibit or block an isomerization step in the visual cycle, for example, by inhibiting or blocking a functional activity of a visual cycle trans-cis isomerase. The 15 compounds described herein may inhibit, directly or indirectly, isomerization of all-trans-retinol to I 1-cis retinol. The compounds may bind to, or in some manner interact with, and inhibit the isomerase activity of at least one isomerase in a retinal cell. Any one of the compounds described herein may also directly or indirectly inhibit or reduce the activity of an isomerase that is involved in the visual cycle. The compound may block or inhibit the capability of the isomerase to bind to one or more substrates, including but not 20 limited to, an all-trans-retinyl ester substrate or all-trans-retinol. Alternatively, or in addition, the compound may bind to the catalytic site or region of the isomerase, thereby inhibiting the capability of the enzyme to catalyze isomerization of at least one substrate. On the basis of scientific data to date, an at least one isomerase that catalyzes the isomerization of a substrate during the visual cycle is believed to be located in the cytoplasm of RPE cells. As discussed herein, each step, enzyme, substrate, intermediate, and 25 product of the visual cycle is not yet elucidated. While a polypeptide called RPE65, which has been found in the cytoplasm and membrane bound in RPE cells, is hypothesized to have isomerase activity (and has also been referred to in the art as having isomerohydrolase activity) (see, e.g., Moiseyev et al., Proc. NatL. Acad. Sci. USA 102:12413-18 (2004); Chen et al., Invest. OphthalmoL Vis. Sci. 47:1177-84 (2006)), other persons skilled in the art believe that the RPE65 acts primarily as a chaperone for all-trans-retinyl esters 30 (see. e.g., Lamb et al. supra). [002671 Exemplary methods are described herein and practiced by persons skilled in the art for determining the level of enzymatic activity of a visual cycle isomerase in the presence of any one of the compounds described herein. A compound that decreases isomerase activity may be useful for treating an ophthalmic disease or disorder. Thus, methods are provided herein for detecting inhibition of isomerase activity 35 comprising contacting (i.e., mixing, combining, or in some manner permitting the compound and isomerase to interact) a biological sample comprising the isomerase and a sulphur-linked compound described herein and then determining the level of enzymatic activity of the isomerase. A person having skill in the art will appreciate that as a control, the level of activity of the isomerase in the absence of a compound or in the presence of a compound known not to alter the enzymatic activity of the isomerase can be determined and 40 compared to the level of activity in the presence of the compound. A decrease in the level of isomerase activity in the presence of the compound compared to the level of isomerase activity in the absence of the compound indicates that the compound may be useful for treating an ophthalmic disease or disorder, such as age-related macular degeneration or Stargardt's disease. A decrease in the level of isomerase activity in the presence of the compound compared to the level of isomerase activity in the absence of the compound 45 indicates that the compound may also be useful in the methods described herein for inhibiting or preventing dark adaptation, inhibiting neovascularization and reducing hypoxia and thus useful for treating an 96 WO 2010/028088 PCT/US2009/055785 5 ophthalmic disease or disorder, for example, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury. [00268 The capability of a sulphur-linked compound described herein to inhibit or to prevent dark adaptation of a rod photoreceptor cell by inhibiting regeneration of rhodopsin may be determined by in vitro assays and/or in vivo animal models. By way of example, inhibition of regeneration may be determined in a mouse 10 model in which a diabetes-like condition is induced chemically or in a diabetic mouse model (see, e.g.. Phipps et al., Invest. OphthalmoL Vis. Sci. 47:3187-94 (2006); Ramsey et al., Invest. Ophthalmol. Vis. Sci. 47:5116-24 (2006)). The level of rhodopsin (a first level) may be determined (for example, spectrophotometrically) in the retina of animals prior to administration of the agent and compared with the level (a second level) of rhodopsin measured in the retina of animals after administration of the agent. A 15 decrease in the second level of rhodopsin compared with the first level of rhodopsin indicates that the agent inhibits regeneration of rhodopsin. The appropriate controls and study design to determine whether regeneration of rhodopsin is inhibited in a statistically significant or biologically significant manner can be readily determined and implemented by persons skilled in the art. [002691 Methods and techniques for determining or characterizing the effect of any one of the compounds described 20 herein on dark adaptation and rhodopsin regeneration in rod photoreceptor cells in a mammal, including a human, maybe performed according to procedures described herein and practiced in the art. For example, detection of a visual stimulus after exposure to light (i.e., photobleaching) versus time in darkness may be determined before administration of the first dose of the compound and at a time after the first dose and/or any subsequent dose. A second method for determining prevention or inhibition of dark adaptation by the 25 rod photoreceptor cells includes measurement of the amplitude of at least one, at least two, at least three, or more electroretinogram components, which include, for example, the a-wave and the b-wave. See, for example, Lamb et al., supra; Asi et al., Documenta Ophthalmologica 79:125-39 (1992). 100270] Inhibiting regeneration of rhodopsin by a sulphur-linked compound described herein comprises reducing the level of the chromophore, 11 -cis-retinal, that is produced and present in the RPE cell, and consequently 30 reducing the level of I I-cis-retinal that is present in the photoreceptor cell. Thus, the compound, when permitted to contact the retina under suitable conditions and at a time sufficient to prevent dark adaptation of a rod photoreceptor cell and to inhibit regeneration of rhodopsin in the rod photoreceptor cell, effects a reduction in the level of II -cs-retinal in a rod photoreceptor cell (i.e., a statistically significant or biologically significant reduction). That is, the level of I1 -cis retinal in a rod photoreceptor cell is greater 35 prior to administration of the compound when compared with the level of 1 1-cis-retinal in the photoreceptor cell after the first and/or any subsequent administration of the compound. A first level of 11 cis-retinal may be determined prior to administration of the compound, and a second level of I1-cis-retinal may be determined after administration of a first dose or any subsequent dose to monitor the effect of the compound. A decrease in the second level compared to the first level indicates that the compound inhibits 40 regeneration of rhodopsin and thus inhibits or prevents dark adaptation of the rod photoreceptor cells. 1002711 An exemplary method for determining or characterizing the capability of a sulphur-linked compound to reduce retinal hypoxia includes measuring the level of retinal oxygenation, for example, by Magnetic Resonance Imaging (MRI) to measure changes in oxygen pressure (see, e.g., Luan et al., Invest. Ophtralmol. Vis. Sci. 47:320-28 (2006)). Methods are also available and routinely practiced in the art to 45 determine or characterize the capability of compounds described herein to inhibit degeneration of a retinal cell (see, e.g., Wenzel et al., Prog. Retin. Eye Ra. 24:275-306 (2005)). 97 WO 2010/028088 PCT/US2009/055785 5 [00272j Animal models may be used to characterize and identify compounds that may be used to treat retinal diseases and disorders. A recently developed animal model may be useful for evaluating treatments for macular degeneration has been described by Ambati et al. (Nat. Med. 9:1390-97 (2003); Epub 2003 Oct 19). This animal model is one of only a few exemplary animal models presently available for evaluating a compound or any molecule for use in treating (including preventing) progression or development of a 10 retinal disease or disorder. Animal models in which the ABCR gene, which encodes an ATP-binding cassette transporter located in the rims of photoreceptor outer segment discs, may be used to evaluate the effect of a compound. Mutations in the ABCR gene arc associated with Stargardt's disease, and heterozygous mutations in ABCR have been associated with AMD. Accordingly, animals have been generated with partial or total loss of ABCR function and may used to characterize the sulphur-linked 15 compounds described herein. (See, e.g., Mata et al., Invest. Ophthalmol. Sci. 42:1685-90 (2001); Weng et al., Cell 98:13-23 (1999); Mata et al., Proc. Nail. Acad Sci. USA 97:7154-49 (2000); US 2003/0032078; U.S. Patent No. 6,713,300). Other animal models include the use of mutant ELOVL4 transgenic mice to determine lipofuscin accumulation, electrophysiology, and photoreceptor degeneration, or prevention or inhibition thereof (see, e.g., Karan et al., Proc. Nat. Acad. Sci. USA 102:4164-69 (2005)). 20 j002731 The effect of any one of the compounds described herein may be determined in a diabetic retinopathy animal model, such as described in Luan et al. or may be determined in a normal animal model, in which the animals have been light or dark adapted in the presence and absence of any one of the compounds described herein. Another exemplary method for determining the capability of the agent to reduce retinal hypoxia measures retinal hypoxia by deposition of a hydroxyprobe (see, e.g,, de Gooyer et al. (Invest. 25 Ophthalmol. Vis. Sc. 47:5553-60 (2006)). Such a technique may be performed in an animal model using Rho/Rho- knockout mice (see de Gooyer et al,, supra) in which at least one compound described herein is administered to group(s) of animals in the presence and absence of the at least one compound, or may be performed in normal, wildtype animals in which at least one compound described herein is administered to group(s) of animals in the presence and absence of the at least one compound. Other animal models 30 include models for determining photoreceptor function, such as rat models that measure elotroretinographic (ERG) oscillatory potentials (see, e.g., Liu et al., Invest. Ophthalmol. Vis. Sci. 47:5447-52 (2006); Akula et al., Invest. Ophthalmol. Vis. Sci. 48:4351-59 (2007); Liu et al., Invest. Ophthalmol. Vis. Sci. 47:2639-47 (2006); Dembinska et al., Invest. Ophthalmol. Vis. Sc 43:2481-90 (2002); Penn et al., Invest. Ophthalmol. Vis. Sci. 35:3429-35 (1994); Hancock et al,, Invest Ophthalmol. Vis. Scl, 45:1002-1008 (2004)). 35 (00274] A method for determining the effect of a compound on isomerase activity may be performed in vitro as described herein and in the art (Stecher et al., J. Biol, Chem. 274:8577-85 (1999); see also Golczak et al., Proc. Nal. Acad. Sci. USA 102:8162-67 (2005)). Retinal pigment epithelium (RPE) microsome membranes isolated from an animal (such as bovine, porcine, human, for example) may serve as the source of the isomerase. The capability of the sulphur-linked compounds to inhibit isomerase may also be 40 determined by an in vivo marine isomerase assay. Brief exposure of the eye to intense light ("photobleaching" of the visual pigment or simply "bleaching') is known to photo-isomerize almost all 11 cls-retinal in the retina. The recovery of 11-cis-retinal after bleaching can be used to estimate the activity of isomerase in vivo (see, e.g., Maeda et al., J. Neurochem. 85:944-956 (2003); Van Hooser et al., J Biol. Chem. 277:19173-82, 2002). Electroretinographic (ERG) recording may be performed as previously 45 described (HIaeseleer et al., Nat Neurosci. 7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci. 22 Suppl 2:315-25 (1997); Keating et al., Documenta Ophthalmologica 100:77-92 (2000)). See also Deigner et al., 98 WO 2010/028088 PCTIUS2009/055785 5 Science, 244: 968-971 (1989); Gollapalli et al., Biochim. Biophys. Adca 1651: 93-101 (2003); Parish, et al., Proc. Nat. Acad Sci. USA 95:14609-13 (1998); Radu et al., Proc Natl Acad Sci USA 101: 5928-33 (2004). 1002751 Cell culture methods, such as the method described herein, are also useful for determining the effect of a compound described herein on retinal neuronal cell survival. Exemplary cell culture models are described herein and described in detail in U.S. Patent Application Publication No. US 2005-0059148 and U.S. Patent 10 Application Publication No. US2004-0147019 (which are incorporated by reference in their entirety), which are useful for determining the capability of a sulphur-linked compound as described herein to enhance or prolong survival of neuronal cells, particularly retinal neuronal cells, and of retinal pigment epithelial cells, and inhibit, prevent, slow, or retard degeneration of an eye, or the retina or retinal cells thereof, or the RPE, and which compounds are useful for treating ophthalmic diseases and disorders. 15 1002761 The cell culture model comprises a long-term or extended culture of mature retinal cells, including retinal neuronal cells (e.g., photoreceptor cells, amacrine cells, ganglion cells, horizontal cells, and bipolar cells). The cell culture system and methods for producing the cell culture system provide extended culture of photoreceptor cells. The cell culture system may also comprise retinal pigment epithelial (RPE) cells and Mler glial cells. 20 100277] The retinal cell culture system may also comprise a cell stressor. The application or the presence of the stressor affects the mature retinal cells, including the retinal neuronal cells, in vitro, in a manner that is useful for studying disease pathology that is observed in a retinal disease or disorder. The cell culture model provides an in vitro neuronal cell culture system that will be useful in the identification and biological testing of a sulphur-linked compound that is suitable for treatment of neurological diseases or 25 disorders in general, and for treatment of degenerative diseases of the eye and brain in particular. The ability to maintain primary, in vitro-cultured cells from mature retinal tissue, including retinal neurons over an extended period of time in the presence of a stressor enables examination of cell-to-cell interactions, selection and analysis of neuroactive compounds and materials, use of a controlled cell culture system for in vitro CNS and ophthalmic tests, and analysis of the effects on single cells from a consistent retinal cell 30 population. [00278] The cell culture system and the retinal cell stress model comprise cultured mature retinal cells, retinal neurons, and a retinal cell stressor, which may be used for screening and characterizing a sulphur-linked compound that are capable of inducing or stimulating the regeneration of CNS tissue that has been damaged by disease. The cell culture system provides a mature retinal cell culture that is a mixture of 35 mature retinal neuronal cells and non-neuronal retinal cells. The cell culture system comprises all the major retinal neuronal cell types (photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells), and may also include other mature retinal cells such as RPE and MOller glial cells. By incorporating these different types of cells into the in vitro culture system, the system essentially resembles an "artificial organ" that is more akin to the natural in vivo state of the retina. 40 100279] Viability of one or more of the mature retinal cell types that are isolated (harvested) from retinal tissue and plated for tissue culture may be maintained for an extended period of time, for example, from two weeks up to six months. Viability of the retinal cells may be determined according to methods described herein and known in the art. Retinal neuronal cells, similar to neuronal cells in general, are not actively dividing cells in vivo and thus cell division of retinal neuronal cells would not necessarily be indicative of viability. An 45 advantage of the cell culture system is the ability to culture amacrine cells, photoreceptors, and associated ganglion projection neurons and other mature retinal cells for extended periods of time, thereby providing 99 WO 2010/028088 PCT/US2009/055785 5 an opportunity to determine the effectiveness of a sulphur-linked compound described herein for treatment of retinal disease. 1002801 The biological source of the retinal cells or retinal tissue may be mammalian (e.g., human, non-human primate, ungulate, rodent, canine, porcine, bovine, or other mammalian source), avian, or from other genera. Retinal cells including retinal neurons from post-natal non-human primates, post-natal pigs, or 10 post-natal chickens may be used, but any adult or post-natal retinal tissue may be suitable for use in this retinal cell culture system. [00281] In certain instances, the cell culture system may provide for robust long-term survival of retinal cells without inclusion of cells derived from or isolated or purified from non-retinal tissue. Such a cell culture system comprises cells isolated solely from the retina of the eye and thus is substantially free of types of 15 cells from other parts or regions of the eye that are separate from the retina, such as the ciliary body, iris, choroid, and vitreous. Other cell culture methods include the addition of non-retinal cells, such as ciliary body cell and/or stem cells (which may or may not be retinal stem cells) and/or additional purified glial cells. [002821 The in vitro retinal cell culture systems described herein may serve as physiological retinal models that can 20 be used to characterize aspects of the physiology of the retina. This physiological retinal model may also be used as a broader general neurobiology model. A cell stressor may be included in the model cell culture system. A cell stressor, which as described herein is a retinal cell stressor, adversely affects the viability or reduces the viability of one or more of the different retinal cell types, including types of retinal neuronal cells, in the cell culture system. A person skilled in the art would readily appreciate and understand that as 25 described herein a retinal cell that exhibits reduced viability means that the length of time that a retinal cell survives in the cell culture system is reduced or decreased (decreased lifespan) and/or that the retinal cell exhibits a decrease, inhibition, or adverse effect of a biological or biochemical function (e.g., decreased or abnormal metabolism; initiation of apoptosis; etc.) compared with a retinal cell cultured in an appropriate control cell system (e.g., the cell culture system described herein in the absence of the cell stressor). 30 Reduced viability of a retinal cell may be indicated by cell death; an alteration or change in cell structure or morphology; induction and/or progression of apoptosis; initiation, enhancement, and/or acceleration of retinal neuronal cell neurodegeneration (or neuronal cell injury). [00283] Methods and techniques for determining cell viability are described in detail herein and are those with which skilled artisans are familiar. These methods and techniques for determining cell viability may be 35 used for monitoring the health and status of retinal cells in the cell culture system and for determining the capability of the sulphur-linked compounds described herein to alter (preferably increase, prolong, enhance, improve) retinal cell or retinal pigment epithelial cell viability or retinal cell survival. [00284] The addition of a cell stressor to the cell culture system is useful for determining the capability of a sulphur-linked compound to abrogate, Inhibit, eliminate, or lessen the effect of the stressor. The retinal cell 40 culture system may include a cell stressor that is chemical (e.g., A2E, cigarette smoke concentrate); biological (for example, toxin exposure; beta-amyloid; lipopolysaccharides); or non-chemical, such as a physical stressor, environmental stressor, or a mechanical force (e.g., increased pressure or light exposure) (see, e.g., US 2005-0059148). [00285] The retinal cell stressor model system may also include a cell stressor such as, but not limited to, a stressor 45 that may be a risk factor in a disease or disorder or that may contribute to the development or progression of a disease or disorder, including but not limited to, light of varying wavelengths and intensities; A2E; 100 WO 2010/028088 PCT/US2009/055785 5 cigarette smoke condensate exposure; oxidative stress (e.g., stress related to the presence of or exposure to hydrogen peroxide, nitroprusside, Zn++, or Fe++); increased pressure (e.g., atmospheric pressure or hydrostatic pressure), glutamate or glutamate agonist (e.g., N-methyl-D-aspartate (NMDA); alpha-amino-3 hydroxy-5-methylisoxazole-4-proprionate (AMPA); kainic acid; quisqualic acid; ibotenic acid; quinolinic acid; aspartate; trans-I-aminocyclopentyl-1,3-dicarboxylate (ACPD)); amino acids (e.g., aspartate, L 10 cysteine; beta-N-methylamine-L-alanine); heavy metals (such as lead); various toxins (for example, mitochondrial toxins (e.g., malonate, 3-nitroproprionic acid; rotenone, cyanide); MPTP (1-methyl-4 phenyl-1,2,3,6,-tetrahydropyridine), which metabolizes to its active, toxic metabolite MPP+ (1-methyl-4 phenylpryidine)); 6-hydroxydopamine; alpha-synuclein; protein kinase C activators (e.g., phorbol myristate acetate); biogenic amino stimulants (for example, methamphetamine, MDMA (3-4 15 methylenedioxymethamphetamine)); or a combination of one or more stressors. Useful retinal cell stressors include those that mimic a neurodegenerative disease that affects any one or more of the mature retinal cells described herein. A chronic disease model is of particular importance because most neurodegenerative diseases are chronic. Through use of this in vitro cell culture system, the earliest events in long-term disease development processes may be identified because an extended period of time is 20 available for cellular analysis. [002861 A retinal cell stressor may alter (i.e., increase or decrease in a statistically significant manner) viability of retinal cells such as by altering survival of retinal cells, including retinal neuronal cells and RPE cells, or by altering neurodegeneration of retinal neuronal cells and/or RPE cells. Preferably, a retinal cell stressor adversely affects a retinal neuronal cell or RPE cell such that survival of a retinal neuronal cell or RPE cell 25 is decreased or adversely affected (i.e., the length of time during which the cells are viable is decreased in the presence of the stressor) or neurodegeneration (or neuron cell injury) of the cell is increased or enhanced. The stressor may affect only a single retinal cell type in the retinal cell culture or the stressor may affect two, three, four, or more of the different cell types. For example, a stressor may alter viability and survival of photoreceptor cells but not affect all the other major cell types (e.g., ganglion cells, 30 amacrine cells, horizontal cells, bipolar cells, RPE, and Muller glia). Stressors may shorten the survival time of a retinal cell (in vivo or in vitro), increase the rapidity or extent of neurodegeneration of a retinal cell, or in some other manner adversely affect the viability, morphology, maturity, or lifespan of the retinal cell. (00287] The effect of a cell stressor (in the presence and absence of a sulphur-linked compound) on the viability of 35 retinal cells in the cell culture system may be determined for one or more of the different retinal cell types. Determination of cell viability may include evaluating structure and/or a function of a retinal cell continually at intervals over a length of time or at a particular time point after the retinal cell culture is prepared. Viability or long term survival of one or more different retinal cell types or one or more different retinal neuronal cell types may be examined according to onc or more biochemical or biological parameters 40 that are indicative of reduced viability, such as apoptosis or a decrease in a metabolic function, prior to observation of a morphological or structural alteration. [00288] A chemical, biological, or physical cell stressor may reduce viability of one or more of the retinal cell types present in the cell culture system when the stressor is added to the cell culture under conditions described herein for maintaining the long-term cell culture. Alternatively, one or more culture conditions may be 45 adjusted so that the effect of the stressor on the retinal cells can be more readily observed. For example, the concentration or percent of fetal bovine serum may be reduced or eliminated from the cell culture when 101 WO 2010/028088 PCT/US2009/055785 5 cells are exposed to a particular cell stressor (see, e.g., US 2005-0059148). Alternatively, retinal cells cultured in media containing serum at a particular concentration for maintenance of the cells may be abruptly exposed to media that does not contain any level of serum. (00289] The retinal cell culture may be exposed to a cell stressor for a period of time that is determined to reduce the viability of one or more retinal cell types in the retinal cell culture system. The cells may be exposed to 10 a cell stressor immediately upon plating of the retinal cells after isolation from retinal tissue. Alternatively, the retinal cell culture may be exposed to a stressor after the culture is established, or any time thereafter. When two or more cell stressors are included in the retinal cell culture system, each stressor may be added to the cell culture system concurrently and for the same length of time or may be added separately at different time points for the same length of time or for differing lengths of time during the culturing of the 15 retinal cell system. A sulphur-linked compound may be added before the retinal cell culture is exposed to a cell stressor, may be added concurrently with the cell stressor, or may be added after exposure of the retinal cell culture to the stressor. (002901 Photoreceptors may be identified using antibodies that specifically bind to photoreceptor-specific proteins such as opsins, peripherins, and the like. Photoreceptors in cell culture may also be identified as a 20 morphologic subset of immunocytochemically labeled cells by using a pan-neuronal marker or may be identified morphologically in enhanced contrast images of live cultures. Outer segments can be detected morphologically as attachments to photoreceptors. 1002911 Retinal cells including photoreceptors can also be detected by functional analysis. For example, electrophysiology methods and techniques may be used for measuring the response of photoreceptors to 25 light. Photoreceptors exhibit specific kinetics in a graded response to light. Calcium-sensitive dyes may also be used to detect graded responses to light within cultures containing active photoreceptors. For analyzing stress-inducing compounds or potential neurotherapeutics, retinal cell cultures can be processed for immunocytochemistry, and photoreceptors and/or other retinal cells can be counted manually or by computer software using photomicroscopy and imaging techniques. Other immunoassays known in the art 30 (e.g., ELISA, immunoblotting, flow cytometry) may also be useful for identifying and characterizing the retinal cells and retinal neuronal cells of the cell culture model system described herein. [00292] The retinal cell culture stress models may also be useful for identification of both direct and indirect pharmacologic agent effects by the bioactive agent of interest, such as a sulphur-linked compound as described herein. For example, a bioactive agent added to the cell culture system in the presence of one or 35 more retinal cell stressors may stimulate one cell type in a manner that enhances or decreases the survival of other cell types. Cell/cell interactions and cell/extracellular component interactions may be important in understanding mechanisms of disease and drug function. For example, one neuronal cell type may secrete trophic factors that affect growth or survival of another neuronal cell type (see, e.g., WO 99/29279). [00293] In another embodiment, a sulphur-linked compound is incorporated into screening assays comprising the 40 retinal cell culture stress model system described herein to determine whether and/or to what level or degree the compound increases or prolongs viability (i.e., increases in a statistically significant or biologically significant manner) of a plurality of retinal cells. A person skilled in the art would readily appreciate and understand that as described herein a retinal cell that exhibits increased viability means that the length of time that a retinal cell survives in the cell culture system is increased (increased lifespan) 45 and/or that the retinal cell maintains a biological or biochemical function (normal metabolism and organelle function; lack of apoptosis; etc.) compared with a retinal cell cultured in an appropriate control cell system 102 WO 2010/028088 PCT/US2009/055785 5 (e.g., the cell culture system described herein in the absence of the compound). Increased viability of a retinal cell may be indicated by delayed cell death or a reduced number of dead or dying cells; maintenance of structure and/or morphology; lack of or delayed initiation of apoptosis; delay, inhibition, slowed progression, and/or abrogation of retinal neuronal cell neurodegeneration or delaying or abrogating or preventing the effects of neuronal cell injury. Methods and techniques for determining viability of a retinal 10 cell and thus whether a retinal cell exhibits increased viability are described in greater detail herein and are known to persons skilled in the art. [00294] In certain embodiments, a method is provided for determining whether a sulphur-linked compound, enhances survival of photoreceptor cells. One method comprises contacting a retinal cell culture system as described herein with a sulphur-linked compound under conditions and for a time sufficient to permit 15 interaction between the retinal neuronal cells and the compound. Enhanced survival (prolonged survival) may be measured according to methods described herein and known in the art, including detecting expression of rhodopsin. 100295] The capability of a sulphur-linked compound to increase retinal cell viability and/or to enhance, promote, or prolong cell survival (that is, to extend the time period in which retinal cells, including retinal neuronal 20 cells, are viable), and/or impair, inhibit, or impede degeneration as a direct or indirect result of the herein described stress may be determined by any one of several methods known to those skilled in the art. For example, changes in cell morphology in the absence and presence of the compound may be determined by visual inspection such as by light microscopy, confocal microscopy, or other microscopy methods known in the art. Survival of cells can also be determined by counting viable and/or nonviable cells, for instance. 25 Immunochemical or immunohistological techniques (such as fixed cell staining or flow cytometry) may be used to identify and evaluate cytoskeletal structure (e.g., by using antibodies specific for cytoskeletal proteins such as glial fibrillary acidic protein, fibronectin, acting, vimentin, tubulin, or the like) or to evaluate expression of cell markers as described herein. The effect of a sulphur-linked compound on cell integrity, morphology, and/or survival may also be determined by measuring the phosphorylation state of 30 neuronal cell polypeptides, for example, cytoskeletal polypeptides (see, eg., Sharma et al., J Biol. Chem. 274:9600-06 (1999); Li et al., J. Neurosci. 20:6055-62 (2000)). Cell survival or, alternatively cell death, may also be determined according to methods described herein and known in the art for measuring apoptosis (for example, annexin V binding, DNA fragmentation assays, caspase activation, marker analysis, e.g., poly(ADP-ribose) polymerase (PARP), etc.). 35 [00296] In the vertebrate eye, for example, a mammalian eye, the formation of A2E is a light-dependent process and its accumulation leads to a number of negative effects in the eye. These include destabilization of retinal pigment epithelium (RPE) membranes, sensitization of cells to blue-light damage, and impaired degradation of phospholipids. Products of the oxidation of A2E (and A2E related molecules) by molecular oxygen (oxiranes) were shown to induce DNA damage in cultured RPE cells. All these factors lead to a 40 gradual decrease in visual acuity and eventually to vision loss, If reducing the formation of retinals during vision processes were possible, this reduction would lead to decreased amounts of A2E in the eye. Without wishing to be bound by theory, decreased accumulation of A2E may reduce or delay degenerative processes in the RPE and retina and thus may slow down or prevent vision loss in dry AMD and Stargardt's Disease. 45 [00297] In another embodiment, methods are provided for treating and/or preventing degenerative diseases and disorders, including neurodegenerative retinal diseases and ophthalmic diseases, and retinal diseases and 103 WO 2010/028088 PCT/US2009/055785 5 disorders as described herein. A subject in need of such treatment may be a human or non-human primate or other animal who has developed symptoms of a degenerative retinal disease or who is at risk for developing a degenerative retinal disease. As described herein a method is provided for treating (which includes preventing or prophylaxis) an ophthalmic disease or disorder by administrating to a subject a composition comprising a pharmaceutically acceptable carrier and a sulphur-linked compound (e.g., a 10 compound having the structure of Formula (1), and substructures thereof.) As described herein, a method is provided for enhancing survival of neuronal cells such as retinal neuronal cells, including photoreceptor cells, and/or inhibiting degeneration of retinal neuronal cells by administering the pharmaceutical compositions described herein comprising a sulphur-linked compound. [00298] Enhanced survival (or prolonged or extended survival) of one or more retinal cell types in the presence of a 15 sulphur-linked compound indicates that the compound may be an effective agent for treatment of a degenerative disease, particularly a retinal disease or disorder, and including a neurodegenerative retinal disease or disorder. Cell survival and enhanced cell survival may be determined according to methods described herein and known to a skilled artisan including viability assays and assays for detecting expression of retinal cell marker proteins. For determining enhanced survival of photoreceptor cells, opsins 20 may be detected, for instance, including the protein rhodopsin that is expressed by rods. [002991 In another embodiment, the subject is being treated for Stargardt's disease or Stargardt's macular degeneration. In Stargardt's disease, which is associated with mutations in the ABCA4 (also called ABCR) transporter, the accumulation of all-trans-retinal has been proposed to be responsible for the formation of a lipofuscin pigment, A2E, which is toxic towards retinal cells and causes retinal degeneration and 25 consequently loss of vision. [00300] In yet another embodiment, the subject is being treated for age-related macular degeneration (AMD). In various embodiments, AMD can be wet- or dry-form. In AMD, vision loss primarily occurs when complications late in the disease either cause new blood vessels to grow under the macula or the macula atrophies. Without intending to be bound by any particular theory, the accumulation of all-trans-retinal has 30 been proposed to be responsible for the formation of a lipofuscin pigment, N-retinylidene-N retinylethanolamine (A2E) and A2E related molecules, which are toxic towards RPE and retinal cells and cause retinal degeneration and consequently loss of vision. [00301] A neurodegenerative retinal disease or disorder for which the compounds and methods described herein may be used for treating, curing, preventing, ameliorating the symptoms of, or slowing, inhibiting, or 35 stopping the progression of, is a disease or disorder that leads to or is characterized by retinal neuronal cell loss, which is the cause of visual impairment. Such a disease or disorder includes but is not limited to age related macular degeneration (including dry-form and wet-form of macular degeneration) and Stargardt's macular dystrophy. [00302] Age.related macular degeneration as described herein is a disorder that affects the macula (central region of 40 the retina) and results in the decline and loss of central vision. Age-related macular degeneration occurs typically in individuals over the age of 55 years. The etiology of age-related macular degeneration may include both environmental influences and genetic components (see, e.g., Lyengar et al., Am. J. Hum. Genet. 74:20-39 (2004) (Epub 2003 December 19); Kenealy et al., Mol. Vis. 10:57-61 (2004); Gorin et al., Mol. Vis. 5:29 (1999)). More rarely, macular degeneration occurs in younger individuals, including 45 children and infants, and generally, these disorders results from a genetic mutation. Types ofjuvenile macular degeneration include Stargardt's disease (see, e.g., Glazer et al., Ophthalmol. Clin North Am. 104 WO 2010/028088 PCT/US2009/055785 5 15:93-100, viii (2002); Weng et al., Cell 98:13-23 (1999)); Doyne's honeycomb retinal dystrophy (see, e.g., Kermani et al., Hum. Genet. 104:77-82 (1999)); Sorsby's fundus dystrophy, Malattia Levintinese, fumdus flavimaculatus, and autosomal dominant hemorrhagic macular dystrophy (see also Seddon et al., Ophthalmology 108:2060-67 (2001); Yates et al., J. Med Genet. 37:83-7 (2000); Jaakson et al., Hum. Mutat. 22:395-403 (2003)). Geographic atrophy of the RPE is an advanced form of non-neovascular dry 10 type age-related macular degeneration, and is associated with atrophy of the choriocapillaris, RPE, and retina. [003031 Stargardt's macular degeneration, a recessive inherited disease, is an inherited blinding disease of children. The primary pathologic defect in Stargardt's disease is also an accumulation of toxic lipofuscin pigments such as A2E in cells of the retinal pigment epithelium (RPE). This accumulation appears to be responsible 15 for the photoreceptor death and severe visual loss found in Stargardt's patients. The compounds described herein may slow the synthesis of 1 1-cis-retinaldehyde (I IcRAL or retinal) and regeneration of rhodopsin by inhibiting isomerase in the visual cycle. Light activation of rhodopsin results in its release of all-trans retinal, which constitutes the first reactant in A2E biosynthesis. Treatment with sulphur-linked compounds may inhibit lipofuscin accumulation and thus delay the onset of visual loss in Stargardt's and AMD patients 20 without toxic effects that would preclude treatment with a sulphur-linked compound. The compounds described herein may be used for effective treatment of other forms of retinal or macular degeneration associated with lipofuscin accumulation, j003041 Administration of a sulphur-linked compound to a subject can prevent formation of the lipofuscin pigment, A2E (and A2E related molecules), that is toxic towards retinal cells and causes retinal degeneration. In 25 certain embodiments, administration of a sulphur-linked compound can lessen the production of waste products, e.g., lipofuscin pigment, A2E (and A2E related molecules), ameliorate the development of AMD (e.g., dry-form) and Stargardt's disease, and reduce or slow vision loss (e.g., choroidal neovascularization and/or chorioretinal atrophy). In previous studies, with 13-cis-retinoic acid (Accutane@ or Isotretinoin), a drug commonly used for the treatment of acne and an inhibitor of I l-cis-retinol dehydrogenase, has been 30 administered to patients to prevent A2E accumulation in the RPE. However, a major drawback in this proposed treatment is that 13-cis-retinoic acid can easily isomerize to all-trans-retinoic acid. All-frans retinoic acid is a very potent teratogenic compound that adversely affects cell proliferation and development. Retinoic acid also accumulates in the liver and may be a contributing factor in liver diseases. [003051 In yet other embodiments, a sulphur-linke d compound is administered to a subject such as a human with a 35 mutation in the ABCA4 transporter in the eye. The sulphur-linked compound can also be administered to an aging subject. As used herein, an aging human subject is typically at least 45, or at least 50, or at least 60, or at least 65 years old. In Stargardt's disease, which is associated with mutations in the ABCA4 transporter, the accumulation of all-trans-retinal has been proposed to be responsible for the formation of a lipofuscin pigment A2E (and A2E related molecules), that is toxic towards retinal cells and causes retinal 40 degeneration and consequently loss of vision. Without wishing to be bound by theory, a sulphur-linked compound described herein may be a strong inhibitor of an isomerase involved in the visual cycle. Treating patients with a sulphur-linked compound as described herein may prevent or slow the formation of A2E (and A2E related molecules) and can have protective properties for normal vision. 1003061 In other certain embodiments, one or more of the compounds described herein may be used for treating 45 other ophthalmic diseases or disorders, for example, glaucoma, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, an inflammatory retinal disease, proliferative vitreoretinopathy, retinal 105 WO 2010/028088 PCTIUS2009/055785 5 dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, optical neuropathy, and retinal disorders associated with other neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease or other neurodegenerative diseases that affect brain cells, a retinal disorder associated with viral infection, or other conditions such as AIDS. A retinal disorder also includes light damage to the retina that is related to increased light exposure (ie., overexposure to light), 10 for example, accidental strong or intense light exposure during surgery; strong, intense, or prolonged sunlight exposure, such as at a desert or snow covered terrain; during combat, for example, when observing a flare or explosion or from a laser device, and the like. Retinal diseases can be of degenerative or non degenerative nature. Non-limiting examples of degenerative retinal diseases include age-related macular degeneration, and Stargardt's macular dystrophy. Examples of non-degenerative retinal diseases include 15 but are not limited hemorrhagic retinopathy, retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, or ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder 20 associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, and a retinal disorder associated with AIDS. [003071 In other certain embodiments, at least one of the compounds described herein may be used for treating, curing, preventing, ameliorating the symptoms of, or slowing, inhibiting, or stopping the progression of, certain ophthalmic diseases and disorders including but not limited to diabetic retinopathy, diabetic 25 maculopathy, diabetic macular edema, retinal ischemia, ischemia-reperfusion related retinal injury, and retinal blood vessel occlusion (including venous occlusion and arterial occlusion). [00308] Diabetic retinopathy is a leading cause of blindness in humans and is a complication of diabetes. Diabetic retinopathy occurs when diabetes damages blood vessels inside the retina. Non-proliferative retinopathy is a common, usually mild form that generally does not interfere with vision. Abnormalities are limited to the 30 retina, and vision is impaired only if the macula is involved. If left untreated retinopathy can progress to proliferative retinopathy, the more serious form of diabetic retinopathy. Proliferative retinopathy occurs when new blood vessels proliferate in and around the retina. Consequently, bleeding into the vitreous, swelling of the retina, and/or retinal detachment may occur, leading to blindness. [00309] Other ophthalmic diseases and disorders that may be treated using the methods and compositions described 35 herein include diseases, disorders, and conditions that are associated with, exacerbated by, or caused by ischemia in the retina. Retinal ischemia includes ischemia of the inner retina and the outer retina. Retinal ischemia can occur from either choroidal or retinal vascular diseases, such as central or branch retinal vision occlusion, collagen vascular diseases and thrombocytopenic purpura. Retinal vasculitis and occlusion is seen with Eales disease and systemic lupus erythematosus. 40 1003101 Retinal ischemia may be associated with retinal blood vessel occlusion. In the United States, both branch and central retinal vein occlusions are the second most common retinal vascular diseases after diabetic retinopathy. About 7% to 10% of patients who have retinal venous occlusive disease in one eye eventually have bilateral disease. Visual field loss commonly occurs from macular edema, ischemia, or vitreous hemorrhage secondary to disc or retinal neovascularization induced by the release of vascular endothelial 45 growth factor. [00311] Arteriolosclerosis at sites of retinal arteriovenous crossings (areas in which arteries and veins share a 106 WO 2010/028088 PCT/US2009/055785 5 common adventitial sheath) causes constriction of the wall of a retinal vein by a crossing artery. The constriction results in thrombus formation and subsequent occlusion of the vein. The blocked vein may lead to macular edema and hemorrhage secondary to breakdown in the blood-retina barrier in the area drained by the vein, disruption of circulation with turbulence in venous flow, endothelial damage, and ischemia. Clinically, areas of ischemic retina appear as feathery white patches called cotton-wool spots. 10 [00312) Branch retinal vein occlusions with abundant ischemia cause acute central and paracentral visual field loss corresponding to the location of the involved retinal quadrants. Retinal neovascularization due to ischemia may lead to vitreous hemorrhage and subacute or acute vision loss. [003131 Two types of central retinal vein occlusion, ischemic and nonischemic, may occur depending on whether widespread retinal ischemia is present. Even in the nonischenic type, the macula may still be ischemic. 15 Approximately 25% central retinal vein occlusion is ischemic. Diagnosis of central retinal vein occlusion can usually be made on the basis of characteristic ophthalmoscopic findings, including retinal hemorrhage in all quadrants, dilated and tortuous veins, and cotton-wool spots. Macular edema and foveal ischemia can lead to vision loss. Extracellular fluid increases interstitial pressure, which may result in areas of retinal capillary closure (ie., patchy ischemic retinal whitening) or occlusion of a cilioretinal artery. 20 [00314] Patients with ischemic central retinal vein occlusion are more likely to present with a sudden onset of vision loss and have visual acuity of less than 20/200, a relative afferent pupillary defect, abundant intraretinal hemorrhages, and extensive nonperfusion on fluorescein angiography. The natural history of ischemic central retinal vein occlusion is associated with poor outcomes: eventually, approximately two thirds of patients who have ischemic central retinal vein occlusion will have ocular neovascularization and 25 one-third will have neovascular glaucoma. The latter condition is a severe type of glaucoma that may lead to rapid visual field and vision loss, epithelial edema of the cornea with secondary epithelial erosion and predisposition to bacterial keratitis, severe pain, nausea and vomiting, and, eventually, phthisis bulbi (atrophy of the globe with no light perception). [00315] As used herein, a patient (or subject) may be any mammal, including a human, that may have or be 30 afflicted with a neurodegenerative disease or condition, including an ophthalmic disease or disorder, or that may be free of detectable disease. Accordingly, the treatment may be administered to a subject who has an existing disease, or the treatment may be prophylactic, administered to a subject who is at risk for developing the disease or condition. Treating or treatment refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such 35 as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being. [00316] The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination. Accordingly, the term "treating" includes the administration of the 40 compounds or agents described herein to treat pain, hyperalgesia, allodynia, or nociceptive events and to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with pain, hyperalgesia, allodynia, nociceptive events, or other disorders. The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or sequelae of the disease in the subject. Treatment also includes restoring or improving retinal neuronal cell functions 45 (including photoreceptor function) in a vertebrate visual system, for example, such as visual acuity and visual field testing etc., as measured over time (e.g., as measured in weeks or months). Treatment also 107 WO 2010/028088 PCT/US2009/055785 5 includes stabilizing disease progression (i.e., slowing, minimizing, or halting the progression of an ophthalmic disease and associated symptoms) and minimizing additional degeneration of a vertebrate visual system. Treatment also includes prophylaxis and refers to the administration of a sulphur-linked compound to a subject to prevent degeneration or further degeneration or deterioration or further deterioration of the vertebrate visual system of the subject and to prevent or inhibit development of the 10 disease and/or related symptoms and sequelae. [003171 Various methods and techniques practiced by a person skilled in the medical and ophthalmological arts to determine and evaluate a disease state and/or to monitor and assess a therapeutic regimen include, for example, fluorescein angiogram, fundus photography, indocyanine green dye tracking of the choroidal circulatory system, opthalmoscopy, optical coherence tomography (OCT), and visual acuity testing. 15 [003181 A fluorescein angiogram involves injecting a fluorescein dye intravenously and then observing any leakage of the dye as it circulates through the eye. Intravenous injection of indocyanine green dye may also be used to determine if vessels in the eye are compromised, particularly in the choroidal circulatory system that is just behind the retina. Fundus photography may be used for examining the optic nerve, macula, blood vessels, retina, and the vitreous. Microaneurysms are visible lesions in diabetic retinopathy that may be 20 detected in digital fundus images early in the disease (see, e.g., U.S. Patent Application Publication No. 2007/0002275). An ophthalmoscope may be used to examine the retina and vitreous. Opthalmoscopy is usually performed with dilated pupils, to allow the best view inside the eye. Two types of ophthalmoscopes may be used: direct and indirect. The direct ophthalmoscope is generally used to view the optic nerve and the central retina. The periphery, or entire retina, may be viewed by using an indirect 25 ophthalmoscope. Optical coherence tomography (OCT) produces high resolution, high speed, non invasive, cross-sectional images of body tissue. OCT is noninvasive and provides detection of microscopic early signs of disruption in tissues. 1003191 A subject or patient refers to any vertebrate or mammalian patient or subject to whom the compositions described herein can be administered. The term "vertebrate" or "mammal" includes humans and non 30 human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals, such as domestic pets (such as cats, dogs, horses), farm animals, and zoo animals. Subjects in need of treatment using the methods described herein may be identified according to accepted screening methods in the medical art that are employed to determine risk factors or symptoms associated with an ophthalmic disease or condition described herein or to determine the status of an existing ophthalmic disease or condition in a 35 subject. These and other routine methods allow the clinician to select patients in need of therapy using the methods and formulations described herein. Pharmaceutical Compositions [00320] In certain embodiments, a sulphur-linked compound may be administered as a pure chemical. In other embodiments, the sulphur-linked compound can be combined with a pharmaceutical carrier (also referred to herein as a pharmaceutically acceptable excipient (i.e., a pharmaceutically suitable and acceptable 40 carrier, diluent, etc., which is a non-toxic, inert material that does not interfere with the activity of the active ingredient)) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 2 1 ' Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference, in its entirety. 45 (003211 Accordingly, provided herein is a pharmaceutical composition comprising one or more sulphur-linked 108 WO 2010/028088 PCT/US2009/055785 5 compounds, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, of a compound described herein, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the 10 composition. A pharmaceutically acceptable or suitable composition includes an ophthalnologically suitable or acceptable composition. [09322] Thus, another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having a structure of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable solvate, hydrate, salt, N-oxide or prodrug thereof: (RII), RY Z R12 15 R 11 Formula (I) wherein, Z is a bond, -C(R')(I)-, -C(R!)(R)-C(R)(R 2 )-, -X-C(R)(R 2 )-, -C(R')(R' 0

)-C(R)(R

2

)-C(R

6 )(R")-, X-C(R 3

)(R

32

)-C(R')(R

2 )- or -C(R*)(R')-X-C(Re)(R")-; Y is -SO 2

NR

4 -, -S-C(R1 4 )(Rs)-, -S(=O)-C(R' t

)(R'

5 )-, or -S(=0)2-CR'4)(R) 20 R and R 2 are each independently selected from hydrogen, halogen, C,-C 5 alkyl, fluoroalkyl, -OR 6 or NR 7 Ra; or R' and R 2 together form an oxo;

R

1 , R 32 , R 38 and R 39 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl;

R

40 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R 40 and RW, together with the nitrogen atom to which they are attached, form a heterocycle; 25 each R'4 and R' is independently selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, aralkyl, carbocyclyl, heteroaryl or C-attached heterocyclyl; or R' 4 and R' together with the carbon atom to which they are attached, form a carbocyclyl or heterocycly; or optionally, R5 and either one R' 4 or R" 5 , together with the carbon atom to which they are attached, form a carbocycle or heterocycle; R3 and R 37 are each independently selected from hydrogen, halogen, C-C 5 alkyl, fluoroalkyl, -OR 6 or 30 NR 7

R

8 ; or R 3 ' and R" together form an oxo; or optionally, R 6 and R' together form a direct bond to provide a double bond; or optionally, R 36 and R' together form a direct bond, and R 3 7 and R 2 together form a direct bond to provide a triple bond;

R

3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are 35 attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;

R

5 is C2-Cis alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; each R 7 and R are independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, -C(=O)RD, SO2R", C0 2

R

3 or SO 2

NR

24 R2; or R 7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocycly]; 40 X is -0-, -S-, -S(=O)-, -S(=O) 2 -, -N(R)-, -C(=0)-, -C(=CH)-, -C(=N-NR 3 1)-, or -C(=N-ORII)- R? and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, -OR', -NR7R! or carbocycly]; or R 9 and R' 0 form an oxo; or optionally, R9 and R' together fbrm a direct bond to provide a 109 WO 2010/028088 PCT/US2009/055785 5 double bond; or optionally, R 9 and R 1 together form a direct bond, and R1 0 and R 2 together form a direct bond to provide a triple bond; R" and R 2 are each independently selected from hydrogen, alkyl, carbocyclyl, -C(=O)R, SO 2 R, C0 2

R

13 or SO2NR24R 2 s; or R" and R 2 , together with the nitrogen atom to which they are attached, form an N heterocyclyl; 10 each R1 3 is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; each R, R, R 3 and R' is independently hydrogen or alkyl; each R 24 and R is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; each R 3 is independently selected from halogen, OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 15 [00323] A pharmaceutical composition (e.g.. for oral administration or delivery by injection, or combined devices, or for application as an eye drop) may be in the form of a liquid or solid, A liquid pharmaceutical composition may include, for example, one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol 20 or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is commonly used as an excipient, and an injectable pharmaceutical composition or a composition that is delivered ocularly is preferably sterile. 25 [003241 At least one sulphur-linked compound can be administered to human or other nonhuman vertebrates. In certain embodiments, the compound is substantially pure, in that it contains less than about 5% or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. In other embodiments, a combination of one or more sulphur-linked compounds can be administered. 30 [00325) A sulphur-linked compound can be delivered to a subject by any suitable means, including, for example, orally, parenterally, intraocularly, intravenously, intraperitoneally, intranasally (or other delivery methods to the mucous membranes, for example, of the nose, throat, and bronchial tubes), or by local administration to the eye, or by an intraocular or periocular device. Modes of local administration can include, for example, eye drops, intraocular injection or periocular injection. Periocular injection typically involves 35 injection of the synthetic isomerization inhibitor, ie., sulphur-linked compound as described herein, under the conjunctiva or into the Tennon's space (beneath the fibrous tissue overlying the eye). Intraocular injection typically involves injection of the sulphur-linked compound into the vitreous. In certain embodiments, the administration is non-invasive, such as by eye drops or oral dosage form, or as a combined device. 40 [003261 A sulphur-linked compound can be formulated for administration using pharmaceutically acceptable (suitable) carriers or vehicles as well as techniques routinely used in the art. A pharmaceutically acceptable or suitable carrier includes an ophthalmologically suitable or acceptable carrier. A carrier is selected according to the solubility of the sulphur-linked compound. Suitable ophtbalmological compositions include those that are administrable locally to the eye, such as by eye drops, injection or the like. In the 45 case of eye drops, the formulation can also optionally include, for example, ophthalmologically compatible agents such as isotonizing agents such as sodium chloride, concentrated glycerin, and the like; buffering 110 WO 2010/028088 PCT/US2009/055785 5 agents such as sodium phosphate, sodium acetate, and the like; surfactants such as polyoxyethylene sorbitan mono-oleate (also referred to as Polysorbate 80), polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil, and the like; stabilization agents such as sodium citrate, sodium edentate, and the like; preservatives such as benzalkonium chloride, parabens, and the like; and other ingredients. Preservatives can be employed, for example, at a level of from about 0.001 to about 1.0% weight/volume. 10 The pH of the formulation is usually within the range acceptable to ophthalmologic formulations, such as within the range of about pH 4 to 8, or pH 5 to 7, or pH 6 to 7, or pH 4 to 7, or pH 5 to 8, or pH 6 to 8, or pH4to6, orpH 5to6,orpH7to8. 1003271 In additional embodiments, the compositions described herein further comprise cyclodextrins. Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as a 15 cyclodextrin, p-cyclodextrin, or y-cyclodextrin respectively. Cyclodextrins have been found to be particularly useful in pharmaceutical formulations. Cyclodextrins have a hydrophilic exterior, which enhances water-soluble, and a hydrophobic interior which forms a cavity. In an aqueous environment, hydrophobic portions of other molecules often enter the hydrophobic cavity of cyclodextrin to form inclusion compounds. Additionally, cyclodextrins are also capable of other types of nonbonding 20 interactions with molecules that are not inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on a-cyclodextrin, 21 hydroxyl groups on p-cyclodextrin, and 24 hydroxyl groups on y-cyclodextrin. One or more of these hydroxyl groups can be reacted with any of a number of reagents to form a large variety of cyclodextrin derivatives. Some of the more common derivatives of cyclodextrin are hydroxypropyl ethers, sulfonates, and sulfoalkylethers. 25 Shown below is the structure of p-cyclodextrin and the hydroxypropyl-p-cyclodextrin (HPpCD). O ::: RO fR=H RO R i OR hydroxypropyl -cylodextPn O R R' 00 10 RO O R [00328] The use of uyclodextrins in pharmaceutical compositions is well known in the art as cyclodextrins and cyclodextrin derivatives are often used to improve the solubility of a drug, Inclusion compounds are involved in many cases of enhanced solubility; however other interactions between cyclodextrins and 30 insoluble compounds can also improve solubility. H ydroxypropyl-p-cyclodextrin (HPpCD) is commercially available as a pyrogen free product. It is a nonhygroscopic white powder that readily dissolves in water. HPpCD is thermally stable and does not degrade at neutral pH. [00329] Ophthalmic formulations utilizing cyclodextrins have been disclosed. For example, US 5,227,372 discloses methods related to retaining ophthalmological agents in ocular tissues. US Patent Application 35 Publication 2007/0149480 teaches the use of cyclodextrins to prepare ophthalmic formulations of a small molecule kinase inhibitor with poor water solubility. [00330] The concentration of the cyclodextrin used in the compositions and methods disclosed herein can vary 111 WO 2010/028088 PCT/US2009/055785 5 according to the physiochemical properties, pharmacokinetic properties, side effect or adverse events, formulation considerations, or other factors associated with the therapeutically active agent, or a salt or prodrug thereof. The properties of other excipients in a composition may also be important. Thus, the concentration or amount of cyclodextrin used in accordance with the compositions and methods disclosed herein can vary. In certain compositions, the concentration of the cyclodextrin is from 10% to 25%. 10 [00331] For injection, the sulphur-linked compound can be provided in an injection grade saline solution, in the form of an injectable liposome solution, slow-release polymer system or the like. Intraocular and periocular injections are known to those skilled in the art and are described in numerous publications including, for example, Spaeth, Ed., Ophthalmic Surgery: Principles ofPractic, W. B. Sanders Co., Philadelphia, Pa., 85-87, 1990. 15 [003321 For delivery of a composition comprising at least one of the compounds described herein via a mucosal route, which includes delivery to the nasal passages, throat, and airways, the composition may be delivered in the form of an aerosol. The compound may be in a liquid or powder form for intramucosal delivery. For example, the composition may delivered via a pressurized aerosol container with a suitable propellant, such as a hydrocarbon propellant (e.g., propane, butane, isobutene). The composition may be delivered via a 20 non-pressurized delivery system such as a nebulizer or atomizer, [003331 Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the 25 like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21' Ed. Mack Pub. Co., Baston, PA (2005)). [00334] The sulphur-linked compounds described herein may be formulated for sustained or slow-release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, periocular, intraocular, rectal or subcutaneous implantation, or by implantation at the desired target 30 site, Sustained-release formulations may contain an agent dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active compound contained within a sustained-release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature 35 of the condition to be treated or prevented, [00335] Systemic drug absorption of a drug or composition administered via an ocular route is known to those skilled in the art (see, e.g., Lee et al., Int. J. Pharm. 233:1-18 (2002)). In one embodiment, a sulphur-linked compound is delivered by a topical ocular delivery method (see, e.g., Curr. Drug Metab. 4:213-22 (2003)). The composition may be in the form of an eye drop, salve, or ointment or the like, such as, aqueous eye 40 drops, aqueous ophthalmic suspensions, non-aqueous eye drops, and non-aqueous ophthalmic suspensions, gels, ophthalmic ointments, etc. For preparing a gel, for example, carboxyvinyl polymer, methyl cellulose, sodium alginate, hydroxypropyl cellulose, ethylene maleic anhydride polymer and the like can be used. [003361 The dose of the composition comprising at least one of the sulphur-linked compounds described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health 45 status, age, and other factors that a person skilled in the medical art will use to determine dose, When the composition is used as eye drops, for example, one to several drops per unit dose, preferably 1 or 2 drops 112 WO 2010/028088 PCT/US2009/055785 5 (about 50 pl per I drop), may be applied about I to about 6 times daily. [00337) Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of 10 administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). For prophylactic use, a dose should be sufficient to prevent, delay the onset of, or diminish the severity of a disease associated with neurodegeneration of retinal neuronal cells 15 and/or degeneration of other mature retinal cells such as RPE cells. Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient. [003381 The doses of the sulphur-linked compounds can be suitably selected depending on the clinical status, condition and age of the subject, dosage form and the like, In the case of eye drops, a sulphur-linked 20 compound can be administered, for example, from about 0.01 mg, about 0.1 mg, or about 1 mg, to about 25 mg, to about 50 mg, to about 90 mg per single dose. Eye drops can be administered one or more times per day, as needed. In the case of injections, suitable doses can be, for example, about 0.0001 mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, to about 25 mg, to about 50 mg, or to about 90 mg of the sulphur-linked compound, one to seven times per week. In other embodiments, about 1.0 to about 30 25 mg of the sulphur-linked compound can be administered one to seven times per week. [00339] Oral doses can typically range from 1.0 to 1000 mg, one to four times, or more, per day. An exemplary dosing range for oral administration is from 10 to 250 mg one to three times per day. If the composition is a liquid formulation, the composition comprises at least 0.1% active compound at particular mass or weight (e.g, from 1.0 to 1000 mg) per unit volume of carrier, for example, from about 2% to about 60%. 30 [003401 In certain embodiments, at least one sulphur-linked compound described herein may be administered under conditions and at a time that inhibits or prevents dark adaptation of rod photoreceptor cells. In certain embodiments, the compound is administered to a subject at least 30 minutes (half hour), 60 minutes (one hour), 90 minutes (1.5 hour), or 120 minutes (2 hours) prior to sleeping. In certain embodiments, the compound may be administered at night before the subject sleeps. In other embodiments, a light stimulus 35 may be blocked or removed during the day or under normal light conditions by placing the subject in an environment in which light is removed, such as placing the subject in a darkened room or by applying an eye mask over the eyes of the subject. When the light stimulus is removed in such a manner or by other means contemplated in the art, the agent may be administered prior to sleeping. [00341] The doses of the compounds that may be administered to prevent or inhibit dark adaptation of a rod 40 photoreceptor cell can be suitably selected depending on the clinical status, condition and age of the subject, dosage form and the like. In the case of eye drops, the compound (or the composition comprising the compound) can be administered, for example, from about 0.01 mg, about 0.1 mg, or about 1 mg, to about 25 mg, to about 50 mg, to about 90 mg per single dose. In the case of injections, suitable doses can be, for example, about 0.0001 mg, about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, to 45 about 25 mg, to about 50 mg, or to about 90 mg of the compound, administered any number of days between one to seven days per week prior to sleeping or prior to removing the subject from all light 113 WO 2010/028088 PCT/US2009/055785 5 sources. In certain other embodiments, for administration of the compound by eye drops or injection, the dose is between 1-10 mg (compound)/kg (body weight of subject) (ie., for example, 80-800 mg total per dose for a subject weighing 80 kg), In other embodiments, about 10 to about 30 mg of compound can be administered one to seven times per week. Oral doses can typically range from about 1.0 to about 1000 mg, administered any number of days between one to seven days per week. An exemplary dosing range for 10 oral administration is from about 10 to about 800 mg once per day prior to sleeping. In other embodiments, the composition may be delivered by intravitreal administration. 1003421 Also provided are methods of manufacturing the compounds and pharmaceutical compositions described herein. A composition comprising a pharmaceutically acceptable excipient or carrier and at least one of the sulphur-linked compounds described herein may be prepared by synthesizing the compound according to 15 any one of the methods described herein or practiced in the art and then formulating the compound with a pharmaceutically acceptable carrier. Formulation of the composition will be appropriate and dependent on several factors, including but not limited to, the delivery route, dose, and stability of the compound. [00343] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be 20 construed to limit the invention in any way. [00344] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described 25 herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. EXAMPLES [00345] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture 30 and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Flash column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Proton and carbon nuclear magnetic resonance spectra were obtained with a Varian VnmrJ 400 at 400 MHz for proton and 100 MHz for carbon, or with a BRUKER 400 MHz with Multi Probe/Dual Probe at 400 MHz for proton and 100 MHz for carbon, as noted, Spectra are given in ppm (8) and coupling 35 constants, J are reported in Hertz. For proton spectra either tetramethylsilane was used as an internal standard or the solvent peak was used as the reference peak. For carbon spectra the solvent peak was used as the reference. HPLC was performed using 1) Agilent HP 1100 system with diode array detection at 220 nm on Phenomenex Gemini 4.6x250 mm or 4.6x150 mm 5p columns, mobile phase 0.1% TFA CH 3 CN H 2 0 gradient with mass-spectral detection using electrospray ionization (ES+) mode or 2) Waters Acquity 40 UPLC System with Diode array detection on Acquity D3EH C-18 (2.1 x 100 mm, 1.7 pim)/Acquity UPLC BEH Shield RP-18 (2.1 x 100mm, 1.7 pm) columns, mobile phase 5 mM Ammonium Acetate/0.I% TFA in water or with 0.1% TFA/ACN/MeOH gradient with mass-spectral detection using electrospray ionization (ES+ I ES- ) mode in Waters Single Quadrupole Detector. Chiral HPLC analysis was performed using a Chiralpak IA column (4.6x250 mm, 5A) on an Agilent HP 1100 system with diode array detection 45 with heptane - EtOH with 0.1% ethanesulfonic acid as an eluent. 114 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 1 PREPARATION OF 3-(3-(CYCLDHEXYLMETHYLTHIO)PHENYL)PROP-2-YN-1-AMINE S K N H 2 10 [003461 3-(3-(Cyclohexylmethylthio)phenyl)prop-2-yn-1-amine was prepared following the method shown in Scheme 1. SCHEME l Br S Br / NHBoc 4 HS Br K 2 C0 3 Cul, PdCI 2 (PPh 3

)

2

CH

3 CO CH 3 Et 3 N, DMF 1. HCI / EtOH S NHBoe 2. NaHCO 3

NH

2 15 1003471 Step 1: 3-Bromobenzenethiol (1) (1.0 mL, 8.46 mmol) was added to a mixture of bromomethylcyclohexane (2) (1.53 g, 8.61 mmol), K2CO 3 (2.47 g, 17.90 mmol) in acetone and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then filtered and the filter cake was washed with acetone Concentration of the filtrate under reduced pressure gave thioether 3 as a light yellow oil, Yield (2.37 g, 99%); 'H NMR (400 MHz, CDCl 3 ) 8 7.41 (t, J= 1.8 Hz, 1H), 7,23-7.27 (m, 1H), 20 7.17-7.22 (m, 1H), 7.11 (t, J= 7.8 Hz, 1 H), 2.80 (d, J= 6.8 Hz, 2H), 1.84-1.86 (in, 2H), 1.68-176 (in, 2H), 1,62-1.68 (in, IH), 1.48-1.60 (m, 1H), 1.09-1.30 (m, 3H), 0.96-1.06 (m, 2H). 1003481 Step 2: A solution of bromide 3 (0.508 g, 1.78 mmol), propargyl carbamate 4 (0.414 g, 2.67 mmol) and triethylanine (5 mL) in anhydrous DMF was degassed by bubbling argon for 2 min. CuI (0.010 g, 0.053 mmol) and PdCI 2 (PPbh)2 (0.040 g, 0.057 mnol) were added and the mixture was degassed by bubbling 25 argon, and then by applying vacuum/argon three times. The reaction mixture was heated under argon at 80 *C for 5 hr, cooled and concentrated under reduced pressure. Purification by flash chromatography (5% to 30% EtOAc - hexanes gradient) gave carbanate 5 as a light yellow oil. Yield (0.273 g, 43%); 'H NMR (400 MHz, CDC 3 ) 8 7.31-7.33 (m, 1H), 7.19-7.24 (m, IH), 7.15-7.18 (in, 2H), 4.74 (br.s, 1H), 4.14 (d, J= 4.1 Hz, 2H), 2.80 (d, J= 6.7 Hz, 2H), 1.84-1.86 (m, 2H), 1.68-1.76 (m, 2H), 1.62-1.68 (in, IIH), 1.48-1.60 30 (in, 1H), 1.46 (s, 9H), 1.09-1.30 (m, 3H), 0.96-1.06 (m, 2H). 1003491 Step 3: Ethanolic HCI (7.6M, 2 mL) was added to a solution of carbamate 5 (0.273 g, 0.76 mmol) in anhydrous THF and the reaction mixture was srirred at room temperature for 2.5 hr, Saturated NaHCO 3 was added to the mixture and the mixture was stirred overnight, The mixture was extracted with EtOAc twice and the combined organic layers were concentrated under reduced pressure. Purification by flash 35 chromatography (10% to 50% of 10% 7N NH 3 /MeOH/CH 2

CI

2 - CH 2 C1 2 gradient) gave Example 1 as a 115 WO 2010/028088 PCT/US2009/055785 5 colorless oil. Yield (0.116 g, 59%); 'H NMR (400 MHz, CDC 3 ) 8 7.31-7.33 (m, IH), 7.19-7.24 (m, I H), 7.15-7.18 (m, 2H), 3.65 (s, 2H), 2.79 (d, J= 6.8 Hz, 2H), 1.84-1.92 (m, 2H), 1.60-1.76 (m, 5H), 1.46-1.59 (m, IH), 1.09-1.24 (m, 3H), 0.93-1.04 (m, 2H); RP-HPLC purity 91.4% (AUC); ESI MS mi 260.51 [M+H]*. 10 EXAMPLE 2 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLSULFNYL)PHBENYL)PROP-2-YN- 1-AMINE It NH 2 [00350] 3-(3-(Cyclohexylmethylsulfmyl)pbenyl)prop-2-yn-I-amine was prepared following the method used in 15 Example . [00351] Step 1:To a stirred solution of thioether 3 (0.451 g, 1.58 mmol) in CH 3 CN at room temperature was added iron (Ill) chloride (9.9 mg, 0.061 mmol) followed by, after 5 min, periodic acid (0.403 g, 1.77 mmol). The reaction mixture was stirred 30 min. The reaction was quenched by the addition of an aqueous solution of sodium thiosulfate. The mixture was extracted with EtOAc three times and the combined organic layers 20 washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give 1-bromo-3-(cyclohexylmethylsulfinyl)benzene as a light brown oil, which crystallized upon standing to a solid. Yield 0.469 g, 99%); IH NMR (400 MHz, CDCI 3 ) 5 7.77 (t, J= 1.8 Hz, lH), 7.58-7.62 (m, 1H), 7.49-7.53 (m, 1H), 7.37 (t, J= 7.8 Hz, I H), 2.78 (dd, J= 4.5, 13.1 Hz, lH), 2.47 (dd, J= 9.4,13.1 Hz, 1H), 2.06-2.14 (m, 1H), 1,90-2.04 (m, 1H), 1.64-1.79 (m, 4H), 1.01-1.39 (m, 5H). 25 100352] Step 2: Sonogashira coupling of 1-bromo-3-(cyclohexylmethylsulfinyl)benzene with propargyl carbamate 4 following the method used in Example I gave tert-butyl 3-(3-(cyclohexylmethylsulfinyl)phenyl)prop-2 ynylcarbamate as a brown oil. Yield (0.384 g, 68%); 1 H NMR (400 MHz, CDCI 3 ) 8 7.64 (t, J= 1.6 Hz, 1H), 7.57 (dt, J= 1.6, 7.6 Hz, 1H), 7,49 (dt, J= 1.6, 7.6 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 4.75 (br.s, lH), 4.14 (m, 2H), 2.76 (dd, J= 4.7, 13.1 Hz, 1H), 2.46 (dd, J= 9.2, 13.1 Hz, 1H), 2.04-2.12 (m, I H), 1.88-2.00 30 (m, 1H), 1.57-1.78 (m, 4H), 1.46 (s, 9H), 1.00-1.45 (m, 5H). [00353] Step 3: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfinyl)phenyl)prop-2-ynylcarbamate following the method used in Example I gave Example 2 as a colorless oil. Yield (0.149 g, 53%); 'H NMR (400 MHz, CDCI 3 ) 8 7.63 (t, J= 1.4 Hz, 1 H), 7.54 (dt, J= 1.6, 7.4 Hz, 1H), 7.48 (dt, J= 1.4, 7.6 Hz, IH), 7.43 (t, J =7.4 Hz, 1H), 3.64 (s, 2H), 2.75 (dd, J = 4.7, 13.1 Hz, 1H), 2.45 (dd, J = 9.2, 13.1 Hz, 1H), 2.03-2.12 35 (m, 1H), 1.87-1.97 (m, 1H), 1.50-1.76 (m, 6H), 0.98-1.37 (m, 5H); RP-HPLC purity 91.3% (AUC); ESI MS m/z 276.49 [M+H)*. EXAMPLE 3 40 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)PROP-2-YN- I -AMINE

NH

2 116 WO 2010/028088 PCT/US2009/055785 5 [00354] 3-(3-(Cyclohexylmethylsulfonyl)phenyl)prop-2-yn-l-amine was prepared following the method used for Example 1. 100355] Step 1: Hydrogen peroxide (30%, 1.6 mL, 15.7 mmol) was added to a mixture of thioether 3 (0.454 g, 1.59 mmol) and (NH 4

)

6 Mo 7 Og4H 2 0 (ammonium molybdate tetrahydrate) (0.585 g, 0.474 mmol) in absolute EtOH. The reaction mixture was stirred at room temperature for 2 br, then concentrated under reduced 10 pressure. Water was added to the residue and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and the filtrate was concentrated under reduced pressure to yield 1 -bromo-3-(cyclohexylmethylsulfonyl)benzene as a white solid. Yield (0.471 g, 93%); ' H NMR (400 MHz, CDC 3 ) 6 8.05 (t, J= 1.8 liz, 1H), 7.83 (dt, J= 1.2, 7.8 Hz, I H), 7.76 (ddd, J= 1.0, 1.8, 8.0 Hz, 1H), 7.43 (t, J= 15.0 Hz, 1H), 2.97 (d, J= 6.3 Hz, 2H), 1.95-2.06 15 (in, I H), 1.84-1.92 (m, 2H), 1.59-1.72 (m, 3H), 1.20-1.34 (m, 2H), 1.00-1.20 (m, 3H). [003561 Step 2: Sonogashira coupling of 1-bromo-3-(cyclohexylmethylsulfonyl)benzene with propargyl carbamate 4 following the method used in Example 1 gave tert-butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)prop-2 ynylcarbamate as a brown oil, Yield (0.446 g, 77%); 'H NMR (400 MHz, CDC1 3 ) 8 7.93 (t, J= 1.8 Hz, 1H), 7.82 (dt, J= 1.4, 7.8 Hz, I H), 7.76 (dt, J= 1.4, 7.8 Hz, 1H), 7.49 (t, J= 7.8 Hz, IH), 4.77 (br.s, 1H), 20 4.16 (d, J 5.1 Hz, 2H), 2.96 (d, J= 6.3 Hz, 2H), 1.92-2.03 (m, 1H), 1.82-1.90 (m, 2H), 1.57-1.71 (in, 3H), 1.47 (s, 9H), 1.20-1.33 (m, 2H), 1.00-1.20 (m, 3H). [003571 Step 3: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)prop-2-ynylcarbamate following the method used in Example 1 gave Example 3 as a colorless oil. Yield (0.171 g, 52%); 'H NMR (400 MHz, CDC13) 8 7.94 (t, J= 1.5 Hz, 1H), 7.81 (dt, J= 1.4, 7.8 Hz, 114), 7.63 (dt, J= 1.2, 7.8 Hz, 1 H), 7.49 25 (t, J= 7.8 Hz, I H), 3.67 (s, 2H), 2.96 (d, J= 6.3 Hz, 2H), 1.92-2.04 (m, 1H), 1.82-1.90 (m, 2H), 1.57-1.71 (m, 3H), 1.38-1.55 (br.s, 2H), 1.20-1.33 (m, 2H), 1.00-1.20 (m, 3H); RP-HPLC purity 93.6% (AUC); ESI MS m/z 292.54 [M+H]*. EXAMPLE 4 30 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)PROPAN-1-AMINE S NH 2 [00358] 3-(3-(Cyclohexylmethylthio)pheny)propan- 1-amine was prepared following the method shown in Scheme 2. 35 SCHEME2 K NH 2 tlH 2 ,PC

NH

2 r s ~~EtOH " JNH Step 1: A solution of Example 1 (0.100 g, 0.385 mmol) in ethanol was degassed by bubbling argon for 2 min. Pd/C (10% wt, 0.041 g) was added and the reaction mixture atmosphere was changed to hydrogen by alternating between 40 vacuum and hydrogen twice. The mixture was stirred under a H 2 -filled balloon overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by flash 117 WO 2010/028088 PCT/US2009/055785 5 chromatography (10% to 100% of 10% 7N NH 3 /McOH/CH 2

C

2 - CH2C 2 gradient) gave Example 4 as a colorless oil. Yield (0.06 g, 60%); 'H NMR (400 MHz, CD 3 OD) 8 7.17 (t, J - 7.6 Hz, 1H), 7.04 - 7.10 (in, 2H), 6.93 - 6.97 (m, IH), 2.80 (d, 6.8 Hz, 2H), 2.54 - 2.57 (in, 4H), 1.75 - 1.85 (m, 2H), 1.52 -1.68 (in, 5H), 1.38 - 1.50 (m, lH), 1.02 -1.22 (in, 3H), 0.89 -1.02 (m, 2H); RP-HPLC purity 1003591 96.9/ (AUC); EST MS m/z 264.47 [M+H]*. 10 EXAMPLE PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)PROPAN- 1-AMINE N

NH

2 Cr 15 [00360] 3-(3-(Cyclohexylmethylsulfonyl)phenyl)propan-1-amine was prepared following the method used for Example 4. [00361] Step 1: Hydrogenation of Example 3 following the conditions used in Example 4 gave, after purification by flash chromatography Example 5 as a colorless oil. Yield (0.171 g, 52%); 'H NMR (400 MHz, CDOD) 8 7.75-7.77 (m, 1 H), 7.72 (dt, J= 1.6, 7.4 Hz, I H), 7.57 (dt, J= 1.4, 7.6 Hz, 1H), 7.53 (t, J - 7.6 Hz, 1H), 20 3.08 (d, J= 5.9 Hz, 2H), 2,77 (t, J= 7.6 Hz, 2H), 2.65 (t, J= 7.4 Hz, 2H), 1.75-1.89 (m, 5H), 1.54-1.70 (m, 3H), 1.13-1.30 (m, 3H), 1.00-1.13 (in, 2H); RP-HPLC purity 98% (AUC); ES] MS m/z 296.57 {M+H]*. EXAMPLE 6 25 PREPARATION OF 3-(3-(2-ETHYLBUTYLTWO)PHENYL)PROP-2-YN-1-AMINE S NH 2 [00362] 3-(3-(2-Ethylbutylthio)phenyl)prop-2-yn-1-amine was prepared following the method used in Example 1. [00363] Step 1: Alkylation of 3-bromobenzenethiol (1) with 2-ethylbutyl methanesulfonate following the method used in Example 1 followed by purification by flash chromatography with hexanes gave (3 30 bromophenyl)(2-ethylbutyl)sulfane as a colorless oil. Yield (0.386 g, 69%); 'H NMR (400 MHz, CDCl,) 8 7.42 (t, J= 2.0 Hz, 1H), 7.24 - 7.27 (m, [H), 7.19 - 7.23 (in, 1H), 7.11 (t, J= 8.0 Hz, I H), 2.88 (d, J= 6.0 Hz, 2H), 1.38 - 1.48 (m, 5H), 0.89 (t, J = 7.2 Hz, 6H). [00364] Step 2: Sonogashira coupling of (3-bromophenyl)(2-ethylbutyl)sulfane with alkyne 4 following the method used in Example I gave, after purification by flash chromatography (2% to 15% EtOAc - hexanes 35 gradient) tert-butyl 3-(3-(2-ethylbutylthio)phenyl)prop-2-ynylcarbamnate as a yellow oil, Yield (0.169 g, 37%); 'H NMR (400 MHz, CDC 3 ) 8 7.33 -7.35 (in, 1 H), 7.21 - 7.27 (m, 1H), 7.16- 7.19 (m, 2H), 4.78 (brs, 1H), 4.13 (d, J= 3.6 Hz, 2H), 2.87 (d, J = 5.6 Hz, 2H), 1.36 - 1.55 (m, 14H), 0.87 (t, J = 7.2 H z, 6H). [00365] Step 3: Deprotection of tert-butyl 3-(3-(2-ethylbutylthio)phenyl)prop-2-ynylcarbamate following the method used in Example 1 followed by purification by flash chromatography (10% to 50% of 10% 7N 40 NEH3/MeOH/CH 2 Cl 2 - CH 2

C

2 gradient) gave Example 6 as a red oil. Yield (0.099 g, 77%); 'H NMR (400 MHz, CDC 3 ) 8 7.33 - 7.35 (m, 1H), 7.19 - 7.26 (m, I H), 7.15 --7.19 (in, 2H), 3.64 (s, 2H), 2.88 (d, J= 5.6 118 WO 2010/028088 PCT/US2009/055785 5 Hz, 2H), 1.36 - 1.58 (n, 7H), 0.87 (t, J= 7.2 Hz, 6H); RP-HPLC purity 98.6% (AUC); ES1 MS m/z 248.15 [M+H]*. EXAMPLE 7 10 PREPARATION OF 3-(3-(2-ETHYLBUTYLTHIO)PHENYL)PROPAN-1-AMINE SNH2 [003661 3-(3-(2-Ethylbutylthio)phenyl)propan-1-amine was prepared following the method used in Example 4. [003671 Step 1: Hydrogenation of Example 6 following the method used in Example 4 gave Example 7 as a yellow oil. Yield (0,050 g, 77%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.17 (t, J = 7.6 Hz, 1H), 7.07 - 7.13 (in, 2H), 15 6.93 - 6.98 (in, 1H), 2.87 (d, J = 5.2 Hz, 2H), 2.48 - 2.57 (in, 4H), 2.28 (brs, 2H), 1.60 (dt, J = 7.2 Hz, 2H), 1.30 - 1.46 (in, 5H), 0.81 (t, J= 7.2 Hz, 6H); RP-HPLC purity 90.8% (AUC); ESI MS m/z 252.22 [M+H]*. EXAMPLE 8 20 PREPARATION OF 3-AMINO-1-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)PROPAN-1-OL S

NH

2 OH 100368] 3-Amino-1-(3-(cyclohexylmethylthio)phenyl)propan-l-ol was prepared following the method shown in Scheme 3. SCHvE 3 1. n-BuLL. ThF 0

CH

3 CN, t-BuOK r 2. DMF, THF S 6 NTHF o 3 C 6 BHTHF NH 2 25 K) T OH N THF <2H [003691 Step 1: n-BuLi (2.5 M, 2.0 mL) was added to a cold (-78 *C) solution of bromide 3 (1.167 g, 4.09 mmol) in anhydrous THF under argon and the reaction mixture was stirred at -78 *C for 3 min. DMF (1.0 mL, 12,9 mmol) was added and the reaction mixture was stirred at -78 *C for 15 min and then at room temperature for 5 min. Aqueous NH 4 Cl (25%, 10 mL) was added to the reaction mixture while stirring. After 5 min, the 30 layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered. The filtrate was concentrated under reduced pressure and then dried in vacuum overnight to give aldehyde 6 as a light yellow oil. Yield (0.921 g, 96%); 'H NMR (400 MHz, DMSO-d) 8 9.95 (s, 1H), 7.77 (t, J= 1.8 Hz, 1H), 7.65 (dt, J= 1.4, 7.4 Hz, 1H), 7.60 (dt, J= 1.6, 8.2 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 2.92 (d, J= 6.8 Hz, 1H), 1.75-1.86 (in, 2H), 1.53-1.70 (in, 35 4H), 1.43-1.53 (in, 1H), 1.06-1.22 (m, 3H), 0.90-1.06 (in, 2H). [003701 Step 2: To a -50 *C (dry ice/MeCN bath) solution of t-BuOK (1M/THF, 6.0 mL) in anhydrous THF was 119 WO 2010/028088 PCTIUS2009/055785 5 added under argon a solution of anhydrous CH 3 CN (0.25 mL, 4.75 mmol) in THF. The reaction mixture was stirred at -50 *C under argon for 5 min. A solution of aldehyde 6 (0.921 g, 3.93 mmol) in THIF was added and the reaction mixutre became dark blue at first and then orange. The reaction mixture was stirred at -50 *C for 1.5 h and then at room temperature for 3 min. The reaction was quenched by the addition of aqueous NH 4 C (25%). The layers were separated and the aqueous layer was extracted with EtOAc. The 10 combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatorgaphy (10/o to 50% EtOAc - hexanes gradient) gave hydroxynitrile 7 as a colorless oil. Yield (0.669 g, 62%); 1H NMR (400 MHz, DMSO-d) 6 7.31-7.33 (m, IH), 7.26 (t, J= 7.3 Hz, 1H), 7.14 7.20 (m, 2H), 5.93 (d, J= 4.5 Hz, 1H), 4.82-4.87 (m, 1H), 2.75-2.90 (m, 4H), 1.76-1.84 (m, 2H), 1.60-1.68 (m, 2H), 1.53-1.60 (m, 1H), 1.40-1.51 (in, TH), 1.03-1.22 (i, 3H), 0.90-1.02 (in, 2H). 15 1003711 Step 3: To a stirred solution of hydroxynitrile 7 (0.660 g, 2.40 mmol) in anhydrous THF under argon was added Borane-THF complex solution (IM/THF, 5 mL) and the reaction mixture was heated under reflux for 2.5 hr. After cooling to room temperature, saturated NaHCO was carefully added to the reaction mixture followed by brine, and after vigorous stirring, the layers were separated and the organic layer was concentrated under reduced pressure. Purification by flash chromatography (4% 7N NH 3 /MeOH in CHzC2) 20 gave Example 8 as a colorless oil. Yield (0,480 g, 72%); 'H NMR (400 MHz, CD 3 OD) 8 7.32 (t, J= 1.6 Hz, IH), 7.23 (t, J- 7.6 Hz, 1H), 7.18 (dt, J= 1.6, 7.8 Hz, 1H), 7.12 (dt, J= 1.6, 7.2 Hz, IH), 4.68 (dd, J= 5.3, 8.0 Hz, IH), 2.81 (d,J= 6.9 Hz, 2H), 2.63-2.78 (m, 2H), 1,76-1.93 (m, 4H), 1,67-1.76 (m, 2H), 1.60. 1.67 (m, 1H), 1.43-1.54 (m, 1H), 1.13-1.30 (m, 3H), 0.95-1.07 (m, 2H); "CNMR (CD 3 0D, 100 MHz) 6 145.4, 137.0, 127.8, 126.5, 125.2, 122.3, 71.2, 40.9, 39.6, 37.6, 36.9, 31.9, 25.5, 25.2; RP-HPLC purity 25 97% (AUC); ESI MS m/z 280.44 [M+H]*. EXAMPLE 9 PREPARATION OF 3-AMINo-1-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)PROPAN- 1-OL r 11"

ANH-

2 30 0 OH [003721 3-Amino-1-(3-(cyclohexylmcthylsulfonyl)phenyl)propan- 1-ol was prepared following the method shown in Scheme 4. SCHEME

SNH

2

CF

3 COOEt NHCOCF3 K)OH THF B OH (NH4)eMoO 4H 2 0 1NHCOCF K2CO 3

H

2 0 2 , EtOH KQ6 9 OH MeOH, H 2 0 NH 0 OH 35 1003731 Step 1: A solution of Example 8 (0.411 g, 1.47 mmol) and ethyl trifluoroacetate (0.5 mL, 4.19 mmol) in 120 WO 2010/028088 PCT/US2009/055785 5 anhydrous THF was stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure to give trifluoroacetamide 8 as a colorless oil, which was used in the next step withour further purification. Yield (0.545 g, 99%). [003741 Step 2: Oxidation of thioether 8 following the method used in Example 3 followed by purification by flash chromatography (20% to 60% EtOAc - hexanes gradient) gave sulfone 9 as a colorless oil. Yield (0.472 g, 10 80%); ' H NMR (400 MHz, DMSO-d) 8 9.35 (br.t, IH), 7.83-7.85 (m, 1 H), 7.75 (dt, J= 1.4, 7.6 Hz, 1H), 7.65-7.68 (m, lH), 7.59 (t, J= 7.8 Hz, 1H), 5.57 (br.s, IH), 4.71 (dd, J= 4.5, 7.6 Hz, 1H), 3.18-3.32 (m, 21), 3.15 (d, J= 5.9 Hz, 2H), 1.67-1.90 (m, 5H), 1.46-1.61 (m, 3H), 0.94-1.18 (m, 5H). [00375) Step 3: A mixture of sulfone 9 (0.472 g, 1.16 mmol) and K 2

CO

3 (0.583 g, 4.22 mmol) in MeOH:H2O (2:1) was stirred at room temperature for 17 hr. The mixture was concentrated under reduced pressure. 15 Purification by flash chromatography (30% to 80% of 10% 7N NH3/MeOH/CH 2

CI

2 - CH 2

CI

2 gradient) gaveExample 9 as a colorless oil. Yield (0.254 g, 71%); 'H NMR (400 MHz, CDjOD) 8 7.93 (t, J= 1.8 Hz, 1H), 7.79 (dt, J 1.4, 7.8 Hz, 1H), 7,67-7.72 (m, 11), 7.59 (t, J = 7.8 Hz, 1H), 4.86 (t, J= 6.5 Hz, 1H), 3.09 (d, J= 5.9 Hz, 2H), 2.77 (t, J= 7.2 Hz, 2H), 1.76-1.90 (in, 5H), 1.57-1.71 (in, 3H), 1.13-1.30 (in, 3H), 1.01-1.15 (m, 2H); "C NMR (CD 3 0D, 100 MHz) 8 147.7,140.4,131.1, 129.3, 126.3, 124.8, 71.4, 62.1, 20 41.4, 38.3, 33.1, 32.8, 25.7; RP-HPLC purity 96% (AUC); ESI MS m/z 312.48 [M+H]*. EXAMPLE 10 PREPARATION or 3-AMINo-1-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)PROPAN- I-ONE 25 NH 2 25 0 0 [003761 3-Amino-1-(3-(cyclohexylnethylsulfonyl)phenyl)propan- -one was prepared following the method used shown in Scheme 5. SCHEMES ol:2 H 0N 2 O2I. 0 OH CHCI 1 OH 6 00N O HCI/EtOH 002 r gJ(. Ny 1 E1OAc I ~ N H 2 HCI 30 [00377] Step 1: A solution of Example 9 (0.115 g, 0.368 mmol) and Boc 2 0 (0.0962 g, 0.441 mmol) in anhydrous

CH

2

CI

2 was stirred at room temperature for I h. The solvents were removed under reduced pressure. Purification by flash chromatography (20% to 70% EtOAc - hexanes gradient) gave carbamate 10 as a colorless oil. Yield (0.129 g, 85%); 'H NMR (400 MHz, CDC 3 ) 8 7.87 (t, J= 1.6 Hz, 1H), 7.76 (dt, J= 1.2, 7.8 Hz, 1H), 7.64-7.68 (m, 1H), 7.51 (t, J= 7.8 Hz, 1H), 4.92 (br.s, IH), 4.79 (dd, J= 3.3, 10.0 Hz, 35 1 H), 3.54 (br.t, 1 H), 3.14 (dt, J= 4.7, 14.5 Hz, 1H), 2.96 (d, J= 6.3 Hz, 2H), 1.92-2.02 (m, 11), 1.78-1.88 121 WO 2010/028088 PCT/US2009/055785 5 (m, 3H), 1.70-1.80 (in, 1H), 1.56-1.70 (in, 3H), LA4 (s, 9H), 0.98-1.30 (m, 5H). 1003781 Step 2: A mixture of alcohol 10 (0.129 g, 0.313 mmol) and MnO 2 (0.807 g, 9.28 mmol) in anhydrous

CH

2

CI

2 was stirred at room temperature for 16 hr. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give ketone 11 as a colorless oil which was used in the next step without additional purification. Yield (0.113 g, 86%). 10 [003791 Step 3: To a solution of carbamate 11 (0.113 g, 0.277 mmol) in EtOAc (5 mL) was added ethanolic HCI (7.4M, 2.0 mL) and the reaction mixture was stirred at room temperature for 2 hr. Hexane was added to reaction mixture and stirring was continued for an additional 2 h. The precipitate was collected by filtration, washed with hexane, and dried in vacuum to give Example 10 hydrochloride as a white powder. Yield (0.060 g, 62%); 'H NMR (400 MHz, CD 3 0D) 8 8.49 (t, J= 1.6 Hz, IN), 8.35 (dt, J= 1.4, 7.8 Hz, 15 1H), 8.19 (ddd, J= 1.2, 1.8, 7.8 Hz, 1H), 7.82 (t, J= 7.8 Hz, 1H), 3.53 (t, J= 6.1 Hz, 2H), 3.37 (t, J= 6.1 Hz, 2H), 3.16 (d, J= 6.1 Hz, 2H), 1.80-1.94 (m, 3H), 1.57-1.72 (in, 3H), 1.04-1.32 (m, 5H); RP-HPLC purity 97.8% (AUC); ESI MS m/z 310.52 [M+Hf. EXAMPLE 11 20 PREPARATION OF (E)-3-(3-(CYCLOHEXYLMETYLTHIO)PHENYL)PROP-2-EN-1-AMINE S NH 2 [00380] (E)-3-(3-(Cyclohexylmethylthio)phenyl)prop-2-en-1-amine was prepared following the method shown in Scheme 6. 25 SCHEME 6 fS h c .- .NHCOCFa 12 N O SA'1Br

-

A '- NHCOCF 3 Pd(OAc) 2 , P(o-tol) 2 a1 Et 3 N, DMF K2CO3

NH

2 MeOH, H 2 0 1003811 Step 1: A solution of bromide 3 (0.432 g, 1.52 mmol), trifluoroacetamide 12 (0.380 g, 2.48 mmol), tri-o tolylphosphine (0.040 g, 0.130 mol) and triethylainne (3 mL) in anhydrous DMF was degassed by bubbling argon for 3 min. Palladium (I) acetate was added, argon was bubbled through the reaction 30 mixture for 30 sec, and vacuum/argon was applied three times. The reaction mixture was heated under argon at 90 *C for 4 h, then stirred at room temperature for 16 hrs. The mixture was concentrated under reduced pressure. Purification by flash chromatography (5% to 30% EtOAc - hexanes gradient) gave alkene 13 as light yellow oil which crystallized upon standing. Yield (0.30 g, 55%); 'H NMR (400 MHz, CDCI,) 6 7.27-7.30 (m, 1H), 7.18-7.23 (in, 2H), 7.14 (dt, J= 2.0,6.7 Hz, 1H), 6.54 (t, J= 15.8 Hz, 1H), 35 6.37 (br.s, 1), 6.16 (dt, J= 6.5, 15.7 Hz, 1H), 4.14 (t, J = 6.1 Hz, 2H), 2.81 (d, J= 6.85 Hz, 2H), 1.84-1.92 (m, 2H), 1.60-1.76 (in, 3H), 1.47-1.59 (in, 1H), 1.09-1.28 (in, 3H), 0.94-1.06 (in, 2H). 1003821 Step 2: Deprotection of trifluoroacetamide 13 following the method used in Example 9 gave Example 11 as a colorless oil. Yield (0.089 g, 40%); 'H NMR (400 MHz, CD 3 OD) 8 7.30-7.33 (m, 1H), 7.13-7.23 (in, 122 WO 2010/028088 PCT/US2009/055785 5 3H), 6.48 (dt, J= 1.4, 15.8 Hz, 1H), 6.33 (dt J= 6.1,15.8 Hz, 1H), 3.38 (dd, J= 1.4,6.1 Hz, 2H), 2.81 (d, J= 67 Hz, 2H), 1.84-1.92 (m, 2H), 1.67-1.76 (m, 2H), 1.60-1.67 (m, 1H), 1.43-1.54 (m, 1H), 1.10-1.29 (m, 3H), 0.94-1.06 (m, 2H); RP-HPLC purity 95.A% (AUC); ESI MS m/z 262,62 [M+H]. EXAMPLE 12 10 PREPARATION OF 2-(3-(CYCLOHEXYLMETHYLTHIO)PHENOXY)ETHANAMINE S I C 3 .

N H 2 1003831 2-(3-(Cyclohexylmethylthio)phenoxy)ethanamine was prepared following the method shown in Scheme 7. SCHEME 7 0 C) -8-Ci H 1 0 H HON 01 $ ' N 0 14 0 Et 5 N, CH 2 C1 2 0 6 0 0 ii H Q r 8 NYOS 16 H OH H 16 OH K 2

CO

3 , acetone 17 Gs 2

CO

3 , DMF 15O HC EtOH V NH2 -HCI 15 18 0EtOAc [00384] Step 1: tert-Butyl 2-hydroxyethylcarbamate (14) (5.5 mL, 35.5 mmol) was added to a solution of methanesulfonyl chloride (4.0 mL, 51.5 mmol) in anhydrous CH 2 C1 2 followed by Et 3 N (7 mL, 50.2 mmol) and the mixture was stirred at room temperature for 18 h. The solution was washed with aqueous HCl (0.5M), brine, saturated NaHCO 3 , dried over anhydrous Na 2 SO4 and concentrated under reduced pressure 20 to give crude mesylate 15 as a yellow oil, which was used without further purification. Yield (8.5 g, quant); 'H NMR (400 MHz, CDC 3 ) 8 4.91 (br s, 1H), 4.27 (t, J= 5.3 Hz, 2H), 3,46 (d, J= 4.3 Hz, 2H), 3.02 (s, 3H), 1.43 (s, 9H). [00385] Step 2: Alkylation of 3-mercaptophenol 16 with bromide 2 following the method used in Example 1 gave phenol 17 as a pale yellow oil. Yield (1.848 g, quant.); 'H NMR (400 MHz, CDC 3 ) 8 6.97 (t, J= 8.0 Hz, 25 1 H), 6.595 (t, J= 2.0 Hz, 1H), 6,51-6,54 (in, 1 H), 6.44 (ddd, J= 0.8, 2.3, 8.0 Hz, 1H), 2.72 (d, J= 6.85 H4z, 2H), 1.74-1.83 (in, 2H), 1.52-1.68 (m, 3H), 1.36-1.48 (m, 1H), 1.06-1.20 (in, 3H), 0.86-1.00 (m, 2H). (003861 Step 3: Crude mesylate 15 (0.910 g, 3.80 mmol) was added to a stirred mixture of phenol 17 (0.745 g, 3,35 mmol) and cesium carbonate (1.373 g, 4.21 mmol) in anhydrous DMF. The reaction mixture was stirred at 60 *C for 2 hr, then at 40 0C for 20 hrs. The mixture was diluted with water and extracted twice with 30 EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Purification by flash chromatography ( 10% to 40% EtOAc - hexanes gradient) gave a mixture of carbamate 18 and unreacted phenol 17 (3.5:1 molar) as a colorless oil, which was used in the next step without further purification. Yield (0.874 g, 71%). 123 WO 2010/028088 PCT/US2009/055785 5 [00387] Step 4: Deprotection of carbamate 18 was done following the method used in Example I with the following exceptions. The reaction mixture was stirred for 1.5 h, then concentrated under reduced pressure, and the residue was triturated with CH 2 C1 2 . The precipitate was collected by filtration and dried under vacuum to give Example 12 hydrochloride as a white solid. Yield (0.127 g, 61%); '1H NMR (400 MHz,

CD

3 OD) 8 7.21 (t, J= 8.2 Hz, IH), 6.92-6.95 (n, 2H), 6.79 (ddd, J= 1.0, 2.3, 8.4 Hz, 1H), 4.20 (t, J= 4.9 10 Hz, 2H), 3.34 (t, J= 5.1 Hz, 2H), 2.81 (d, J= 6.85 Hz, 2H), 1.85-1.92 (m, 2H), 1.60-1.76 (m, 3H), 1.43 1.55 (m, 1H), 1.11-1,29 (in, 3H), 0.95-1.07 (m, 2H); RP-HPLC purity 99.7% (AUC); ESI MS m/z 266.43 [M+H'. EXAMPLE 13 15 PREPARATION OF 2-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENOXY)ETHANAMINE [00388] 2-(3-(Cyclohexylmethylsulfonyl)phenoxy)etbanamine was prepared following the method used in Example 3. 20 [00389] Step 1: Oxidation of tert-butyl 2-(3-(cyclohexylmethylthio)phenoxy)ethylcarbamate (18) following the method used in Example 3, followed by flash chromatography (10% to 50% EtOAc - hexanes gradient), gave a mixture of tert-butyl 2-(3-(cyclohexylmethylsulfonyl)phenoxy)ethylcarbamate and 3 (cyclohexylmethylsulfonyl)phenol (3.5:1 molar ratio) as a colorless oil, which was used in the next step without purification. Yield (0.231 g, 97%). 25 (00390] Step 2: Deprotection of crude tert-butyl 2-(3-(cyclohexylmethylsulfonyl)phenoxy)ethylcarbamate following the method used in Example 12 except that the precipitate was collected by filtration, washed with EtOAc and hexanes, gave Example 13 hydrochloride as a white solid. Yield (0.101 g, 67%); ' H NMR (400 MHz, CD 3 0D) 8 7.59 (t, J= 7.8 Hz, 1H), 7.55 (dt, J- 1.6, 7.8 Hz, 1H), 7.50-7.52 (m, 1H), 7.35 (ddd, J= 1.4, 2.5, 7.6 Hz, IH), 4.32 (t, J= 4.9 Hz, 2H), 3.40 (t, J= 5.1 Hz, 2H), 3.11 (d, J= 5.9 Hz, 2H), 1.79 30 1,90 (n, 3H), 1,57-1.72 (m, 3H), 1.14-1.31 (m, 3H), 1.15-1.14 (m, 2H); "C NMR (CD 3 0D, 100 MHz) 8 158.7, 141.8, 130.8, 120.7, 120.0, 113.4, 64.7, 61.9,39.0, 33.1, 32.8,25.7; RP-HPLC purity 99.6% (AUC); ESI-MS m/z 298.52 [M+H]*. EXAMPLE 14 35 PREPARATION OF (E)-3-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)PROP-2-EN-1-AMINE

NH

2 S Cr0 [003911 (E)-3-(3-(cyclohexylmethylsulfonyl)phenyl)prop-2-en-1-amine was prepared following the methods used in Examples 3 and 11. 40 (00392] Step 1: Heck coupling of 1-bromo-3-(cyclohexylmethylsulfony)benzene and allyl trifluoroacetamide 12 following the method used in Example 11 gave (E)-N-(3-(3-(cyclohexylmethylsulfonyl)phenyl)ally)-2,2,2 124 WO 2010/028088 PCTIUS2009/055785 5 trifluoroacetamide as a light yellow oil. Yield (0.220 g, 68%); 'H NMR (400 MHz, CDCI 3 ) 8 7.85 (t, J = 1.6 Hz, lH), 7.77 (dt, J= 1.4, 7.8 Hz, IH), 7.56-7.60 (in, 1H), 7.50 (t, J= 7.6 Hz, 1H), 6.59 (d, J= 15.85 Hz, 1H), 6.59 (br.s, 1H), 6.28 (dtJ=6.3, 15.8 Hz, lH), 4.17 (t,J=5.9 Hz, 2H),2.97 (dJ=6.3 Hz,2H), 1.94-2.15 (in, 11-1), 1.83-1.90 (m, 2H), 1.55-1.71 (in, 3H), 1,20-1.30 (m, 2H), 1.00-1.20 (in, 3H). 100393] Step 2: Deprotection of (E)-N-(3-(3-(cyclohexylmethylsulfonyl)phenyl)allyl)-2,2,2-trifluoroacetamide 10 following the method used in Example 9, followed by purification by flash chromatography (10% to 75% of 10% 7N NH3/MeOH/CH 2

CI

2 - CH 2

C

2 gradient), gave Example 14 as a colorless oil, Yield (0.096 g, 58%); 'H NMR (400 MHz, CD 3 OD) 8 7.91 (t, J= 1.8 Hz, 1 H), 7.72-7.76 (in, 2H), 7.56 (t, J= 7.8 Hz, 1 H), 6.61-6.67 (m, 1 H), 6.51 (dt, J= 5.7, 16.0 Hz, 1H), 3.43 (dd, J= 1.4, 5.7 Hz, 2H), 3.10 (d, J= 5.9 Hz, 2H); 1.77-1.91 (in, 3H), 1.57-1.70 (in, 3H), 1.14-1.31 (m, 3H), 1.10-1.14 (in, 2H); RP-HPLC purity 98.6% 15 (AUC); ESI-MS m/z 294.55 [M+H]*. EXAMPLE 15 PREPARATION OF 3-(3-AMINOPROP- I -YNYL)-N-cYCLOHEXYLBENZENESULFONAMDE 200 INH 2 20 Cf IA [003941 3-(3-Aminoprop-1-ynyl)-N-cyclohexylbenzenesulfonamide was prepared following the method shown in Scheme 8. SCHEMES NH2

NH

2 #r NHBoc 4 -S Br CH 2

C

2 Br Cu, PdC 2 (PhP) 2 19 C 20 EtN, DMF Ho I HCI/EtOH N, 0 NHBoc EtOAc NH HCI 25 [003951 Step 1: Cyclohexylamine (0.5 iL, 4.37 mmol) was added under argon atmosphere to a solution of sulfonyl chloride 19 (1.064 g, 4.16 mmol) and triethylamine (0.65 mL, 4.66 mmol) in anhydrous CH 2 C1 2 and the reaction mixture was stirred at room temperature for 20 inns. The mixture was partitioned between CH 2 C1 2 and aqueous NH 4 CI (25%), the aqueous layer was extracted with CH 2 C1 2 , the combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and the filtrate was concentrated under reduced 30 pressure to give sulfonamide 20 as a colorless oil. Yield (1.39 g, quant.); 'H NMR (400 MHz, CDCI 3 ) 8 8.02 (t, J= 2.0 Hz, 1H), 7,80 (ddd, J= 1.2, 1.4, 7.8 Hz, 1H), 7.68 (ddd, J= 1.0, 1.8, 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 4.45 (d, J= 7.0 Hz, 1H), 3.10-3.22 (m, 1H), 1.72-1.80 (m, 2H), 1.59-1.68 (in, 2H), 1.48-1.56 (m, 1H), 1.05-1.31 (in, 5H). 1003961 Step 2: Sonogashira coupling of aryl bromide 20 with alkyne 4 following the method used in Example 1, 35 followed by purification by flash chromatography (20% to 50% EtOAc-hexanes gradient), gave alkyne 21 as a yellow oil. Yield (0.305 g, 53%); 'H NMR (400 MHz, CDC 3 ) 8 7.91 (t, J= 1,6 Hz, 1 H), 7.79 (dt, J= 1.0, 7.8 Hz, 1 H), 7.56 (dt, J= 1.2, 7.6 Hz, 1H), 7.43 (t, J= 7.8 Hz, 1 H), 4.78 (br.s, 1H), 4.41 (d, J= 7.2 Hz, 125 WO 2010/028088 PCT/US2009/055785 5 1H), 4.15 (d, J= 4.9 Hz, 2H), 3.10-3.20 (m, 1H), 1.70-1.78 (m, 2H), 1.58-1.67 (m, 2H), 1.40-1.55 (m, 10H), 1.02-1.31 (m, 5H). [00397] Step 3: Deprotection of carbamate 21 following the method used in Example 10 with the following exception. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The residue was triturated with EtOAc and the precipitate was collected by filtration, washed with EtOAc and 10 dried in vacuum to give Example 15 hydrochloride as a light-colored solid. Yield (0.183 g, 79%); 'H NMR (400 MHz, CD 3 0D) 6 7.94 (t, J= 1.6 Hz, 1H), 7.88 (dt, J= 1.2, 8.0 Hz, 1H), 7.69 (dt, J= 1.2, 7.6 Hz, I H), 7.57 (t, J= 7.6 Hz, 1H), 4.06 (s, 2H), 2.96-3.04 (m, 1H), 1,60-1.68 (m, 4H), 1.48-1.56 (m, 1 H), 1.07-1.25 (m, 5H); "C NMR (100 MHz, CD 3 0D) 8 143.3, 135.1, 129.6, 129.55, 127.3, 122.6, 84.9, 82.1, 52.8, 33.7, 29.5, 25.1, 24.8; RP-HPLC purity 99.2% (AUC); ESI-MS m/z 293.49 [M+H]*. 15 EXAMPLE 16 PREPARATION OF 3-(3-AMINOPROPYL)-N-CYCLOHEXYLBENZENESULFONAMIDE HO 0 N I '.NH 2 20 [003981 3-(3-Aminopropyl)-N-cyclohexylbenzenesulfonamide was prepared following the method used for Example 4. [00399] Step 1: Hydrogenation of Example 15 following the method used for Example 4 gave Example 16 hydrochloride as a white solid. Yield (0.0780 g, 87%); 1H NMR (400 MHz, CD 3 0D) 6 7.68-7.75 (m, 211), 7.47-7.52 (m, 2H), 2.95 (t, J= 7.6 Hz, 2H), 2.81 (t, J= 7.6 Hz, 2H), 1.94-2.03 (in, 2H), 1.60-1.68 (m, 4H), 25 1.47-1.55 (m, 2H), 1.07-1.24 (m, 5H); RP-HPLC purity 96.0% (AUC); ESI-MS m/z 297.55 [M+H]. EXAMPLE 17 PREPARATION OF (R)-3-AMINo-l-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)PROPAN-1-OL 30 OH [004001 (R)-3-amino-1-(3-(cyclohexylmethylthio)phenyl)propan-l-o was prepared following the method shown in Scheme 9. SCHEME 9 126 WO 2010/028088 PCT/US2009/055785 IOAc 0 S 8 NHCOCF 3

CH

2 C ,NHCOCF 3 8(OH-IpcC 2 BC22N (+)-pC2BCl

NHCOCF

3 THF 23 OH MeOH, H 2 0 (::: S,-(::Ly -,_NI-I 2 5 NH2 1004011 Step 1: Dess-Martin periodinane (0.861 g, 2.03 mmol) was added under argon atmosphere to a stirred solution of alcohol 8 (0.78 g, 2.08 mmol) in anhydrous CH2C. The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was purified by flash chromatography (10% to 40% EtOAc - hexanes gradient) to give ketone 22 as a colorless oil. Yield (0.306 10 g, 39%); 'H NMR (400 MHz, CDC1 3 ) 8 7.85 (t, J= 1.8 Hz, 1H), 7.68 (dt, J= 1.2, 7.8 Hz, IH), 7.51 (ddd, J = 1.2, 2.0, 7.8 Hz, LH), 7.37 (t, J= 7.8 Hz, 1H), 7.09 (br.s, 1H), 3.78 (q, J= 5.9 Hz, 2H), 3.26 (t, J 5.7 Hz, 2H), 2.85 (d, J= 6.9 Hz, 2H), 1.85-1.93 (m, 2H), 1.69-1.76 (in, 2H), 1.61-1.69 (m, LH), 1.49-1.61 (m, 1H), 1.09-1.29 (m, 3H), 0.96-1.09 (m, 2H). [00402) Step 2: Preparation of (+)-diisopinocampheylchloroborane solution ((+)-Ipc 2 BCl). To an ice-cold solution 15 of (-)-a-pinene (7.42 g, 54.56 mmol) in hexanes (5 mL) under argon was added chloroborane-methyl sulfide complex (2.55 ml, 24.46 mmol) over 1.5 min. The mixture was stirred for 2.5 min, allowed to warm to room temperature and then heated at 30 *C for 2.5 h. The resulting solution was approximately 1.6 M. 1004031 A solution of (+)-Ipc 2 BC (1.6 M, 2.2 ml, 3.52 mmol) was added under argon to a solution of ketone 22 20 (0.300 g, 0.803 mmol) in anhydrous THF and the reaction mixture was stirred at room temperature for 3 days. The mixture was partitioned between saturated NaH CO 3 and THF, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% to 50% EtOAc - hexanes gradient) to give (R)-alcohol 23 as a colorless oil. Yield (0.039 g, 13%); 'H NMR 25 (400 MHz, CDCbs) 8 7.35 (br.s, 1H), 7,23-7.28 (in, 2H), 7.21 (dt, J= 1.4, 7.8 Hz, 1H), 7.07-7.11 (m, IH), 4.83 (dd, J= 4.1, 8.4 Hz, 1 H), 3.62-3.71 (m, IH), 3.35-3.44 (n, 1H), 2.82 (d, J= 6.5 Hz, 2H), 2.33 (br.s, 1 H), 1.84-2.20 (m, 4H), 1.60-1.76 (m, 3H), 1.48-1.60 (m, 1H), 1.08-1.28 (in, 3H), 0.96-1.08 (m, 2H). [00404] Step 3: Deprotection of trifluoroacetamide 23 following the method used in Example 9 followed by purification by flash chromatography (10% to 100% of 10% 7N NH 3 /MeOH/CH 2

C

2 - CH 2

C

2 gradient), 30 gave Example 17 as a colorless oil. Yield (0.029 g, 98%); SH NMR (400 MHz, CD 3 0D) 6 7.32 (t, J= 1.6 Hz, 1H), 7.23 (t, J= 7.6 Hz, 1H), 7.18 (dt, J= 1.6, 7.8 Hz, 1H), 7.12 (dt, J 1.6, 7.2 Hz, 1 H), 4.68 (dd, J= 5.3, 8.0 Hz, I H), 2.81 (d, J= 6.9 Hz, 2H), 2.63-2.78 (m, 2H), 1.76-1.93 (in, 4H), 1.67-1.76 (m, 2H), 1.60 1.67 (in, 1H), 1.43-1.54 (m, 1H), 1.13-1.30 (m, 3H), 0.95-1.07 (in, 2H); ' 3 C NMR (CD 3 OD, 100 MHz) 6 145.4, 137.0, 127.8, 126.5, 125.2, 122.3, 71.2, 40.9, 39.6, 37.6, 36.9, 31.9, 25.5, 25.2; RP-HPLC purity 35 91.4% (AUC); ESI-MS m/z 280.52 [M+H)*. 127 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 18 PREPARATION OF(R)-3-AMINO-1-(3-(BUTYLTHIO)PENYL)PROPAN-1-OL S ' NH 2 OH 1004051 (R)-3-Amino-1-(3-(butylthio)phenyl)propan-1-ol was prepared following the method shown in Scheme 10. 10 SCHEB 10 BrrC: t-BuOK, THF Br CN TH 24 26 OH NH2CF 3 COOEt NHCOCF PCC 8 A ,NH 2 THF Br x NCOCF CHtCb2 26 OH 27 OH Br

NHCOCF

3 (+)-lpc2BCl Br

NHCOCF

3 Br )Y THF B 28 0 29 Ohi SH

K

2 CO0 Pdzdba 3 , dppf S NHCOCF 3 MeOH:H 2 O Et 3 N, DMF 30 OH S . NH 2 OH (004061 Step 1: To a cold (-50 *C) stirred solution of potassium tert-butoxide (IM/THF, 703 mL, 703 mmol) under argon was added CH 3 CN (27.73 g, 675.6 mmol) via syringe over 5 min and the reaction mixture was stirred at -50*C for 30 min. A solution of 3-bromobenzaldehyde (24) (100 g, 540.5 mmol) in anhydrous THF was 15 added over 5 min. The reaction mixture was stirred for 30 min at -50 *C and allowed to warm to room temperature. The mixture was partitioned between THF and NH 4 CI (25%), organic layer was washed with saturated brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dried in vacuo overnight to give hydroxynitrile 25 as a pale yellow oil. Yield (117.6 g, 96%); 'H NMR (400 MHz, DMSO-d) 8 7.60 (t, J= 1.6 Hz, 1H), 7.46 (ddd,.J= 7.6, 2.0,1.2 Hz, 20 1H), 7.40 (dd, J= 7.6, 2.0 Hz, 111), 7.31 (t, J = 7.6 Hz, 1H), 6.05 (d, J= 4.8 Hz, 1H), 2.94-2.80 (in, 2H). [00407] Step 2: To a solution of hydroxynitrile 23 (117.5 g, 519.8 mmol) in anhydrous THF under argon was slowly added borane-methylsulfide (68 mL, 675.7 mmol) over 30 min via a dropping funnel. The reaction mixture was heated under reflux for 2.5 hr and then cooled to room temperature. A solution of HCl (1.25M in EtOH) was slowly added for 30 min and the mixture was concentrated under reduced pressure, Water 25 was added and the pH of the mixture was adjusted to 12 with aqueous NaOH ( 50 /owt). The product was extracted with CH 2 Cl 2 , the extract was dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to give hydroxyamine 26 as a colorless oil. Yield (104 g, 87%); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.49 (in, 1H), 7.37 (dt, J= 7.2, 1.6 Hz, 1H), 7.23-7.31 (in, 2W), 4.66 (t, J= 6.8 Hz, IH), 2.61 (in, 2H), 1.61 (q, J= 6.8 Hz, 2H). 128 WO 2010/028088 PCT/US2009/055785 5 [00408] Step 3: To a cooled (0 *C) solution of 3-amino-1-(3-bromophenyl)propan-1-ol (24) (40 g, 173.8 mmol) in MTBE was added ethyl trifluoroacetate (28 mL, 234.7 mmol) over 7 min and the reaction mixture was stirred at room temperature for 50 min. Concentration under reduced pressure gave trifluoroacetamide 27 as a colorless oil. Yield (55.35 g, 98%); 'H NMR (400 MHz, DMSO-d 6 ) 5 9.33 (s, 1 H), 7.51 (t, J= 2.0 Hz, 1H), 7.41 (dt, J= 7.6, 2.0 Hz, 1H), 7,25-7.32 (m, 2H), 5.46 (d, J= 6.4 Hz, 1H), 4.55-4.60 (m, 1H), 3.20 10 3.23 (m, 2H), 1.75-1.82 (m, 2H). [004091 Step 4: To a solution of aryl bromide 27 (1.055 g, 3.23 mmol) in CH 2

C

2 was added pyridinium chlorochromate (0.915 g, 4.20 mmol) and Celite (1.96 g). The reaction mixture was stirred at room temperature for I h, 50 min then a second portion of pyridinium chlorochromate (0.4936 g, 2.30 mmol) was added. Stirring was continued for 1 h, solids were removed by filtration through Celite. The filtrate was 15 concentrated under reduced pressure and the residue was purified by flash chromatography (10% to 50% EtOAc - hexanes gradient) to give ketone 28 as a white solid. Yield (0.647 g, 62%): 'H NMR (400 MHz, DMSO-d 6 ) 8 9.40 (br s, 1 H), 8.06 (t, J 2.0 Hz, LH), 7.93 (d, J= 7.6 Hz, 1H), 7.83 (ddd, J = 7.6, 2.0, 0.8 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 3.50 (t, J = 6.8 Hz, 2H), 3.30 (t, I= 6.8 Hz, 2H). [004101 Step 5: To an ice-cold solution of ketone 28 (0.647 g, 1.99 mmol) in THF under argon atmosphere was 20 added freshly prepared (+)-Ipc 2 B-Cl (2.5 mL of a 1.6 M solution in hexane, 4.0 mmol). The reaction was allowed to warm to room temperature and stirred for 2.5 h. Additional (+)-lpc 2 B-Cl solution was added (1 mL, 1.67 mmol) and the mixture was stirred for 2.5 h. The reaction mixture was partitioned between saturated aqueous NaHCO 3 and EtOAc. The combined organics were washed with brine, dried over Na 2

SO

4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% 25 EtOAc-hexanes gradient) gave (R)-N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (29) as a colorless oil. Yield (0.62 g, 95%): 1 H NMR (400 MHz, CDC1 3 ) 8 7.50 (t, J = 1.6 Hz, IH), 7.43 (dt, J = 7.2, 2.0 Hz, JH), 7.21-7.27 (m, 2H), 4.84 (dt, J= 8.8, 3.2 Hz, lH), 3.65-3.73 (m, IH), 3,36-3.43 (m, 1H), 2.47 (dd, J= 2.9, 1.0 Hz, 1H), 1.80-2.00 (m, 2H). [00411] Step 6: A solution of bromide 29 (0.333 g, 1.02 mmol) in anhydrous DMF was deoxygenated by bubbling 30 argon for 7 min. Diphenylphosphinoferrocene (0.137 g, 0.248 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.064 g, 0.070 mmol) and EtN (1 mL) were added to the reaction mixture and the mixture was deoxygenated by bubbling argon for another 2 min followed by the alternating application of vacuum and argon three times. The reaction mixture was stirred under argon for 5 min, n-butyl mercaptan (0.5 mL, 4.68 mmol) was added and the reaction was stirred under argon at +70 *C 35 for 20 hirs. The reaction mixture was concentrated under reduced pressure Purification by flash chromatography (20% to 30% EtOAc - hexanes gradient) gave thioether 30 as a colorless oil. Yield (0.102 g, 30%); 'H NMR (400 MHz, DMSO-) 8 9.32 (br.s, IH), 7.21-7.26 (n, 2H), 7.12-7.16 (m, I H), 7.08 7. 11 (m, IH), 5.34 (d, J - 4.7 Hz, 1H), 4.51-4.56 (m, 1H), 3.19-3.24 (m, 2H), 2.92 (t, J= 7.2 Hz, 2H), 1.72 1.81 (in, 2H), 1.48-1.57 (m, 2H), 1.32-1.42 (in, 2H). 0.85 (t, J= 7.2 Hz, 3H). 40 [00412] Step 7: Deprotection of trifluoroacetamide 30 following the method used in Example 9, followed by purification by flash chromatography (20% to 100% of 10% 7N NH3/MeOH/CH 2

C

2 - CHzCl 2 gradient), gave Example 18 as a light yellow oil. Yield (0.033 g, 77%); 'H NMR (400 MHz, CD 3 0D) 5 7.33 (t, J= 1.8 Hz, IH), 7.24 (t, J= 7.6 Hz, lH), 7.19 (dt, J= 1.6, 8.0 Hz, 1H), 7.14 (dt, J= 1.6, 7.2 Hz, 1H), 4.69 (dd, J= 5.3, 8.0 Hz, 1H), 2.93 (t, J= 7.2 Hz, 2H), 2.66-2.79 (m, 2H), 1.76-1.91 (m, 2H), 1,55-1.64 (m, 2H), 45 1.40-1.50 (m, 2H), 0.91 (t, J= 7.4 Hz, 3H); 1C NMR (CD30D, 100 MHz) 8 146.2, 137.2, 128.6, 127.5, 126.1, 123.1, 72.1, 41.4, 38.4, 32.7, 31.2, 21.7, 12.7; RP-HPLC purity 92.8% (AUC); ESI-MS m/z 240.14 129 WO 2010/028088 PCT/US2009/055785 5 [M+H)*. EXAMPLE 19 PREPARATION OF (R)-3-AMINo-l-(3-(BUTYLSULFONYL)PHENYL)PROPAN-1-OL ~ *..NH 2 10 0 OH 100413) (R)-3-Amino- 1-(3-(butylsulfonyl)phenyl)propan- 1-ol was prepared following the method used in Examples 3 and 9. 100414 Step 1: Oxidation of (R)-N-(3-(3-(butylthio)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (30) following the method used in Example 3 followed by purification by flash chromatography (20% to 50% 15 EtOAc - hexanes gradient) gave (R)-N-(3-(3-(butylsulfonyl)phenyl)-3-hydroxypropyl)-2,2,2 trifluoroacetamide as a colorless oil. Yield (0.070 g, 87%); 'H NMR (400 MHz, CDCl 3 ) 8 7,81 (t, J= 1.6 Hz, IH), 7.73 (dt, J= 1.2, 7.8 Hz, 1 H), 7.59-7.63 (m, 1 H), 7.53 (br. s, IH), 7.51 (t, J 7.6 Hz, lH), 4.88 (dd, J= 3.1, 9.2 Hz, lH), 3.60-3.69 (m, lH), 3.46 (br.s, IH), 3,34-3.44 (m, lH), 3.00-3.07 (in, 2H), 1.95 2.00 (in, 1H), 1.82-1.92 (m, 1H), 1,60-1.68 (in, 2H), 1.31-1.41 (m, 2H), 0.87 (t, J= 7.2 Hz, 3H). 20 100415] Step 2: Deprotection of (R)-N-(3-(3-(butylsulfonyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide following the method used in Example 9, followed by purification by flash chromatography (50% to 100% of 10% 7N NH 3 /MeOH/CH 2 Cl 2 - CH 2

C

2 gradient), gave Example 19 as a colorless oil. Yield (0.049 g, 95%); H NMR (400 MHz, CD 3 OD) 8 7.93 (t, J= 1.6 Hz, 1H), 7.79 (dt, J= 1.2, 7.8 Hz, 1H), 7.68-7.72 (in, 1H), 7.60 (t, J = 7.8 Hz, 1H), 4.86 (t, J= 6.5 Hz, IH), 3.16-3.21 (m, 2H), 2.74-2.81 (in, 2H), 1.85 (q, J= 25 6.5 Hz, 2H), 1.57-1.66 (in, 2H), 1.33-1,43 (in, 2H), 0.88 (t, J= 7.2 Hz, 3H); "C NMR (CD 3 OD, 100 MHz) 8 147.7, 139.4, 131.2, 129.3, 126.6, 125.1, 71.4, 55.3,41.4, 38.3, 24.7, 21.2, 12.6; RP-HPLC purity 95.8% (AUC); ESI-MS m/z 272.44 [M+H]*. EXAMPLE 20 30 PREPARATION OF 3-(3-(CYCLOPENTYLMETHYLTHIO)PHENYL)PROP-2-YN-1-AMINE CrS NH 2 1004161 3-(3-(Cyclopentylmethylthio)phenyl)prop-2-yn-1-amine was prepared using the following method. [004171 Step 1: A mixture of cyclopentylmethyl methanesulfonate (1.2 g, 7.3 mmol), 3-bromobenzenethiol (1) 35 (1.26 g, 6.64 mmol) and potassium carbonate (1.83 g, 13.28 mmol) in acetone was stirred at room temperature for 16 hrs. The reaction mixture was partitioned between water and ethyl acetate, The organic layer was washed with brine, dried over MgSO 4 , filtered, and the filtrate was concentrated in vacuo. Sodium borohydride (0.13 g, 3.3 mmol) was added to a solution of the residue in isopropanol, the mixture was stirred at room temperature for lh and concentrated in vacuo. The residue was dissolved in 40 dichloromethane and the solids were removed by filtration. The filtrate was concentrated in vacuo. Purification by flash chromatography (hexanes), gave (3-bromophenyl)(cyclopentylmethyl)sulfanc) as a 130 WO 2010/028088 PCT/US2009/055785 5 yellow oil. Yield (0.98 g, 54%); 'H NMR (400 MHz, CDC 3 ) 5 7.42 (t, J= 2.0 Hz, 1H), 7.24-7.24 (m, 1H), 7.19-7.26 (m, 1H), 7.11 (t, J= 8.0 Hz, 1H), 2.91 (d, J=7.6 Hz, 2H), 2.11 (sept, 7.6 Hz, 1H), 1.80-1,90 (m, 2H), 1.58-1.70 (m, 2H), 1.50-1.58 (m, 2H), 1.22-1.34 (n, 2H). 100418] Step 2: Sonogashira coupling of (3-bromophenyl)(cyclopentylmethyl)sulfane) with 2,2,2-trifluoro-N-(prop. 2-ynyl)acctamide following the method used in Example 1, followed by purifaction by flash 10 chromatography (5% to 20% EtOAc-hexanes gradient) gave N-(3-(3-(cyclopentylmethylthio)phenyl)prop 2-ynyl)-2,2,2-trifluoroacetamide as a red solid. Yield (0.63 g, 51%); 'H NMR (400 MHz, CDC 3 ) 5 7.34 7.37 (in, 1K), 7.26-7.30 (in, 1H), 7.18-7.22 (m, 2H), 6.49 (brs, lIH), 4.37 (d, J= 5.2 Hz, 2H), 2.91 (d, J= 7.2 Hz, 2H), 2.10 (sept, 1H), 1.80-1.90 (m, 2H), 1.58-1.68 (m, 2H), 1.48-1.58 (m, 2H), 1.22-1.34 (in, 2H). [00419] Step 3: Deprotection of N-(3-(3-(cyclopentylmethylthio)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide 15 following the method used in Example 1, except the following. The reaction mixture was concentrated in vacuo, and the residue partitioned between CH 2

CI

2 and aqueous NaHCO/brine. The organic layer was dried over anhydrous MgSO 4 , filtered and the residue was concentrated under reduced pressure. Purification by flash chromatography (10% to 50% of 10% 7N NHy/MeO/CH2Cl 2

-CH

2 Cl2 gradient) gave Example 20 as a red oil. Yield (0.100 g, 89%); 'H NMR (400 MHz, CDCI 3 ) 8 7.33-7.35 (in, 1H), 7.19-7.26 20 (in, 1H), 7.16-7.19 (in, 2H), 3.64 (s, 2H), 2.90 (d, J= 7.2Hz, 2H), 2.09 (sept, J= 7.2 Hz, lH), 1.78-1.88 (in, 2H), 1.48-1.68 (in, 6H), 1.22-1.32 (in, 2H); RP-HPLC purity 94.7% (AUC); ESI-MS m/z 246,45 [M+H]*. EXAMPLE 21 25 PREPARATION OF 3-(3-(CYCLOHEPTYLMETHYLTHIO)PHENYL)PROP-2-YN-1-AMINE S K NH 2 [00420] 3-(3-(Cycloheptylmethylthio)phenyl)prop-2-yn-1-amine was prepared following the method used in Example 20. [004211 Step 1: Alkylation of thiol 1 with cycloheptylmethyl methanesulfonate following the method used in 30 Example 20 gave (3-bromophenyl)(cycloheptylmethyl)sulfane as a colorless oil. Yield (2.5 g, 80%); 'H NMR (400 MHz, CDCl 3 ) 57.41 (t, J= 1.6 Hz, 1fH), 7.23-7.27 (m, 1H), 7.18-7.21 (in, 1H), 7.11 (t, J= 8.0 Hz, 1H), 2.81 (d, J= 7.2 Hz, 2H), 1.82-1.90 (in, 2H), 1.60-1.78 (m, 3H), 1.36-1.60 (in, 6H), 1.24-1.36 (m, 2H). [00422] Step 2: Sonogashira coupling of (3-bromophenyl)(cycloheptylmethyl)sulfane with 2,2,2-trifluoro-N-(prop 35 2-ynyl)acetamide following the method used in Example 20 gave, after flash chromatography purification (5% to 20% EtOAc-hexancs gradient) N-(3-(3-(cycloheptylmethylthio)phenyl)prop-2-ynyl)-2,2,2 trifluoroacetamide as a red solid. Yield (0.86 g, 47%); 'H NMR (400 MHz, CDCl 3 ) & 7.33-7.50 (m, IH), 7.24-7.28 (m, I H), 7.18-7.21 (m, 2H), 6.51 (s, 1H), 4.38 (d, J= 5.2 Hz, 2H), 2.82 (d, 6.8 Hz, 2H), 1.82 1.90 (m, 2H), 1.60-1.78 (m, 3H), 1.36-1.60 (in, 6H), 1.22-1.36 (m, 2H). 40 [004231 Step 3: Deprotection of N-(3-(3-(cycloheptylmethylthio)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide following the method used in Example 2D followed by purification by flash chromatography (0% to 50/o of 10% 7N NH 3 /MeOH/CH 2 Cl 2

-CH

2 Cl 2 gradient) gave Example 21 as a red solid. Yield (0.075 g, 67%); 'H NMR (400 MHz, CDC1 3 ) 8 7.31-7.34 (in, 1H), 7.17-7.24 (m, 3H), 3.63 (s, 2H), 2.81 (d, J= 6.8 Hz, 2H), 131 WO 2010/028088 PCTIUS2009/055785 5 1.81-1.90 (m, 2H), 1.58-1.78 (m, 3H), 1.35-1.58 (m, 8H), 1.24-1.35 (m, 2H); RP-HPLC purity 92.7% (AUC); ESI-MS m/z 274.54 [M+H]*. EXAMPLE 22 10 PREPARATION OF 3-(3-(2-PROPYLPENTYLTHIO)PHENYL)PROP-2-YN- 1-AMINE S NH 2 [00424] 3-(3-(2-Propylpentylthio)phenyl)prop-2-yn-1-amine was prepared following the method used in Example 20. 1004251 Step 1: Alkylation of thiol I with 2-propylpentyl methanesulfonate following the method used in Example 15 20 gave (3-bromophenyl)(2-propylpentyl)sulfane as a colorless oil. Yield (2.5 g, 80%); 'H NMR (400 MHz, CDCI) 8 7.42 (t, J= 1.6 Hz, 1H), 7.23-7.27 (m, 1H), 7.18-7.21 (m, lH), 7.10 (t, J= 8.0 Hz, IH), 2.88 (d, J= 6.4 Hz, 2H), 1.60-1.70 (m, IH), 1.24-1.46 (m, RH), 0.89 (t, J = 7.2 Hz, 6H). (004261 Step 2: Sonogashira coupling of (3-bromophonyl)(2-propylpentyl)sulfane with 2,2,2-trifluoro-N-(prop-2 ynyl)acetamide following the method used in Example 20, followed by purification by flash 20 chromatography (5% to 20% EtOAc-hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-(2 propylpentylthio)phenyl)prop-2-ynyl)acetanide as a red oil. Yield (0.84 g, 53%); 'H NMR (400 MHz,

CDCI

3 ) 8 7.34-7.36 (m, 1H), 7.26-7.30 (m, 1H), 7.18-7.21 (m, 2H), 6.49 (s, 1 H), 4.37 (d, J = 5.2 Hz, 2H), 2.89 (d, 6.4 Hz, 2H), 1.60-1.70 (m, 1H), 1,22-1.46 (in, 8H), 0.88 (t, J= 7.2 Hz, 6H). [004271 Step 3: Deprotection of 2,2,2-trifluoro-N-(3-(3-(2-propylpentylthio)pheny)prop-2-ynyl)acetamide 25 following the method used in Example 20, followed by purification by flash chromatography (0% to 50% of 10% 7N NH 3 /MeOH/CH 2

C

2

-CH

2 Cl 2 gradient) gave Example 22 as a red solid. Yield (0.093 g, 78%); ' H NMR (400 MHz, CDC 3 ) 8 7.32-7.34 (in, 1H), 7.18-7.24 (m, 1H), 7.15-7.18 (mi, 2H), 3.63 (s, 2H), 2.87 (d, J= 6.0 Hz, 2H), 1.59-1.70 (n, LH), 1.47 (brs, 2H), 1,26-1.43 (m, 8H), 0.87 (t, J= 7.2 Hz, 6H); RP-HPLC purity 96.4% (AUC); ESI-MS m/z 276.53 [M+H]*. 30 EXAMPLE 23 PREPARATION OF 3-(3-(BENZYLTHIo)PHENYL)PRoP-2-YN-1 -AMINE S NH 2 35 1004281 3-(3-(Benzylthio)phenyl)prop-2-yn-1-amine was prepared following the method used in Example 20. [004291 Step 1: Alkylation of thiol 1 with benzyl bromide following the method used in Example 20 gave benzy(3 bromophenyl)sulfane as a yellow oil, Yield (2.85 g, 95%); 'H NMR (400 MHz, CDCla) 6 7.44 (t, J= 2.0 Hz, 1 ), 7.24-7.33 (m, 6H), 7.18-7.20 (m, 1 H), 7.10 (t, J= 7.6 Hz, I H), 4.11 (s, 2H). [004301 Step 2: Sonogashira coupling of benzyl(3-bromophenyl)sulfane with 2,2,2-trifluoro-N-(prop-2 40 ynyl)acetainde following the method used in Example 20, followed by purification by flash chromatography (5% to 20% EtOAc-hexanes gradient) gave N-(3-(3-(benzylthio)phenyl)prop-2-ynyl) 132 WO 2010/028088 PCT/US2009/055785 5 2,2,2-trifluoroacetamide as a yellow solid. Yield (0.56 g, 45%); H NMR (400 MHz, CDCl 3 ) 8 7.36-7.38 (m, 1H), 7,16-7.30 (m, 8H), 6.64 (brs, IH), 4.36 (d, J= 5.6 Hz, 2H), 4.11 (s, 2H). [00431] Step 3: Deprotection of N-(3-(3-(benzylthio)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetainde following the method used in Example 20, followed by purification by flash chromatography flash chromatography (0% to 50% of 10/6 7N NH 3 /MeOH/CH 2

CI

2 -CHzC 2 gradient) gave Example 23 as a red solid. Yield (0.117 g, 10 quant.); 1 H NMR (400 MHz, CDCI,) 8 7.36-7.38 (m, 1 H), 7.26-7.30 (m, 4H), 7.13-7.26 (m, 4H), 4.10 (s, 2H), 3.62 (s, 2H), 1.42 (br.s, 2H); RP-HPLC purity 93.1% (AUC); BSI-MS m/z 254.51 [M+H]*. EXAMPLE 24 15 PREPARATION OF 3-(3-(2-EmHYLBUTYLSULFONYL)PHENYL)PROP-2-YN-1-AMINEL

SNH

2 0 [00432] 3-(3-(2-Ethylbutylsulfonyl)phenyl)prop-2-yn.l-amine was prepared following the method used in Examples 6 and 19. [00433] Step 1: Oxidation of N-(3-(3-(2-ethylbutylthio)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide following the 20 method used in Example 3 followed by purification by flash chromatography (20% to 50% EtOAc hexanes gradient) gave N-(3-(3-(2-ethylbutylsulfonyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide as a colorless oil Yield (0.202 g 77%); 'H NMR (400 MHz, CDC 3 ) 8 7.92 (t, J= 1.6 Hz, 1H), 7.80 (dt, J= 1.6, 8.0 Hz, 1H), 7.62 (dt, J= 1.6, 7.6 Hz, 1H), 7.47 (t, J= 8.0 Hz, 1 H), 3.65 (brs, 2H), 2.97 (d, J = 5.2 Hz, 2H), 2.96- 3.02 (m, 1H), 1.38 - 1.54 (m, 4H), 0.79 (t, J- 7.6 Hz, 6H). 25 [004341 Step 2: Deprotection of N-(3-(3-(2-ethylbutylsulfonyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide following the method used in Example 20 followed by purification by flash chromatography (0% to 100% of 101% 7N NH3/MeOH/CH 2 Clz - CH 2 C1 2 gradient) gave Example 25 as a red solid. Yield (0.055 g, 35%); H NMR (400 MHz, CDC 3 ) 8 7.94 (t, J= 1.6 Hz, 1 H), 7.81 (dt, J= 1.6, 7.6 Hz, IH), 7.63 (dt, J= 1.6, 7.6 Hz, 1H), 7.48 (t, J= 8.0 Hz, 1 H), 3,66 (brs, 2H), 2.98 (d, J= 6,0 Hz, 2H), 1.89 (sept, 6.0 Hz, 1H), 1.52 30 (brs, 2H), 1.40 - 1.48 (m, 4H), 0.80 (t, J= 7.2 Hz, 6H); RP-HPLC purity 96.8% (AUC); ESI-MS m/z 280.50 [M+H]*. EXAMPLE 25 35 PREPARATION OF (E)-3-((3-(3-AMINOPROP-l-ENYL)PHENYLTHlO)METHYL)PENTAN-3-OL OH O

NH

2 [00435] (E)-3-((3-(3-Aminoprop-l-enyl)phenylthio)methyl)pentan-3-o was prepared following the method shown in Scheme 11. SCHEME 11 133 WO 2010/028088 PCT/US2009/055785 H BrNHCOCF, O _OH 12 K2CO3, acetone 32 Pd(OAc) 2 , P(0-t1) 3 31 Et 3 N, DMF OH NHCOCF KCO . OH NH 2 5 MeOH, H 2 O 5 33 100436 Step 1: Reaction of 2,2-diethyloxirane (31) with 3-bromobenzenethiol (1) following method described in Example 1 gave 3-((3-bromophenylthio)methyl)pentan-3-ol (32) as light yellow oil. Yield (1.2 g, 78%); 'H NMR (400 MHz, CDCI 3 ) 8 7.52 (t, J= 2.0 Hz, 1H), 7.27-7.32 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 3.08 (s, 2H), 1.55-1.62 (m, 4H), 0.88 (t, J= 7.6 Hz, 6H). 10 1004371 Step 2: A mixture of bromide 32 (0.25 g, 0.76 nunol), N-allyl-2,2,2-trifluoroacetamide (12) (0.15 g, 1.0 mmol), tri-(o-tolyl)phosphine (0.0631 g, 0.207 mmol), Pd(OAc) 2 (0.025 g, 0.1 mmol), Et 3 N (1 mL, 7 mmol) and anhydrous DMF was degassed by bubbling with argon and then heated at 85 *C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. EtOAc was added to the residue and the resulting precipitate was filtered off. The filtrate was concentrated under reduced 15 pressure. Purification by flash chromatography (30 to 50% EtOAc - hexanes gradient) gave (E)-N-(3-(3-(2 ethyl-2-hydroxybutylthio)phenyl)allyl)-2,2,2-trifluoroacetamide (33) as a yellow oil. Yield (0.25 g, 91%): 'H NMR (400 MHz, DMSO-d) 8 9.69 (t, J= 5.6 Hz, 1H), 7.36 (s, 1H), 7.18-7.26 (in, 3H), 6.48 (d, J= 16 Hz, 1H), 6.25 (dt, J= 16, 6.0 Hz, 1H), 4.35 (s, 1H), 3.95 (t, J=5.6 Hz, 2H), 2.98 (s, 2H), 1.24-1.48 (in, 4H), 0.77 (t, J 7.6 Hz, 6H). 20 [004381 Step 3: To a solution of trifluoroacetamide 33 (0.24 g, 0.66 mmol) in MeOH was added K 2 C0 3 (1.0 g, 7.0 mmol). Water was added until all material dissolved. The mixture was stirred under argon at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was partitioned between MTBE and brine. The combined organic layers were washed with brine, dried over Na 2

SQ

4 , and concentrated under reduced pressure to give Example 25 as a light yellow oil. Yield (0.160 g, 91%); 'H 25 NMR (400 MHz, CD 3 OD) 8 7.41 (s, I H), 7.20-7.24 (in, 3H), 6.49 (d, J = 15,6 Hz, 1H), 6.34 (dt, J = 16, 6.0 Hz, 1H), 5.48 (s, 1H), 3.39 (d, J= 5,2 Hz, 2H), 3.05 (s, 2H), 1.56-1,62 (in, 4H), 0.86 (t, J= 7.6 Hz, 6H). EXAMPLE 26 30 PREPARATION OF 3-((3-(3-AMTNOPROPYL)PENYLTHIO)METHYL)PENTAN-3-OL OH OH NH 2 [004391 3-((3-(3-Aminopropyl)phenylthio)methyl)pcntan-3-oI was prepared following the method desribed in Example 4. [00440] Hydrogenation of Example 25 following the method desribed in Example 4 gave Example 26 as a light 35 yellow oil. Yield (0.12 g, 60%); 'H NMR (400 MHz, CD 3 OD) 8 7.15-7,23 (in, 3H), 7.00-7.02 (in, 1H), 3.03 (s, 2H), 2.64 (t, J - 7.2 Hz, 2H ), 2.61 (t, J= 8.0 Hz, 2H ), 1.72-1.80 (in, 2H), 1,55-1.61 (in, 4H), 0.85 134 WO 2010/028088 PCT/US2009/055785 5 (t, J= 7.6 Hz, 6H). EXAMPLE 27 PREPARATION OF 1-((3-(3-AM1NO-1-HYDROXYPROPYL)PlHENYLTHIO)METHYL)CYCLOHEXANOL OH S NH 10 NH 2 10 OH 1004411 1-((3-(3-Amino-1-hydroxypropy)phenylthio)methyl)cyclohexanol was prepared following the method shown in Scheme 12. SCHEME 12 O HS Br OH SN 1. n-BuLl, THF SI r 2. DMF, THF K2CO3, acetone - 34 OH I OH

CH

3 CN, t-BuOK c H N THF 3S OH

BH

3 THF OH I NH 2 THF Cr OH i5 [00442] Step 1: Reaction of 1-oxaspiro[2.5]octane with 3-bromobenzenethiol (1) following method in Example 25 gave 1-((3-bromophenylthio)methyl)cyclohexano as light yellow oil. Yield (1.2 g, 45%); 'H NMR (400 MHz, CDOD) 8 7.53 (t, J- 2.0 Hz, 1H), 7.27-7.33 (n 2H), 7.12 (t, J- 7.6 Hz, I H), 3.01 (s, 2H), 1.39 1.58 (m, 9H), 1.20-1.28 (m, 111). 20 [004431 Step 2: Formylation of aryl bromide 34 following the method described in Example 8 gave benzaldehyde 35 as a light yellow oil. Yield (0.32 g, 32%); 'H NMR (400 MHz, CD 3 OD) 8 9.97 (s, I H), 7.88 (t, J= 1.2 Hz, 1H), 7.64-7.67 (m, 2H), 7.43 (t, J= 7.6 Hz, 1H), 3.15 (s, 2H), 1.40-1.71 (m, 9H), 1.20-1.31 (m, 1H). [00444] Step 3: Reaction of aldehyde 35 with CH 3 CN following the method described in Example 8 gave hydroxynitrile 36 as a light yellow oil. Yield (0.26 g, 56%); 'H NMR (400 MHz, CD 3 0D) 6 7.37-7.45 (m, 25 2H), 7.29 (t, J= 7.6 Hz, IH), 7.17-7.19 (m, I H), 5.00 (t, J= 6.4 Hz, 1H), 3.11 (s, 2H), 2.74 (d, J= 6.4 Hz, 2H), 1.40-1.70 (m, 9H), 1.18-1.30 (m, IH). [004451 Step 4: Reduction of hydroxynitrile 36 following the method described in Example 8 gave Example 27 free amine as a colorless oil. H C gas was bubbled into the solution of Example 27 in MTBE. The mixture was concentrated under reduced pressure and dried in vacuum to give Example 27 hydrochloride as a colorless 30 oil. Yield (0.26 g, 88%); 1 H NMR (400 MHz, CD 3 OD) 6 7.41 (t, J= 2.0 Hz, I H), 7.24-7.31 (m, 2H), 7.15 7.17 (m, 1H), 4.80 (dd, J= 8.4, 4.8 Hz, 1 H), 2.98-3.12 (m, 4H), 1.90-2.04 (m, 2H), 1.40-1.70 (m, 9H), 1.20-1.30 (m, 1H). EXAMPLE 28 135 WO 2010/028088 PCT/US2009/055785 5 PREPARATION OF 3-AMINo-1-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)PROPAN-1 -ONE S

NH

2 100446] 3-Amino-1-(3-(cyclohexylmethylthio)phenyl)propan-1-one was prepared following the method shown in Scheme 13. 10 SCHEME 13

NH

2 Bo 2 O NHBoc THF OH 37 AcOAc HCIIEtOH 0 NHBoc

CH

2

C

2 38 0 ROM S

NH

2 'HCI [00447] Step 1: A solution of Example 8 (1.7 g, 6.1 mmol) and Boc 2 0 (1.3 g, 6.1 mmol) in anhydrous CH 2 C1 2 was stirred at room temperature for 18 h and concentrated under reduced pressure. Purification by flash 15 chromatography (40% to 50% EtOAc - hexanes gradient) gave carbamate 37 as a colorless oil. Yield (1.8 g, 79%); 'H NMR (400 MHz, CDCl 3 ) 8 7.30 (s, 1H), 7.13-7.25 (in, 2H), 7.11 (d, J= 7.6 Hz, IH), 4.78-4.92 (m, IH), 4.69 (dd, J= 8.0, 4.8 Hz, 1H), 3.42-3.54 (in, IH), 3.12-3.18 (m, IH), 2.81 (d, J- 6.8 Hz, 2H), 1.78-1.92 (m, 511), 1.38-1.76 (m, 4H), 1.45 (s, 911), 1.13-1.28 (in, 3H), 1.04-1.16 (in, 2H). 1004481 Step 2: Dess-Martin periodinane (2.1, 4.8 mmol) was added under argon atmosphere to a stirred solution of 20 alcohol 37 (1.8 g, 4.8 mmol) in anhydrous CH 2

C

2 . The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was purified by flash chromatography (45% to 50% EtOAc - hexanes gradient) to give ketone 38 as a colorless oil, Yield (1,45 g, 81%); 'H NMR (400 MHz, CDCI 3 ) 8 7.52 (t, J= 1.2 Hz, 1H), 7.69 (dt, J= 6.4, 1.2 Hz, 1H), 746-7.49 (m, 1H), 7.35 (d, J= 7.6 Hz, IH), 5,04-5.16 (m, I H), 3.52 (q, J= 6.0 Hz, 2H), 3.17 (t, J= 6.0 Hz, 2H), 2.85 (d, J= 6.8 Hz, 2H), 25 1.75-1.90 (m, 2H), 1.50-1.76 (m, 4H), 1.42 (s, 9H), 1.12-1,28 (m, 3H), 0.96-1.06 (in, 2H). [004491 Step 3: To a solution of carbamate 38 (0.19 g, 0.51 mmol) in EtOAc was added ethanolic HCI (7.OM, 5.0 mL) and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, EtOAc was added and the mixture was sonicated. White powder was collected via filtration and dried to give Example 28 hydrochloride as a white solid. Yield (0.14 g, 86%); 30 'H NMR (400 MHz, CD 3 0D) 8 7.91 (t, J = 2.0 Hz, IH), 7.79 (dt, J= 7.6, 1.2 Hz, 1H), 7.58 (ddd, J= 7.6, 1.6,1.2 Hz, 1H), 7.44 (t, J= 8.0 Hz, IH), 3.44 (t, J= 5.6 Hz, 2H), 3,33 (t, J= 5.6 Hz, 2H), 2.88 (d, J= 6.8 Hz, 2H), 1.86-1.94 (m, 2H), 1.62-1.79 (m, 3H), 1.46-1.56 (in, 1H), 1.16-1.28 (m, 3H), 0,98-1.00 (in, 2H). EXAMPLE 29 136 WO 2010/028088 PCT/US2009/055785 5 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)BUTAN-1-AMINE S cro NH2 I' o CH- 3 1004501 3-(3-(Cyclohexylmethylsulfonyl)phenyl)butan-1-anine was prepared following the method shown in Scheme 14. 10 SCHEME 14 A NHBoc :-Bu2K THx NHBoc 0 t-uOKTHF39

H

2 , Pd/C . NHBoc (NH 4 )BMoyO7 2 4H20 EtOAc Hr 202, EOH 40 9 NHBoc HCI EtOH . NH 2 EtOAco 4-1 (004511 Step 1: To a suspension of the methyltriphonylphosponium bromide (2.4 g, 6.6 mmol) in THF was added t BuOK (IM in THF, 7.1 mmol) at room temperature. After stirring for 90 min, a solution of ketone 38 (1.25 15 g, 3.35 mmol) in anhydrous THF was added. The resulting mixture was stirred at room temperature for 18 hrs and partitioned between saturated NH 4 Cl and MTBE, Organic layer was dried over Na 2

SO

4 and concentrated under reduced pressure. Purification by flash chromatography (25 to 30% EtOAc - hexanes gradient) gave olefin 39 as a colorless oil. Yield (0.3 g, 24%); 'H NMR (400 MHz, CDOD) 6 7.34-7.35 (m, 1H), 7.16-7.26 (in, 3H), 6.44-6.54 (in, 1M), 5.31 (s, 1H), 5.10 (d, J= 1.2 H z, iH), 3.09-3,14 (m, 2H), 20 2.82 (d, J = 6.4 Hz, 2H), 2,65 (t, J = 7.2 Hz, 2H), 1.88-1.91 (m, 2H), 1.60-1.76 (m, 3H), 1.44-1,56 (in, I H), 1.40 (s, 9H), 1.16-1.36 (in, 3H), 0.96-1.10 (m, 2H). [004521 Step 2; Hydrogenation of olefin 39 following the method used in Example 4 gave tert-butyl 3-(3 (cyclohexylmethylthio)phenyl)butylcarbamate (40) as a colorless oil. Yield (0.08 g, 93%); 'H NMR (400 MHz, CD 3 OD) 6 7.18 (t, J= 7.6 Hz, 1H), 7.09-7.15 (m, 2H), 7.99 (dt, J= 7.6,1.2 Hz, IH), 2.86-2.96 (m, 25 2H), 2.79 (d, J= 6.4 Hz, 2H), 2.66-2.76 (in, 1H), 1.87-1.91 (in, 2H), 1,60-1.76 (in, 5H), 1.44-1.54 (in, iH), 1.40 (s, 9H), 1.18-1.26 (in, 6H), 0.96-1.06 (in, 2H). [004531 Step 3: Oxidation of thioether 40 following the method used in Example 3 gave sulfone 41 as a white solid. Yield (0.088 g, 100%); 'H NMR (400 MHz, CD 3 OD) 6 7.72-7.74 (m, 2H), 7.55-7.58 (m, 2H), 6.54 (bs, I H), 3.09 (d, J= 6,0 Hz, 2H), 2.86-2.96 (m, 3H), 1.76-1.88 (in, 5H), 1.56-1.70 (m, 3H), 1.40 (s, 9H), 1.02 30 1.27 (in, 6H). [004541 Step 4: Deprotection of carbamate 41 following the method used in Example 10 gave Example 29 as a white solid. Yield (0.07 g, 99%); 'H NMR (400 MHz, CD 3 QD) 8 7.78-7.80 (m, 2H), 7.58-7.64 (m, 2H), 3.09 (d, J = 6.0 Hz, 211), 2.86-3.04 (in, 2H), 2.66-2.74 (m, 1H), 1.94-2.02 (m, 2H), 1.76-1.92 (in, 3H), 137 WO 2010/028088 PCT/US2009/055785 5 1.56-1.72 (m, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.02-1.30 (m, 5H). EXAMPLE 30 PREPARATION OF 4-AMINO-2-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)BUTAN- 1-OL

NH

2 10 OH [004551 4-Amino-2-(3-(cyclohexylmethylthio)phenyl)butan-1-ol was prepared following the method shown in Scheme 15. SCHEME 15 NHBoc BH 3 THF, 11202 NHBoc NaOH,TI-F O 39 42 HCI-EtOH - NH 2 EtOAc O 15 [004561 Step 1: To a solution of tert-butyl 3-(3-(cyclohexylmethylthio)phenyl)but-3-enylcarbamate (39) (0.16 g, 0.43 mmol) in THF was added BHgTHF (1 M in THF, 1.1 ml, 1.1 nnol) at room temperature. After stirring for 18 hr, aqueous NaOH (1 M, 3.0 ml, 3.0 mmol) was added and the mixture was stirred at 60 *C for 2.5 hrs. H 2 0 2 (3 ml, 30%) was added to the reaction mixture and stirred at 60 *C for additional 2 hr. The 20 reaction mixture was extracted with MTBE (2 x 50 ml). Organic layer was dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure. Purification by flash chromatography (50 to 75% EtOAc hexanes gradient) gave alcohol 42 as a colorless oil. Yield (0.04 g, 24%); 'H NMR (400 MHz, CD 3 OD) 8 7.13-7.23 (m, 3H), 7.00-7.03 (in, IH), 6.42-6.50 (in, 1H), 3.63 (dd, J = 6.8, 2.8 Hz, 2H), 2.91 (q, J = 7.2 Hz, 2H), 2.80 (d, J = 6.4 Hz, 2H), 2.68-2.70 (m, 1H), 1.85-2.00 (m, 3H), 1.62-1.76 (m, 4H), 1.44-1.56 (m, 25 1 H), 1.39 (s, 9H), 1.14-1.26 (in, 3H), 0.95-1.06 (m, 2H), (004571 Step 2: Deprotection of carbamate 42 following the method used in Example 10 gave Example 30 hydrochloride as a white solid. Yield (0.03 g, 100%); 'H NMR (400 MHz, CD 3 0D) 8 7.17-7.27 (m, 3H), 7.02-7.06 (in, 1H), 3.61-3.72 (m, 2H), 2.70-3.82 (in, 5H), 2.10-2.20 (m, 1H), 1.74-2.00 (m, 3H), 1.60-1.76 (m, 3H), 1.44-1.56 (m, 1H), 1.14-1.30 (m, 3H), 0.98-1.06 (m, 2H). 30 EXAMPLE 31 PREPARATION OF N-(3-(3-(CYCDHEXYLMETHYLTHIO)PHENYL)-4-YDROXYBUTYL)ACETAMIDE OH NHAc OH 35 [004581 N-(3-(3-(Cyclohexylmethylthio)phonyl)-4-hydroxybutyl)acetainde was prepared as derscribed below, 138 WO 2010/028088 PCT/US2009/055785 5 (00459) A mixture of Example 27 (0.2 g, 0.61 mmol), Ac 2 O (0.4 g, 3.9 mmol) and triethylamine (0.31g, 3.1 mnmol) in CH 2

CI

2 was stirred room temperature for 18 hours and concentrated under reduced pressure. Purification by flash chromatography (50 to 60% EtOAc - hexanes gradient) gave Example 31 as a light yellow oil. Yield (0.15 g, 66%); 'H NMR (400 MHz, DMSO-ds); 8 7.62 (t, J = 5.6 Hz, 1H), 7.26 (s, IH), 7.15-7.22 (m, 3H), 7.04-7.07 (m, IH), 5.22 (d, J= 4.8 Hz, IH), 4.89 (q, J= 4.8 Hz, 1 H), 4.37 (s, 1 H), 2.98-3.08 (m, 4H), 10 1.76 (s, 3H), 1.65 (q, J 6.8 Hz, 1H), 1.30-1.56 (m, 9H), 1.06-1.18 (m, 1H). EXAMPLE 32 PREPARATION oF 3--AMINo-1-(3-(3-BROMOBENZYLTHo)PHENYL)PROPAN-1-OL Br NH2 15 1l OH (00460] 3-Amino-1-(3-(3-bromobenzylthio)phenyl)propan-l-ol was prepared following the method shown in Scheme 16. ScHEmE 16 + OH NHBoc Pd(PPhs)4 NHBoc + Br O H 02C03, toluene OH Nr HCI-EtOH r NHBotOAc TBAF, THF OH 47 0 Br NNH 2 -HCI 20 OH 1004611 Step 1: To an argon saturated mixture of carbamate 44 (0.39 g, 1.2 mmol), silane 43 (0.26 ml, 1.2 mmol) and cesium carbonate (0.6 g, 1.8 mmol) in toluene was added Pd(PPh 3

)

4 (0.03 g, 0.026 mmol). The resulting mixture was stirred under argon at +105 *C for 20 hrs, cooled to room temperature, filtered through Colite and concentrated under reduced pressure. Purification by flash chromatography (30% to 25 40% EtOAc - hexanes gradient) gave carbanate 45 as a light yellow oil. Yield (0.1 g, 16%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.38 (s, 1H), 7.11-7.27 (m, 3H), 6.70-6.76 (m, IH), 5.21 (d, J = 4.4 Hz, IH), 4.44-4.52 (m, IH), 2.88-2.98 (m, 2H), 1.58-1.68 (m, 2H), 1.34 (s, 9K), 1.12-1.22 (in, 3H), 0.94-1.02 (m, 18H). [004621 Step 2: To an argon saturated solution of carbamate 45 (0.09 g, 0.19 mmol) and 3-bromobenzyl bromide (46) (0.06 g, 0.23 mmol) in THF was added TBAF (1M in THF, 0.3 mmol). The resulting mixture was 30 stirred at room temperature for 20 hrs under argon. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was dried over Na 2 S0 4 , concentrated under reduced pressure. Purification by flash chromatography (40% to 50% EtOAc-hexanes gradient) gave thioether 47 as a light yellow oil. Yield (0.03 g, 35%); 'H NMR (400 MHz, CD 3 0D) 8 7.41 (t, J = 2.0 Hz, lH), 7,29-7.33 (m, 2H), 7.11-7.22 (m, 5H), 6.48-6.56 (m, 1 H), 4.60 (t, J - 6.4 Hz, 111), 4.09 (s, 2H), 3.04-3.14 (m, 2H), 1.78 (q, J = 6.8 Hz, 2H), 139 WO 2010/028088 PCT/US2009/055785 5 1,41 (s, 9H). [004631 Step 3: Deprotection of carbamate 47 following the method used in Example 10 gave Example 32 as a white solid. Yield (0.02 g, 86%); 'H NMR (400 MHz, CD 3 OD) 8 7.42 (t, J = 1.6 Hz, lH), 7.32-7.35 (m, 2H), 7.13-7.26 (i, 5H), 4.77 (q, J - 4.4 Hz, 1H), 4.12 (s, 2H), 2.96-3.10 (in, 2H), 1.86-2.02 (m, 2H). EXAMPLE 33 10 PREPARATION OF 3-AMINO- 1-(3-(CYCLOHEXYLMBTHYLTHIO)PHENYL)-2-METHYLPROPAN-1 -OL KW S OH NH 2 [004641 3-Amino-1-(3-(cyclohexylmethylthio)phenyl)-2-methylpropan-1-ol was prepared following the method used in Example 8. 15 [004651 Step 1: Addition of propionitrile to aldehyde 6 gave 3-(3-(cyclohexylmethylthio)phenyl)-3-hydroxy-2 methylpropanenitrile as a colorless oil. Yield (1.32 , 89%); 'H NMR (400 MHz, DMSO-d6) 8 7.04-7.34 (in, 4H), 5.98 (d, J= 4.5 Hz, 0.58), 5.96 (d, J= 4.3 Hz, 0.5H), 4.67 (t, J= 4.9 Hz, 0.5 H), 4.59 (t, J- 4.9 Hz, 0.5H), 3.08-3.16 (m, 0.5H), 3.00-3.08 (in, 0.5H), 2.83 (d, J = 6.65 Hz, 2H), 1.76-1.84 (in, 2H), 1.52 1.69 (m, 3H), 1.38-1.51 (in, IH), 1.17 (d, J= 7.2 Hz, 1.5H), 1.05-1.20 (m, 3H), 1.05 (d, J= 7.2 Hz, 1.5H), 20 0.9-1.01 (M, 2H). [00466] Step 2: Borane-dimethylsulfide reduction of 3-(3-(cyclohexylmcthylthio)phenyl)-3-hydroxy-2 methylpropanenitrite followed by flash chromatography purification (10% to 50% of 20% 7N

NH

3 /MeOH/CH 2

C

2 - CH 2

C

2 gradient) gave Example 33 as a colorless oil. Yield (0.444 g, 67%); 'H NMR (400 MHz, CD 3 OD) 8 7.26-7.32 (in, 1 H), 7.14-7.26 (in, 2H), 7.07-7.11 (m, 1H), 4.64 (d, J= 4.7 Hz, 0.5H), 25 4.37 (d, J = 8.0 Hz, 0.5H), 2.80 (d, J=6.65 Hz, 2H), 2.78-2.85 (in, 0.5H), 2.63-2.70 (in, 1H), 2.46 (dd, J= 6.65, 12.7 Hz, 0.5H), 1.58-1.84 (m, 6H), 1.40-1.54 (m, 1H), 1.10-1.27 (m, 3W), 0.94-1.06 (m, 2H), 0.84 (d, J= 6.85 Hz, 1.5H), 0.71 (d, J= 7.0 Hz, 1.5H); ESI MS m/z 294.1 [M+H]*. EXAMPLE 34 30 PREPARATION OF 3-AMINO-I -(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)-2-METHYLPROPAN- 1-01.

NH

2 S 0 OH [004671 3-Amino- I-(3-(cyclohexylmethylsulfonyl)phenyl)-2-methylpropan- I -ol was prepared following the method used in Examples 8 and 9. 35 [00468J Step 1: Oxidation of 3-(3-(cyclohexylmethylthio)phenyl)-3-hydroxy-2-methylpropanenitrile following the method used in Example 9 followed by flash chromatography purification (20% to 80% EtOAc - hexanes) gave 3-(3-(cyclohexylmethylsulfonyl)phenyl)-3-hydroxy-2-methylpropanenitrie as a colorless oil, Yield (0.52 g, 90%); ' H NMR (400 MHz, DMSO-d) 8 7.92-7.95 (n, 1H), 7.78-7.84 (m, IH), 7.70-7.78 (m, I H), 7.61-7.66 (m, 1H), 6.23 (d, J= 4.7 Hz, 0.5H), 6.22 (d, J= 4.3 Hz, 0.5H), 4.88 (t, J= 4.9 Hz, 0.5H), 4.79 (t, 40 J= 4.7 Hz, 0.5H), 3.12-1.25 (in, 3 H), 1.63-1.77 (in, 3H), 1.45-1.61 (m, 3H), 1.23 (d, J= Hz, 1.5H), 1.06 (d, 140 WO 2010/028088 PCT/US2009/055785 5 J= Hz, 1.5H), 0.91-1.20 (in, 5H). [004691 Step 2: Borane-DMS reduction of 3-(3-(cyclohexylmethylsulfonyl)phenyl)-3-hydroxy-2 methylpropanenitrile following the method used in Example 8 gave after flash chromatography purification (20% to 100% of 20% 7N NH 3 /MeOH/CH 2 Cl 2 - CH 2

C

2 gradient) gave Example 34 as a colorless oil. Yield (0.179 g, 35%); 'H NMR (400 MHz, CD 3 OD) & 7.90-7.93 (m, 111), 7.76-7.84 (m, IH), 7.66-7.70 (m, 10 1H), 7.56-7.63 (m, 1H), 4.89 (d, J= 4.0 Hz, I H), 3.10 (d, J= 5.7 Hz, 2H), 2.78 (dd, J= 6.6, 12.9 Hz, 0.5H), 2.59 (dd, J= 6.5, 12.7 Hz, 0.5H), 1.74-1.94 (m, 5H), 1.12-1.28 (m, 3H), 1.00-1.11 (m, 2H), 1.55 1.70 (m, 3H), 0.78 (d, J= 7.0 Hz, 3H); ESI MS m/z 326.1 [M+H]*. EXAMPLE 35 15 PREPARATION OF 3-AMINO-1-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)-2-METHYLPROPAN- 1-ONE S 'NH 2 0 [00470] 3-Amino-I -(3-(cyclohexylmethyltbio)phenyl)-2-methylpropan-1-one was prepared following the method described below. 20 1004711 Step 1: Reaction between Example 26 and Boc 2 0 following the method used in Example 10 gave (tert butyl 3-(3-(cyclohexylmethylthio)phenyl)-3-hydroxy-2-methylpropylarbamate) which was used in the next step without purification. Yield (0.524 g, quant.). 1004721 Step 2: Oxidation of (tert-butyl 3-(3-(cyclohexylmethylthio)phenyl)-3-hydroxy-2-methylpropylcarbamate) with Dess-Martin periodinane following the method used in Example 17 followed by flash chromatography 25 purification (5% to 30% EtOAc - hexanes gradient) gave tert-butyl 3-(3-(cyclohexylmethylthio)phenyl)-2 methyl-3-oxopropylcarbamate as a colorless oil. Yield (0.389 g, 98%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.76-8.00 (m, 1H), 7.68-7.73 (m, IH), 7.51-7.56 (m, IH), 7.43 (t, J= 7.8 Hz, 111), 6.93 (br. t, J= 5.3 Hz, IH), 3.65-3.74 (in, 11H), 3.17-3.26 (m, 1H), 2.86-2.96 (m, 3H), 1.77-1.86 (m, 2H), 1.61-1.70 (in, 2H), 1.53 1.61 (m, 1H), 1.40-1.51 (m, 1H), 1.36 (s, 9H), 1.10-1.22 (m, 3H), 1.02 (d, J= 6.9 Hz, 3H), 0.93-1.05 (m, 30 2H). [00473] Step 3: To a solution of tert-butyl 3-(3-(cyclohexylimethylthio)phenyl)-2-methyl-3-oxopropylcarbamate (0.147 g, 0.40 mmol) in anhydrous diethyl ether was added 5.5 N HCI/i-PrOH solution (2 mL). The reaction mixture was stirred at room temperature for 12 hrs and concentrated under reduced pressure. MTBE was added to the oily residue and the mixture was sonicated. The precipitate was collected by 35 filtration to give Example 35 hydrochloride as a white solid. Yield (0.060 g, 46%); 'H NMR (400 MHz,

CD

3 OD) 8 7.87-7.91 (M, 1H), 7.76-7.80 (m, 1H), 7.55-7.60 (in, IH), 7.46 (t, J= 7.8 Hz, 1H), 3.83-3.92 (m, 1H), 3.36 (dd, J= 8.4, 12.9 Hz, 1H), 3.08 (dd, J= 4.3, 12.9 Hz, IH), 2.82-2.94 (m, 2H), 1.86-1.94 (m, 2H), 1.60-1.77 (in, 3H), 1.44-1.57 (m, 1H), 1.27 (d, J= 7.2 Hz, 3H), 1.15-1.30 (m, 3H), 0.98-1.10 (in, 2H); ESI MS m/z 292.1 [M+H]*. 40 141 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 36 PREPARATION OF 3-AMINO- -(3-(CYCLOHEXYLMETHYLSULPONYL)PHENYL)-2-METHYLPROPAN-1-ONE

NH

2 [00474] 3-Amino-1-(3-(cyclohexylmethylsulfonyl)phenyl)-2-methylpropan-1-one was prepared following the 10 method used in Examples 9 and 28. [004751 Step 1: Oxidation of tert-butyl 3-(3-(cyclohexylmethylthio)phenyl)-2-methyl-3-oxopropylcarbamate following the method used in Example 9 followed by flash chromatography purification (10% to 80% EtOAc - hexanes gradient) gave tert-butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)-2-methyl-3 oxopropylcarbamate as a colorless oil. Yield (0.201 g, 78%). 15 100476] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)-2-methyl-3 oxopropylcarbamate following the method used in Example 35 gave Example 36 hydrochloride as a white solid. Yield (0.097 g, 54%); 'H NMR (400 MHz, CD 3 OD) 8 8.48 (t, J= 1.6 Hz, IH), 8.35 (dt, J= 1.2, 8.0 Hz, 1H), 8.20 (dt, J= 1.2, 8.0 Hz, 1H), 7.84 (t, J= 7.8 Hz, I H), 3.91-4.01 (m, 1H), 3.41 (dd, J= 8.4, 12.9 Hz, 1 H), 3.17 (d, J= 6.1 Hz, 2H), 3.13 (dd, J= 4.5,12.9 Hz, iH), 1.78-1.94 (m, 3H), 1,58-1,73 (m, 3H), 20 1.30 (d, J= 7.2 Hz, 3H), 1.05-1.34 (m, 5H); ESI MS m/z 324.1 [M+H]'. EXAMPLE 37 PREPARATION oF 3-AMINO- 1-(3-(CYCLOHEX-2-ENYLMETHYLTHIO)PHENYL)PROPAN- 1-OL 25 NH 2 25 OH1 (00477] 3-Amino-I.-(3-(cyclohex-2-enylmethylthio)phenyl)propan-1-ol was prepared following the methods described in Example 32. 1004781 Step 1: Alkylation of carbamate 45 with cyclohex-2-enylmethyl methanesulfonate following the method described in Example 32 gave tert-butyl 3-(3-(cyclohex-2-enylmethylthio)phenyl)-3 30 hydroxypropylcarbamate as a light yellow oil. Yield (0.04 g, 34%); 'H NMR (400 MHz, CD 3 OD) 8 7.31 7.33 (m, IH), 7.18-7.24 (m, 2H), 7.12 (d, J = 7.2 Hz, IH), 5.58-5.66 (n, 2H), 4,63 (t, J = 6.8 Hz, 1H), 3.11 (t, J = 6.4 Hz, 2H), 2.90 (d, J= 6.4 Hz, 2H), 2.16-2.28 (m, IH), 1.96-2.06 (m, 2H), 1.74-1.86(m, 5H), 1.42 (s, 9H), 0.94-1.40 (m, 1H). (00479] Step 2: Deprotection of terr-butyl 3-(3-(cyclohex-2-enylmethylthio)phenyl)-3-hydroxypropylcarbamate 35 following the method used in Example 10 gave Example 37 as a white solid. Yield (0.03 g, 90%); 'IH NMR (400 MHz, CD 3 0D) 5 7.37 (m, 1 H), 7.22-7.32 (m, 2H), 7.16-7.18 (m, 1H), 5.58-5.66 (m, 2H), 4.78-4.82 (m, 1H), 3.00-3.14 (m, 2H), 2.91 (d, J= 6.4 Hz, 2H), 2.16-2.28 (m, 1H), 1.87-2.02 (i, 4H), 1.74-1.86 (m, 2H), 1.27-1.40 (m, 2H). 40 EXAMPLE 38 142 WO 2010/028088 PCT/US2009/055785 5 PREPARATION OF 3-AMINO-1-(3-(PHENETHYLTHIo)PHENYL)PRoPAN-1-OL S NH 2 OH [004801 3-Amino-l-(3-(phenethylthio)phenyl)propan-1-o was prepared following the method described in Example 32, 100481] Step 1: Alkylation of carbamate 45 with (2-bromoethyl)benzene following the method described in 10 Example 32 gave tert-butyl 3-hydroxy-3-(3-(phenethylthio)phenyl)propylcarbamate as a light yellow oil. Yield (0.15 g, 76%); 'H NMR (400 MHz, CD30D) 8 7.35 (s, 1H), 7.14-7.29 (in, 8H), 4.64 (t, J = 6.8 Hz, 1H), 3.09-3.19 (m, 4H), 2.88 (t, J= 6.8 Hz, 2H), 1.84 (q, J= 6.8 Hz, 2H), 1.41 (s, 911). [004821 Step 2: Deprotection of tert-butyl 3-hydroxy-3-(3-(phenethylthio)phenyl)propylcarbamate following the method used in Example 10 gave Example 38 as a white solid. Yield (0.10 g, 77%); 'H NMR (400 MHz, 15 CD 3 OD) 87.39 (t,.J = 1.6Hz, 1H), 7.24-7.31 (m, 411), 7.15-7.22 (m, 4H), 4.80 (t, J =4.8 Hz, 1H), 3.18 (t, J = 8.0 Hz, 2H), 3.00-3.12 (m, 2H), 2.88 (t, J= 6.8 Hz, 21H), 1.90-2.05 (m, 2H). EXAMPLE 39 20 PREPARATION OF 4--AMINo-1-(3-(2-PROPYLPENTYLTHIO)PHENYL)BuTAN-2-OL S

NH

2 100483] 4-Amino-l-(3-(2-propylpentylthio)phenyl)butan-2-o was prepared following the methods described in Example I and Scheme 17. SCHEME 17 OMs O C HS Br K 2

CO

3 , acetone 49 n-BuU, BF 3 -OEt2 1 THF N OH Ci NaCN, DMSO S CN 61 62 BH-Me 2 S S NH 25 ThF * oj NH [004841 Step 1: Alkylation of 3-bromobenzenethiol I with 2-propylpentyl methanesulfonate 48 (5.3 g, 29.0 mmol) following the method described in Example 1 gave (3-bromophenyl)(2-propylpentyl)sulfane as a light yellow oil. Crude product was directly used in next reaction without further purification. 100485] Step 2: To a solution of (3-bromophenyl)(2-propylpentyl)sulfane (5.0 g, 28.5 mmol) in THF at -78 *C was 30 added n-BuLi (2.5 M in hexane, 10 mmol). After stirring at -78 *C for 15 min, BF3gt 2 O (1.46 ml, 10.5 mmol) was added followed by epichlorohydrin (0.82 ml, 10.5mmol). The resulting mixture was stirred at 78 "C for 1 hour, then quenched by addition of aq. N1 4 C1 (10 ml). Aqueous layer was extracted with ethyl 143 WO 2010/028088 PCT/US2009/055785 5 acetate twice. Combined organic layers were dried over Na2S0 4 and concentrated under reduced pressure. Purification by flash chromatography (50% to 65% EtOAc - hexanes gradient) gave 1-chloro-3-(3-(2 propylpentylthio)phenyl)propan-2-o (51) as a light yellow oil. Yield (0.55 g, 27%); 'H NMR (400 MHz, DMSO-d)8 7.12-7.22 (in, 3H), 7.12 (d, J = 7.6 Hz, 1H), 5.16 (d, J= 5.2 Hz, [H), 3.81-3.86 (m, 1H), 3.51 (dd, J = 10.8, 4,4 H, 1H), 3.43 (dd, J = 10.8, 5.2 Hz, 1HI), 2.87 (d, J - 6.4 Hz, 2H), 2.75 (dd, J= 13.6, 5.2 10 Hz, 1H), 2.62 (dd, J = 13.6, 7.6 Hz, 1HN), 1.20-1.38 (m, 9H), 0.78-0.86 (in, 6H). [004861 Step 3: To a solution of chloride 51 (0.20 g, 0.68 mmol) in anhydrous DMSO was added NaCN (0.05 g, 1.0 mmol). The resulting mixture was stirred at +50 * for 18 hours, partitioned between H20 and ethyl acetate. Organic layer was dried over Na 2

SO

4 and concentrated under reduced pressure to give nitrile 52 as a light yellow oil that was directly used in next reaction without further purification. Yield (0.19 & 97%). 15 004871 Step 4: Reduction of nitrile 52 following the method used in Example 8 gave Example 39 as a light yellow oil. Yield (0.12 g, 62%); 'H NMR (400 MHz, CD 3 OD) 8 7.13-7.21 (in, 3H), 7.01 (dt,J = 7.6, 1.6 Hz, 1 H), 3.81-3.88 (in, 1HN), 2.88 (d, J = 6.0 Hz, 2H), 2.68-2.80 (in, 4H), 1.27-1.56 (in, 11H), 0.85-0.91 (in, 61H). EXAMPLE 40 20 PREPARATION OF 1 -AMINO-3-(3-(2-PROPYLPENTYLTHIO)PHENYL)PROPAN-2-OL 01OH

NH

2 [004881 l-Amino-3-(3-(2-propylpentylthio)phenyl)propan-2-o was prepared following the methods described in Scheme 18. 25 SCHEME 18 NH OH S P thN NPhth 81KI, DMF 84

N

2 H -H 2 0 OH MeOH 2 1004891 Step 1: To a solution of chloride 51 (0.25 g, 0.80 mmol) in DMF was added potassium phthalimide (53) (0.3 g, 1.85 minol) and KI (0.3 g, 1.84 mmol). The resulting mixture was stirred at 100 *C for 18 hrs and concentrated under reduced pressure. The residue was partitioned between H20 and EtOAc. Organic layer 30 was dried over anhydrous Na 2

SO

4 and concentrated. Purification by flash chromatography (5% to 50% EtOAc - hexanes gradient) gave phthalimide 54 as a light yellow oil. Yield (0.16 g, 47%); 'H NMR (400 MI-, CD 3 OD) 8 7.74-7.86 (in, 4H), 7.19-7.22 (in, 1H), 7.12 (t, J- 7.2 Hz, 1H), 7,01-7.08 (m, 2H), 4.15 4.22 (m, IH), 3.74 (dd, J = 14.0, 8.0 Hz, 1 H), 3.65 (dd,J = 13.2,4.8 Hz, I H), 2.87 (d, J - 6.8 Hz, 2H), 2.77 (d, J= 6.8 Hz, 2H), 1.57-1.67 (in, 1H), 1.24-1.44 (in, 8H), 0.85-0.93 (m, 6H). 35 1004901 Step 2; A mixture of 2-(2-hydroxy-3-(3-(2-propylpentylthio)phenyl)propyl)isoindoline-1,3-dione (0.16 g, 0.38 mmol) and N 2

H

4

-H

2 0 (0.6 ml) in MeOH was stirred at 65 " for 5 brs and concentrated under reduced pressure. Water and MTBE was added to the residue and the mixture was stirred for 20 mins. The organic layer was dried over anhydrous Na 2

SO

4 and concentrated to give Example 40 as a light yellow oil. Yield 144 WO 2010/028088 PCT/US2009/055785 5 (0.11 g, 94%); 'H NMR (400 MHz, CD 3 0D) 8 7.07-7.18 (m, 3H), 6.96-6.99 (m, 1H), 3.43-3.47 (in, IH), 2.87 (d, J = 6.0 Hz, 2H), 2.63 (dd, J = 13.2, 5.2 Hz, 1H), 2.50 (t, J = 7,6 Hz, 1H), 2.31-2.45 (n, 2H), 1.54 1.62 (m, 1H), 1.20-1.38 (in, 8H), 0,78-0.88 (m, 6H). EXAMPLE 41 10 PREPARATION OF (E)-3-(3-(CYCLOHEXYLMETHYLTHIO)-5-(TRIFLUOROMETHYL)PHENYL)PROP-2-EN- 1-AMINE

CF

3 1004911 (E)-3-(3-(Cyclohexylmethylthio)-5-(trifluoromethyl)phenyl)prop-2-en-1-amine was prepared following the methods described in Scheme 19, 15 SCHEME 19

CF

3 1,-Phenanthroline CF3 + PhCOSH Cul, DIPEA 0 N ( 2 Br 5' Ph S Br 1 Br Toluene 57 K 2 C00, MaOH 55

CF

3 ,:,., NHCOCF 3

CF

3 12 S Br SNHCOCF3 8 Br Pd(OAc) 2 . P(o-tol)3 58DMF 5

CF

3

K

2

CO

3 ...- .X NH 2 MeOH-H 2 0 (r [00492] Step 1: To a solution of 1-bromo-3-iodo-5-(trifluoromethyl)benzene (55) (2.0 g, 5.7 mmol), thiobenzoic acid (56), (0.67 ml, 5.7 mmol), 1,10-phenanthroline (0.21 g, 1.08 mmol) in toluene were added DIPEA (2 ml) and Cul (0.11 g, 0.57 minol). The resulting mixture was degassed by bubbling argon for 2 min and 20 stirred at 110 *C for 24 hrs under argon. The reaction mixture was filtered through Celite and concentrated under reduced pressure. Purification by flash chromatography (5% to 15% EtOAc - hexanes gradient) gave benzothioate 57 as a light yellow oil. Yield (1.7 g, 82%); 'H NMR (400 MHz, CD 3 0D) 8 7.96-8.04 (m, 4H), 7,80-7.83 (m, 1H), 7.69 (tt, J = 6.0, 1.6 Hz, 1H), 7,53-7.58 (m, 2H). [00493] Step 2: A mixture of benzothioate 57 (1.7 g, 4.7 mmol), Cs 2

CO

3 (2.1 g, 6.1 mmol) in MeOH was degassed 25 by bubbling argon for 2 min and stirred at room temperature for 3 hrs. Cyclohexylinethyl bromide (2) (1.0 ml, 6.9 mmol) was added to the reaction mixture and stirring was continued for 18 hrs. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between H20 (60 ml) and EtOAc (60 ml). Organic layer was dried over Na 2

SO

4 and concentrated. Purification by flash chromatography (5% to 10/o EtOAc - hexanes gradient) gave thioether 58 as a light yellow oil. Yield (1.58 30 g, 95%); 'H NMR (400 MHz, CD 3 0D) 8 7.66-7.68 (in, 11H), 7.54-7.57 (m, 1 H), 7,47-7.49 (in, 1H), 2.91 (d, J = 6.8 Hz, 2H), 1.81-1.94 (in, 2H), 1.48-1.78 (m, 4H), 0,96-1.32 (in, 5H). [00494] Step 3: Coupling of aryl bromide 58 and N-allyl-2,2,2-trifluoroacetamide following the method described 145 WO 2010/028088 PCT/US2009/055785 5 in Example 25 gave (E)-trifluoroacetamide 59 as a light yellow oil. Yield (0.98 g, 51%); 'H NMR (400 MHz, DMSO-d 6 ) 8 9.70 (t, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 6.67 (dt, J = 8.8, 5.6 Hz, 1H), 6.58 (d, J = 16.4 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 2.96 (d, J = 6.8 Hz, 2H), 1.75-1.85 (m, 2H), 1.40.69 (m, 4H), 0,95-1.20 (m, 5H). [004951 Step 4: Deprotection of trifluoroacetamide 59 following the method described in Example 25 gave 10 Example 41 as a light yellow oil, Yield (0.15 g, 97%); 'H NMR (400 MHz, DMSO-d 6 ) 5 7.55 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1 H), 6.52-6.56 (m, 2H), 3.24-3.36 (m, 2H), 2.94 (d, J = 6.8 Hz, 2H), 1.40-1.84 (m, 6H), 0.94-1.22 (i, SH). EXAMPLE 42 15 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLTIO)PHENYL)-3-HYDROXYPROPANIMIDAMDE S .x NH 2 OH NH [00496] 3-(3-(Cyclohexylmethylthio)phenyl)-3-hydroxypropanimidainde was prepared following the methods described in Scheme 20. 20 SCHEME 20 1.HCEtOH NH HCI $7 OH N t.HC, EtOH 1004971 Step 1: HCI gas was bubbled into an ice cold solution of the nitrile 7 (0.65 g, 2.36 mmol) in absolute EtOH for 3 min. The mixture was allowed to warm to room temperature and stirred. The solvent was removed under reduced pressure. To the residue was added absolute EtOH with cooling in an ice bath. NH 3 gas was 25 bubbled into the solution for 5 min. The mixture was allowed to warm to room temperature and stirred for 18 hrs, then concentrated under reduced pressure. To the residue was added absolute EtOH with cooling in an ice bath. HCI gas was bubbled into the solution for 1 min and the mixture was concentrated under reduced pressure. The residue was dissolved in H 2 0 and extracted with EtOAc. The aqueous layer was evaporated to dryness and dried under high vacuum overnight to give Example 42 as a fluffy white solid. 30 Yield (0.06 g, 7.7%); 1 H NMR (400 MHz, D 2 0) 7.23-7.27 (m, 2H), 7.14 (t, J= 7,6 Hz, 2H), 4.91 (dd, J= 9.6,4.0 Hz, 1 H), 2.79 (d, J= 6.0 Hz, 2H), 2.68 (dd, J= 14.0, 4.0 Hz, I H), 2.55 (dd, J= 14.0, 10.0 Hz, 1H), 1.72-1.80 (m, 2H), 1.36-1.62 (n, 4H), 0.88-1.16 (m, 5H). EXAMPLE 43 35 PREPARATION OF 3-AMINo-1-(3-(CYCLOHEXYLMETHYLTHIO)-5-(TRIFLUOROMETHOXY)PHENYL)PROPAN-1-OL

OCF

3

NH

2 OH [00498] (3-Amino-1-(3-(cyclohexylmethylthio)-5-(trifluoromethoxy)phenyl)propan-1-o was prepared following 146 WO 2010/028088 PCT/US2009/055785 5 the methods described in Examples 8 and Examples 41. [00499j Step 1: Reaction of 1-bromo-3-iodo-5-(trifluoromethoxy)benzene with thiobenzoic acid 56 following the method described in Example 42 gave S-3-bromo-5-(trifluoromethoxy)pheny benzothioate as a light yellow oil. Yield (1.6 g, 79%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.95-7.97 (m, 2H), 7.86 (s, 1H), 7.85 (s, IH), 7.74 (tt, J - 6.0, 1.6 Hz, 1H), 7.58-7.67 (m, 3H). 10 [00500] Step 2: Reaction of S-3-bromo-5-(trifluoromethoxy)pheny benzothioate with cyclohexylmethyl bromide 2 following the method described in Example 42 gave (3-bromo-5 (trifluoromethoxy)phenyl)(cyclohexylmethyl)sulfane as a light yellow oil. Yield (1.50 g, 94%); 'H NMR (400 MHz, DMSO-d) 6 7.50 (t, J = 1.6 Hz, 1H), 7.37-7.39 (m, 1H), 7.28-7.29 (m, 1H), 2.94 (d, J = 6.4 Hz, 2H), 1.41-1.83 (m, 6H), 0.92-1,22 (m, 5H). 15 [00501] Step 3: Reaction of (3-bromo-5-(trifluoromethoxy)phenyl)(cyclohexylmethyl)sulfane with DMF following the method described in Example 8 gave 3-(cyclohexylmcthylthio)-5-(trifluoromethoxy)benzaldehyde as a light yellow oil. Yield (1.0 g, 83%); lH NMR (400 MHz, DMSO-d 6 ) 8 9.97 (s, 1H), 7.81 (t, J = 1.2 Hz, 1 H), 7.55-7.59 (m, 2H), 2.99 (d, J= 7.6 Hz, 2H), 1.78-1.85 (m, 2H), 1.46-1.69 (m, 4H), 0.96-1.20 (m, 5H). 1005021 Step 4: Reaction of 3-(cyclohexylmethylthio)-5-(trifluoromethoxy)benzadehyde with CH 3 CN following 20 the method described in Example 8 gave 3-(3-(cyclohexylmethylthio)-5-(trifluoromethoxy)phenyl)-3 hydroxypropanenitrilc as a light yellow oil. Yield (0.80 g, 70%); 'H N MR (400 MHz, CD30D) 6 7.36 (t, J = 1.2 Hz, lH), 7.12 (s, 1H), 7.09 (s, 1H), 4.97 (d, J = 6.0 Hz, IH), 2.76-2.90 (m, 4H), 1.84-1.94 (m, 2H), 1.46-1.76 (m, 4H), 1.16-1.30 (m, 3H), 0.98-1.08 (n, 2H). [00503] Step 5: Reduction of 3-(3-(cyclohexylmethylthio)-5-(trifluoromethoxy)phenyl)-3-hydroxypropanenitrile 25 following the method described in Example 8 gave Example 43 as a light yellow oil. Yield (0.74 g, 97%); 'H NMR (400 MHz, DMSO-d) 8 7.22 (s, 1H), 7.06 (s, 1H), 7.03 (s, I H), 4.67 (t, J = 5.6 Hz, IH), 2.88 (d, J = 6.4 Hz, 2H), 2.54-2.66 (m, 2H), 1.75-1.84 (m, 2H), 1.36-1.68 (m, 6H), 0.92-1.22 (m, 5H). EXAMPLE 44 30 PREPARATION OF 3-AMINO-1-(3-(CYCLOHEXYLMETHYLSULFONYL)-5-(TRIFLUOROMETHOXY)PHENYL)PROPAN-1-OL

OCF

3 9 K...-NH 2 0 1 1 0 OH [00504] 3-Amino-1-(3-(cyclohexylmethylsulfonyl)-5-(trifluoromethoxy)phenyl)propan-1-ol was prepared following the methods described in Examples 28 and Examples 29. 35 [005051 Step 1: Reaction of Example 43 with Boc 2 O following the method described in Example 28 gave tert-butyl 3-(3-(cyclohexylmethylthio)-5-(trifluoromcthoxy)phenyt)-3-hydroxypropylcarbamate as a colorless oil that was used in next reaction without further purification. [005061 Step 2: Oxidation of tert-butyl 3-(3-(cyclohexylmethylthio)-5-(trifluoromethoxy)phenyl)-3 hydroxypropylcarbamate following the method described in Example 29 gave tert-butyl 3-(3 40 (cyclohexylmethylsulfonyl)-5-(trifluoromethoxy)phenyl)-3-hydroxypropycarbamate as a light yellow oil. The crude product was dissolved in EtOAc (10 ml) and treated with HCI/EtOH (6.95 M, 5 ml) following the method described in Example 29 to give Example 44 as a light yellow solid. Yield (0.35 g, 45%); 'H 147 WO 2010/028088 PCTIUS2009/055785 5 NMR (400 MHz, DMSO-d 6 ) 6 7.80-8.00 (m, 4H), 7.76 (s, 1H), 7.69 (s, 1H), 5.94-6.06 (m, 1H), 4.89 (dd, J = 8.4, 3.6 Hz, 1H), 3.29 (d, J - 6.4 Hz, 2H), 2.80-2.88 (m, 2H), 1.68-2.00 (m, 5H), 1.50-1,62 (m, 3H), 0.98-1.20 (m, 5H). EXAMPLE 45 10 PREPARATION OF 3-AMINo-1-(3-(CYCLOHEXYLMETHYLTHIo)PHENYL)-3,3-DDEUTEROPROPAN-1-OL Cr 8 N

NH

2 [005071 3-Amino-1-(3-(cyclohexylmethylthio)phenyl)-3,3-dideuteropropan-1--ol was prepared following the method shown in Scheme 21. 15 SCHEME 21 S

LWD

4 SJ - NH 2 -a C -N Et 2 O6Hb H O QO DN [005081 Step 1: LiAID 4 (0.225 g, 5.35 mmol) was added under Ar to a cooled (0 *C) stirred solution of hydroxynitrile 7 (0.792 g, 2.88 mmol) in anhydrous ether. The reaction mixture was stirred for 1h and 20 aqueous saturated solution of Na 2

SO

4 was slowly added. The mixture was stirred until white precipitate formed, anhydrous MgSO 4 was added and the mixture was filtered, concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc -hexanes gradient) gave Example 45 as a colorless oil. Yield (0.226 g, 28%); 'H NMR (400 MHz, CD 3 OD) 6 7.32 (t, J= 1.8 Hz, 1H), 7.15-7.26 (m, 2H), 7.13 (dt, J= 1.2, 7.4 Hz, 1H), 4.69 (dd, J= 5.3,8.0 Hz, lH), 2.81 (d, J= 6.9 Hz, 2H), 1.60-1.94 (m, 25 7H), 1.42-1.57 (m, 1H), 1.10-1.29 (m, 3H), 0.95-1.07 (m, 2H); ESI MS m/z 282.1 [M+H]*. EXAMPLE 46 PREPARATION OF 3-AMINO-I-(3-(CYCLOHEXYLMETHYLTHIO)PHENYL)-3,3-DIDEUTEROPROPAN-1-OL 0 rjj N NH 2 30 OHD D [005091 3-Amino-1-(3-(cyclohexylmethylthio)phenyl)-3,3-dideuteropropan-1-ol was prepared following the method shown in Scheme 22. SCHEME22 NH2 N 4_00EE H NHCOCF 3 ODD 2. (NH 4

)

5 Mo 7 24 *4H 2 08 H"0

H

2 0 2 60 1.K2CO, MeOH:H 2 O N NH 2 . HCI 2. HCI1-PrOH, EtOAc

OH

0 D 148 WO 2010/028088 PCT/US2009/055785 5 [00510] Step 1: A mixture of Example 45 (0.169 g, 0.604 mmol), ethyl trifluoroacetate (0.1 ml, 0.838 mmol) and EtOH was stirred at room temperature for 20 min. Ammonium molybdate (0.139 g, 0,112 mmol) was added to the reaction mixture followed by H202 (30%, 0.7 mL, 6.85 mmol). The reaction mixture was stirred for lh 40 min and concentrated under reduced pressure. Purification by flash chromatography (20% 10 to 80% EtOAc - hexanes gradient) gave sulfone 60 as a colorless oil which was directly used in the next step. Yield (0.219 g, 89%); LC-MS (14.99 min). [00511] Step 2: A mixture of trifluoroacetamide 60 (0.21 g, 0.514 mmol), K 2 C0 3 (0.323 g, 2.34 mmol) and MeOH:H20 (3:1) was stirred at oom temperature for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in MTBE-MeOH and filtered. The filtrate was concentrated 15 under reduced pressure, the residue was dissolved in EIOAc and HCI/i-PrOH (5.5 M) was added. The precipitate was collected by filtration to give Example 46 hydrochloride as a white solid, Yield (0.14 g, 76%); 'H NMR (400 MHz, CD 3 OD) a 7.96 (t, J- 1.6 Hz, IH), 7.83 (dt, J= 1.2, 6.5 Hz, 1H), 7.72-7,76 (m, 1H), 7.63 (t, J= 7.6 Hz, 1H), 4.95 (dd, J= 3.9, 9.2 Hz, 1H), 3.10 (d, J= 5.9 Hz, 2H4), 1.90-2.10 (in, 214), 1.55-1.90 (m, 3H), 1.58-1.72 (m, 3H), 1.02-1.31 (in, 5H); ESI MS m/z 314.1 [M+H]f. 20 EXAMPLE 47 PREPARATION OF 3-AMINO-1-(3-(CYCLOHEXYLMnHLTHIo)PENYL)-2,2-DDEUTEROPROPAN- I -OL (j CSD

NH

2 OH 25 j00512] 3-Amino-i-(3-(cyclohexylmethylthio)phenyl)-2,2-dideuteropropan-1-o was prepared following the method shown in Example 8. [00513] Step 1: 1,1,1-Trideuteroacetonitrile addition to aldehyde 6 following the method used in Example 8 gave 3 (3-(cyclohexylmethylthio)phenyl)-2,2-dideutero-3-hydroxypropanenitrile as a colorless oil. Yield (0.5 g, 84%); 'H NMR (400 MHz, DMSO-d) 5 7.30-7.34 (m, 1H), 7.26 (t, J= 4.7 Hz, 1H), 7.15-7.20 (in, 2H), 30 5.92 (d, J= 4.5 Hz, I H), 4.84 (d, J= 4.0 Hz, 1H), 2.84 (d, J= 6.8 Hz, 2H), 1.77-1.84 (m, 21-), 1.52-1.69 (m, 3H), 1.40-1.52 (in, IH), 1.08-1.21 (in, 3H4), 0.9-1.03 (in, 2H). 1005141 Step 1: Borane reduction of 3-(3-(cyclohexylmethylthio)phenyl)-2,2-dideutero-3-hydroxypropanenitrile following the method used in Example 8 gave Example 47 as a colorless oil. Yield (0.42 g, 82%); 'H NMR (400 MHz, DMSO-d) a 7.18-7.22 (in, 2H), 7,04-7,14 (in, 2H), 4.60 (s, I H), 2.81 (d, J ' 6.8 Hz, 2H), 2.58 35 (dt, J= 12.1, 7.6 Hz, 2H), 1.76-1.85 (in, 2H), 1.51-1.68 (m, 3H), 1.37-1.50 (m, 1 H), 1.06-1.20 (in, 3H), 0.9 1.04 (in, 2H). EXAMPLE 48 40 PREPARATION OF 3-AMINO-i-(3-(CYCLOHEXYLMETHYLTHIO)PENYL)-1-DEUTEROPROPAN-1-OL S OH [00515] 3-Amino-I-(3-(cyclohexylmethylthio)phenyl)-1-deuteropropan-1-ol was prepared following the method 149 WO 2010/028088 PCT/US2009/055785 5 below. 100516] Step 1: To a suspension of NaBD 4 (0.066 g, 1.16 mmol) in i-PrOH was added a solution of Example 28 hydrochloride (0.084 g, 0.266 mmol) in i-PrOH. The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was partitioned between aq. NH 4 Cl and EtOAc, aqueous layer was extracted with EtOAc. Combined organic layers were washed with NaHCO 3 , 10 brine, and concentrated under reduced pressure. Purification by flash chromatography (10% to 50% of 20% 7N NH 3 /MeOH/CH 2

CI

2 - CH 2 Cl 2 gradient) gave Example 48 as a colorless oil. Yield (0.036 g, 48%); 'IH NMR (400 MHz, CD 3 0D) 8 7.32 (t, J= 1.8 Hz, IH), 7.22 (q, J= 7.4 Hz, 1H), 7.18 (dt, J= 8.0, 1.4 Hz, IH), 7.12 (dt, J= 1.6, 7.4 Hz, 1 H), 2.81 (d, J= 6.85 Hz, 2H), 2.68-2.79 (m, 2H), 1.76-1.93 (m, 4H), 1.60 1.76 (m, 3H), 1.44-1.55 (m, I H), 1.10-1.28 (m, 3B), 0.94-1.16 (m, 2H); ES] MS m/k 281,2 [M+H] t . 15 EXAMPLE 49 PREPARATION op 3-AMINo-1-(3-(CYCLOHEXYLDDEUTEROMETHYLTHIO)PHENYL)PROPAN-l-OL DO A 8 N NH 2 20 [005171 3-Amino-1-(3-(cyclohexyldideuteromethylthio)phenyl)propan-1 -ol was prepared following the method used in Examples I and 8. [00518] Step 1: Ms-Cl (1.8 mL, 23.2 mmol) was added under argon to a cold (0 0 C) stirred solution of cyclohexyldideuteromethanol (2.52 g, 22.5 mmol) and Et 3 N (3.5 mL, 25.1 nmol) in anhydrous CH 2 C1 2 . The reaction mixture was stirred at 0 *C for 30 min and concentrated under reduced pressure. The residue 25 was suspended in MTBE, washed with NH 4 CI-brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure to give cyclohexyldideuteromethyl methanesulphonate as a white solid. Yield (4.14 g, 97%); 'H NMR (400 MHz, CDC 3 ) 8 2.98 (s, 3 H), 1.64-1.80 (m, 6H), 1.09-1.33 (m, 3H), 0.93-1.16 (m, 2H). [005191 Step 2: Alkylation of thiol 1 with cyclohexyldideuteromethyl methanesulphonate following the method 30 used in Example I gave after flash chromatography purification (0% to 20% EtOAc - hexanes gradient) (3 bromophenyl)(cyclohexyldideuteromethyl)sulfane as a colorless oil, Yield (3.28 g, 86%); 'H NMR (400 MHz, CDC 3 ) 5 741 (t, J= 1.8 Hz, 1 H), 7.25 (ddd, J= 1.2, 2.0, 7.8 Hz, 1H), 7.19 (ddd, J= 1.0, 1.8, 7.8 Hz, I H), 7.11 (t, J= 7.8 Hz, 1H), 1.84-1.90 (m, 2H), 1.61-1.76 (m, 3H), 1.48-1.56 (m, I H), 1.08-1.30 (m, 3H), 0.94-1.05 (m, 2H), 35 1005201 Step 3: Formylation of (3-bromophenyl)(cyclohexyldideuteromethyl)sulfane following the method used in Example 8 gave after flash chromatography purification (5% to 20% EtOAc - hexanes gradient) 3 (cyclohexyldideuteromethylthio)benzaldehyde as a colorless oil. Yield (1.60 g, 60%); 'H NMR (400 MHz,

CDC

3 ) 8 9.97 (s, I H), 7.76 (t, J= 1,6 Hz, 1 H), 7.62 (dt, J- 1.4, 7.4 Hz, I H), 7.51-7.54 (m, IH), 7.42 (t, J = 7.6 Hz, 1H), 1.84-1.92 (m, 2H), 1.60-1.77 (m, 3H), 1.50-1.59 (m, 1H), 1.10-1.30 (m, 3H), 0.95-1.07 (m, 40 2H). [005211 Step 4: Acetonitrile addition to 3-(cyclohexyldideuteromethylthio)benzadehyde following the method used in Example 8 gave 3-(3-(cyclohexyldideuteromethylthio)phenyl)-3-hydroxypropanenitrile as a light yellow oil. Yield (1.89 g, quant.); '1H NMR (400 MHz, DMSO-d 6 ) 8 7.32 (t, J= 1.8 Hz, 1H), 7.26 (t, J = 7.6 Hz, I H), 7.14-7.20 (m, 2H), 5.93 (d, J = 4.3 Hz, 1H), 4.84 (dd, J= 5.1, 11.0 Hz, 1 H), 2.87 (Abd, J= 150 WO 2010/028088 PCT/US2009/055785 5 5.1, 16.8 Hz, IH), 2.79 (ABd, J= 6.7, 16.8 Hz, 1H), 1.76-1.85 (m, 2H), 1.50-1.70 (m, 3H), 1.40-1.50 (m, IH), 1.30-1.21 (m, 3H), 0.90-1.15 (m, 2H). [00522J Step 5: Borane reduction of 3-(3-(cyclohexyldideuteromethylthio)phenyl)-3-hydroxypropannitrile following the method used in Example 8 gave crude Example 49. Purification by flash chromatography (20% to 100% 20% 7N NH 3 /MeOH/CH 2 Cl 2 - CH 2

C

2 gradient) gave Example 49 as a colorless oil. Yield 10 (1.18 g, 63%); 'H NMR (400 MHz, CD 3 QD) 8 7.32 (m, 1H), 7.22 (q, J= 7.6 Hz, I H), 7.16 (dt, J- 1.6, 7.8 Hz, I H), 7.10-7.15 (m, I H), 4.68 (dd, J= 5.3, 7.8 Hz, 1H), 2.67-2.77 (m, 2H), 1.60-1.92 (m, 7H), 1.43-1.54 (m, 1H), 1.10-1.28 (m, 3H), 0.95-1.06 (m, 2H); ESI MS m/z 282.2{M+H]*. EXAMPLE 50 15 PREPARATION OF 3-AMINO-I -(3-(CYCLOHEXYLD1DEUTEROMETHYLSULFONYL)PHENYL)PROPAN- I -OL dI 0 NH 2 [00523J 3-Amino-1.(3-(cyclohexyldideuteromethylsulfonyl)phenyl)propan-1..o was prepared following the method used in Example 46. 20 {00524] Step 1: Protection of Example 49 followed by oxidation to sulfone following the method used in Example 46 gave N-(3-(3-(cyclohexyldidcuteromethylsulfonyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.788 g, 70%); 'H NMR (400 MHz, DMSO-d 6 )8 9.35 (br.t, 1H), 7.85 (in, IH), 7.72-7.77 (m, 1H), 7.64-7.70 (m, 1H), 7.59 (t, J= 7.8 Hz, 1H), 5.58 (d, J= 4.7 Hz, 1H), 4.69-4.74 (m, 1 H), 3.17-3.34 (m, 2H), 1.66-1.90 (m, 5H), 1.A6-1.63 (m, 3H), 0.95-1.20 (m, 5H). 25 (00525) Step 2: Deprotection of N-(3-(3-(cyclohexyldideuteromethylsulfonyl)phenyl)-3-hydroxypropyl)-2,2,2 trifluoroacetamide following the method used in Example 46 gave Example 50 hydrochloride as a white solid. Yield (0.46 g, 95%); '1H NMR (400 MHz, CD 3 OD) 8 7.96 (t, J= 1.8 Hz, 1H), 7.81-7.85 (m, 1H), 7.71-7.75 (m, 1H), 7.63 (t, J= 7.8 Hz, IH), 4.95 (dd, J= 3.7, 9.0 Hz, 1H), 3.05-3.17 (m, 2H), 1.90-2.10 (m, 2H), 1.77-1.90 (n, 3H), 1.57-1.71 (m, 3H), 1.15-1.30 (m, 3H), 1.02-1.15 (m, 2H); ESI MS m/z 314.1 30 [M+H]f. EXAMPLE 51 PREPARATION OF 3-AMINo-1-(3-((PERDEUTEROCYCLOHEXYL)MEHYLTHIO)PHENYL)PROPAN-1 -ONE D D D

NH

2 D D 0 35 D DD [005261 3-Amino-1 -(3-((perdeuterocyclohexyl)metbylthio)phenyl)propan-1-one was prepared following the method used in Example 49. [005271 Step 1: To a solution of perdeuteracyclohexanecarboxylic acid (1.71 g, 12.3 mmol) in anhydrous DMSO was added finely powdered KOH (0.729 g, 13.0 mmol). The mixture was stirred at room temperature for 25 40 min and methyl iodide (196 g, 13.8 mmol) was added. The reaction mixture was stirred at room temperature for 20 hrs and partitioned between water and Et 2 O. Organic layer was washed with brine, 151 WO 2010/028088 PCT/US2009/055785 5 treated with activated charcoal, dried over anhydrous MgSO 4 and concentrated under reduced pressure to give methyl perdeuterocyclohexanecarboxylate as a colorless oil. Yield (1.86 g, 996); 'H NMR (400 MHz, DMSO-d) 8 3.55 (s). [005281 Step 2: DIBAL-H (1 M in heptane, 25 mL) was added under argon to a cooled (0 "C) solution of methyl perdeuterocyclohexanccarboxylate (1.86 g, 12.15 mmol) in anhydrous CH 2 C1 2 .The reaction mixture was 10 stirred under argon at 0 *C for 30 min and sodium potassium tartrate (10%, 45 mL) was added The mixture was stirred at room temperature for 20 hrs, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with NH4CI, dried over anhydrous MgSO 4 and concentrated under reduced pressure to give (perdeuterocyclohexyl)methanol as a colorless oil, Yield (1.37 g, 90%); 'H NMR (400 MHz, DMSO-d) 8 4.26 (t, J= 5.2 Hz, IH), 3.14 (d, J= 5.6 Hz, 2H). 15 1005291 Step 3: Mesylation of perdeuterocyclohexylmethanol following the method used in Example 49 gave (perdeuterocyclohexyl)methyl methanesulphonate as an off-white solid. Yield (2.02 g, 91%); 'H NMR (400 MHz, CDC 3 ) 8 4.00 (s, 2H), 2.98 (s, 3H). [00530) Step 4: Alkylation of 3-bromobenzenethiol (1) following the method used in Example 49 gave (3 bromophenyl)((perdeuterocyclohexyl)methyl)sulfane as a colorless oil. Yield (1,95 g, 82%); 'H NMR (400 20 MHz, CDCI 3 ) 8 7.41 (t, J= 1.95 Hz, 1H), 7.25 (ddd, J= 1.0, 1.8, 7.8 Hz, 1H), 7.17-7.22 (in, IH), 7.11 (t, J = 8.0 Hz, 1H), 2.80 (s, 2H). 100531] Step 5: Formylation of (3-bromophenyl)((perdeuterocyclohexyl)methyl)sulfane following the method used in Example 8 gave 3-((perdeuterocyclohexyl)methylthio)benzaldehyde as a light yellow oil, Yield (1.58 g, quant.); 'H NMR (400 MHz, CDCl,) 8 9.97 (s, 1H), 7.76 (m, 1H), 7,60-7.63 (m, 1H), 7.50-7.55 (in, lH), 25 7.42 (t, J= 7.6 Hz, 1H), 2,86 (s, 2H). [00532] Step 6: Acetonitrile addition to 3-((perdeuterocyclohexyl)methylthio)benzaldehyde following the method used in Example 8 gave 3-hydroxy-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propanenitilc as a yellow oil. Yield (1.40 g, 77%); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.32 (t, J = 1.8 Hz, 1H), 7.26 (t, J- 7.6 Hz, lH), 7.14-7.20 (m, 2H), 5.93 (d, J= 4.5 Hz, 1H), 4.84 (dd, J = 4.9, 11.2 Hz, 1H), 2.75-2,90 (n, 4H). 30 [00533] Step 7: LiAIH 4 reduction of 3-hydroxy-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propanonitrile following the method used in Example 45 gave crude 3-amino-1-(3-((perdeuterocyclohexyl)methylthio) phenyl)propan-l-ol as a colorless oil. Yield (0.76 g, 62%); 'H NMR (400 MHz, CD 3 0D) 8 7.32 (t, J= 1.8 Hz, 1 H), 7.23 (t, J= 7.6 Hz, 1H), 7.17 (dt, J= 1.6, 7.8 Hz, 1 H), 7.11-7.14 (in, 1H), 4.68 (dd, J= 5.1, 8.0 Hz, 1H), 2.80 (s, 2H), 2.65-2.77 (in, 2H), 1.75-1.91 (in, 2H). 35 [00534] Step 8: Boc 2 0 (0.69 g, 3.16 minmol) was added to a stirred solution of 3-amino-l-(3 ((perdeuterocyclohexyl)methylthio)phenyl)propan-l-o (0.76 g, 2.62 mmol) in anhydrous CH 2

CI

2 . The reaction mixture was stirred at room temperature for 20 min. Celite (2.72 g) and PCC (1.16 g, 5.38 mmol) were then added and the reaction mixture was stirred at room temperature for 14 hrs. Solvent was removed under reduced pressure; the residue was suspended in 30% EtOAc - hexanes and stirred. The mixture was 40 filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (5% to 30% EtOAc - hexanes gradient) gave tert-butyl 3-oxo-3-(3 ((perdeuterocyclohexyl)methylthio)phenyl)propylarbamate as a colorless oil. Yield (0.56 g, 55%); 'H NMR (400 MHz, CDC 3 ) 8 7.85 (t, J= 1.8 Hz, 1H), 7.67-7.71 (m, 1H), 7.47 (ddd, J= 1.2, 2.0, 7.8 Hz, IH), 7.35 (t, J= 7.6 Hz, IH), 5.08 (br.s, 1H), 3.53 (q,J= 5.5, 11.0 Hz, 2H), 3.17 (t, J- 5.9 Hz, 2H), 2.84 (s, 45 2H), 1.42 (s, 9H). [00535] Step 9: Deprotection of tert-butyl 3-oxo-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propylcarbamate 152 WO 2010/028088 PCT/US2009/055785 5 following the method used in Example 10 except that 5.5 M HCI/i-PrOH was used gave Example 51 hydrochloride as a white solid. Yield (0.43 g, 92%); 'H NMR (400 MHz, CD3OD) 8 7.90-7.92 (m, lH), 7.77-7.81 (m, 1H), 7.56-7.59 (m, 1H), 7.44 (t, J= 7.8 Hz, IH), 3.44 (t, J = 6.1 Hz, 2H), 3.33 (t, J 5.9 Hz, 2H), 2.87 (s, 2H); ESI MS m/ 289.3 [M+Hf. 10 EXAMPLE 52 PREPARATION OF 3-Amo- 1-(3-((PERDEUTEROCYCLOHEXYL)METHYLSULFONYL)PHENYL)PROPAN-1-ONE D DD NH 2 D_ DO O D D [00536] 3-Amino- 1-(3-((perdeuterocyclohexyl)methylsulfonyl)phenyl)propan- 1-one was prepared following the 15 method used in Examples 3 and 51. [005371 Step 1: Oxidation of tert-butyl 3-oxo-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propylcarbamate with ammonium molybdate and H 2 02 following the method used in Example 3 gave tert-butyl 3-oxo-3-(3 ((perfluorocyclohexyl)methylsulfonyl)pheny)propylcarbamate as a colorless oil. Yield (0.32 g, 96%); 'H NMR (400 MHz, DMSO-d 6 ) 8 8.33 (m, IH), 8.22-8.26 (m, 1H), 8.10-8.30 (m, 1H), 7.79 (t, J- 7,8 Hz, 20 1 H), 6.82 (br. t, IH), 3.18-3.32 (m, 6H), 1.33 (s, 9H). 100538] Step 2: Deprotection of tert-butyl 3-oxo-3-(3 ((perfluorocyclohexyl)methylsulfonyl)phenyl)propylcarbamate following the method used in Example 51 gave Example 52 hydrochloride as a white solid. Yield (0.172 g, 63%); 'H NMR (400 MHz, CD 3 OD) 5 8.49 (t, J= 1.8 Hz, I H), 8.33-8.37 (m, 1 H), 8.16-8.21 (m, I H), 7.82 (t, J= 7.8 Hz, 1 H), 3.53 (t, J= 6.1 Hz, 25 2H), 3.37 (t, J= 5.9 Hz, 2H), 3.16 (s, 2H); ESI MS m/z 321.3 [M+H+. EXAMPLE 53 PREPARATION OF 3-AMINo--(3-((PERDEUTEROCYCLOHEXYL)METHYLTHIO)PHENYL)PROPAN- l-OL D D

NH

2 30 DKI$IID D OH [005391 3-Amino-l-(3-((perdeuterocyclohexyl)methylthio)phenyl)propan-1-ol was prepared following the method described below. [00540 Step 1: To a solution of Example 51 hydrochloride (0.3 44 g, 1.06 mmol) in THF-MeOH (10:3) was added Et 3 N (0.4 mL) followed by Boc 2 O (0.244 g, 1.12 nmol). The reaction mixture was stirred at room 35 temperature for 20 min and concentrated under reduced pressure. The residue was suspended in EtOAc/hexanes and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-oxo 3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propylcarbamate as a colorless oil which was used in the next step without further purification. Yield (0.446 g, quant. %). [005411 Step 2: tert-Butyl 3-oxo-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propylarbamate (0.140 g, 0,361 40 mmol) was dissolved in i-PrOH and NaBH4 (0.036 g, 0.944 mmol) was added. The reaction mixture was stirred at room temperature for 18 hrs and partitioned between aq. NaH CO 3 and EtOAc. Aqueous layer was 153 WO 2010/028088 PCT/US2009/055785 5 additionally extracted with EtOAc, combined organic layers were washed with brine and concentrated under reduced pressure to give tert-butyl 3-hydroxy-3-(3 ((perdeuterocyclohexyl)methylthio)phenyl)propylcarbamate as a colorless oil. Yield (0.098 g, 70%); '1H NMR (400 MHz, CD 3 OD) 8 7.28-7.32 (m, 1 H), 7.14-7.25 (m, 2H), 7.09-7.14 (m, 1H), 6.56 (br.t, 1H), 4.62 (t, J= 6.65 Hz, IH), 3.08-3.16 (m, 2H), 2.80 (s, 2H), 1.83 (q, J= 6.9 Hz, 2H), 1.42 (s, 9H). 10 1005421 Step 3: tert-Butyl 3-hydroxy-3-(3-((perdeuterocyclohexyl)methylthio)phenyl)propylcarbamate was deprotected following the method used in Example 51 to give, after flash chromatography purification (10% to 50% of 20% 7N NH 3 /McOH/CH 2

C

2 - CH 2

C

2 gradient) Example 53 as a colorless oil. Yield (0.048 g, 59%); 'H NMR (400 MHz, CDOD) 8 7.32-7.34 (m, 1H), 7.22 (q, J= 7.63 Hz, 1H), 7.18 (dt, J= 1.4, 7.8 Hz, I H), 7.11-7.15 (m, IH), 4.70 (5.5, 7.8 Hz, 1H), 2.72-2.86 (m, 4H), 1.78-1.92 (m, 2H); ESI MS 15 m/z 291.3 [M+HJ. EXAMPLE 54 PREPARATION of 3-AMINo-1-(3-(CYCLH EXYLMETHYLSULFONYL)PHENYL)-2,2-DIDEUTEROPROPAN- 1-OL DP NH 2 20 0 OH I005431 3-Amino-I-(3-(cyclobexylmethylsulfonyl)phenyl)-2,2-dideuteropropan-1-ol was prepared following the method described below. 1005441 Step 1: Example 47 was reacted with BocO following the method shown in Example 51 to give tert-butyl 3-(3-(cyclohexylmethylthio)phenyl)-2,2-dideutero.3-hydroxypropylcarbamate as a colorless oil. Yield 25 (0.35 g, 83%); 'H NMR (400 MHz, CD 3 0D) 5 7.31 (m, iH), 7.14-7.25 (m, 2H), 7.09-7.13 (m, 11-1), 4.61 (s, 1H), 3.10 (s, 2H), 2.81 (d, J= 6.6 Hz, 2H), 1.84-1.94 (m, 2H), 1.60-1.76 (m, 3H), 1.44-1.55 (m, 1H), 1.42 (s, 9H), 1.15-1.26 (m, 3H), 0.8-1.06 (m, 2H). [00545) Step 2: tert-ButyI 3-(3-(cyclohexylmethylthio)pbenyl)-2,2-dideutero-3-hydroxypropylcarbamate was oxidized with H 2 0 2 following the method shown in Example 46 to give tert-butyl 3-(3 30 (cyclohexylmethylsulfonyl)phenyl)-2,2-dideutero-3-hydroxypropylcarbamate as a colorless oil. Yield (0.37 g, 98%); 1 H NMR (400 MHz, DMSO-ds) 8 7.83 (m, 1H), 7.70-7.75 (m, 1H), 7.60-7.67 (m, 1H), 7.58 (t, J= 7.6 Hz, IH), 6.78 (br.t, 1H), 5.44 (d, J= 3.5 Hz, 1H), 4.66 (s, 1H), 3.15 (d, J= 5.9 Hz, 2H), 2.93 (dt, J= 5.9, 12.1 Hz, 2H), 1.65-1.77 (m, 3H), 1.46-1.62 (in, 3H), 1.35 (s, 9H), 0.95-1.20 (m, 5H). [005461 Step 3: tert-Butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)-2,2-dideutero-3-hydroxypropylcarbamate was 35 deprotected following the method shown in Example 51 to give Example 54 as a colorless oil. Yield (0.14 g, 91%); 1 H NMR (400 MHz, DMSO-dk) 8 7.75-7.90 (m, 511), 7.58-7.70 (m, 2H), 5.78 (br.d, J= 3.7 Hz, I H), 4.81 (br.s, 1H), 3.16 (d, J- 6.12 Hz, 2H), 2.80-2.86 (n, 2H), 1.65-1.80 (m, 3H), 1.49-1.63 (m, 3H), 0.95-1.20 (m, 5H). 40 EXAMPLE 55 PREPARATION OF 3-(3-AMINOPRoPYL)-5-(CYCLOH EXYLMETHYLSULFONYL)PHENOL 154 WO 2010/028088 PCT/US2009/055785 OH cr J6

NH

2 5 [00547j 3-(3-Aminopropyl)-5-(cyclohexylmethylsulfonyl)pheno was prepared following the method shown in Scheme 23. SCHEME 23 OH 08nBrCa H Br______ _ n PhCOSH 66 O~n Gr K 2 00 3 ,NMP I Br Cul, 1,10-phenentroline 61 82 DIPEA, toluene PhCOS Br 63 Br 2 OBn OBn n-BuLl Cs 2 00 3 , MeOH s 4Br DMF, THF <"66 K> S 64 K' 66 OBn t-BuOK, CH 3 CN 1. BH 3 'Me 2 S, THF THF r" OH N 2. HCI/MeOH OBn CBn 1. Boc 2 C, EtOH NHBoc 67 OH (NH4)eMoAO2 4 4H 2 0 68 OH OH

H

2 , Pd(OH) 2 HCIi-PrOH N NHBoc NH2 - HCI EtCH EtOAC 10 69 [005481 Step 1: Alkylation of phenol 61 with bromide 2 following the method used in Example I gave benzyl ether 62 as a colorless oil. Yield (2.14 g, 99%); 'H NMR (400 MHz, CDCI 3 ) 8 7.45 (t, J- 1.4 Hz, IH), 7.31-7.41 (m, 5H), 7.26 (dd, J= 1.4, 2.2 Hz, I H), 7.09 (t, J= 2.0 Hz, lH), 5.00 (s, 2H). [005491 Step 2: Reaction between iodide 62 and thiobenzoic acid 56 following the method used in Example 41 15 gave thiobenzoate 63 as a light yellow oil. Yield (1.89 g, 87%); '1H NMR (400 MHz, CDC 3 )8 7.97-8.02 (m, 2H), 7.59-7.64 (m, 1H), 7.47-7.51 (m, 2H), 7.30-7.44 (m, 5H), 7.28 (t, J= 1.6 Hz, IH), 7.21 (t J= 2.0 Hz, 1H), 7.09-7.12 (m, 1H), 5.06 (s, 2H). [005501 Step 3: Reaction between thiobenzoate 63 and bromide 2 following the method used in Example 41 except that Cs 2 C0 3 was used instead of K 2 C0 3 gave thioether 64 as a light yellow oil. Yield (1.50 g, 84.5%); 'H 20 NMR (400 MHz, CDCI,) 8 7.30-7.45 (m, 5H), 6.99 (m, 1H), 6.89 (m, 1H), 6.80 (m, 1H), 5.01 (s, 2H), 2.77 (d,JJ- 6.85 Hz, 2H), 1.80-1.90 (m, 2H), 1.60-1.76 (m, 3H), 1.46-1.58 (m, 1H), 1.08-1.30 (m, 3H), 0.90 1.04 (m, 2H). 1005511 Step 4; Formylation of aryl bromide 64 following the method used in Example 8 gave aldehyde 65 as a 155 WO 2010/028088 PCT/US2009/055785 5 colorless oil. Yield (0.513 g, 40%); 'H NMR (400 MHz, CDC1 3 ) 6 9.90 (s, 11), 7.30-7.45 (m, 6H), 7.21 7.23 (m, 1H), 7.13 (t, J- 2.15 Hz, 1H), 5.10 (s, 2H), 2.83 (d, J= 6.85 Hz, 2H), 1.84-1.92 (m, 2H), 1.61 1.78 (m, 3H), 1.46-1.60 (m, 1H), 1.11-1.28 (m, 3H), 0.94-1.06 (m, 2H). [005521 Step 5: Acetonitrile addition to aldehyde 65 following the method used in Example 8 gave hydroxynitrile 66 as a colorless oil, Yield (0.426 g, 76%); 'H NMR (400 MHz, DMSO-d) 8 7.33-7.45 (m, 411), 7.27-7.33 10 (in, 1H), 6.85-6.92 (m, 1H), 6.82-6.85 (m, 1H), 6.76-6.80 (m, 1H), 5.93 (d, J= Hz, IH), 5.07 (s, 2H), 4.80 (dd, J= Hz, 1H), 2.74-2.89 (m, 4H), 1.73-1.82 (m, 2H), 1.50-1.68 (M, 3H), 1.36-1.50 (m, 1H), 1.028-1.20 (m, 3H), 0.89-1.00 (in, 2H). [00553] Step 6; A solution of hydroxynitrile 66 (0.425 g, 1.16 mmol) and borane-dimethylsulfide (0.5 mL, 5.27 mmol) in anhydrous THF was boiled under reflux for 18 hrs. The reaction mixture was cooled to room 15 temperature, and MeOH was carefully added until no gas formation was observed. Then HCI/MeOH (1.25 M) was added to the mixture and it was boiled under reflux for 2 hrs and concentrated under reduced pressure to give amine 67 hydrochloride as a light yellow oil which was used in the next step without additional purification. Yield (0.555g, quant.). [00554] Step 7: To a solution of amine 67HCI (0.252 g, 0.621 mmol) in EtOH was added Et 3 N (0.12 mL, 0.86 20 mmol) followed by BoczO (0.18 g, 0.825 mmol). The mixture was stirred at room temperature for 10 min. Ammonium molybdate (0.0778 g, 0.63 mmol) followed by H0z (30%, 0.4 mL) were added and the reaction mixture was stirred at room temperature for 1 h after which it was concentrated under reduced pressure. The residue was partitioned between EtOAc and aq, NH 4 CI and aqueous layer was additionally extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous MgSO 4 , 25 and concentrated under reduced pressure. Purification by flash chromatography (20% to 100% EtOAc hexanes gradient) gave carbamate 68 as an amorphous solid.. Yield (0.17 g, 54%); IH NMR (400 MHz,

CDC

3 ) 5 7.27-7.44 (in, 8H), 5.08 (s, 2H), 5.00 (br.s, 1H), 4.73 (dd, J= 3.1, 9.6 Hz, 1H), 3.46 (br, s, 1H), 3.09-3.13 (m 1H), 2.91 (d, J= 6.26 Hz, 2H), 1.87-2.00 (in, IH), 1.74-1.86 (in, 3H), 1.54-1.74 (in, 4H), 1.42 (s, 9H), 0.94-1.30 (m, 5H). 30 [00555] Step 8: A mixture of benzyl ether 68 (0.17 g, 0.336 mmol), Pd(OH) 2 (20% on activated C) (0.050 g) and absolute EtOH was stirred under an atmosphere of hydrogen gas at room temperature for 1.5 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give phenol 69 as a colorless oil which was used in the next step without further purification. Yield (0.129 g, 92 %). [00556] Step 9: Deprotection of carbamate 69 following the method used in Example 10 gave Example 55 35 hydrochloride as a white solid. Yield (0.084 g, 77%); 'H NMR (400 MHz, DMSO-d 6 ) 6 10.21 (s, I H), 7.84 (br. s, 3H), 7.15 (m, 1H), 7.07 (t, J= 2.15 Hz, 1H), 6.93 (m, 1H), 3.09 (d, J= 5.9 Hz, 2H), 2.74 (t, J= 7.4 Hz, 2H), 2.65 (t, J= 7.6 Hz, 21), 1.66-1.85 (m, 5H), 1.47-1.63 (m, 3H), 0.95-1.20 (m, 5H); ESI MS in/z 312.2 [M+H]*. 40 EXAMPLE 56 PREPARATION OF (E)-3-(3-(BuIYLTHIo)PHENYL)PRoP-2-EN-I-AMINE x

NH

2 [005571 (E)-3-(3-(butylthio)phenyl)prop-2-en-1-amine was prepared following the method shown in Scheme 24. 156 WO 2010/028088 PCT/US2009/055785 5 SCHEME 24 r NHCOCF 3 n-BuBr S Br 12- NHCOCF 3 HS Br K 2 C0 3 , Pd(OAc) 2 , P(o-to) 3 71 I Acetone 70 Et 3 N, DMF

K

2

CO

3 N MeO:H 2 0 [00558] Step 1: 3-Bromobenzenethiol (1) (5 g, 26.45 mmol) was added to a mixture of n-butylbromide (3.62 g, 26.71 mmol) and K 2

CO

3 (10.95 g, 79.35 mmol) in acetone and the reaction mixture was stirred at room 10 temperature for 18 h. The reaction mixture was then filtered and the filter cake was washed with acetone. Concentration of the filtrate under reduced pressure gave thioether 70 as a light yellow oil. Yield (6.01 g, 93.4 %); 'H NMR (400 MHz, CDC 3 ) 8 7.43-7.42 (t, J= 2 Hz, IH), 7.29-7,28 (t, J= 1.2 Hz, lH), 7.23-7.21 (m, IH), 7.14-7.11 (t, J= 7.6 Hz, IH), 2.94-2.90 (t, = 7.2 Hz, 2H), 1.67-1.57 (n, 2H), 1.48-1.41 (in, 2H), 0.95-0.91 (t, J =7.6 Hz, 3H) 15 100559] Step 2: A solution of aryl bromide 70 (2 g, 8.23 mmol), allyl trifluoroacetamide 12 (2.0 g, 13.16 mmol), tri-o-tolylphosphine (0.250 g, 0.823 mmol) and triethylamine (12 mL) in anhydrous DMF was degassed by bubbling argon for 3 min. Palladium (11) acetate (0.185 g, 0.823mmol) was added to the mixture and argon was bubbled through the reaction mixture for another 30 seconds after which vacuum/argon was applied three times. The reaction mixture was heated under argon at 90 *C for 4 h, The mixture was concentrated 20 under reduced pressure to give dark brown viscous liquid. Purification by flash chromatography (5% to 30% EtOAc - hexanes gradient) gave (E)-N-(3-(3-(butylthio)phnyl)allyl)-2,2,2-trifluoroacetamide (71) as light yellow oil which solidified upon standing. Yield (1.2 g, 46 %); 'H NMR (400 MHz, CDC 3 ) 6 7.31 (in, IH), 7.26 (m, IH), 7.23 (m, 1H), 7.17-7.15 (m, 1H), 6.57-6.53 (d, J= 15.6 Hz, 1H), 6.17 (dt, J= 6.4, 15.6 Hz, 1 H), 4.14 (t, J= 6 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 1.67-1.59 (m, 2H), 1.50-1.41 (in, 2H), 0.92 (t, 25 J=7.2, 3H). 1005601 Step 3: A mixture of trifluoroacetamide 71 (1 g, 3.15 nnol) and K2CO3 (1.6 gm, 12.61mmol) in MeOH:water (2:1) was stirred at room temperature for 5 hr. The mixture was concentrated under reduced pressure. Purification by flash column chromatography (5%-20% of MeOH - CH 2 Ch gradient) gave Example 56 as a colorless oil. Yield (0,65 g, 93%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.30 (m, 1H), 7.25 (t, 30 J=7.4 Hz, I H), 7.203 (d, J=7.2 Hz, IH), 7.149 (d, J =7.6 Hz, IH), 6.77 (d, J= 16 Hz, 1H), 6.37 (dt, J =5.2, 15.6 Hz, 1H), 3.28 (d, J=5.2 Hz, 2H), 2.97 (t, J= 7.2 Hz, 2H), 1.54 (in, J =7.2 Hz, 2H), 1.40 (m, J =7.2 Hz, 2H), 0.877 (t, J=7.6, 3H). 'C NMR (DMSO-d, 100 MHz) 8 137.7,136.8,132.0,129.1, 128.2, 126.5, 125.3, 123.1, 43.2, 31.5, 30.6, 21.2, 13.4; RP-HPLC purity 99.2% (AUC); ESI MS m/z 222.17 [M+H]. 35 EXAMPLE 57 PREPARMAION OF 3-(3-(BUTYLTIO)PHENYL)PROPAN-1-AMINE 157 WO 2010/028088 PCT/US2009/055785 5 S /. NH- 2 [005611 3-(3-(butylthio)phenyl)propan-1-amine was prepared following the method used in Example 4. [00562] Step 1: Hydrogenation of Example 56 gave, after purification by flash chromatography (5% to 20% of MeOH -- DCM gradient) Example 57 as a pale yellow semi solid. Yield (0.58 g, 95%); 'H NMR (400 MHz, DMSO-d) 6 7.23 (t, J= 7.6 Hz, 1 H), 7.14 (s, 1H), 7.13 (d, J= 7.2 Hz, 1 H), 7.006 (d, J -7.2 Hz, 1H), 2.94 10 (t, J= 6.8 Hz, 2H), 2.67 (t, J 7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.75 (quintet, J=7.2 Hz, 2H), 1.54 (quintet, J=7.2 Hz, 2H), 1.40 (sextet, J=7.2 Hz, 2H), 0.87 (1,? J=7.2, 311); "C NMR (DMSO-d, 100 MHz) 8 142.2, 136.4, 128.9, 127.7,125.5, 125.3, 31.8, 31.6, 30.6, 30.5, 21.2, 13.4; RP-HPLC purity 95.35% (AUC); ESI MS m/z 224.24 [M+H]*. 15 EXAMPLE 58 PREPARATION OF (E)-3-(3-(BUTYLSULPINYL)PENYL)PROP-2-EN-1 -AMINE N2 SA / NH 2 0 [005631 (E)-3-(3-(Butyisulfinyl)phenyl)prop-2-en-1-amine was prepared following the method shown in Scheme 20 25. SCHEME 25 r Cx'NHCOCF 3 12 H 14, FeC I3 SIOr CH 3 Br Pd(OAc)A 2 , P(o-to) 3 70 0 72 Et 3 N, DMF N 12003 N 1 S NHCOOF 3 K2r0

NH

2 73 MeOH:H 2 0 0 730 [005641 Step 1: To a stirred solution of thioether 70 (2.0 g, 8.16 mmol) in CH 3 CN at room temperature was added 25 iron (111) chloride (50 mg, 0.311 mmol) followed by, after 5 min, periodic acid (1.12 g, 9.2 mmol). The reaction mixture was stirred for 30 min. The reaction was quenched by the addition of an aqueous solution of sodium thiosulfate (20%, 30 mL). The mixtrue was extracted with EtOAc three times and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 , filtered and concentrated under reduced pressure to produce sulfoxide 72 as a light brown oil, which crystallized upon standing. Yield (2.0 g, 93%); 30 'H NMR (400 MHz, CDCI,) 8 7.77 (m, 111), 7.62 (d, J=- 7.6, 1H), 7.52 (d, J= 7.6, 111), 7.39 (t, J 7.7 Hz, I H), 2.79 (t, J= 7.2 Hz, 2H), 1.79-1.70 (m, 1H), 1.63-1.60 (in, IH), 1.51-1.39 (m, 2H), 0.93 (t, J= 7.2, 3H). [00565J Step 2; Heck coupling between aryl bromide 72 and allyl trifluoroacetamide 12 following the method used in Example 56 gave alkene 73 as light yellow oil which was solidified upon standing. Alkene 73 was used 35 in the next step without further purification. Yield (1.4 g, 61%). [005661 Step 3: Deprotection of trifluoroacetamide 73 following the method used in Example 56 gave after 158 WO 2010/028088 PCT/US2009/055785 5 purification by flash column chromatography (5%-20% of MeOH - DCM gradient) Example 58 as a colorless oil. Yield (0.6 g, 84%); 'H NMR (400 MHz, CDCI 3 ) 6 7.65 (m, 1H), 7.56-7.46 (m, 3H), 6.54 (d, J = 15.6 Hz, 1H), 6.45 (dt, J =5.6, 16 Hz, 1H), 3.49 (d, 111.6 Hz, 2H), 2.99-2.92 (m, 1H), 2.79-2.72 (m, 1H), 1.62-1.56 (m, IH), 1.37-1.32(m, 2H), 0.85 (t, J=7.2 Hz, 3H); RP-HPLC purity 96.26% (AJC); ESI MS m/z 238.27 [M+H]. 10 EXAMPLE 59 PREPARATION OF 3-(3-(BUTYLSULFINYL)PHENYL)PROPAN-1-AMINE S , NH 2 0 15 1005671 3-(3-(Butylsulfmyl)phenyl)propan-1-amine was prepared following the method used in Example 57. [00568] Step 1: Hydrogenation of Example 58 gave Example 59 as a pale yellow semi solid. Yield (0.55 g, 95%); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.48-7.43 (m, 3H), 7.36 (d, J= 6.8, IH), 3.48 (br.s, 4H), 2.94-2.88 (m, I H), 2.76-2.69 (m, 3 H), 2.58 (t, J=6.8 Hz, 2H), 1.69 (quintet, J= 7.2 Hz, 2H), 1.59-1.55 (m, 1H), 1.38 1.29 (m, 3H), 0,84 (t, 1=6.8 Hz, 3H); "C NMR (DMSO-d, 100 MHz) 5 144.2, 143.3, 130.6,129.0, 123.4, 20 121.3, 55.1, 40.3, 33.4, 32.1, 23.4, 21.1,13.5; RP-HPLCpurity 98.97% (AUQ; ESI MS m/z 240.21 [M+H]*, EXAMPLE 60 25 PREPARATION OF 3-(3-(CYCLOPENTYLMETHYLTHIO)PHENYL)PROPAN-1 -AMINE S NH 2 [005691 3-(3-(Cyclopentylmethylthio)phenyl)propan-l-amine was prepared following the method shown in Scheme 26. 30 SCHEME 26 OTs ; ;.NHCOCF 3 12 - r,*'S Br Pd(CAr.)2. Hs1Br f-BuOK, DMF P(o-tol), 74 Et 3 N ,DMF .S ..- NHCOCF3 K2CO JNS A. NH 2 0 ,- 75 MeOH:H 2 0 7. H2/Pd-C EtOH Cr.. z

NH

2 [00570] Step 1: 3-Bronobenzencthiol (1) (4.46 g, 23.59 mnol) was added to a mixture of t-BuOK (8.82 g, 78.63 159 WO 2010/028088 PCTIUS2009/055785 5 mmol) in DMF and stirred at 0 *C for 10 min. Cyclopentylmethyl-4-methylbenzenesulfonate was added to the above reaction mixture at 0 *C and the reaction mixture was stirred at room temperature for 3 h. Water was added to the reaction mixture, and aqueous layer was extracted with ethyl acetate three times, dried over Na 2

SO

4 and concentrated under vacuo to give thioether 74 as a pale yellow oil. Yield (5.1 g, 95.5%); 'H NMR (400 MHz, CDCI) 8 7.42 (m, IH), 7.26 (d, J= 7.2 Hz 1H), 7.21 (d, J =8 Hz, I H), 7.12 (t, J= 7.8 10 Hz, 1 ), 2.91 (d, J= 7.2 Hz, 2H), 2.17-2.05 (m, lH), 1.87-1.81 (m, 2H), 1.68-1.63 (m, 2H), 1.57-1.55 (in, 2H), 1.33-1.26 (m, 2H). 1005711 Step 2: Heck coupling between aryl bromide 74 and allyl trifluoroacetamide 12 following the method used in Example 56 gave alkene 75 as light yellow oil which was solidified upon standing. Yield (1.0 g, 39.5%); 'H NMR (400 MHz, CDC 3 ) 8 7.36 (m, 1 H), 7.31 (m, 1 H), 7.24-7.22 (d, J = 4.8 Hz, IH), 7.15 (d, J= 2.8 15 Hz, IH), 6.55 (d, J -16 Hz, 1H), 6.39 (s, 1H), 6.20-6.13 (m, 1H), 4,14 (t, J=6.4 Hz, 2H), 2.93 (d, J= 7.2 Hz, 2H), 2.15-2.05 (m, IH), 1.86-1.84 (m, 2H), 1.64-1.63 (m, 2H), 1.57-1.55 (m, 2H), 1.33-1.26 (in, 2H), [00572] Step 3: Allyl trifluoroacetamide 75 was deprotected following the method used in Example 58 to give amine 76 as a colorless oil. Yield (0.6 g, 83%); 'H NMR (400 MHz, CDCI,) 5 7.37-7.36 (m, 1), 7.26-7.14 (m, 3H), 6.46 (d, J= 16 Hz, 1H), 6.23 (dt, J= 5.6, 15.6 Hz, 11-), 3.47 (dd, J= 1.6,4 Hz, 2H), 2.92 (d, J= 20 7.2 Hz, 2H), 2.15-2.06 (m, IH), 188-1.81 (m, 2H), 1.68-1.59 (m, 2H), 1.56-1.51 (m, 2H), 1.33 (s, 2H), 1.29-1.25 (m, 2H); RP-HPLC purity 95.4% (AUC); ESI MS m/z 248.18 [M+H)*. [00573] Step 4: Hydrogenation of allyl amine 76 following the method used in Example 57 gave Example 60 as a pale yellow semi solid. Yield (0.17 g, 84%); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.22 (t, J=8 Hz, 1H), 7.13 (d, J= 7.2 Hz, 2H), 6.99 (d, J- 8 Hz, IH), 6.05 (br.s, 21), 2.94 (d, J= 7.2 Hz, 2H), 2.67 (t, J= 7.2 Hz, 25 2H), 2.59 (d, J- 7.6, 1H), 2.07-1.99 (m, 1H), 1.77-1.71 (m, 4H), 1.63-1.59 (m, 2H), 1.53-1.49 (m, 21H), 1.28-1.23 (m, 2H); "C NMR (DMSO-d, 100 MHz) 8 142.19,136.78, 128.89, 127.68, 125.44, 125.31, 39.14, 38,84, 38.04, 31.85, 31.76, 30.71, 24.67; RP-HPLC purity 95.13% (AUC); ESI MS m/z 250.22 [M+H]}. 30 EXAMPLE 61 PREPARATION OF 3-(3-(CYCLOPENTYLMETHYLSULFINYL)PHENYL)PROPAN- 1-AMINE S NH 2 [00574] 3-(3-(Cyclopentylmethylsulfinyl)phenyl)propan-1-amine was prepared following the method used in 35 Examples 58 and 59. 1005751 Step 1: Oxidation of (3-bromophenyl)(cyclopentylmethyl)sulfane 74 following the method used in Example 58 gave 1-bromo-3-(cyclopentylmethylsulfinyl)benzene as a light yellow oil. Yield (2.0 g, 94%); 'H NMR (400 MHz, CDCI,) 8 7.79 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.53 (d, J= 7.6 Hz, 1H), 7.38 (t, J =7.6 Hz, IH), 2.03 (dd, J= 5,6, 12.8 Hz, IN), 2.66 (dd, J= 8.8, 13.2 Hz, 1H), 2.36-2.28 (m, IN), 2.07-2,01 40 (m, 1H), 1.89-1.86 (m, 1H), 1.66-1.52 (m, 6H). [00576] Step 2: Heck coupling between 1-bromo-3-(cyclopentylmethylsulfinyl)benzene and allyl trifluoroacetamide 12 following the method used in Example 58 gave (E)-N-(3-(3 (cyclopentyimethylsulfinyl)phenyl)allyl)-2,2,2-trifluoroacetamide as light yellow oil, Yield (1.0 g, 40%); 160 WO 2010/028088 PCT/US2009/055785 5 'H NMR (400 MHz, CDC 3 ) 8 7.64 (m, 1), 7.53-7.44 (m, 311), 6.71 (br.d, 18), 6.60 (d, J= 16 Hz, 1 H), 6.29 (dt, J= 8.4, 16 Hz, IH), 4.16 (t, J= 6 Hz, 2H), 2.93 (dd, J= 6, 12.6 Hz, 1 H), 2.66 (dd, J - 8.8, 12.8, 1H), 2.33-2.29 (m, IH), 2.04-2.01 (m, IH), 1.89-1.86 (m, 1H), 1.67-1.56 (in, 4H), 1.36-1.21 (m, 2H). [00577 Step 3: Deprotection of (E)-N-(3-(3-(cyclopentylmethylsulfinyl)phenyl)allyl)-2,2,2-trifluoroacetanide following the method used in Example 58 gave (E)-3-(3-(cyclopentylmethylsulflnyl)pheny)prop-2-en-1 10 amine as a pale yellow semi solid. Yield (0.6 g, 82%); 'H NMR (400 MHz, CDCI 3 ) 8 7.66 (in, lH), 7.47 7.42 (in, 3H), 6.56 (d, J= 16 Hz, iH), 6.43 (dt, J= 5.6,16 Hz, lH), 3.53 (d, J= 5.6 Hz, 2H), 2,94(dd, J= 6, 12.8 Hz, 1H), 2.66 (dd, J= 8.8, 12.8, 1H), 2.32-2.28 (m, lH), 2.03-1.98 (m, 1H), 1.90-1.85 (m, 1H), 1.68 1.55 (m, 4H), 1.35-1.22 (in, 2H); RP-HPLC purity 95.4% (AUC); ESI MS m/z 248.18 [M+H]*. 1005781 Step 4: Hydrogenation of (E)-3-(3-(cyclopentylmethylsulfinyl)phenyl)prop-2-en-1-amine following the 15 method used in Example 59 gave Example 61 as a pale yellow oil. Yield (0.24 g, 79%); 'H NMR (400 MHz, DMSO-d) 8 7.50 (in, IH), 7.47 (m, 1H), 7.47 (d, 2.4 Hz, I H), 7.37-7.35 (in, 1 H), 2.84 (d, 3.6 Hz, I H), 2.821 (d, 1.6 Hz, 1H), 2.69 (t, J- 8 Hz, 2H), 2.566 (t, J= 10.8 Hz, 2H), 2.15 (quintet, J= 7.2 Hz, 1 H), 1.86-1.84 (m, 1 H), 1.73-1.64 (in, 4H), 1.61-1.55 (m, 2H), 1.52-1.47 (m, 2H), 1.38-1.33 (m, 1H), 1.22 1.19 (m, 2H); "C NMR (DMSO-d, 100 MHz) 8 144.82, 143.52, 130.67, 129.04, 123.36, 121.26,62.64, 20 40.61, 34.24, 34.00, 32.25, 32.06, 31.51, 24.54, 24.40; RP-HPLC purity 95.1% (AUC); ESI MS m/z 266.23 [M+H]*. EXAMPLE 62 25 PREPARATION OF (E)-3-(3-(2-PROPYLPENTYL SULFONYL)PHENYL)PROP-2-EN-1-AMINE NH2 [005791 (E)-3-(3-(2-Propylpentylsulfonyl)phenyl)prop-2-en-1-amine was prepared following the method used in Examples 22, 3, and 56. 1005801 Step 1: Oxidation of (3-bromophenyl)(2-propylpentyl)sulfane following the method used in Example 3 30 gave 1-bromo-3-(cyclchexylmethylsulfonyl)benzene as a white solid, Yield (2.4 g, 72%); 1H NMR (400 MHz, CDCI 3 ) 8 8.05 (In, 1H), 7.85 (d, J=8 Hz, 1 H), 7,78 (d, J= 7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 11), 3.02 (d, J=5.6 Hz, 2H), 1.98-2.04 (m, 1H), 1.35-1.40 (m, 8H), 0.851 (t, J=7.2 Hz, 6H). [005811 Step 2: Heck coupling between 1-bromo-3-(cyclohexylmethylsulfonyl)bcnzene and allyl trifluoroacetamide 12 following the method used in Example 56 gave after purification by flash 35 chromatography (5% to 30% EtOAc/hexane gradient) (E)-2,2,2-trifluoro-N-(3-(3-(2 propylpentylsulfonyl)phenyl)allyl)acctamide as light yellow oil which was solidified upon standing. Yield (1.5 & 66.6%); 'H NMR (400 MHz, CDCl 3 ) 8 7.81 (m, 1H), 7.78 (d,J =7.6 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 6.70 (bs, 1H), 6.59 (d, J =16 H, 1H), 6.28 (dt, J=6.4, 16 Hz, 1H), 4.17 (t, J =6 Hz, 2H), 3.01 (d, J= 6 Hz, 2H), 2.04-1.97 (m, IH) 1.39-1.30 (m, 4H), 1.25-1.19 (in, 4H), 0.83 (t, J =7.2 40 Hz, 6H). [00582] Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(2-propylpentylsulfonyl)phenyl)ally)acetamide following the method used in Example 56 after purification by flash column chromatography (5% to 20% of MeOH - DCM gradient) gave Example 62 as a yellow solid. Yield (0.7 g, 50%); 11 NMR (400 MHz, 161 WO 2010/028088 PCT/US2009/055785 5 CDCI 3 ) 8 7.93 (m, 1H), 7.73 (d, J =8.0 Hz, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.46 (t, J -7.6 Hz, IH), 6.61 (d, J = 16 Hz, 1H), 6.45 (dt, J =6, 16 Hz, 1H), 3.76 (brs, 2H), 3.60 (d, J= 5.6 Hz, 2H), 3.01 (d, J =6 Hz, 2H), 2.02-196 (m, 1H), 1.40-1.31 (m, 4H), 1.27-1.16 (in, 4H), 0.82 (t, J =7.2 Hz, 6H); "C NMR (DMSO-d 6 , 100 MHz) 6 140.4, 137.9, 130.96, 130.6, 129.8, 129.1, 126.3, 124.8, 58.5, 42.0, 34.7, 32.0, 18.5, 13.9; RP HPLC purity 95.96% (AUC); ESI MS m/z 310.34 [M+H]*. 10 EXAMPLE 63 PREPARATION OF (E)-3-(3-AM1NOPROP-1-ENYL)-N-PROPYLBENZENESULFONAMIDE H j N X NH 2 It 0 15 100583] (E)-3-(3-amninoprop-1 -enyl)-N-propylbenzenesulfonamide was prepared following the method used in Examples 15 and 56. (00584] Step 1: Sulphonation of n-propylamine with sulfonyl chloride 19 following the method used in Example 15 gave 3-bromo-N-propylbenzenesulfonamide as a colorless liquid. Yield (2.15 g, 99%); 'H NMR (400 MHz,

CDCI

3 ) 8 8.01 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.71 (d, J -7.6 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 4.38 (bs, 1H), 20 2.95 (q, J =6.8 Hz, 2H), 1.53 (q, J =7.2 Hz, 2H), 0.89 (t, J =7.2 Hz, 3H). [005851 Step 2: Heck coupling between 3-bromo-N-propylbenzenesulfonamide and allyl trifluoroacetamide 12 following the method used in Example 56 gave after purification by flash chromatography (0% to 30% EtOAc - hexanes gradient) (E)-2,2,2-trifluoro-N-(3-(3-(N-propylsulfamoyl)phenyl)allyl)acetamide as a colorless oil, Yield (1.6 g, 76%); 'H NMR (400 MHz, CDCI,) 7.85 (m, I H), 7.76 (d, J =7.6 Hz, IH), 7.55 25 (d, J -8 Hz, I H), 7.483 (t, J =7.6 Hz, 1H), 6.62 (d, J=16 Hz, IH), 6.48 (bs, 1H), 6.284 (dt, J =6.4 Hz, 16 Hz, 1H), 4.35 (t, J =6.4 Hz, 1 H), 4.19-4.09 (m, 2H), 2.96-2.91 (m, 2H), 1.501(q, J =7.2 Hz, 2H), 0.88 (t, J =7.2 Hz, 3H). (005861 Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(N-propylsulfamoyl)phenyl)allyl)acetamide following the method used in Example 56 gave after purification by flash chromatography (0% to 20% of 30 MeOH:CH 2

CL

2 gradient) (E)-3-(3-aminoprop-1-enyl)-N-propylbenzenesulfonamide 6 as a colorless oil. Yield (0.95 g, 82%); 'H NMR (400 MHz, DMSO with D 2 0) 5 7.75 (m, Il), 7.65 (d, J=7.6 Hz, I H), 7.603 (d, J =7.6 Hz, IH), 7.52 (t, J =7.6 Hz, 1H), 6.57 (d, J=16 Hz, 1H), 6.45 (dt, J =5.6, 16 Hz, 1H), 3.30 (d, j =4.8 Hz, 2H), 2.66 (t, J =7,2 Hz, 2H), 1.38-1,31 (in, 2H), 0.779 (t, J -7.6 Hz, 3H). RP-HPLC purity 99.43% (AUC); ESI MS mz 253.21 [M-H]. 35 EXAMPLE 64 PREPARATION OF 3-(3-AMINOPROPYL)-N-PROPYLBENZENESULFONAMIDE HO I

NH

2 40 100587] 3-(3-Aminopropyl)-N-propylbenzenesulfonamide was prepared following the method used in Example 16. [00588] Step 1: Hydrogenation of Example 63 gave, after purification by flash chromatography (0% to 20% of 162 WO 2010/028088 PCT/US2009/055785 5 MeOH:CH 2 C1 2 gradient) Example 64 as a colorless oil. Yield (0.2 g, 50%); 'H NMR (400 MHz, DMSO with D 2 0) 8 7.60 (d, J=1.6 Hz, 1H), 7.585 (d, J =1.6 Hz, 1H), 7.51-7.47 (m, 2H), 2.70-2.64 (m, 4H), 2.59 (t, J =7.2 Hz, 2H), 1.74-1.66 (m, 2H), 1.38-1.29 (m, 2H), 0.76 (t, J =7.2 Hz, 3H); "C NMR (DMSO-d 6 , 100 MHz) 8 143.0, 140.6, 132.1, 129.0, 125.9, 123.8, 44.3, 32.6,31.9, 22.3, 11.0; RP-HPLC purity 98.76% (AUC); ESI MS m/z 257.23 [M+H]*. 10 EXAMPLE 65 PREPARATION OF 3-(3-AMINOPROPYL)-N-CYCLOPENTYLBENBNESULFONAMIDE -\ NH 2 15 [00589 3-(3-Aiminopropyl)-N-cyclopentylbenzenesulfonamide was prepared following the method used in Example 63. [00590] Step 1: Reaction between suffonyl chloride 19 and pentylamine gave 3-bromo-N-cyclopentylbenzene sulfonamide as colorless oil. Yield (2.3 g, 98%); 'H NMR (400 MHz, CDC 3 ) 8 8.02 (s, 1H), 7.81 (d, J =7.6 Hz, 1H), 7.69 (dJ=7.2 Hz, 1H), 7.39 (t, J= 8 Hz, 1H), 4.56 (d, J=8 Hz, 1H), 3.65-3.60 (m, 1H), 20 1.84-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.53-1.50 (m, 2H), 1.42-1.38 (m, 2H). 1005911 Step 2: Heck coupling between 3-bromo-N-cyclopentylbenzenesulfonamide and N-allyl-2,2,2 trifluoroacetamide gave (E)-N-(3-(3-(N-cyclopentylsulfamoyl)phenyl)allyl)-2,2,2-trifluoroacetamide as colorless oil, Yield (2.0 g, 70%) 'H NMR (400 MHz, CDCI3) 8 8.01 (s, I H), 7.87 (s, lH), 7.76 (d,1=7.6 Hz, I H), 7.55 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 6.61 (d, J=16 Hz, 1H), 6.53 (s, 1H), 6.28 (dt, J 25 -6.4, 15.6 Hz, 1H), 4.41 (d, J -7.2 Hz, 1H), 4.22-4.12 (m, 2H), 3.64-3.57 (m, 11), 1.82-1.76 (m, 2H), 1.61-1.56 (m, 2H), 1.52-1.49 (m, 2H), 1.38-1.32 (m, 2H). [005921 Step 3: Deprotection of (E)-N-(3-(3-(N-cyclopentylsulfamoyl)phenyl)allyl)-2,2,2-trifluoroacetamide gave Example 65 as a pale yellow oil. Yield (1.2 g, 81%); 'H NMR (400 MHz, CDCI,) 8 7.87 (s, I H), 7.71 (d, J =7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.44 (t, J =8 Hz, I H), 6.54 (d, J=16 Hz, 1H), 6.46 (dt, J=5.6, 16 30 Hz, I H), 4.47 (s, 1H), 3.62-3.58 (m, 1H), 3.52-3.48 (m, 211), 1.90-1.80 (m, 2H), 1.63-1.57 (m, 2H), 1.51 1.48 (m, 2H), 1.54-1.35 (m, 2H); "C NMR (DMSO-d 6 ) 8 142.0,137.7,132.1, 129.5,129.4,128.2,125.0, 123.6, 54.4, 42.6, 32.3, 22.7. RP-HPLC purity 95.01% (AUC); ESI MS m/z 279.30 [M-H). EXAMPLE 66 35 PREPARATION OF 3-(3-(BUTYLSULFONYL)PHENYL)PROPAN-1-AMINE NH 0 [005931 3-(3-(Butylsulfonyl)phenyl)propan-1-amine was prepared following the method below. 1005941 Step 1: Oxidation of thioether 70 following the method used in Example 3 gave I -bromo-3-(butylsulfonyl) 40 benzene. Yield (2.5 g, 90/o); 'H NMR (400 MHz, CDClJ) 8 7.77 (t, J= 1.6 Hz, 1H), 7.61 (dJ= 8Hz, 1H), 7.51 (d,J= 7.6 Hz, IIH), 7.38 (t, J-7.6Hz, 1H), 2.79 (t, J=7.8Hz, 2H), 1.81-1.70 (i, 1W), 1.65-1.60 (i, 163 WO 2010/028088 PCT/US2009/055785 5 1H), 1.52-1.43 (m, 2H), 0.93 (t, J= 7.2 Hz, 3H). 100595] Step 2: A mixture of 1-bromo-3-(butylsulfonyl)benzene (2 g, 7.24 mmol) and protected allyl amine 12 (1.2 g, 7.97mmol), tetrabutylammonium acetate (4g) and Pd(OAc) 2 (0.5g, 2.17mmol) was purged with argon for 3 min and then heated at +90 *C for 2 h. The reaction mixture was diluted with NH 4 CI (25m) and extracted with ethyl acetate three times. Combined organic layers were dried over Na 2

SO

4 , and concentrated under 10 reduced pressure. Purification by flash chromatography (30 to 50% EtOAc-hexanes gradient) gave (E)-N (3-(3-(butylsulfonyl)phenyl)alyl)-2,2,2-trifluoroacetamide a light yellow oil. Yield (1.3 g, 52%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.65 (s, 1H),7.52-7.44 (m, 3H), 6.62 (d, J= 15.6 Hz, 1H), 6.289 (dt, J =6.4 Hz, 16 Hz, 1H), 4.17 (t, J =6.4, 2H), 2.79 (t, J= 7.6 Hz, 2H), 1.74-1.71 (in, IH), 1.63-1.58 (m, IH), 1.49-1.42 (m, 2H), 0.92 (t, J=7.6 Hz, 3H). 15 [00596j Step 3: Deprotection of (E)-N-(3-(3-(butylthio)phenyl)allyl)-2,2,2-trifluoroaetamide following the method used in Example 56 gave (E)-3-(3-(butylsulfonyl)phenyl)prop-2-en-1-amine. Yield (0.524 g, 70%); '1H NMR (400 MHz, CD 3 OD) 6 7.74 (s, 1H), 7.63-7.59 (m, 1H), 7.57-7,52 (in, 2H), 6.72 (d, J=16 Hz, IH), 6.48 (dt, J = 6.0, 16 Hz, 1H), 3.54 (dd, J - 1.2, 6.4 Hz, 2H), 3.00-2.93 (m, lH), 2.91-2.84 (m, 1H), 1.70 1.67 (m, 1H), 1.61-1.52 (m, 1H), 1.48-137 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H). 20 [00597j Step 4: Hydrogenation of (E)-3-(3-(buty]sulfonyl)phenyl)prop-2-en-1-amine following the method used in Example 4 gave, after purification by flash chromatography (10% to 100% of 10/6 7N NH3/MeOH/CH 2 Cl - CH 2 Cl 2 gradient) Example 66 as a light yellow oil. Yield (0.080 g, 54%); 'H NMR (400 Mliz, CD 3 OD) 7.77 (s, 1H), 7.73 (d, J =6.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, IH), 7.55 (t, J=7.6 Hz, 1H), 3.19 (t, J= 7.6 Hz, 2H), 2.78 (t, J = 8 Hz, 2H), 2.68 (t, J = 6.8 Hz, 2H), 1.82 (quint, J = 7.6 Hz, 2H), 1.66-1.58 (in, 2H), 1.44 25 1.38 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H). RP-HPLC purity 95.05% (AUC); ESI MS m/ 255.38 [M+H}*. EXAMPLE 67 PREPARATION OF (E)-3-(3-(2-PRPYLPENTYLSULFNYL)PHBNYL)PRoP-2-EN- 1-AMINE S l- NH 2 30 0 [00598] (E)-3-(3-(2-Propylpentylsulfinyl)phenyl)prop-2-n-1 -amine is prepared from (E)-2,2,2-trifluoro-N-(3-(3-(2 propylpentylsuifinyl)phenyl)allyl)acetamide. (E)-2,2,2-Trifluoro-N-(3-(3-(2 propylpentylsulfmyl)phenyl)allyl)acetamide was prepared as described in the method below. [00599 Step 1: Oxidation of (3-bromophenyl)(2-propylpentyl)sulfane following the method used in Example 58 35 gave I-bromo-3-(2-propylpenty)sulfinyl)benzene. Yield (2.0 g, 95%); 'H NMR (400 MHz, CDCb3) 8 7.79 (in, I H), 7.61 (d, J= 7.6 Hz, I H), 7.53 (d, J= 7.6 Hz, IH), 7.39 (t, J = 8 Hz, I H), 2.84 (dd, J= 4.4, 13 Hz, 1H), 2.59 (bs, 1H), 1.60-1.54 (m, JH), 1.47-1.42 (m, 2H), 1.40-1.35 (in, 4H), 1.33-1.28 (in, 2H), 0,93-0.80 (m, 6H). [00600 Step 2: Heck coupling of 1-bromo-3-(2-propylpentylsulfinyl)benzene and allyl amide 12 following the 40 method used in Example 56 gave (E)-2,2,2-trifluoro-N-(3-(3-(2 propylpentylsuifinyl)phenyl)allyl)acetamide as a light yellow oil, Yield (2.0 g, 8 1%); 'H NMR (400 MHz,

CDC

3 ) 8 7.78 (t, J= 2 H, IH), 7.62-7.60 (i, IH), 7.53-7.51(m, I H), 7.38 (t, J= 8 Hz, I H), 6.41 (br.s, 1H), 5.89-5.80(m, IH), 5,29-5.23 (m, 1H), 3.99 (t, J= 6 Hz, 2H), 2.83 (dd, J= 4.8, 13 Hz, 1H), 2.55 (dd, J 9.2, 13 Hz; 1H), 2.00 (br.s, 1H), 1.45-1.40 (in, 2H), 1.39-1.30 (in, 6H), 0.94-0.86 (m, 6H). 164 WO 2010/028088 PCT/US2009/055785 5 [006011 Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(2-propylpentylsulfinyl)phenyl)allyl)acetamide following the method used in Example 56 gives Example 67. EXAMPLE 68 10 PREPARATION oF 3-(3-AMINOPROPYL)-N-(HEPTAN-4-YL)BENZENESULFONAMIDE HNH 'S [00602] 3-(3-Aminopropyl)-N-(heptan-4-yl)benzenesulfonanide was prepared following the method used in Examples 63 and 64. [006031 Step 1: Sulfonation of heptan-4-amine by sulfonyl chloride 19 gave 3-bromo-N-(heptan-4-yl)benzene 15 sulfonamide as a colorless liquid. Yield (1.29 g, 99%); 'H NMR (400 MHz, CDC 3 ) 8 8.02 (s, 1H), 7.79 (d, J =8 Hz, 1 H), 7.68 (d, J=8 Hz, 1H), 7.38 (t, J =8 Hz, 1H), 4.18 (d, J =8.8 Hz, 1H), 3.30-3,27 (m, 1H), 1.43-1.37 (m, 2H), 1.35-1.31 (m, 4H), 1.29-1.21 (m, 2H), 0.80 (t, J =7.2 Hz, 6H). [006041 Step 2: Heck coupling of 3-bromo-N-(heptan-4-yl)benzencsulfonamide and allyl amide 12 following the method used in Example 56 gave (E)-2,2,2-trifluoro-N-(3-(3-(N-heptan-4 20 ylsulfamoyl)phenyl)allyl)acetamide as a colorless oil. Yield(0.75 g, 50%); 'H NMR (400 MHz, CDC 3 ) S 7.86 (s, 1H), 7.75 (d, J =7.6 Hz, 111), 7.53 (d, J -7.6 Hz, 1H), 7.46 (t, J=7,6 Hz, 1H), 6.61 (d, J =16 Hz, 1H), 6.46 (br.s, 1H), 6.27 (dt, J=6.4, 16 Hz, 1H), 4.19 (t, J =6 Hz, 2H), 3,29-3.25 (m, lH), 1.40-1.31 (m, 2H), 1.28-1.20 (m, 4H), 1.19-1.13 (m, 2H), 0.77 (t, J=7.2 Hz, 6H). [00605] Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(N-heptan-4-ylsulfamoyl)phenyl)allyl)acetamide gave 25 (E)-3-(3-aminoprop-1 -enyl)-N-(heptan-4-yl)benzenesulfonamide. Yield (0.55 g, 96%); 'H NMR (400 MHz, CDC1 3 ) & 7.76 (s, 1 H), 7.63-7.61 (m, 2H), 7.53 (t, J=8 Hz, 1 H), 6.61 (d, J =16 Hz, 1H), 6.42 (dt, J =5.6 Hz and 16 Hz, 1H), 3.37 (d, J=5.2, 2H), 3,06-3.03 (m, 1 H), 1.33-1.25 (m, 4H), 1.23-1.17 (m, 4H), 1.09-1.03 (m, 2H), 0.65 (t, J=7.2 Hz, 6H), "C NMR (DMSO-d, 100 MHz) 8 142.8,137.7,132.6, 129.3, 127.8, 124.8, 123.4, 52.7, 42,8,36.5, 18.0, 13.6; RP-HPLC tR - 5.10 min, 99.69% (AUC); ESI MS m/z 30 309.51 [M-H]. [00606] Step 4; Hydrogenation of (E)-3-(3-aminoprop-l-enyl)-N-(heptan-4-yl)benzenesulfonamide following the method used in Example 16 gave crude Example 68 as a colorless oil which was purified in the next two steps. [00607] Step 5: To a stirred solution of 3-(3-aminopropyl)-N-(heptan-4-yl)benzenesulfonamide (0.3 g, 0.96 mmol), 35 TEA (0.106 g, 0.1 mmol) in CH 2

CI

2 , Boc 2 0 (0.23 g, 0.1 mmol) was added at 0"C under inert environment and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was partitioned between water and DCM. Organic layer was concentrated under reduced pressure followed by purification by column chromatography (silica gel, 0% to 30% of ethyl acetate - hexane gradient) to give tert-butyl 3-. (3-(N-heptan-4-ylsulfamoyl)phenyl)propylcarbamate as a colorless oil. Yield (0.39 g, 99%);' H NMR (400 40 MHz, CDC13) 8 7.70-7.68 (m, 211), 7.42-7.35 (m, 2H), 4.55 (br.s, IH), 4.27 (d, J=7.6 Hz, 1H), 3.27-3.22 (m, 1H), 3.17-3.12 (m, 2H), 2.71(t, 1=7.6 Hz, 2H), 1.81 (quintet, J=7.6 H7, 2H), 1.45 (s, 9H), 1.38-1.31 (m, 2H), 1.28-1.21 (m, 6H), 0.76 (t, '=7.2,66H). [00608] To a stirred solution of tert-butyl 3-(3-(N-heptan-4-yIsulfamoyl)phenyl)propylcarbaiate (0.39 g, 0.945 mmol) in DCM, HCI-dioxane (4M, 5.0 mL) was added dropwise at 0*C under inert environment. The 165 WO 2010/028088 PCT/US2009/055785 5 reaction mixture was stitted at room temperature for 4 hrs and concentrated at reduced pressure to give yellow liquid which was washed with diethyl ether. The resulting liquid was dried under high vaccun pump to give 3-(3-aminopropyl)-N-(heptan-4-yl)benzenesulfonamide hydrochloride as yellow semi solid. Yield (0.3 g, 91%); 'H NMR (400 MHz, CD 3 QD) 8 7.73-7.71 (m, 2H), 7.51-7.49 (m, 2H), 3.20-3.10 (m, 1H), 2.96 (t, J=7.6 Hz, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.01-1.97 (n, 2H), 1.36-1.15 (m, 8H), 0.75 (t, J=7.2 10 Hz, 6H); "C NMR (DMSO-d, 100 MHz) 8 144.0, 143.2, 133.3, 130.3, 127.6, 125.9, 54.7, 40.2, 38.3, 33.2, 30,1, 19.6, 14.1; RP-HPLC tR - 5.10 min, 99.69% (AUC); ESI MS m/z 309.51 [M-H]t EXAMPLE 69 15 PREPARATION OF (E)-3-(3-(cycLOHEXYLMETHYLSULFINYL)PHENYL)PRoP-2-EN-1-AMINE S N NH 2 0 100609] (E)-3-(3-(Cyclohexylmethylsulfinyl)phenyl)prop-2-en- 1-amine was prepared following the method used in Examples 2, 66, and 9. [006101 Step 1: Heck coupling of 1-bromo-3-(cyclohexylmethylsulfinyl)benzene and allyl aide 12 following the 20 method used in Example 66 gave (E)-N-(3-(3-(cyclohexylmethylsulfinyl)phenyl)ally)-2,2,2 trifluoroacetamide. Yield (1.0 g, 27%); 'H NMR (400 MHz, DMSO-d) 8 9.75 (in, 1H), 7.72 (m, 1H) 7.58 (d, J =4.4 Hz, 1H), 7.53 (d, J = 4.4Hz, 2H), 6.614 (d, J =16 Hz,IH), 6.393 (dt, J = 6, 16 Hz, 1H), 4.02 (t, J = 5.6 Hz, 2H), 2.76-2.65 (n, 2H), 1.94 (d, =12 Hz, 1H), 1.71-1.60 (m, 4H), 1.28-1.01 (m, 6H); 11C NMR (DMSO-d) 6 156.7, 156.3, 156.0, 155.6, 145.7,137.3,130.2, 129.8, 129.5, 128.7, 126.7, 122.8, 121.1, 25 63.9,40.9, 32.6, 32.5, 31.4, 25.6, 25.4, 25.2. RP-HPLC tR - 6.07 min, 95.02% (AUC); ESI MS 372.4 m/z [M-H). [00611] Step 2: Deprotection of (E)-N-(3-(3-(cyclobexylinethylsulfinyl)phenyl)allyl)-2,2,2-trifluoroacetamide following the method used in Example 9 gave Example 69 as a light yellow oil, Yield (0.098 g, 88%); 'H NMR (400 MHz, CD 3 0D) 8 7.69-7.72 (n, 1H), 7.55-7.62 (m, IH), 7.48-7.53 (m, 2H), 6.59-6.64 (m, 1H), 30 6.48 (dt, J= 5,9,15.8 Hz, 1H), 3.42 (dd, J= 1.2, 5.7 Hz, 2H), 2.81 (dd, J= 5.1, 13.3 Hz, 1fH), 2.70 (dd, J 8.8, 13,3 Hz, 1H), 1.98-2.06 (m, LH), 1.63-1.92 (m, 5H), 1.08-1.37 (m, 5H); RP-HPLC purity 94.3% (AUC); ES! MS 278.8 mz [M+H]*. EXAMPLE 70 35 PREPARATION OF 3-(3-(PHENETHYLTHIO)PHENYL)PROPAN-1-AMINE SA

NH

2 [00612] 3-(3-(Phonethylthio)phenyl)propan-1-amine was prepared following the method used in Examples 56 and 57, 40 100613] Step 1: Alkylation of thiophenol 1 by (2-bromoethyl)benzene following the method used in Example 56 gave, after purification by column chromatography on a silica gel (230-400 silica-mesh, 100% hexane) (3 bromophenyl)(phenethyl)sulfane. (Yield 6.0 g, 96.77%); 'H NMR (400 MHz,CDC1j) 8 7.45 (m, 1H), 7.31 166 WO 2010/028088 PCT/US2009/055785 5 (t, J= 7.6 Hz, 3H), 7.21 (t, J = 8 Hz, 4H), 7.14 (t, J=7.6 Hz, 1 H), 3.17 (t, J-7.2 Hz, 2H), 2.93 (t, J= 7.2 Hz, 2H). [00614 Step 2: Heck coupling of (3-bromophenyl)(phonethyl)sulfane and allyl amide 12 gave (E)-2,2,2-trifluoro N-(3-(3-(phenethylthio)phenyl)allyl)acetamide as a pale yellow solid. Yield (0.7 g, 31.8%); 'H NMR (400 MHz, CDC 3 ) 8 7.33 (m, 2H), 7.31-7.26 (m, 3H), 7.22 (t, J= 6.8 Hz, IMH), 7.20-7.17 (m, 3H), 6.55 (d, J = 10 16 Hz, 1H), 6.38 (br.s, 1H), 6.17 (dt, J =6.4, 15.6 Hz, 1H), 4.15 (t, J= 6.4, 2H), 3.20-3.16 (in, 2H), 2.93 (t, J= 7.6 Hz, 2H); RP-HPLC t, = 6.83 min, 97.53% (AUC); HSI MS m/z 364.33 [M-H]. [00615] Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(phonethylthio)phenyl)allyl)acetamide gave Example 70 as a light yellow oil. Yield (0.070 g, 64%); 'H NMR (400 MHz, CD 3 0D) 5 7.34-7.36 (m, 1H), 7.13-7.28 (m, 8H), 6.46-6.52 (m, 1H), 6.34 (dt, J= 6.1, 16.0 Hz, 1H), 3.38 (dd, J= 1.4, 5.9 Hz, 2H), 3.12-3.18 (m, 15 2H), 2.84-2.89 (n, 2H); RP-HPLC purity 97.1% (AUC); ESI MS m/z 253.7 [M+H-NH 3 ]*. EXAMPLE 71 PREPARATION OF 3-AMINO-1-(3-(3-PHENYLPROPYLTHIO)PHENYL)PROPAN- I -OL N s A

NH

2 20 OH [00616] 3-Amino-1-(3-(3-phenylpropylthio)phenyl)propan-1-ol was prepared following the method used in Example 8. [00617] Step 1; Alkylation of thiophenol 1 by (3-bromopropyl)benzene gave, after purification by column chromatography on a silica gel (230-400 silica-mesh, 100%A hexane) (3-bromophenyl)(3 25 phenylpropyl)sulfane. Yield (4.51g, 56%); 'H NMR (400 MHz, CDCI 3 ) 8 7.40 (t, J - 1.6 Hz, 1H), 7.31 7.26 (m, 3H), 7.22-7.16 (m, 4H), 7.11 (t, J= 8 Hz, IH), 2.91 (t J= 7.2 Hz, 2H), 2.76 (t, J= 7.6 Hz, 2H), 1.97 (quint., 2H). [00618 Step 2: Formylation of (3-bromophenyl)(3-phenylpropyl)sulfane gave, after purification by column chromatography on a silica gel (230-400 silica-mesh, 5% EtOAc - hexane) 3-(3-phenylpropylthio) 30 benzaldehyde. Yield (2775 g, 52.79%); 'H NMR (400 MHz, DMSO-d 6 ) 8 9.97 (s, 1H), 7.79 (m, 1H), 7.69 (d,J = 7.2 Hz, 1H), 7.62 (d, J= 8 Hz, 1H), 7.53 (t,1= 7.6 Hz, 1H), 7.27(t J= 7.6 Hz, 2H), 7.28 (t, J= 7.6 Hz, 3H), 3.04 (t, J= 7.2 Hz, 2H), 2.72 (t, J= 7.6 Hz, 2H), 1.88 (quint., J = 7.2 Hz, 2H). [00619] Step 3: Acetonitrile addition to 3-(3-phenylpropylthio)benzaldehyde gave, after purification by column chromatography on a silica gel (230-400 silica-mesh, 40% EtOAc - hexanes) 3-hydroxy-3-(3-(3 35 phenylpropylthio)phenyl)propanenitrile. Yield (1.40g, 43%). 'H NMR (400 MHz, DMSO-d 6 ) 8 7.34 (s, I H), 7.30 (d, J= 6.8 Hz, 1 H), 7.26 (d,1 = 6.8 Hz, 3H), 7.19 (t, J= 6.8 Hz, 4H), 5.9 (d, J= 4.4 Hz, 1H), 4.88-4.84 (m, 1H), 2.9 (t, J= 7.2 Hz, 2H), 2.86-2.77 (m, 2H), 2.70 (t, J= 7.6 Hz, 2H),1,84 (t, J= 7.2 Hz, 2H). [00620] Step 4: Borane-DMS reduction of 3-hydroxy-3-(3-(3-phenylpropylthio)phenyl)propanenitrile gave, after 40 purification by column chromatography on a silica gel (230-400 silica-mesh, 10% MeOH - CH 2 C1 2 ) Example 71. Yield (0.242 mg 34%). 'H NMR (400 MHz, CD 3 0D) 8 7.32 (m, IH), 7.25 (t, J= 7.6 Hz, 3H), 7.19-7.13 (m, 5H), 4.704 (dd, J = 5.2, 7.6 Hz, 1H), 2.9 (t, J= 7.2 Hz, 2H), 2.84-2.73 (m, 4H), 1.95-1.87 (m, 2H), 1.87-1.82 (m, 2H). "C NMR (DMSO) 5 147.3, 142.7, 138.0, 129.9, 129.5, 129.4, 128.8, 127.5, 126.9, 124.4, 73.2, 44.2, 39.5, 35.5, 33.4, 32.1; RP-HPLC purity 95.93% (AUC); ESI MS m/z 302.37 167 WO 2010/028088 PCT/US2009/055785 5 [M+HJ'. EXAMPLE 72 PREPARATION OF (E)-3-(3-(BUTYLSULFONYL)PHENYL)PROP-2-EN-1-AMINE

NH

2 10 0 [00621] (E)-3-(3-(Butylsulfonyl)phenyl)prop-2-en-I-amine was prepared following the method used in Example 66, (00622] Yield (0.524 g, 70%); 'H NMR (400 MHz, CD 3 0D) 8 7.74 (m, 1H), 7.63-7.59 (m, 1H), 7.57-7.52 (in, 2H), 6.72 (d, J=16 Hz, 1H), 6.477 (dt, J 6.0, 16 Hz, 1H), 3.543 (dd, J 1.2, 6.4 Hz, 2H), 3.00-2.93 (m. IH), 15 2.91-2.84 (m, 1H), 1.70-1.67 (m, 1H), 1.61-1.52 (m, 1H), 1.48-137 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H); RP HPLC, tx = 3.86 min, 98.8% (AUC); ESI MS m/z 238.4 [M-NH2]*. EXAMPLE 73 20 PREPARATiON OF (E)-3-(3-(cYcLoPENLm HmLTIo)PEisNYL)Rop-2-EN-1-AMtNE S NH 2 1006231 (E)-3-(3-(Cyclopentylmethylthio)phenyl)prop-2-en-I-amine (76) was prepared following the method used in Example 60 and 58. [00624] Allyl trifluoroacetamide 75 was deprotected following the method used in Example 58 to give amino 76 as 25 a colorless oil. Yield (0.083 g, 81%); 'H NMR (400 MHz, CD 3 0D) b 7.32-7.34 (m., 1H), 7.15-7.22 (m, 3H), 6.49 (dt, J= 1.4, 15.8 Hz, 1H), 6.23 (dt, J= 6.1, 15.8 Hz, IH), 3.38 (dd, J= 1.6, 6.1 Hz, 2H), 2.92 (d, J= 7.2 Hz, 2H), 2.08 (septet, J= 7.6 Hz, IH), 1.78-1.87 (m, 2H), 1.498-1.70 (m, 4H), 1.25-1.35 (m, 2H); RP-HPLC, tR = 11.00 min, 97.8% (AUC); ESI MS m/z 231.2 (M+H-NHal]. 30 EXAMPLE 74 PREPARATION OF 3-AMINo-l -(3-(CYCLOPENTYLMETHYLTHIO)PHENYL)PROPAN-1-OL g S _ NH 2 OH [00625] 3-Amino-1-(3-(cyclopentylmethylthio)phenyl)propan-1-o was prepared following the method used in 35 Examples 60 and 8. [00626] Step 1: Formylation of aryl bromide 74 following the method used in Example 4 gave, after purification by flash chromatography (5% EtoAc - hexanes) 3-(cyclopentylmethylthio)benzaldehyde as a light yellow oil. Yield (2.1 g, 43%); 1H NMR (400 MHz, CDC 3 ) 8 9.97 (s, 1H), 7.78 (s, 1H), 7.63 (d, J= 7.6 Hz, I H), 7.55 (d, J= 7.6 Hz, 1H), 7.43 (t, J= 7.6 Hz, I H), 2.99 (d, J= 7.6 Hz, 2H), 2.15-2.11 (m, 1H), 1.89-1.84 (m, 168 WO 2010/028088 PCT/US2009/055785 5 2H), 1.68-1.63 (in, 4H), 1.33-1.25 (m, 2H). 1006271 Step 2: Acetonitrile addition to 3-(cyclopentylmethylthio)benzaldehyde following the method used in Example 8 gave, after purification by column chromatography (10% to 50% EtOAc - hexanes gradient) 3 (3-(cyclopentylmethylthio)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (1.5 g, 60%); 'H NMR (400 MHz, CDCI3) 8 7.31 (in, 1H), 7.30-7.21 (in, 2H), 7.17-7.15 (m, IH), 5.01 (t, J = 6.4 Hz, 1H), 2.94 (d, 10 J= 6.8 Hz, 2H), 2.77 (d, J= 0.8 Hz, 2H), 2.36-2.10 (m, 1H), 2.04-1,83 (in, 2H), 1.81-1.63 (m, 2H), 1.62 1.52 (in, 2H), 1.33-1.25 (m, 2H). 100628) Step 3: Borane-dinethylsulfide reduction of 3-(3-(cyclopentylmethylthio)phenyl)-3-hydroxypropanenitrile following the method used in Example 33 gave, after purification by flash chromatography (5-10% 7N

NH

3 /MeOH in CH 2 Cl 2 ) Example 74 as a colorless oil. Yield (1.1 g, 72%); 'H NMR (CD 3 0D, 400 MHz) 6 15 7.36 (in, IH), 7.30-7.22 (m, 2H), 7.16 (d, J= 7.2 Hz, IH), 4.78 (dd, J= 5.2, 7.6 Hz, IH), 3.07-3.01 (m, 2H), 2.99 (d, J = 6.4 Hz, 2H), 2.14-2.03 (m, 1H), 2.00-1.94 (m, 2H), 1.86-1.80 (m, 2H), 1.70-1.65 (m, 2H), 1.62-1.55 (in, 2H), 1.37-1.29 (in, 2H); RP-HPLC, t R = 6.06 min, 95.03% (AUC); ESI MS m/z 266.30 [Mt]f. 20 EXAMPLE 75 PREPARATION OF 3-AMINO-1-(3-(CYCLOPENTYLMBTHYLTHIO)PHENYL)PROPAN- 1-ONE CrS J: NH2 [00629] 3-Amino-l-(3-(cyclopentylmethylthio)phenyl)propan-1-one was prepared following the method used in 25 Example 28. 100630] Step 1: Protection of Example 74 with Boo 2 O following the method used in Example 28 gave tert-butyl 3 (3-(cyclopentylmcthylthio)phenyl)-3-hydroxypropycarbamate as a colorless oil. Yield (1.0 g, 72%); 'H NMR (CDC 3 , 400 MHz) 7,31 (m, 1H), 7.26-7.21 (in, 2H), 7.13 (d,J= 7.2 Hz, 1), 4.88 (bs, IH), 4.70 (br.s, 1H), 3.50 (br.s, 111), 3,28 (br.s, iH), 3.18-3.15 (in, IN), 2.93 (d,J=7.6 Hz, 2H), 2.13-2.09 (in, IH), 30 1.85-1.81 (in, 4H), 1,68-1.58 (m, 2H), 1.56-1.49 (m, 2H), 1.45 (s, 9H), 1.35-1.25 (in, 2H). 100631] Step 2: Oxidation of tert-butyl 3-(3-(cyclopentylnethylthio)phcnyl)-3-hydroxypropylcarbanate with Des Martin periodinane gave, after purification by column chromatography (10% to 40% EtOAc - hexanes gradient) tert-butyl 3-(3-(cyclopentylmethylthio)phenyl)-3-oxopropylcarbamate as a colorless oil. Yield (0.55 g, 69%); 'H NMR (400 MHz, CDCl,) 8 7.87 (m, IH), 7.70 (d, J= 7.6 Hz, 1H), 7.50 (d, J= 7.6 Hz, 35 1H), 7.36 (t, J= 7.6 Hz, 1H), 6.99 (br.s, IH), 3.53 (t, J= 4.8 Hz, 2H), 3.18 (t, J= 4.8 Hz, 2H), 2.97 (d, J= 7.2 Hz, 2H), 2.16-2.06 (m, 1H), 1.88-1.84 (in, 2H), 1.65-1.60 (m, 2H), 1.57-1.54 (m, 2H), 1.42 (s, 9H), 1.32-1,27 (in, 21). [006321 Step 3: Deprotection of tert-butyl 3-(3-(cyclopentylmethylthio)phenyl)-3-oxopropycarbamate gave Example 75 hydrochloride as a white solid. Yield (0.15 g, 83%); 'H NMR (D 2 0, 400 MHz) 8 7.93 (in, 11), 40 7.81 (d, J= 7.6 Hz, IH), 7.67 (d, J= 8 Hz, 1H, 7.48 (tJ = 7.6 Hz, iH), 3.51 (t,J = 6.0 Hz, 2H), 3.40 (t, J = 5.6 Hz, 2H), 3.04 (d, J= 7.2 Hz, 2H), 2.12-2.05 (m, IH), 1.81-1.75 (m, 2H), 1.64-1.58 (in, 2H), 1.54-1.48 (m, 2H), 1.30-1.21 (m, 2H); "C NMR (CD 3 0D, 100 MHz): 8 198.4,142.2,140.4,137.8,134.5,130.4, 128.5, 126.3,40.6,40.1, 36.5, 35.9, 33.3, 26.1. RP-HPLC, t, = 5.48 min, 95.11% (AUC); ES! MS m/z 169 WO 2010/028088 PCT/US2009/055785 5 264.26 [M+H]. EXAMPLE 76 PREPARATION OF (E)-3-(3-(PHENETHYLSULFONYL)PHENYL)PROP-2-EN-1-AMINE 0' 9 ;'

NH

2 10 0 [006331 (E)-3-(3-(Phenethylsulfonyl)phenyl)prop-2-en-1-amine was prepared following the method used in Examples 70 and 62. [006341 Step 1: Oxidation of (3-bromophenyl)(phonethyl)sulfane following the method used in Example 62 gave 1 bromo-3-(phenethylsulfonyl)benzene. Yield 3.4g, 94.4%; 'H NMR (400 MHz, CDCI,) & 8.05 (s, 1H), 7.85 15 (d, J= 8.0 Hz, 1H), 7.77 (d, J= 7.6 Hz, I H), 7.44 (t, 1=8.0 Hz, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J- 6.8 Hz, 2H), 3.40- 3.35 (m, 2H), 3.08-3.04 (m, 2H). [006351 Step 2: Heck coupling of 1-bromo-3-(phenethylsulfonyl)benzone and allyl amide 12 following the method used in Example 56 gave, after purification by flash chromatography (5/-30% EtOAc - hexanes gradient) (E)-2,2,2-trifluoro-N-(3-(3-(phonethylsulfonyl)phenyl)allyl)acetamide as a pale yellow semi solid. Yield 20 (1.0 g, 42%); 'H NMR (CDC 3 , 400 MHz) 6 7.89 (m, 1H), 7.81 (d, J= 7.6 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1H), 7.53 (t, J= 7.6 Hz, 1H), 7.28-7.18 (in, 3H), 7.12 (d, J= 6.8 Hz, 2H), 6.62 (d, J= 15.6 Hz, 114), 6.52 (s, 1H), 6.303 (dt, J= 6.4 and 16 Hz, 1H), 4.22 -4.17 (m, 2H), 3.40-3.34 (m, 2H), 3.09-3.03 (m, 2H); RP HPLC, ta 5 6.06 min, 88% (AUC); ESI MS m/z 396.27 [M-H]-. 500636) Step 2: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(phenethylsulfonyl)phenyl)allyl)acetamide following 25 the method used in Example 62 gave Example 76 as a colorless oil. Yield (0.079 g, 70%); 'H NMR

(CD

3 0D, 400 MHz) 6 7.91 (t, J= 1.76 Hz, 1H), 7.71-7.78 (m, 2H), 7.55 (t, J= 7.8 Hz, 1H), 7.18-7.24 (m, 2H), 7.10-7.17 (m, 3H), 6.59-6.65 (m, 1H), 6.50 (dt,1=5.7, 15.8 Hz, 1H), 3.46-3.52 (m, 2H), 3.43 (dd, j= 1.4, 5.9 Hz, 2H), 2.93-2.98 (in, 2H); RP-HPLC, ta= 8,41 min, 93.6% (AUC); ESI MS m/z 285.2 [M+H

NH

2 ]+. 30 EXAMPLE 77 PREPARATION OF 3-(3-(PHENETHYLTTO)PHENYL)PROPAN-1-AMINE NS . N H 2 35 [006371 3-(3-(Phenethylthio)phenyl)propan-I-amine was prepared following the method used in Example 76, 4, 56. 1006381 Step 1: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-(phenethylsulfonyl)phenyl)allyl)acetamide gave 2,2,2-trifluoro-N-(3-(3-(phenthylsulfonyl)phenyl)propyl)acetamide as a yellos semi solid, Yield (0.53 g, 99%);' HNMR (CDCl 3 , 400 MHz) 6 7.309 (t, J= 19 Hz, 2H), 7.23-7.15 (m, 6H), 7.00 (d, J=5.6 Hz, 1H), 6.20 (bs, 1H), 3.40 (q,1=6.4 Hz, 2H), 3.17 (t, J= 7.8 Hz, 2H), 2.93 (t, J 8.0 Hz, 2H), 2.65 (t, 1J 7.6 Hz, 40 2H), 1.92 (quintet, 2H). [00639] Step 2: Deprotection of 2,2,2-trifluoro-N-(3-(3-(phenethylsulfonyl)phenyl)propyl)acetamide following the method used in Example 56 gave, after purification by column chromatography (10% 7N NH3 in 5%-20% of MeOH - DCM gradient) Example 77 as a yellow oil. Yield (0.250 g, 75%); 'H NMR (CDC 3 with 5% 170 WO 2010/028088 PCT/US2009/055785 5 D20, 400 MHz) 8 7.30 (t, J=7.6 Hz, 2H), 7.24-7.21 (m, 3H), 7.19-7.17 (m, 3H), 7.01 (d, J= 6.8 Hz, IH), 3.17 (t,1=7.6,2H), 2.92 (t,J= 7.6 Hz, 2H), 2.73 (br.s, 2H), 2.63 (t, J= 7.6 Hz, 2H), 1.75 (quintet,J= 7.2 Hz, 2H); "C NMR (DMSO-d, 100 MHz) 8 143.3, 140.0, 135.8, 128.9, 128.5, 128.3, 127.9, 126.2, 125.7, 125.5, 41.0, 38.9, 34.7, 34.6, 33.4, 32.3; RP-HPLC tR = 6.21 min, 95.03% (ALJC); ESI MS m/z 272.30 [M+HJ*. 10 EXAMPLE 78 PREPARATION OF (E)-1 -((3-(3-AMINOPROP-1-ENYL)PHENYLTHIO)MEmHYL)CYCLOHEXANOL OH I ci-:rN NH 2 Cr 15 [00640] (E)-]-((3-(3-Aminoprop-1-enyl)phenylthio)methyl)cyclohexano was prepared following the method used in Example 25 and 56. (006411 Step 1: Reaction between 1-oxaspiro(2.5]octane and thiophenol 1 following the method used in Example 25 gave 1-((3-bromophenylthio)methyl)cyclohexanol as a light yellow oil. Yield (2.8 g, 70%); 'H NMR (CDCI, 400 MHz) 8 7.53 (s, 1H), 7.31 (dd, J= 8.0, 12 Hz, 2H), 7.12 (t, J- 8.0 Hz, 1H), 3.10 (s, 2H), 1.95 20 (s, 11), 1.68-1.58 (m, 4H), 1.51-1.42 (m, 4 H), 1.25-1.21 (m, 2H). [006421 Step 2: Heck coupling of 1-((3-bromophenyltbio)methyl)cyclohexano and allyl amide 12 following the method used in Example 56 gave, after purification by column chromatography (40 % EA - hexanes) (E) 2,2,2-trifluoro-N'-(3-(3-(1-hydroxycyclohexyl)methylthio)phenyl)allyl)acetamide as a light yellow oil. Yield (1.0 g, 43%); 'H NMR (CD 3 0D, 400 MHz) 8 7,42 (m, 1H), 7.27 (dt, J= 2.0, 6.4 Hz, 1 H), 7.24-7.20 25 (m, 2H), 6.55 (d, J=16 Hz, 1H), 6.24 (dt, J= 6.4, 16 Hz, 1H), 4.05 (d, J 6 Hz, 2H), 3.1 (s, 2H), 1,68-1.62 (m, 4H), 1.51-1.59 (m, 3H), 1.44-1.47 (m, 2H), 1.29-1.30 (m, IH). (00643j Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-((l hydroxycyclohexyl)methylthio)phenyl)allyl)acetamide gave, after purification by flash chromatography (20% to 50% of 20% 7N NH 3 /MeOH/CH2C 2 - CH 2

C

2 gradient) Example 78 as a colorless oil. Yield 30 (0.060 g, 81%); 'H NMR (CD 3 0D, 400 MHz) 8 7,40-7.41 (m, 1H), 7.17-7.26 (m, 4H), 6.49 (dt, J = 1.4, 16.0 Hz, IH), 6.34 (dt, J= 6.1, 15.8 Hz, 1H), 3.39 (dd, J = 1.6, 6.1 Hz, 2H), 3.07 (s, 211), 1.49-1.68 (m, 7H), 1.40-I.47 (m, 2H), 1.20-1.30 (m, 1H); RP-HPLC tR = 8.68 min, 97.1% (AUC); ESI MS m/z 243.2 [M

NH

3

-H

2 0+H]*. 35 EXAMPLE 79 PREPARATION OF (E)-3-(3 -AMINOPROP-1 -ENYL)-N-(HEPTAN-4-YL)BBNZENESULFONAMIDE HNH N",11 . NH1 2 0 [00644] (E)-3-(3-Aninoprop-1-enyl)-N-(heptan-4-yl)benzenesulfonamide was prepared following the method used 40 in Example 68. [00645) Yield (0.55 S, 96%); 'H NMR (400 MHz, CDCI 3 ) 8 7.76 (s, 1H), 7.63-7.61 (m, 2H), 7.53 (t, J =8 Hz, I H), 171 WO 2010/028088 PCTIUS2009/055785 5 6.61 (d, J =16 Hz, 1H), 6.42 (dt, J -5.6 Hz and 16 Hz, 1H), 3.37 (d, J =5.2, 2H), 3.06-3,03 (m, I H), 1.33 1.25 (m, 4H), 1.23-1.17 (m, 4H), 1.09-1.03 (m, 2H), 0.65 (t, J -7.2 Hz, 6H); "C NMR (DMSO-d 6 , 100 MHz) 8 142.8, 137.7, 132.6, 129.3, 127.8, 124.8, 123.4, 52,7, 42.8, 36.5, 18.0, 13.6; RP-HPLC purity 99.69% (AUC); ESI MS miz 309.51 [M-H], 10 EXAMPLE 80 PREPARATION OF 3-(3-(CYCLOHEXYLMETHYLSULFINYL)PHENYL)PROPAN-1-AMINE 0 S N NH 2 1006461 3-(3-(Cyclohexylmethylsulfinyl)phenyl)propan-1-amine was prepared following the method used in 15 Examples 69 and 59. (006471 Step 1: Hydrogenation of (E)-N-(3-(3-(cyclohexylmethylsulfinyl)phenyl)allyl)-2,2,2-trifluoroacetamide following the method used in Example 59 gave N-(3-(3-(cyclohexylmethylsulfinyl)phenyl)propyl)-2,2,2 trifluoroacetamide as a colorless oil. Yield (0.57 g, 71%) 'H NMR (DMSO-d, 400 MHz) a 9,45 (br.s, 1H), 7.48-7.50 (m, 3H) 7.37 (br.s, 1H), 3.20 (q, J= 6.8 Hz, 2H), 2.67-2.50 (m, 4H), 1.95-1.90 (m, 1H), 1.85 20 1.75 (m, 2H), 1.71-1.59 (m, 41H), 1.28-1.03 (m, 6H); ESI MS m/z 278 [M+Hl. [00648] Step 2: Deprotection of N-(3-(3-(cyclohexylmethylsulfinyl)phenyl)propyl)-2,2,2-trifluoroacetanide following the method used in Example 69 gave Example 80 as a pale yellow oil. Yield (0.265g, 64%); 'H NMR (DMSO-d 6 , 400 MHz) 8 7.56 (m, 1H), 7.47 (d, J= 7.2 Hz, 2H), 7.355 (d, J=6.4 Hz, I H), 2.71-2.66 (m, 4H), 2.54-2.50 (m, 2H), 1.935 (d, J= 12.8 Hz, 1H), 1.68-1.55 (m, 8H), 1.27-1.00 (m, 6H); RP-HPLC t 25 - 4.64 min, 97.31% (AUC); ESI MS i/z 280.28 [M+H]' EXAMPLE81 PREPARATION OF 3-(3-AMINO-2-HYDROXYPROPYL)-N-CYCLOHEXYLBENZENESULFONAMIDE OH 30 [006491 3 -(3-Amino-2-hydroxypropyl)-N-cyclohexylbenzenesulfonamide was prepared as shown in Scheme 27. SCHEME 27 172 WO 2010/028088 PCT/US2009/055785 Br NHBoc Ho N S Br IsN ". A Ho 0 Pd(OAc)2, TBAA T0 MCPBA, Na 2

CO

3 Q '.. 0 NHBoc Et 3 N-HCOOH

CH

2

C

2 O 6 Pd/C, E0H A 11 K 2 C0 3 Ho A OH N t INN NHBoc

,

2

NH

2 5 MoOH:H20 100650] Step 1: Heck coupling between aryl bromide 20 and ally) amide 12 following the method used in Example 66 gave allylcarbamate 77 as an orange oil. Yield (0,71 g, 53%); 'H NMR (400 MHz, CDC 3 ) 5 7,84 (t, J= 1.57 Hz, IH), 7.71 (dt, J= 1.2, 7.8 Hz, 1 H), 7.49-7.54 (m, 1H), 7.39-7.45 (m, 1H), 6.52 (d, J= 16.0 Hz, 1H), 6.30 (dt, J= 5.8, 15.8 Hz, 1H), 4.70 (br.s, 1H), 4.43 (br.d, J= 7.6 Hz, 1H), 3.85-3.95 (m, 2H), 3.10 10 3.20 (m, 1H), 1.68-1,79 (m, 2H), 1.56-1.66 (m, 2H), 1.38-1.54 (m, 10H), 1.05-1.30 (m, 5H). [006511 Step 2: To a solution of allylcarbamate 77 (0.48 g, 1.217 mmol) in CH 2

C

2 was added MCPBA (77%, 0.72 g, 3.2 mmol) followed by NaHCO 3 (0.24 g, 2.86 mmol) and Na 2

CO

3 (0.24 g, 2.27 mmol). The reaction mixture was stirred at room temperature for 3 hrs. Aqueous NaHCO 3 (10%) was added and the product was extracted with CH 2

C

2 three times. Combined organic layers were washed with brine-NaHCO 3 , dried over 15 anhydrous Na 2

SO

4 and concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc - hexanes gradient) gave epoxide 78 as a colorless oil which was used in the next step without further purification. Yield (0.322 g, 64%). [006521 Step 3: A mixture of epoxide 78 (0.278 g, 0.676 mmol), HCOOH'Et 3 N complex (5:2, 1.5 mL), Pd/C (10% wt, 0.048 mg) in absolute EtOH was degassed by applying vacuum/argon 3 times. The reaction mixture 20 was stirred at room temperature for 2 hr, then concentrated under reduced pressure. Purification by flash chromatography (20% to 100% EtOAc - hexanes gradient) gave alcohol 79 as a colorless oil. Yield (0.075 8 g, 27%); 'H NMR (400 MHz, DMSO-d4) 6 7,64-7.67 (m, 1H), 7.60 (dt, J = 2.2,6.5 liz, IH), 7.50 (d, J= 7.4 Hz, I H), 7.39-7.45 (m, 2H), 6.72 (br.t, J=5.5 Hz, 1H), 4.76 (d, J= 5.3 Hz, 1H), 3,60-3.68 (m, 1 H), 2.82-2.89 (m, 3H), 2.77 (dd, J= 4.3, 13.9 Hz, 1H), 2.56 (dd, J= 8.0, 13.7 Hz, 1H), 1.48-1.58 (m, 4H), 25 1.35 (s, 9H), 1.30-1.40 (m, 1H), 0.92-1.12 (m, 5H). [00653] Step 4: A mixture of carbamate 79 (0.0758 g, 0.184 mmol), HC1/i-PrOH (5.5 N, 1.0 mL) in EtOAc was stirred at room temperature for 3 hrs and concentrated under reduced pressure to give Example 81 hydrochloride as a colorless oil. Yield (0.0585 & 91%); 'H NMR (400 MHz, CD 3 OD) 8 7.77-7.80 (n, 1H), 7.73 (dt, J= 1.8, 7.2 Hz, 1H), 7.47-7.54 (m, 2H), 3.99-4.06 (m, 1H), 2.78-3.10 (m, 5H), 1.60-1.70 (m, 4H), 30 1.47-1.54 (in, 1H), 1.08-1.30 (m, 5H); ESI MS m/z 313.0 [M+Hfl. EXAMPLE 82 PREPARATION OF (E)-3-(3-(2-PROPYLPENTYLTnO)PHENYL)PRoP-2-EN-1-AMINE 35 N A NH 2 173 WO 2010/028088 PCTIUS2009/055785 5 (00654] (E)-3-(3-(2-Propylpentylthio)phenyl)prop-2-en-l-amine is prepared from (E)-2,2,2-trifluoro-N-(3-(3-(2 propylpentylthio)phenyl)allyl)acetamide (E)-2,2,2-Trifiuoro-N-(3-(3-(2 propylpentylthio)phenyl)allyl)aoetamide was prepared following the method described below, [006551 Step 1: Heck coupling of (3-bromophenyl)(2-propylpentyl)sulfane and allyl aide 12 following the method used in Example 66 gave, after purification of the crude by flash chromatography (5% to 30% 10 EtOAc - hexane gradient) (E)-2,2,2-trifluoro-N-(3-(3-(2-propylpentylthio)phenyl)allyl)acetamide as a pale yellow semi-solid. Yield (0.85 g, 71 %); 'H NMR (CDC 3 , 400 MHz) 6 7.30 (s, 1H), 7.26-7.22 (in, 2H), 7.14 (d, J= 6.0 Hz, lH), 6.55 (d, J= 15.6 Hz, lH), 6.5 (br.s, 1H), 6.20-6.13 (m, 1H), 4.15 (t, J =6.0 Hz, 2H), 2.90 (d, J = 6.4 Hz, 2H), 1.65 (t, J= 6.0 Hz, I H), 1.44-1.25 (m, 8H), 0.89 (t, J= 6.8 Hz, 6H). RP HPLC purity 94.92% (AUC); ESI MS m/z 372.26 [M-H). 15 [006561 Step 2: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-(2-propylpentylthio)phenyl)allyl)acetamide following the method used in Example 56 gives Example 82. EXAMPLE 83 20 PREPARATION OP 3-(3-(2-PROPYLPENTYLTHIO)PHENYL)PROPAN-1-AMINE S N NH 2 [00657J 3-(3-(2-Propylpentylthio)phenyl)propan-l-amine is prepared following the method used in Example 59. [006581 Step 1. Hydrogenation of Example 82 following the method used in Example 59 gives Example 83. 25 EXAMPLE 84 PREPARATION OF 3-(3-(2-PROPYLPENTYLSULFINYL)PHENYL)PROPAN- I -AMINE S

NH

2 0 [006591 3-(3-(2-Propylpentylsulfinyl)phenyl)propan-1-amine was prepared following the method used in Examples 30 67, 59. 100660] Step 1: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-(2-propylpentylsulfinyl)phenyl)alIyl)acetamide following the method used in Example 59 gave 2,2,2-trifluoro-N-(3-(3-(2 propylpentylsulflnyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (0.5 g, 71%); 'H NMR (400 MHz, CDCI 3 ) 8 8.01 (s, 1H), 7.45-7.39 (m, IH), 7.31 (t, J= 7.2 Hz, 1H), 6.46 (br,s, I H), 3.40 (q, J= 7.2, 35 13.6 Hz, 2H), 2.75 (t, J= 7.6 Hz, IH), 2.55 (dd, J= 8.8, 13.2 Hz, 1H), 2,00-1.95 (m, 2H), 1.57-1.55 (in, lH), 1.45-1.41 (in, 2H), 1.41-1.30 (m, RH), 0.93-0.86 (m, 6H). [00661) Step 2: Deprotection of 2,2,2-trifluoro-N-(3-(3-(2-propylpentylsulfinyl)phenyl)propyl)acetamide following the method used in Example 9 gave Example 84 as a pale yellow semi solid. Yield (0.04 g, 10%); I H NMR (400 MHz, DMSO-d) 8 7.49-7.46 (m, 3H), 7.36 (br.s, 1H), 2.72-2.66 (in, 4H), 2.55-2.53 (in, 2H), 1.85 40 1.75 (i, 1H), 1.68-1.63 (m, 2H), 1.52-1.46 (in, 1H), 1.35-1.19 (m, 8H), 0.85 (t, J= 6.8 Hz, 3H), 0.80 (t, J= 6.8 Hz, 3H); RP-HPLC purity 95.4% (AUC); ESI MS n/z 295.30 [M+Hf. 174 WO 2010/028088 PCTIUS2009/055785 5 EXAMPLE 85 PREPARATION OF 3-(3-(2-PROPYLPNTYLSULFONYL)PHENYL)PROPAN. 1-AMINE N NH 2 S 11 0 [00662] 3-(3-(2-Propylpentylsulfonyl)phenyl)propan-1-amine is prepared following the method used in Example 10 59. 100663] Step 1: Hydrogenation of Example 62 following the method used in Example 59 gives Example 85. EXAMPLE 86 15 PREPARATION OF (E)-3-(3-(CYCLOAPENTYLMETHYLSULFNm)PHENYL)PRoP-2-EN-1-AMINE S NH 2 [00664] (E)-3-(3-(Cyclopentylmethylsulfinyl)phenyl)prop-2-en-1-amine was prepared following the method used in Example 61. [00665] Yield (0.6 g, 82%); 'H NMR (400 MHz, CDC 3 ) 6 7.66 (m, 1H), 7,47-7.42 (m, 3H), 6.56 (d, J= 16 Hz, 20 1 H), 6.43 (dt, J= 5.6,16 Hz, 1H), 3.53 (d, J= 5.6 Hz, 2H), 2.94 (dd, J= 6, 12.8 Hz, 1H), 2.66 (dd, J1 8.8, 12.8, 1H), 2.32-2.28-(m, IH), 2.03-1.98 (m, 1H), 1,90-1.85 (m, 1H), 1.68-1.55 (m, 4H), 1.35-1.22 (m, 211); RP-HPLC purity 95.4% (AUC); E81 MS m/z 248,18 [M+H]t. EXAMPLE 87 25 PREPARATION OF 3-(3-AMINOPROPYL)-N-CYCLOPENTYLBENzENESULFONAMIDE IIHNI (

NH

2 [00666] 3-(3-Aminopropyl)-A-cyclopentylbenzenesulfonamide was prepared following the method used in Example 65. 30 [00667] Step 1: Hydrogenation of Example 65 following the method used in Example 57 gave crude 3-(3 aminopropyl)-N-cyclopvntylbenzenesulfonamide as a colorless oil. Yield (0.3 g, 99%); 'H NMR (400 MHz, DMSO-d + 5% D 2 0) 8 7.62-7.60 (m, 2H), 7.51- 7.44 (m, 2H), 3.37-3.32 (m, 1H), 2.68 (t, J= 8.0 Hz, 2H), 2.59 (t, J= 7.2 Hz, 2H), 1.74-1.67 (m, 2H), 1.54-1.50 (m, 4H), 1.34-1.30 (m, 2H), 1.25-1.20 (m, 2H). 35 [006681 Step 2: Protection of 3-(3-aniinopropyl)-N-cyclopentylbenzenesulfonamide (0.34 g, 1.2 mmol) with Boc20 (0.289 g, 1.32 mmol) gave tert-butyl 3-(3-(N-cyclopentylsulfamoyl)phenyl)propylcarbamate as a pale yellow oil, Yield (0.415 g, 90%); 'H NMR (400 MHz, CDC 3 ) 8 7.70 (d, J= 6.4 Hz, 2H), 7.43-7.36 (m, 2H), 4.56 (s, 2H), 3.63-3.59 (m, 1H), 3.15-3.10 (m, 2H), 2.72 (t, J= 8 Hz, 2H), 1.86 -1.75 (m, 4H), 1.63 1.60 (m, 2H), 1.45 (s, 9H), 1.40-1.35 (m, 2H). 175 WO 2010/028088 PCT/US2009/055785 5 [00669] Step 3: Deprotection of tert-butyl 3-(3-(N-cyclopentylsulfamoyl)phenyl)propylcarbamate gave Example 87 as a yellow semi solid. Yield (0.22 g, 63%); 'iH NMR (400 MHz, CD3OD) 8 7.74-7.71 (m, 2H), 7,51(d, J1= 4.8 Hz, 2H), 3,51-3,46 (m, 1H), 2.96 (t, J= 8.0 Hz, 2H), 2.82 (t, J= 8,0 Hz, 2H), 2,03- 1.96 (n, 2H), 1.71 1.61 (m, 4H), 1.48-1.45 (in, 2H), 1.39-1.29 (m, 2H); "C NMR (CD 3 OD, 100 MHz) 8 143.2, 143.1,133.5, 130.4, 127.7, 126.0, 56.2, 40.3, 33.9, 33.2, 30.1, 24.1; RP-HPLC ta = 4

.

26 min, 95.26% (AUC); ES] MS 10 m/z 283.30 [M+H]f. EXAMPLE 88 PREPARATION OF 3-AMINO-l-(3-(cYcLoPENTYLMETHYLSULFINYL)PHENYL)PROPAN-1-OL y NH 2 15 OOH (00670] 3-Anino-1-(3-(cyclopentylmethylsulfinyl)phenyl)propan-1-ol was prepared following the method used in Examples 75, 58 and 74. [00671] Step 1; tert-butyl 3-(3-(cyclopentylmethylthio)phenyl)-3-hydroxypropylcarbamate was oxidized following the method used in Example 58 to give tert-butyl 3-(3-(cyclopentylmethylsulfinyl)phenyl)-3 20 hydroxypropylcarbamate as a pale yellow oil. Yield (0.2 g, 64%); 'H NMR (CDCl 3 , 400 MHz) 8 7.31 (m, 1H), 7,26-7,21 (m, 2H), 7.13 (d, J - 7.2 Hz, 1H), 4.88 (br.s, 1H), 4.70 (t, J= 5.2 Hz, 1H), 3,50 (ba, IlR), 3.28 (bs, 1 H), 3.20-3.09 (m, 1 H), 2.91-2.96 (m, IH), 2,63-2.68(m, IH) 2.09-2.13 (m, 1H), 1.81-1.85 (m, 4H), 1.58-1.68 (m, 2H), 1,49-1.56 (n, 2H), 1.45 (s, 9H), 1.25-1.35 (m, 2H). [00672] Step 2: To a stirred solution of tert-butyl 3-(3-(cyclopentylmethylsulfinyl)phenyl)-3 25 hydroxypropylcarbamate (0.2 g, 0.524 mmol) in anhydrous DCM, TFA (0.3 g, 2,62 mmol) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 17 hrs and concentrated under reduced pressure. The residue was purified by flash chromatography (5% to 10% MeOH - DCM gradient) to give Example 88 hydrochloride as a white semi-solid, Yield (0.125 g, 84%); 'H NMR (400 MHz, CDOD) 6 7.77 (d, J= 7.2 Hz, 1H), 7.59 (m, 3H), 4.94 (dd, J= 3.6, 8.8 Hz, I H), 3.06-3.16 (m, 2H), 30 2.96-3.02 (m, IH), 2.85-2.90 (m, 1H), 2.21-2.29 (m, IH), 2.03-2.09 (in, 1H), 1.94-2.01 (m, 2H), 1.85-1.87 (m, 1H), 1.65-1.70 (m, 2H), 1,59-1.62 (m, 2H), 1.37-1.42 (m, 1HI), 1.29-1.35 (m, 1H); RP-HPLC purity 94.65% (AUC); ESI MS m/z 282,2 [M+H]*, EXAMPLE 89 35 PREPARATION OF 3-AMINo- 1-(3-(CYCLOPENTYLMTHYLsULFINYL)PHENYL)PRoPAN- 1-ONE NH2 [006731 3-Amino-1-(3-(cyclopentylmethylsulfinyl)phenyl)propan-l-one is prepared following the method used in Example 75. 40 [006741 Step 1: Protection of Example 88 following the method used in Example 75 gives tert-butyl 3-(3 (cyclopentylmethylsulfinyl)phenyl)-3-hydroxypropylcarbamate. 176 WO 2010/028088 PCT/US2009/055785 5 [006751 Step 2: Oxidation of tert-butyl 3-(3-(cyclopentylmethylsufinyl)pheny])-3-hydroxypropylcarbamate gives tert-butyl 3-(3-(cyclopentylmethylsulfmyl)phenyl)-3-oxopropylcarbamate. [006761 Step 3: Deprotection of tert-butyl 3-(3-(cyclopentylmethylsulfinyl)phenyl)-3-oxopropylcarbamate gives Example 89 hydrochloride. 10 EXAMPLE 90 PREPARATION OF 3-AMINO- 1-(3-(CYCLOHEXYLMErMYLSULFINYL)PHENYL)PROPAN-I-ON E N ) NH 2 0 0 (00677] 3-Amino-1-(3-(cyclohexylmethylsulfinyl)pheny)propan-1-one is prepared following the method used in 15 Examples 8, 28, and 58. [006781 Step 1: Protection of Example 8 with Boc 2 0 following the method used in Example 75 gives tert-butyl 3 (3-(cyclohexylmethylthio)phenyl)-3-hydroxypropylcarbamate. [006791 Step 2: Oxidation of rert-butyl 3-(3-(cyclohexyhnethy]thio)phenyl)-3-hydroxypropylcarbamate following the method used in Example 58 gives tert-butyl 3-(3-(cyclohoxylmethylsulfinyl)phenyl)-3 20 hydroxypropylcarbamate. [00680] Step 3; Oxidation of tert-butyl 3-(3-(cyclohoxylmethylsulfinyl)phenyl)-3-hydroxypropylcarbamate following the method used in Example 28 gives tert-butyl 3-(3-(cyclohexylmethylsulfinyl)phenyl)-3 oxopropylcarbamate. [00681] Step 4: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfinyl)phenyl)-3-oxopropylcarbamate 25 following the method used in Example 28 gives Example 90, EXAMPLE 91 PREPARATION OF3-AMINO-1-(3-(BENZYLTHIO)PHENYL)PROPAN-1 -OL N sNO -1 NH 2 30 OH (00682] 3-Amino-1-(3-(benzylthio)phenyl)propan- 1-ol was prepared following the method used in Examples 23 and 8. [00683] Step 1: Formylation of benzyl(3-bromophenyl)sulfane following the method used in Example 8 gave, after purification by column chromatography (silica gel, 100-200 mesh, 1% ethyl acetate in hexanes) 3 35 (benzylthio)benzaldehyde. Yield (0.9 g, 30%); 'H NMR (400 MHz, DMSO-d 6 ) 5 9.96 (s, 11), 7.83 (t, J 1.6, 1H), 7.70-7.63 (in, 2H), 7.51 (t, J= 7.6 Hz, 1H), 7.38 (d, J - 7.2 Hz, 2H), 7.27 (t, J= 7.6 Hz, 211), 7.25-7.21 (in, I H), 4.33 (s, 2H). [006841 Step 2: Acetonitrile addition to 3-(benzylthio)benzaldehyde following the method used in Example 8 gave, after purification by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexanes) 3-(3 40 (benzylthio)phenyl)-3-hydroxypropanenitrile. Yield (0,5g, 67%).'H NMR (400 MHz, DMSO-d 6 ) 8 7.39 (I, 1H), 7.35 (d, J= 6.4 Hz, 2H), 7.29 (t, J= 7.2 Hz, 2H), 7.26-7.16 (in, 4H), 5.96 (d, J= 4.8 Hz, IH), 177 WO 2010/028088 PCTIUS2009/055785 5 4.860 (q, J= 6.4 Hz, 1H), 4.24 (s, 2H), 2.88 (dd, J= 4.8,16.8 Hz, 1H), 2.79 (dd, J= 6.8,16.8 Hz, IH). [00685] Step 3: Borane-DMS reduction of 3-(3-(benzylthio)phenyl)-3-hydroxypropanenitrile gave, after purification by column chromatography (100-200 silica mesh, 10% MeOH in DCM with NH 3 ) Example 91 as a colorless oil. Yield (0.130 g, 51%). 'H NMR (400 MHz, DMSO-d6) 8 7.34 (d, J= 7.2, 2H), 7.30-7.27 (in, 3H), 7.22 (t, J= 7.2, 2H), 7.16 (d, J= 7.6,1H), 7.11 (d, J= 7.6 Hz, 1H), 4.6 (t, J= 6.4, 1H), 4.21 (a, 10 2H), 3.37 (br.s, 1 H), 2.60 (sextet, J= 6.4 Hz, 2H). 1.62-1.57 (n, 2H), RP-HPLC purity 94.80% (AUC); ESI MS m/z 274.16 [M+H]. EXAMPLE 92 15 PREPARATION oF 3-Amio- 1 -(3-(BENZYLsuLFoNYL)PHENYL)PRoPAN-1-OL

NH

2 x 0 OH [00686] 3-Amino-1-(3-(benzylsulfonyl)phenyl)propan-l-o was prepared following the method used in Examples 91 and 3. [006871 Step 1: Oxidation of 3-(3-(benzylthio)phenyl)-3-hydroxypropanenitrile following the method used in 20 Example 3 gave 3-(3-(benzylsulfonyl)phenyl)-3-hydroxypropanenitrile as a white solid. Yield (0.22 g, 78%); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.79 (m, 1H), 7.74 (d, J= 6.8 Hz, 1H), 7.59-7.54 (i, 2H), 7.33 7.25 (m, 3H), 7.12 (d, J= 6.8, 2H), 6.19 (d, J= 4.4 Hz, IH), 5.03 (q, J= 4.8, 11), 4.64 (s, 2H), 2.91 (dd, J = 4.8, 16.8 Hz, 1H), 2,82 (dd, J= 6.8, 16.8 Hz, 1H). [00688] Step 2: Borane-DMS reduction of 3-(3-(benzylsulfonyl)phenyl)-3-hydroxypropanenitrile gave Example 92 25 as a colorless oil. Yield (0.120 mg, 54%). 'H NMR (400 MHz, DMSO-d) 8 7.63 (m, 2H), 7.57-7.49 (m, 2H), 7.31-7.25 (m, 3H), 7.12 (d, J= 6.4,1H), 4.74 (t, J= 6.4, 1H), 4.63 (s, 2H), 2.64-2.55 (in, 2H), 1.59 (q, J= 6.4 Hz, 2H). RP-HPLC purity 95.7% (AUC); ESI MS m/z 306.18 [M+Hf. EXAMPLE 93 30 PREPARATION OF 3-(3-(PHENETHYLSULFONYL)PHENYL)PROPAN-1-AmINE

NH

2 0 [00689] 3-(3-(Phenethylsulfonyl)phenyl)propan-I-amine was prepared following the method used in Example 76, 57. 35 [006901 Step 1: (E)-2, 2

,

2 -Trifluoro-N-(3-(3-(phenethylsulfonyl)phenyl)allyl)acetamide was hydrogenated following the method used in Example 57 to give 2,2,2-trifluoro-N-(3-(3 (phenethylsulfonyl)phenyl)propyl)acetami de as a colorless oil. Yield (0.782 g, 92%); 'H NMR (CDCI 3 , 400 MHz) 8 7.78 (d, J=7.2 Hz, 1 H), 7.75 (s, 111), 7.53-7.46 (in, 2H), 7.28-7.12 (m, 3H), 7.12 (d, J = 7.2,211), 6.37 (br.s, 1H), 3.43 -3.35 (m, 4H), 3.06 (t, J=7.6 Hz, 2H), 2.76 (t, J= 7.8 Hz, 2H), 1.97 (quintet,J =7.6 40 Hz, 2H). [00691] Step 2: Deprotection of 2, 2

,

2 -trifluoro-N-(3-(3-(phenethylsulfonyl)phenyl)propyl)acetamide following the 178 WO 2010/028088 PCT/US2009/055785 5 method used in Example 57 gave, after purification by flash chromatography (5% to 20% of 10% 7N

NH

3 /MeOH/CH 2

CI

2 - CH 2 C1 2 gradient) Example 93 as a colorless oil. Yield (0,376 g, 63%); 'H NMR (CDCI, + 5% D20,400 MHz) 6 7.75 (t, J= 4 Hz, 2H), 7.47 (d, J= 7.6 Hz, 2H), 7.28-7.18 (m, 3H), 7.1 1 (d, J= 6.8 Hz, 2H), 3.37-3.33 (m, 2H), 3,07-3.02 (in, 2H), 2.77-2.71 (in, 4H), 1.80 (quintet, J- 7.6 Hz, 2H); "CNMR (CDCI , 100 MHz) 8 143.0, 138.1, 136.6, 133.0,128.4,127.7, 127.3,126.8, 126.0,124.6, 56.6, 10 40.6, 33.9, 32.1, 27.75; RP-HPLC tR = 4.54 min, 95,62% (AUC); ESI MS m/z 304.28 [M+H]t EXAMPLE 94 PREPARATION OF 3-AMINO-1-(3-(3-CYCLOIEXYLPROPYLTHIO)PHENYL)PROPAN-1-OL 15"

NH

2 15 OH 1006921 3-Amino-l-(3-(3-cyclohexylpropylthio)pheny)propan-1-ol was prepared following the method used in Examples I and 8. 100693J Step 1: Alkylation of thiophenol 1 with 3-cyclohexylpropyl 4-methylbenzenesulfonate following the method used in Example 1 gave (3-bromophenyl)(3-cyclohexylpropyl)sulfane as a colorless liquid. Yield 20 (4.59 g, 73%); 'H NMR (400 MHz, CDC 3 ) 8 7.42 (t, J= 2Hz, 1H), 7.28-7.26 (in, 1H), 7.21 (dd, J=L.6, 6.8 Hz, 1 H), 7.12 (t, J= 7.6 Hz, 1 H), 2.89 (t, J= 7.6 Hz, 2H), 1.69-1.61 (m, 7H), 1.33-1.28 (m, 2H), 1.25-1.11 (m, 4H), 0.91-86 (m, 2H).. [00694] Step 2; Formylation of (3-bromophenyl)(3-cyclohexylpropyl)sulfane following the method used in Example 8 gave, after purification by column chromatography (silica gel, 100-200 mesh, 0% to 20% ethyl 25 acetate in hexanes) 3-(3-cyclohexylpropylthio)benzaldehyde as a pale yellow oil. Yield (2.0 g, 52%); ' H NMR (400 MHz, CDC1 3 ) 8 9.97 (s, 1H), 7.78 (in, 1H), 7.64 (d, J= 7.6 Hz, 11), 7.54 (d, J= 7.6 Hz, IH), 7.43 (t, J= 7.6 Hz, 1H), 2.96 (t, J= 7.6 Hz, 2H), 1.71-1.64 (m, 6H), 1.39-1.31 (m, 2H), 1.30-1.11 (in, 5H), 0.94-0.83 (m, 2H).. [006951 Step 3: Acetonitrile addition to 3-(3-cyclohexylpropylthio)benzaldehyde following the method used in 30 Example 8 gave, after purification by column chromatography (silica gel, 100-200 mesh, 0% to 40% EtOAc - hexanes gradient) 3-(3-(3-cyclohexylpropylthio)phenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (1.76 g, 76%); 1H NMR (400 MHz, CDC1 3 ) 8 7.33 (m, 1H), 7.30-7.28 (m, 2H), 7.17 (d, J= 6.8 Hz, IH), 5.01 (t, J= 5.6 Hz, 1 H), 2.91 (t, J= 7.6 Hz, 2H), 2.76 (t, J= 5.6 Hz, 2H), 2.33 (s, 1H), 1.69-1.62 (m, 7H), 1.34-1.29 (in, 2H), 1.25-1.11 (m, 4H), 0.95-0.79 (m, 2H). 35 [00696 Step 4: Borane-DMS reduction of 3-(3-(3-cyclohexylpropylthio)phenyl)-3-hydroxypropanenitrile following the method used in Example 8 gave, after purification by column chromatography (silica gel 100-200 mesh, 0% to 10% 7N NH 3 /MeOH in CH 2

CI

2 gradient) Example 94 as a light green oil. Yield (0.24 g, 59%); 1H NMR (DMSO-d 6 + 5% D20, 400 MHz) 8 7.25-7.21 (m, 2H), 7.12 (d, J= 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, TH), 4.58 (t, J = 6.4 Hz, 1H), 2.88 (t, J= 7.2 Hz, 2H), 2.58 (t, J= 6.8 Hz 2H), 1.66-1.49 (m, 40 811), 1.29-1.03 (in, 7H), 0.83-0.75 (m, 2H); RP-HPLC purity 92% (AUq; ES1 MS m/z 308.29 [M+H]. EXAMPLE 95 PREPARATION OF 3-AMINO-1-(3-(3-CYCLOHEXYLPROPYLSULFONYL)PHENYL)PROPAN-1-OL 179 WO 2010/028088 PCT/US2009/055785 5 NH 2 5 0 OH 5006971 3-Amino-1-(3-(3-cyclobexylpropylsulfonyl)phenyl)propan-1-o was prepared following the method used in Example 94 and 92. [006981 Step 1: Oxidation of 3-(3-(3-cyclohexylpropylthio)phenyl)-3-hydroxypropanenitrilo following the method used in Example 92 gave 3-(3-(3-cyclohexylpropyisulfonyl)phenyl)-3-hydroxypropanenitrile. Yield (0.2 g, 10 90%); 'H NMR (400 MHz, CDC 3 ) 5 7.96 (s, 11-1), 7.89 (d, J= 7.6 Hz, 1H), 7.73 (d, J= 7.6 Hz, I H), 7.62 (t, J= 7.6 H, 1H), 5.17 (t, J= 6.0 Hz, 1H), 3.07 (t, J= 8.0 Hz, 211), 2.82 (d, J= 6.0 Hz, 2H), 2.7 (br.s, 11-1), 1.77-1.71 (m,4 2B), 1.70-1.61 (m, 2H), 1.25-1.14 (m, 9H), 0.87-0.81 (m, 28). [006991 Step 2: Borane-DMS reduction of 3-(3-(3-cyclohexylpropylsulfonyl)pbenyl)-3-hydroxypropanenitrile following the method used in Example 92 gave Example 95 as a white amorphous solid. Yield (0.14 g, 15 69%); 'H NMR (DMSO-d 6 + 5% D 2 0, 400 MHz) 5 7.82 (s, I H, 7.74 (d, J- 7.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 4.80-4.77 (m, IH), 3.21 (t, J- 8.0 Hz, 2H), 2.71 (t, J= 8.0 Hz, 2H), 1.79 1.66 (m, 2H), 1.60-1.41 (n, 7H), 1.20-1.17 (m, 611), 0.79-0.71 (m, 211); RP-HPLC purity 96% (AUC); EST MS m/z 340.27 [M+H)*. 20 EXAMPLE 96 PREPARATION OF 3-AMINo-1-(3-(3-PRENYLPROPYLSULFONYL)PiENYL)PROPAN-1-OL 0

NH

2 0 OH [007001 3-Amino-1-(3-(3-phenylpropylsulfonyl)phenyl)propan-l-ol was prepared following the method used in 25 Example 71 and 95. (00701] Step 1: Oxidation of 3-hydroxy-3-(3-(3-phenylpropylthio)phenyl)propanenitrile following the method used in Example 95 gave 3-hydroxy-3-(3-(3-phenylpropylsulfonyl)phenyl)propanenitrile. (Yield 1.4 g, 97 %); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.95 (s, 1 H), 7.79 (t, J= 8.4 Hz, 211), 7.65 (t, J = 7.6 Hz, 1H), 7.26 (t, J= 7.6 Hz 2H), 7,18 (d, J= 7.6 Hz, 1H), 7.14 (t, J= 7.6 Hz, 2H), 6.20 (d, J= 4.4 Hz, 110, 5.05 (q, J - 4.8 Hz, 30 1 H), 3.26 (t, J= 7.6 Hz, 2H), 2.71 (dd, J= 4.8, 16.8 Hz, IH), 2.89 (dd , J= 6.4,16.8 Hz, 1H), 2.62 (t, J= 7.6 Hz, 2H), 1.82 (quintet, J= 7.6 Hz, 2H). [007021 Step 2: Borane-DMS reduction of 3-bydroxy-3-(3-(3-phenylpropylsulfonyl)phenyl)propanenitrile gave Example 94. Yield (0.7 g, 50 %). 'H NMR (400 MHz, CD 3 OD) 8 7.92 (s, 11-1), 7.78 (d, J = 7.6 Hz, I H), 7.72 (d, J= 7.6 Hz, IH), 7.61 (t, J= 7.6 Hz, IH), 7.25 (t, J= 7.6 Hz, 2H), 7.17 (t, J= 7.6 Hz, 1H), 7.12 (d, 35 J= 7.2 Hz, 2H), 3.35 (s, 1H), 3.19-3.15 (m, 211), 2.89-2.80 (m, 2H), 2.69 (t, J 7.6 Hz, 2H), 1.99-1.83 (m, 4H). RP-HPLC purity 95.0% (AUC); ESI MS m/z 334.19 (M+H]*. EXAMPLE 97 40 PREPARATION OF (E)-1.((3-(3-AMINOPROP-1-ENYL)PHENYLULFONYL)METHYL)CYCLOHEXANOL 180 WO 2010/028088 PCT/US2009/055785 OH0 NH 5 r [00703] (E)-1-((3-(3-Aminoprop-1-enyl)phenylsulfonyl)methyl)cyclohexanol was prepared following the method used in Examples 78 and 3. [00704] Step 1: Oxidation of 1-((3-bromophenylthio)methyl)cyclohexanol following the method used in Example 3 gave I-((3-bromophenylsulfonyl)methyl)cyclohexano as a white solid. Yield (2.2 g, 78%); 'H NMR (400 10 MHz, CDCb3) 5 8.06 (s, 1H), 7.86 (d, J= 8 Hz, 1 H), 7,78 (d, J= 7.2 Hz, I H), 7.45 (t, J= 8 Hz, IH), 3.43 (s, 1H), 3.30 (s, 2H), 1.84-1,86 (m, 2H), 1.44-1.83 (m, 7H), 1.25-1.32 (m, IH). [00705) Step 2: Heck coupling of 1-((3-bromophenylsulfonyl)methyl)cyclohexanol and allyl amide 12 following the method used in Example 56 gave, after purification by flash chromatography (5% to 30% EtOAc hexanes gradient) (E)-2,2,2-trifluoro-N-(3-(3-((1 15 hydroxycyclohexyl)methylsulfonyl)phenyl)allyl)acetamide as a light yellow oil which crystallized upon standing. Yield (1.2g, 54%); 'H NMR (400 MHz, CDC 3 ) 87.89 (s, IH), 7.81 (d, J= 8 Hz, IH), 7.61 (d, J 8 Hz, 1H), 7.53 (t, J= 8 Hz, 1 H), 6.61 (d, J= 16 Hz, 1H), 6.6 (br.s, 1H), 6.30 (dt, J= 6.4, 16 Hz, 1H), 4.18 (t, J- 6 Hz, 2H), 3.54 (s, IfI), 3.32 (s, 2H), 1.83-1.86 (mx, 2H), 1.43-1.75 (m, 6H), 1.23-1.34 (m, 2H).. [00706) Step 3: Deprotection of (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylsulfonyl) 20 phenyl)allyl)acetamide following the method used in Example 56 gave, after purification by column chromatography (5% to 20% of MeOH/DCM gradient) Example 97 as a colorless oil. Yield (0.300 g, 77%); 'H NMR (DMSO-d, 400 MHz) 6 7.86 (s, I H), 7.71 (d, J- 6.8 Hz, 2H), 7.55 (t, J= 8 Hz, I H), 6.61 (d, J= 16 Hz, 1H), 6.55-6.46 (m, I H), 4.46 (s, IH), 3.41 (s, 2H), 3.34 (d, J= 4.8 Hz, 2H), 1.70-1.60 (in, 5H), 1.55-1.37 (m, 5H), 1.33-1.71 (in, 2H). RP-HPLC purity 84.8% of (E)-isomer and 11.68% of (Z) 25 isomer (AUC); ESI MS m/z 372.26 [M-H]*. EXAMPLE 98 PREPARATION OF 1-((3-(3-AMINOPROPYL)PKENYLHIO)METHYL)CYCLOHEXANOL OH 1

NH

2 30 [007071 1-((3-(3-Aminopropyl)phenylthio)methyl)cyclohexano is prepared following the method used in Example 57. [007081 Step 1: Hydrogenation of Example 78 gives Example 98. 35 EXAMPLE 99 PREPARATION OF 1-((3-(3-AMINoPROPYL)PHENYLSULFONYL)METHYL)CYCLOHEXANOL OH

NH

2 0 [00709] 1-((3-(3-Aminopropyl)phenylsulfonyl)methyl)cyclohexanol was prepared following the method used in 181 WO 2010/028088 PCTIUS2009/055785 5 Examples 97 and 56. 100710] Step 1: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-((I hydroxycyclohexyl)methylsulfonyl)phenyl)allyl)acetamide gave, after purification by flash chromatography (5%-20% of MeOH/DCM gradient) 2,2,2-trifluoro-N-(3-(3-((1 hydroxycyclohexyl)methylsulfonyl)phenyl)propyl)acetamide as a colorless oil. Yield (0.550 g, 95%) 'H 10 NMR (DMSO-d, 400 MHz) S 9.47(s, 1H), 7.74-7.70 (in, 2H), 7.54 (s, 21), 4,46 (s, 1H), 3.40 (s, 2H), 3.20-3.21 (br.s, 2H), 2.70 (t, J= 7.6 Hz, 2H), 1.85-1.76 (m, 2H), 1.59 (d, J= 7.6 Hz, 4H), 1.55-1.51 (in, 2H), 1.47-1.43 (in, 1H), 1.41-1.36 (m, 2H), 1.25-1.13 (m, 1H). [007111 Step 2: Deprotection of 2,2,2-trifluoro-N-(3-(3-((1 hydroxyoyclohexyl)methylsulfonyl)phenyl)propyl)acetamide following the method used in Example 56 15 gave, after purification by flash column chromatography (5%-20% of MeOH/DCM gradient) Example 99 as a colorless oil. Yield (0.3 g, 77%); ' H NMR (DMSO-ds, 400 MHz) 8 7.70 (d, J- 7.6 Hz, 2H), 7.53 (s, 2H), 4.47 (s, 1H), 3.37 (s, 2H), 2.68 (t, J=7.6, 2H), 2.55-2.53 (in, 2H), 1.65 (t, J=7.6, 2H), 1.63-1.59 (m, 2H), 1.57-1.39 (m, 6H), 1.34-1,26 (in, 3H), 1.15-1.12 (in, 1H). RP-UPLC, ta= 1.29 min, 98% (AUC); ESI MS m/z 312.2 [M-H]*. 20 EXAMPLE 100 PRPARATION op 3-AM NO-1-(3-(cYCLOHEXYLMETHYLTHJo)-5-METHYLPHENYL)PROPAN-1-OL

CH

3 C S

NH

2 OH 25 [007121 3-Amino-1-(3-(cyclohexylmethylthio)-5-methylphenyl)propan- 1-ol was prepared following the method used in Examples 55 and 8. (00713) Step 1: Reaction between 1-bromo-3-iodo-5-methylbenzene and thiolbenzoic acid (56) following the method used in Example 55 gave S-3-bromo-5-methylphenyl benzothioate. Yield (0.961 g, 92%); 'H NMR (400 MHz, CDCI 3 ) 8 7.98-8.02 (m, 2H), 7.61 (tt, J= 1.2, 5.5 Hz, 1H), 7.46-7.51 (in, 3H), 7.39-7.42 (m, 30 1H), 7.24-7.27 (in, 1H), 2.37 (m, 3H). 100714] Step 2: Reaction between S-3-bromo-5-methylphenyl benzothioate and bromide 2 following the method used in Example 55 gave (3-bromo-5-methylphenyl)(cyclohexylmethyl)sulfane. Yield (0.68 g, 73%); 'H NMR (400 MHz, CDCl 3 ) 6 7.19-7.21 (m, IH), 7.07-7.09 (in, 1H), 6.99-7.01 (in, IH), 2.78 (d, J= 6.85 Hz, 2H), 2.28 (s, 3H), 1.84-1.92 (m, 2H), 1.61-1.76 (m, 3H), 1.46-1.59 (m, IH), 1.08-1.30 (in, 3H), 0,94-1.06 35 (m, 2H). [00715] Step 3; Formylation of (3-bromo-5-methylphenyl)(cyclohexylmethyl)sulfane following the method used in Example 8 gave 3-(cyclohexylmethylthio)-5-methylbenzaldehyde. Yield (0.382 g, 68%); 'H NMR (400 MHz, CDCb3) S 9.92 (s, 1H), 7,56-7.57 (in, I H), 7.41-7.43 (in, I H), 7.33-7.35 (in, 1H), 2.85 (d, J= 6.85 lHz, 2H), 2.39 (s, 3H), 1.84-1.94 (m, 2H), 1.61-1.76 (m, 3H), 1.46-1.59 (n, iiH), 1.08-1.29 (in, 3H), 0.94 40 1.07 (in, 2H). [00716] Step 4: Acetonitrile addition to 3-(cyclohexylmethylthio)-5-methylbenzaldehyde following the method used in Example 8 gave 3-(3-(cyclohexylmethylthio)-5-methylphenyl)-3-hydroxypropanenitrile. Yield 182 WO 2010/028088 PCT/US2009/055785 5 (0.339 g, 77%); 'H NMR (400 MHz, DMSO-d,) 8 7.11 (m, 1H), 7.00 (m, IH), 6.97 (i, 1H), 5.88 (d, J= 4.50 Hz, 1H), 4.77-4.82 (m, 1H), 2.73-2.88 (m, 4H), 2.24 (s, 3H), 1.76-1.84 (m, 2H), 1.52-1.68 (m, 3H), 1.39-1.51 (m, iH), 1.12-1.24 (m, 3H), 0.91-1.01 (m, 2H). [007171 Step 5: To a solution of 3-(3-(cyclohexylmethylthio)-5-methylphenyl)-3-hydroxypropanenitrile (0.334 g, 1.15 mmol) in anhydrous THF was added BHfMeS complex (0.5 mL, 5.27 mmol) and the reaction 10 mixture was boiled under reflux for 19 hrs then cooled to room temperature. MeOH was added carefully followed by HCI/MeOH (1.25 M) and the mixture was boiled under reflux for 2 hrs and concentrated under reduced pressure. The residue was partitioned between EtOAc and aqueous NaOH (IM), organic layer was concentrated under reduced pressure. Flash chromatography purification (5% to 20% of 20% 7N

NH

3 /MeOH/C~i 2 Cl 2 - CH 2

C

2 gradient) gave Example 100 as a white solid, Yield (0.272 g, 80/g); 'H N MR 15 (400 MHz, CDOD) 8 7.09-7.11 (m, 1 H), 6.99-7.01 (ma, 1H), 6.94-6.96 (m, 1K), 4.64 (dd, J= 5.3, 8.0 Hz, 1H), 2.79 (d, J= 6.85 Hz, 2H), 2.64-2.76 (m, 2H), 2.29 (m, 3H), 1.60-1.92 (m, 7H), 1.42-1.548 (m, 1N), 1.12-1.29 (m, 3H), 0.94-1.06 (m, 2H); ESI MS m/z 294.8 [M+H]*. EXAMPLE 101 20 PREPARATION OF 3-AMINo-1-(3-(BUTYLSULFINYL)PHENYL)PROPAN-l-OL 11 NH 2 0 OH (00718 3-Amino-1-(3-(butylsulfinyl)phenyl)propan-l-o is prepared following the method used in Examples 2, 8. 100719] Step 1: Formylation of (3-bromophenyl)(butyl)sulfane (70) following the method used in Example 8 gives 25 3-(butylthio)benzaldehyde. 1007201 Step 2: Acetonitrile addition to 3-(butylthio)benzaldehyde following the method used in Example 8 gives 3-(3-(butylthio)phenyl)-3-hydroxypropanenitrile. [007211 Step 3: Oxidation of 3-(3-(butylthio)phenyl)-3-hydroxypropanenitrile following the method used in Example 2 gives 3-(3-(butylsulfmyl)phenyl)-3-hydroxypropanenitrile. 30 100722] Step 4: Borane-DMS reduction of 3-(3-(butylsulfinyl)phenyl)-3-hydroxypropanenitrile following the method used in Example 8 gives Example 101. EXAMPLE 102 35 PREPARATION oF 3-amino-I-(3-(butylthio)phenyl)propan-1-one N NH 2 0 [007231 3-Amino-1-(3-(butylthio)phenyl)propan-1-one is prepared following the method used in Examples 28 and 101. [00724) Step 1: Borane-DMS reduction of 3-(3-(butylthio)phenyl)-3-hydroxypropanenitrile gives 3-amino- 1-(3 40 (butylthi o)phenyl)propan- 1-ol. [007251 Step 2: 3-Amino-1-(3-(butylthio)phenyl)propan-1 -ol is protected with Boc2O following the method used in 183 WO 2010/028088 PCT/US2009/055785 5 Example 28 to give tert-butyl 3-(3-(butylthio)phenyl)-3-hydroxypropylcarbamate. 1007261 Step 3: Oxidation of tert-butyl 3-(3-(butylthio)phenyl)-3-hydroxypropylcarbamate following the method used in Example 28 gives tert-butyl 3-(3-(butylthio)phenyl)-3-oxopropylcarbamate. [00727j Step 4: Deprotection of tert-butyl 3-(3-(butylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 28 gives Example 102 hydrochloride. t0 EXAMPLE 103 PREPARATION OF 3-AMINO- 1-(3-(BUTYLSULFINYL)PHENYL)PROPAN-l-ONE N1 JNH 2 o 0 15 100728] 3-Amino-1-(3-(butylsulfinyl)phenyl)propan-1-one is prepared following the methods used in Examples 28, 58 and 102. (00729 Step 1: Oxidation of tert-butyl 3-(3-(butylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 58 gives tert-butyl 3-(3-(butylsulfinyl)pheny)-3-oxopropycarbamate. [00730] Step 2: Deprotection of tert-butyl 3-(3-(butylsulfinyl)phenyl)-3-oxopropylcarbamate following the method 20 used in Example 28 gives Example 103 hydrochloride. EXAMPLE 104 PREPARATION OF 3-AMINO-l-(3-(BUTYLSuLFONYL)PHENYL)PROPAN-1 -ONE

NH

2 25 0 0 [00731] 3-Amino-1-(3-(butylsulfonyl)phenyl)propan-I-one is prepared following the methods used in Examples 3, 28 and 102. [00732] Step 1: Oxidation of tert-butyl 3-(3-(butylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 3 gives tert-butyl 3-(3-(butylsulfonyl)phenyl)-3-oxopropycarbamate 30 100733] Step 2: Deprotection of tert-butyl 3-(3-(butylsulfonyl)phenyl)-3-oxopropylcarbamate following the method used in Example 28 gives Example 104 hydrochloride. EXAMPLE 105 35 PREPARATION OF 3-AMINO-l-(3-(2-PROPYLPENTYLTHIO)PHENYL)PROPAN-1-OL S -NH 2 OH [00734] 3-Amino-l-(3-(2-propylpentylthio)phenyl)propan-l-ol is prepared following the methods used in Examples Sand 22. [00735] Step 1: Formylation of (3-bromopbenyl)(2-propylpentyl)sulfane following the method used in Example 8 184 WO 2010/028088 PCT/US2009/055785 5 gives 3-(2-propylpentylthio)benzaldehyde. [007361 Step 2: Acetonitrile addition to 3-(2-propylpentylthio)benzaldehyde following the method used in Example 8 gives 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propanenitrile. [00737] Step 3: Borane-DMS reduction of 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propanenitrile following the method used in Example 8 gives Example 105. 10 EXAMPLE 106 PREPARATION OF 3-AMINO-1-(3-(2-PROPYLPENTYLSULFINYL)PHENYL)PROPAN-1-OL

NH

2 0 OH 15 1007381 3-Amino-1-(3-(2-propylpentylsulfiny)phenyl)propan-1-ol is prepared following the methods used in Examples 58 and 105. [00739] Step 1: Oxidation of 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propanenitrile following the method used in Example 58 gives 3-hydroxy-3-(3-(2-propylpentylsulfinyl)phenyl)propanenitrilc. [00740] Step 2: Borane-DMS reduction of 3-hydroxy-3-(3-(2-propylpentylsulfinyl)phenyl)propanenitrile following 20 the method used in Example 105 gives Example 106, EXAMPLE 107 PREPARATION OF 3-AMINO-1-(3-(2-PROPYLPENTYLSULFONYL)PHENYL)PROPAN- 1-OL 9 N H 2 250 OH [007411 3-Amino-1-(3-(2-propylpentylsulfonyl)phenyl)propan-1-oI is prepared following the method used in Example 105, 3. [00742] Step 1; Oxidation of 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propanenitrile following the method used in Example 3 gives 3-hydroxy-3-(3-(2-propylpentylsulfonyl)phenyl)propanenitrile, 30 [00743] Step 2: Borane-DMS reduction of 3-hydroxy-3-(3-(2-propylpentylsulfonyl)phenyl)propanenitrile following the method used in Example 8 gives Example 107. EXAMPLE 108 35 PREPARATION OF 3-AMINo-1-(3-(2-PROPYLPENTYLTHIo)PHENYL)PROPAN- 1--ONE S NH 2 0 [00744] 3-Amino-I-(3-(2-propylpentylthio)phenyl)propan-I-one is prepared following the method used in Example 28. [007451 Step 1: Protection of Example 105 with Boc 2 O following the method used in Example 28 gives tert-butyl 40 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propylcarbamate. 185 WO 2010/028088 PCT/US2009/055785 5 [00746] Step 2: Oxidation of tert-butyl 3-hydroxy-3-(3-(2-propylpentylthio)phenyl)propylcarbamate following the method used in Example 28 gives tert-butyl 3-oxo-3-(3-(2-propylpentylthio)pheny)propycarbamate. [001471 Step 3: Deprotection of tert-butyl 3-oxo-3-(3-(2-propylpentylthio)phenyl)propylcarbamate following the method used in Example 28 gives Example 108 hydrochloride. 10 EXAMPLE 109 PREPARATION OF 3-AMNo-1-(3-(2-PROPYLPENTYLSULFINYL)PHENYL)PROPAN-1-ONE

NH

2 0 0 1007481 3-Amino-l-(3-(2-propylpentylsulfinyl)phenyl)propan-1-one is prepared following the method used in 15 Examples 108, and 58. [00749] Step 1: Oxidation of tert-butyl 3-oxo-3-(3-(2-propylpentylthio)phenyl)propylcarbamate following the method used in Example 58 gives tert-butyl 3-oxo-3-(3-(2-propylpentylsulfmyl)phenyl)popylcarbamate. [00750] Step 2: Deprotection of tert-butyl 3-oxo-3-(3-(2-propylpentylsulfinyl)phenyl)propylcarbamate following the method used in Example 28 gives Example 109 hydrochloride. 20 EXAMPLE 110 PREPARATION OF 3-AMINo- 1-(3-(2-PROPYLPENTYLSULFONYL)PHENYL)PROPAN- 1-ONE 01 N r NH 2 o 0 25 [007511 3-Amino-1-(3-(2-propylpentylsulfonyl)phenyl)propan-1-one is prepared following the method used in Examples 108, and 3. [007521 Step 1: Oxidation of tert-butyl 3-oxo-3-(3-(2-propylpentylthio)phenyl)propylcarbamate following the method used in Example 58 gives tert-butyl 3-oxo-3-(3-(2-propylpentylsulfonyl)phenyl)propylcarbamate. 1007531 Step 2: Deprotection of tert-butyl 3-oxo-3-(3-(2-propylpentylsulfonyl)phenyl)propylcarbamate following 30 the method used in Example 108 gives Example 110 hydrochloride. EXAMPLE 111 PREPARATION OF 3-AMINO- 1-(3-((4,4-DIFLuoRocYcLoHEYL)METYLTIO)PHENYL)PRoPAN-1-OL sFN NH 2 F OH 35 F 1007541 3-Amino-l-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)propan-1-oI was prepared following the method shown in Scheme 28. SCHEME 28 186 WO 2010/028088 PCT/US2009/055785 F 80 + 1 HS a t8F CH3CN, t-BuOK D Y -,N BHa-Me2S THF F 83 0 THF F F8 NH2 FliPy OHr~, 3 I FF 5 F [007551 Step 1: Alkylation of thiol 81 with (4,4-difluorocyclohexyl)methyl methanesulfonate (80) following the method used in Example 1 gave, after purification by flash chromatorgaphy (10% to 20% EtOAc - hexanes gradient) thioether 82 as a colorless oil. Yield (0.84 g, 44%): 'H NMR (400 MHz, DMSO-d)8 7.82 (d, J= 1.2 Hz, 1H), 7.75 (d, J= 7.6 Hz, IH), 7.63 (d, J= 8.0 Hz, I H), 7.47 (t, J= 7.6 Hz, IH), 3.84 (s, 3H), 3.02 10 (d, J = 6.4 Hz, 2H), 2.03-1.98 (in, 2H), 1.87-1.66 (in, 5H), 1.34-1,25 (in, 2H). [007561 Step 2; Acetonitrile addition to ester 82 following the method used in Example 8 gave, after purification by flash chromatorgaphy (10% to 20% EtOAc - hexanes gradient) oxonitrile 83 as a colorless oil. Yield (0,55 g, 63%): 'H NMR (400 MHz, CDC 3 ) 5 7.85 (s, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 4.05 (s, 2H), 2.93 (d, Jr 6.4 Hz, 2H), 2.18-2,10 (in, 2H), 1.99-1.96 (in, 2H), 1.73 15 1.62 (in, 3H), 1.44-1.35 (in, 2H). ESI MS m/z 308 [M-H]*. 1007571 Step 3: To a stirred solution of oxonitrile 83 (0.55 g, 1,78 mmol) in anhydrous THF under argon was added

BH

3 -DMS (2 mL) and the reaction mixture was heated under reflux for 18 h. After cooling to 0 *C, the reaction mixture was quenched with methanol. The mixture was refluxed for lh, cooled down to room temperature and concentrated under reduced pressure to dryness. Purification by flash chromatography 20 (5% 7N NH 3 /MeOH in CH 2

C

2 ) gave Example 111 free base as a pale yellow semi-solid. This was dissolved in dry CH 2

C

2 and cooled to 0 *C. HCL-dioxane (4M, 1 mL) was added to the reaction mixture which was stirred for 15 min and evaporated to dryness. Washing with pentane gave Example 111 hydrochloride as pale yellow semi solid. Yield (0.36 g, 58%) 'H NMR (DMSO-d6, 400 MHz) 6 7.27-7.23 (m, 2H), 7.19 (d, J- 7.6 Hz, lH), 7.12 (d, J= 7.6 Hz, IH), 4.64 (t, J= 6.4 Hz, 1H), 4.50-3.80 (br.s, 2H), 25 2.91 (d, J = 7.2 Hz, 2H), 2.58 (t, J= 7.2 Hz, 21H), 2.00-1.98 (m, 2H), 1.90-1.72 (in, 7H), 1.33-1.23 (m, 2H); RP-HPLC purity 93.63%(AUC); ESI MS m/z 316 [M+H]*. EXAMPLE 112 30 PREPARATION OF 3-AMINo-1-(3-((4,4-DFLUOROCYCLOHEXYL)METYLSULFONYL)PHENYL)PROPAN-1-OL IF

NH

2 S It F 0(:r OH F 1007581 3-Amino-1-(3-((4,4-difluorocyclohexyl)methylsulfonyl)phenyl)propan-1-ol is prepared following the method used in Examples 58 and 28. 100759) Step 1: Protection of Example 111 with Boc2O following the method used in Example 10 gives tert-butyl 187 WO 2010/028088 PCT/US2009/055785 5 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3-hydroxypropylcarbamate. [00760] Step 2: Oxidation of tert-butyl 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3 hydroxypropylcarbamate following the method used in Example 58 gives tert-butyl 3-(3-((4,4 difluorocyclohexyl)methylsulfonyl)phenyl)-3-oxopropylcarbamate. [007611 Step 3: Deprotection of tert-buty 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3-oxopropylcarbamate 10 following the method used in Example 28 gives Example 112 hydrochloride. EXAMPLE 113 PREPARATION OF 3-AMNo-1-(3-((4,4-DIFLUOROCYCLOHEXYL)METHYLTHIO)PHENYL)PROPAN-1 -ONE s

NH

2 F7: 0 15 F [007621 3-Amino-1-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)propan-l-one is prepared following the method used in Examples 112 and 28. [00763] Step 1: Oxidation of tert-butyl 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3 hydroxypropylcarbamate following the method used in Example 28 gives tert-butyl 3-(3-((4,4 20 difluorocyclohexyl)methylthio)phenyl)-3-oxopropylcarbamate. 1007641 Step 2: Deprotection of ter tert-butyl 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3 oxopropylcarbamate following the method used in Example 28 gives Example 113 hydrochloride. EXAMPLE 114 25 PREPARATION OF 3-AMINO-1-(3-((4,4-DIELUOROCYCLOHXYL)METYLSULFONYL)PHENYL)PROPAN- I-ONE 0

F'NNH

2 IS F 0O" 0 F [007651 3-Amino-I -(3-((4,4-difluorocyclohexyl)methylsulfonyl)phenyl)propan- 1-one is prepared following the method used in Example 113, 58, and 28. 30 [007661 Step 1: Oxidation of tert-butyl 3-(3-((4,4-difluorocyclohexyl)methylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 58 gives tert-butyl 3-(3-((4,4-difluorocyclohexyl)metbylsulfonyl) phenyl)-3-oxopropylcarbamate. [007671 Step 2: Deprotection of tert-butyl 3-(3-((4,4-difluorocyclohexyl)methylsulfonyl)phenyl)-3 oxopropylcarbamate following the method used in Example 28 gives Example 114 hydrochloride. 35 EXAMPLE 115 PREPARATION OF 3-(3-(5-METHOXYPENTYLTHIO)PHENYL)PROPAN-1-AM1NE NH; 40 [00768] 3-(3-(5-Methoxypentylthio)phenyl)propan-1-amine is prepared following the method used in Examples 1, 188 WO 2010/028088 PCT/US2009/055785 5 4, 56, and 57. 1007691 Step 1: Alkylation of thiol I with 1-bromo-5-methoxypentane following the method used in Example 1 gives (3-bromophenyl)(5-methoxypentyl)sulfane. [00770] Step 2: Heck coupling of (3-bromophenyl)(5-methoxypentyl)sulfane and allyl trifluoroacetami do 12 following the method used in Example 56 gives (E)-2,2,2-trifluoro-N-(3-(3-(5 10 methoxypentylthio)phenyl)allyl)acetamide. [00771] Step 3: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-(5-methoxypentylthio)phenyl)ally)acetamide following the method used in Example 57 gives 2,2,2-trifluoro-N-(3-(3-(5 methoxypentylthio)phenyl)propyl)acetamide. [007721 Step 4: Deprotection of 2,2,2-trifluoro-N-(3-(3-(5-methoxypentylthio)phenyl)propyl)acetamide following 15 the method used in Example 56 gives Example 115. EXAMPLE 116 PREPARATION OF 3-(3-(5-METHOXYPENTYLSULFONYL)PHENYL)PROPAN- I-AMINE 59,1 NH2 20 [007731 3-(3-(5-Methoxypentylsulfonyl)phenyl)propan-l-amine is prepared following the method used in Example 115. [007741 Step 1: Oxidation of 2,2,2-trifluoro-N-(3-(3-(5-methoxypentylthio)phenyl)propyl)acetamide following the method used in Example 58 gives 2,2,2-trifluoro-N-(3-(3-(5 25 methoxypentylsulfonyl)phenyl)propyl)acetamide. [00775] Step 2: Deprotection of 2,2,2-trifluoro-N-(3-(3-(5-methoxypentylsulfonyl)phenyl)propyl)acetamide following the method used in Example 56 gives Example 116. EXAMPLE 117 30 PREPA RATION OF 5-(3-(3-AMINOPROPYL)PHENYLTHIO)PENTAN-1-OL HS _N NH 2 [007761 5-(3-(3-Aminopropyl)phenylthio)pentan-1-o is prepared following the method used in Example 115. [007771 Step 1: Alkylation of thiol 1 with 1-bromo-5-hydroxypentane following the method used in Example 1 35 gives (3-bromophenyl)(5-hydroxypentyl)sulfane. [007781 Step 2: Heck coupling of (3-bromophenyl)(5-hydroxypentyl)sulfane and allyl trifluoroacetamide 12 following the method used in Example 56 gives (E)-2,2,2-trifluoro-N-(3-(3-(5 hydroxypentylthio)phenyl)allyl)acetamide. [00779] Step 3: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-(5-hydroxypentylthio)phenyl)allyl)acetamide 40 following the method used in Example 57 gives 2,2,2-trifluoro-N-(3-(3-(5 hydroxypentylthio)phenyl)propyl)acetamide. [00780] Step 4: Deprotection of 2,2,2-trifluoro-N-(3-(3-(5-hydroxypentylthio)phenyl)propyl)acetamide following the method used in Example 56 gives Example 117. 189 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 118 PREPARATION OF 5-(3-(3-AMINOPROPYL)PHENYLSULFONYL)PENTAN-1-OL 9 N NH 2 0 10 100781] 5-(3-(3-Aminopropyl)phenylsulfonyl)pentan-1-ol is prepared following the method used in Example 116. 100782] Step 1: Oxidation of 2,2,2-trifluoro-N-(3-(3-(5-hydroxypentylthio)phenyl)propyl)acetamide following the method used in Example 58 gives 2,2,2-trifluoro-N-(3-(3-(5 hydroxypentylsulfonyl)phenyl)propyl)acetamide. [00783] Step 2: Deprotection of 2,2,2-trifluoro-N-(3-(3-(5-hydroxypentylsulfonyl)phenyl)propyl)acetanide 15 following the method used in Example 56 gives Example 118. EXAMPLE 119 PREPARATION OF 4-((3-(3-AMINO- 1-HYDROXYPROPYL)PHENYLTHIO)METHYL)HEPTAN-4-OL OH s0 NH 2 20 OH1 100784] 4-((3-(3-Amino-1-hydroxypropyl)phenylthio)methyl)heptan-4-ol was prepared following the method used in Examples 1 and 8. (007851 Step 1: Reaction between 2,2-dipropyloxirane and thiol 1 following the method used in Example 78 gave, after purification by flash chromatorgaphy (10% to 20% EtOAc - hexanes gradient) 4-((3 25 bromophenylthio)methyl)heptan-4-ol as pale yellow oil. Yield (7.0 g, 37%); 'H NMR (CDC 3 , 400 MHz) 5 7.53 (t, J= 1.6 Hz, 1H), 7.30 (m, 2H), 7.13 (t, J= 8.0 Hz, 1 H), 3.09 (s, 2H), 1.92 (s, I H), 1.56-1.48 (m, 4H), 1.40-1.26 (m, 4H), 0.92 (t, J= 7.2 Hz, 6H). [007861 Step 2: Formylation of 4-((3-bromophenylthio)methyl)heptan-4-o following the method used in Example 8 gave 3-(2-hydroxy-2-propylpentylthio)benzaldehyde as a colorless semi-solid. Yield (3.5 g, 60%); 1 H 30 NMR (CDCI,, 400 MHz) 8 9.97 (s, 1 H), 7.53 (t, J= 1.6 Hz, 18), 7.30 (m, 2H), 7.13 (t, J= 8.0 Hz, 1H), 3.09 (s, 2H), 1.92 (s, 1 H), 1.56-1.48 (m, 4R), 1.40-1.26 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H). [007871 Step 3: Acetonitrile addition to 3-(2-hydroxy-2-propylpentylthio)benzaldehyde following the method used in Example 8 gave 3-hydroxy-3-(3-(2-hydroxy-2-propylpentylthio)phenyl)propanenitrile as a colorless semi-solid. Yield (0.7 g, 20%). 'H NMR (CDC 3 , 400 MHz) 6 7.44 (s, I H), 7.39 (d, J= 8.0 Hz, 1H), 7.30 35 (t, J= 8.0 Hz, 1H), 7.21 (d, J= 7.6 Hz, 1H), 5.01 (t, J= 5,8 Hz, 1H), 3.11 (s, 2H), 2.76 (d, J= 6.0 Hz, 2H), 2.56 (br.s, 11), 1.98 (s, 1H), 1.60-1.50 (m, 4H), 1.41-1.24 (m, 4H), 0.90 (t, = 7.2 Hz, 6H). [00788] Step 4: Borane-DMS reduction of 3-hydroxy-3-(3-(2-hydroxy-2-propylpentylthio)phenyl)propanenitrile following the method used in Example 8 gave Example 119 as a colorless semi solid. 'H NMR (DMSO-d 6 , 400 MHz) 8 7.28 (m, I H), 7.24- 7.16 (m, 2H), 7.09 (d, j= 6.8 Hz, I H), 4.63 (t1, J= 6.2 Hz, 1H), 4.40 (br.s, 40 IH), 2.98 (s, 2H), 2.68-2.50 (m, 2H), 1.74-1.59 (in, 2H), 1.44-1.34 (m, 4H), 1.29-1.23 (m, 4H), 0.83 (t, J= 7.2 Hz, 6H). RP-HPLC purity 96.25% (AUC); ES1 MS m/z 312 [M+H]*. 190 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 120 PREPARAnON OF 4-((3-(3-AMINo- 1-HYDROXYPROPYL)PHENYLSULFINYL)METHYL)HEPTAN-4-OL OH NH2 0 OH [00789] 4-((3-(3-Amino-1-hydroxypropyl)phenylsulfinyl)methyl)hcptan-4-oI is prepared following the method used 10 in Examples 9 and 58, [00790] Step 1: Protection of Example 119 following the method used in Example 9 gives 2,2,2-trifluoro-N-(3 hydroxy-3-(3-(2-hydroxy-2-propylpentylthio)phenyl)propyl)acetamide. [00791] Step 2: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-hydroxy-2 propylpentylthio)phenyl)propyl)acetamide following the method used in Example 58 gives 2,2,2-trifluoro 15 N-(3-hydroxy-3-(3-(2-hydroxy-2-propylpentylsulfinyl)phenyl)propyl)acetamide. [00792] Step 3: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-hydroxy- 2 propylpentylsulfinyl)phenyl)propyl)acetamide following the method used in Example 9 gives Example 120. 20 EXAMPLE 121 PREPARATION OF 4-((3-(3-AMINO-1 -HYDROXYPROPYL)PHENYLSULFONYL)METhYL)HEPTAN-4-OL O N NH 2 [00793] 4-((3-(3-Amino-1-hydroxypropyl)phenylsulfonyl)methyl)heptan-4-o is prepared following the method 25 used in Examples 120, 9 and 3. [00794] Step 1: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-hydroxy-2 propylpentylthio)phenyl)propyl)acetamide following the method used in Example 3 gives 2,2,2-trifluoro-N (3-hydroxy-3-(3-(2-hydroxy-2-propylpentylsulfonyl)phenyl)propyl)acctamide. [007951 Step 2: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-hydroxy-2 30 propylpentylsulfonyl)phenyl)propyl)acetamide following the method used in Example 9 gives Example 121. EXAMPLE 122 35 PREPARATION OF 3-AMINo-1-(3-(2-HYDROXY-2-PROPYLPENTYLTHIO)PHENYL)PROPAN-1-ONE OH S

NH

2 0 [00796] 3-Amino- l-(3-(2-hydroxy-2-propylpentylthio)phenyl)propan- 1-one is prepared following the method used in Example 28. [00797] Step 1: Protection of Example 119 following the method used in Example 28 gives tert-butyl 3-hydroxy-3 40 (3-(2-hydroxy-2-propylpentylthio)pheny)propycarbamate. 191 WO 2010/028088 PCTIUS2009/055785 5 {00798 Step 2: Oxidation of tert-butyl 3-hydroxy-3-(3-(2-hydroxy-2-propylpentylthio)phenyl)propylcarbamate following the method used in Example 28 gives tert-butyl 3-(3-(2-hydroxy-2-propylpentylthio)phenyl)-3 oxopropylcarbamate. 1007991 Step 3: Deprotection of tert-butyl 3-(3-(2-hydroxy-2-propylpentylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 28 gives Example 122 hydrochloride. 10 EXAMPLE 123 PREPARATION OF 3-AMINO-1-(3-(2-HYDROXY-2-PROPYLPENTYLSULONYL)PH ENYL)PROPAN- 1-ONE OHO 0 N r NH 2 S 8 0 15 (00800] 3-Amina-1-(3-(2-hydroxy-2-propylpentylsulfonyl)phenyl)propan-l-one is prepared following the method used in Example 122, and 121. 1008011 Step 1: Oxidation of tert-butyl 3-(3-(2-hydroxy-2-propylpentylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 121 gives rert-butyl 3-(3-(2-hydroxy-2 propylpentylsulfonyl)phenyl)-3-oxopropylcarbamate. 20 [00802] Step 2: Deprotection of tert-butyl 3-(3-(2-hydroxy-2-propylpentylsulfonyl)phenyl)-3-oxopropylcarbamate following the method used in Example 122 gives Example 123 hydrochloride. EXAMPLE 124 25 PREPARATION OF 1-((3-(3-AMINO-1-HYDROXYPROPYL)PHENYLTHIO)METHYL)CYCLPENTANOL OH N

NH

2 CjH 1008031 1-((3-(3-Amino- 1-bydroxypropyl)phenylthio)methyl)cyclopentano is prepared following the method used in Example 119. [00804] Step 1: Reaction between 1-oxaspiro[2.4]heptane and thiol 1 gives 1-((3 30 bromophonylthio)methyl)cyclopentanol. [00805] Step 2: Formylation of 1-((3-bromophenylthio)methyl)cyclopentano gives 3-((1 hydroxycyclopentyl)methylthio)benzaldehyde, 1008061 Step 3: Acetonitrile addition to 3-((1-hydroxycyclopentyl)methylthio)benzaldehyde gives 3-hydroxy-3-(3 ((1 -hydroxycyclopentyl)methylthio)phenyl)propanenitrile. 35 [00807] Step 4: Borane-DMS reduction of 3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylthio)phonyl)propanenitrile gives Example 124. EXAMPLE 125 40 PREPARATION OP 1-((3-(3-AMINO-1-HYDROXYPROPYL)PHENYLSULFINYL)MEIHYL)CYCLOPENTANOL 192 WO 2010/028088 PCT/US2009/055785 OH N1H 2 5 0 OH [008081 1-((3-(3-Amino-1-hydroxypropyl)phenysulfiny)mthyl)cyclopentanol is prepared following the method used in Example 120. 1008091 Step 1: Protection of Example 124 gives 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylthio)phenyl)propy)acetamide. 10 1008101 Step 2: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylthio)pheny)propyl)acetamide gives 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylsulfiny)phenyl)propy)acetamide. [00811] Step 3: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)mcthylsulfwyl)phenyl)propyl)acetamide gives Example 125. 15 EXAMPLE 126 PREPARATION OF I-((3-(3-AMINo- 1I-YDROXYPROPYL)PHENYLSULFONYL)METHYL)CYCLOPENTANOL OHO

NH

2 O OH 20 [00812] 1-((3-(3-Amino-1-hydroxypropyl)phenylsulfonyl)methyl)cyclopentanol is prepared following the method used in Example 121. [00813] Step 1: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((I hydroxycyclopentyl)methylthio)phenyl)propyl)acetamide gives 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylsulfonyl)phcnyl)propyl)acetamide. 25 1008141 Step 2: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylsulfonyl)phenyl)propyl)acetamide gives Example 126. EXAMPLE 127 30 PREPARATION OF 3-AMINo-1-(3-((1 -HYDROXYCYCLOPENTYL)METHYLTHIO)PHENYL)PROPAN-1-ONE OH NH1 2 1008151 3-Amino-I -(3-((1-hydroxycyclopentyl)methylthio)phenyl)propan- 1-one is prepared following the method used in Example 122. [00816] Step 1: Protection of Example 124 gives tert-butyl 3-hydroxy-3-(3-((1 35 hydroxycyclopentyl)methylthio)phenyl)propylcarbamate. [008171 Step 2: Oxidation of tert-butyl 3-hydroxy-3-(3-((1 hydroxycyclopentyl)methylthio)phenyl)propylcarbamate gives tert-butyl 3-(3-((1 hydroxycyclopentyl)methylthio)phenyl)-3-oxopropylcarbamate. 193 WO 2010/028088 PCT/US2009/055785 5 1008181 Step 3: Deprotection of tert-butyl 3-(3-((l-hydroxycyclopentyl)methylthio)phenyl)-3-oxopropylcarbamate gives Example 127 hydrochloride. EXAMPLE 128 10 PREPARATION OF 3-AMINO-1-(3-((1-HYDROXYCYCLOPENTYL)METHYLSULFONYL)PHENYL)PROPAN-1-ONE OHO 9NH 2 [00819] 3-Amino- 1-(3-((1-hydroxycyclopentyl)methylsulfonyl)phenyl)propan-1 -one is prepared following the method used in Example 127 and 123. [00820] Step 1: Oxidation of tert-butyl 3-(3-((I-hydroxycyclopentyl)methylthio)phenyl)-3-oxopropylcarbamate 15 gives tert-buty] 3-(3-((1-hydroxycyclopentyl)methylsulfonyl)phenyl)-3-oxopropylcarbamate. [00821] Step 2: Deprotection of fert-buty] 3-(3-((1-hydroxycyclopenty])methylsulfonyl)phenyl)-3 oxopropylcarbamate gives Example 128 hydrochloride. EXAMPLE 129 20 PREPARATION OF 1-((3-(3-AMINO- 1-HYDROXYPROPYL)PHENYLSULFINYL)METHYL)CYCLOHEXANOL OH S

NH

2 C OH [00822] 1-((3-(3-Amino-1-hydroxypropyl)phenylsulfinyl)methyl)cyclohexanol is prepared following the method used in Example 124. 25 [00823] Step 1: Example 27 is protected following the method used in Example 9 to give 2,2,2-Irifluoro-N-(3 hydroxy-3-(3-((I -hydroxycyclohexyl)methylthio)phenyl)propyl)acetamide. 1008241 Step 2: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclohexyl)mcthylthio)phenyl)propyl)acetamide gives 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclohexy)methylsulfinyl)phenyl)propy)acetamide. 30 [008251 Step 3: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 hydroxycyclohexyl)methylsulfinyl)phenyl)propy])acetamide gives Example 129. EXAMPLE 130 35 PREPARATION OF 1-((3-(3-AMINO-1-HYDROXYPROPYL)PHENYLSULFONYL)METHYL)CYCLOHEXANOL OHO 1

NH

2 0t OH [00826] 1-((3-(3-Amino- 1-hydroxypropyl)phenylsulfonyl)methyl)cyclohexanol is prepared following the method used in Example 129 and 126. 1008271 Step 1: Oxidation of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 194 WO 2010/028088 PCTIUS2009/055785 5 hydroxycyclohexyl)methylthio)phenyl)propyl)acetamide following the method used in Example 126 gives 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1 -hydroxycyclohexyl)methylsulfonyl)phonyl)propyl)acetamide. [00828j Step 2: Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((I hydroxycyclohexyl)methylsulfonyl)pheny)propyl)acetande following the method used in Example 129 gives Example 130. 10 EXAMPLE 131 PREPARATION OF 3-AMINO-1-(3-((-HYDROXYCYCLOHEXYL)METHYLTHIO)PIENYL)PROPAN-1 -ONE OH S

NH

2 15 [008291 3-Amino-I -(3-((1 -hydroxycyclohexyl)methylthio)phenyl)propan- 1-one is prepared following the method used in Example 127. [00830 Step 1: Protection of Example 27 with Boc20 following the method used in Example 127 gives tert-butyl 3-hydroxy-3-(3-((1-hydroxycyclohexyl)methylthio)phenyl)propylcarbamate. [00831) Step 2: Oxidation of tert-butyl 3-hydroxy-3-(3-((1-hydroxycyclohexyl)methylthio)phenyl)propylcarbamate 20 gives tert-butyl 3-(3-((1-hydroxycyclohexyl)methylthio)phenyl)-3-oxopropylcarbamate. [00832] Step 3: Deprotection of sed-butyl 3-(3-((1-hydroxycyclobexyl)mcthylthio)phonyl)-3-oxopropylcarbamate gives Example 131 hydrochloride. EXAMPLE 132 25 PREPARATION OF 3-AMINO-1 -(3-((1 -HYDROXYCYCLOHEXYL)METHYLSULFONYL)PHENYL)PROPAN- L-ONE OH9 0

NH

2 [00833] 3-Amino-1-(3-((1-hydroxycyclohexyl)methylsulfonyl)phenyl)propan-1-one is prepared following the method used in Example 131 and 128. 30 [00834] Step 1: tert-Butyl 3-hydroxy-3-(3-((l-hydroxycyclohexyl)methylthio)phenyl)propylcarbamate is oxidized following the method used in Example 128 to give tert-butyl 3-(3-((1-hydroxycyclohexyl)methylsulfonyl) phenyl)-3-oxopropylcarbamate. [00835] Step 2: Deprotection of tert-butyl 3-(3-((I-hydroxycyclohexyl)methylsulfonyl)phenyl)-3 oxopropylcarbamate gives Example 132 hydrochloride. 35 EXAMPLE 133 PREPARATION OF 3-(3-(2-ETMYLBUTYLSULFONYL)PHENYL)PROPAN- 1-AMINE 01 15NH 195 WO 2010/028088 PCT/US2009/055785 5 [008361 3-(3-(2-Ethylbutylsulfonyl)phenyl)propan-1-amine is prepared following the method used in Example 9. [008371 Step 1: Protection of Example 7 gives N-(3-(3-(2-ethylbutylthio)phenyl)propyl)-2,2,2-trifluoroacetamide. 1008381 Step 2: Oxidation of N-(3-(3-(2-ethylbutylthio)phenyl)propyl)-2,2,2-trifluoroacetamide following the method used in Example 9 gives N-(3-(3-(2-ethylbutylsulfonyl)phenyl)propyl)-2,2,2-trifluoroacetamide. 1008391 Step 3: Deprotection of N-(3-(3-(2-ethylbutylsulfonyl)phenyl)propyl)-2,2,2-trifluoroacetamide gives 10 Example 133. EXAMPLE 134 PREPARATION OF 3-AMINO- 1-(3-(2-ETHYLBUTYLSULFINYL)PHENYL)PROPAN- 1 -OL 15 NH 2 15 0OH 1008401 3-Amino-1 -(3-(2-ethylbutylsufinyl)phenyL)propan- 1-ol is prepared following the method used in Example 6, 2, 8, and 9. [00841] Step 1: Formylation of (3-bromophenyl)(2-ethylbutyl)sulfane following the method used in Example 8 gives 3-(2-ethylbutylthio)benzaldehyde. 20 [00842] Step 2: Acetonitrile addition to 3-(2-ethylbutylthio)benzaldehyde following the method used in Example 8 gives 3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropanenitrile. 100843] Step 3: Reduction of 3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropanenitrile following the method used in Example 8 gives 3-amino-i-(3-(2-ethylbutyltibo)phenyl)propan-1-ol. [00844] Step 4: Protection of 3-amino-l-(3-(2-ethylbutylthio)phenyl)propan-1-ol following the method used in 25 Example 9 gives N-(3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide. [00845j Step 5: Oxidation of N-(3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide following the method used in Example 2 gives N-(3-(3-(2-ethylbutylsulfrnyl)phenyl)-3-hydroxypropyl) 2,2,2-trifluoroacetamide. 100846] Step 6: Deprotection of N-(3-(3-(2-ethylbutylsulfinyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamidc 30 following the method used in Example 9 gives Example 134. EXAMPLE 135 PREPARATION OF 3-AMINO-1-(3-(2-ETHYLBUTYLTHIO)PHENYL)PROPAN-1 -ONE 35 0 NH2 [008471 3-Amino-1-(3-(2-ethylbutylthio)phenyl)propan-l-one is prepared following the method used in Example 134, and 131. [008481 Step 1: Protection of 3-amino-1-(3-(2-ethylbutylthio)phenyl)propan-1-o following the method used in Example 131 gives tert-butyl 3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropylcarbamate. 40 [00849] Step 2: Oxidation of tert-butyl 3-(3-(2-ethylbutylthio)phenyl)-3-hydroxypropylcarbamate following the method used in Example 131 gives tert-butyl 3-(3-(2-ethylbutylthio)phenyl)-3-oxopropylcarbamate. 196 WO 2010/028088 PCT/US2009/055785 5 1008501 Step 3: Deprotection of tert-butyl 3-(3-(2-ethylbutylthio)phenyl)-3-oxopropylcarbamate following the method used in Example 131 gives Example 135 hydrochloride. EXAMPLE 136 10 PREPARATION Op 3-AMINO-I-(3-(2-ETHYLBUTYLSULFONYL)PHENYL)PROPAN-1-ONE ii " NH 2 S o 0 1008511 3-Amino-l-(3-(2-ethylbutylsulfonyl)phenyl)propan-l-one is prepared following the method used in Example 135, 132. [008521 Step 1: Oxidation of ten-butyl 3-(3-(2-ethylbutylthio)phenyl)-3-oxopropylcarbamate following the method 15 used in Example 132 gives tert-butyl 3-(3-(2-ethylbutylsulfonyl)phenyl)-3-oxopropylcarbamate. 1008531 Step 2: Deprotection of tert-butyl 3-(3-(2-ethylbutylsulfonyl)phenyl)-3-oxopropylcarbamate following the method used in Example 132 gives Example 136 hydrochloride. EXAMPLE 137 20 PREPARATION OF 3-(3-(2-METHOXYBENZYLTHIO)PHENYL)PROPAN-1-AMINE N S

NH

2 1008541 3-(3-(2-Methoxybenzylthio)phenyl)propan- 1-amine was prepared foll owing the method used in Example 56 and 57. 25 (008551 Step 1: Alkylation of thiol 1 with 2-methoxybenzyl bromide following the method used in Example 56 gave (3-bromophenyl)(2-methoxybenzyl)sulfane as a colorless oil, Yield (4.0 g, 65%). 'H NMR (CDC[ 3 , 400 MHz) 6 7.46 (d, J= 1.2 Hz, 1H),7.29 (d, J= 8.0 Hz, 1H), 7.24 -7.18 (m, 3H), 7,08 (t, J= 8.0 Hz, 1H), 6.88 (t, J= 8.0 H, 2H), 4.15 (s, 2H), 3.80 (s, 3H). 1008561 Step 2: Heck coupling of (3-bromophenyl)(2-methoxybenzyl)sulfane and allyl amide 12 following the 30 method used in Example 56 gave (E)-2,2,2-trifluoro-N-(3-(3-(2-methoxybenzylthio)phenyl)allyl)acetamidde as a pale brown oil. Yield (1.0 g, 40%). 'H NMR (CDC3, 400 MHz) 6 7.32-7.06 (m, 611), 6.87 (d, J= 8.0 Hz, 21), 6.53 (d, J= 16 Hz, 1H), 6.14-6.07 (m, 1H), 4.15 (s, 2H), 4,12 (m, 2H), 3.82 ( s, 3H). [008571 Step 3: Hydrogenation of (E)-2,2,2-trifluoro-N-(3-(3-(2-methoxybenzylthio)phenyl)allyl)acetamide following the method used in Example 57 gave 2,2,2-trifluoro-N-(3-(3-(2 35 methoxybenzylthio)phenyl)propyl)acetamide as a pale brown oil. Yield (0.38g, 38%). 'H NMR (CDC1 3 , 400 MHz) 8 7.23-7.17 (m, 4H), 7.09 (m, I H), 6.97 (m, 1H), 6.87-6.83 (n, 2H), 4,15 (s, 2H),3.82 ( s, 3H), 3.36-3.14 (dd, J= 6.8 Hz, 2H), 2.61 (t, J= 7.6 Hz, 2H), 1.91 (quintet, J= 7.4 Hz, 2H); ESI MS m/z 382 [M+H]*. [00858] Step 4: Deprotection of 2,2,2-trifluoro-N-(3-(3-(2-methoxybenzylthio)phenyl)propyl)acetamide following 40 the method used in Example 56 gave Example 137 as a colorless semi solid Yield (0.2 g, 70%). 'H NMR (DMSO-d, 400 MHz) 8 7.25-7.17 (M, 3H), 7.13 (n, 211), 6.98 (m, IH), 6.87 (t, J= 7.6 Hz, 2H), 4.15 (s, 197 WO 2010/028088 PCT/US2009/055785 5 2H), 3.79 (s, 3H), 2.57-2.53 (m, 4H), 1.63 (quintet, J= 7.2 Hz, 21-1). RP-HPLC purity 97.2% (AUC); ESI MS miz 288.21 [M+Hl. EXAMPLE 138 10 PREPARATION OF 3-(3-(2-METHOXYBENZYLSULFONYI)PHENYL)PROPAN-1-AMINE lob. NH 2 1008591 3-(3-(2-Methxybenzylsulfonyl)phenyl)propan-1-amine was prepared following the method used in Examples 137 and 9. 1008601 Step 1: Oxidation of (3-bromophenyl)(2-methoxybenzyl)sulfane following the method used in Example 9 15 gave 1-((3-bromophenylsulfonyl)methyl)-2-methoxybenzene as a colorless oil. (Yield 0.88 g, 40%). 'H NMR (400 MHz, CDCI,) 8 7.73 (s, 1-), 7.67 (d, J= 8 Hz, 1H), 7.52 (d, J= 7.6 Hz, 1HB) 7.32 (t, J = 7.2, 1H), 7.26 (t, J= 8 Hz, 1H), 6.96 (t, J= 7.6 Hz, IH), 6.66 (d, J= 8 Hz, 2H), 4.45 (s, 2H), 3.38 (s, 3H). 100861] Step 2: Heck coupling between 1-((3-bromophenylsulfonyl)mcthyl)-2-methoxybenzene and allyl acetamide 12 following the method used in Example 66 gave crude (E)-Z2,2-trifluoro-N-(3-(3-(2 20 methoxybenzylthio)phenyl)allyl)acetamide as a colorless oil which was used directly in the next step. Yield (2.0 g); 'H NMR (DMSO-d 6 , 400 MHz) 8 7.95 (s, 1H), 7.75 (d, J= 7.6 Hz ,1H), 7.60 (s, 11-1), 7.57-7.43 (m, 1H), 7.29-7.14 (m, 2H), 6.90 (t, J= 7.6 Hz, 1H), 6.82 (d, J= 8 Hz, IH), 6.59(d, J= 16 Hz, 1H), 6.30 (dt, J = 6, 16 Hz, 1H), 4.55 (s, 2H), 4.01 (s, 2H), 3.81 (s, 3H). 1008621 Step 3: (E)-2,2,2-trifluoro-N-(3-(3-(2-methoxybenzylthio)phenyl)allyl)acetamide was hydrogenated 25 following the method used in Example 4 to give 2,2,2-trifluoro-N-(3-(3-(2 methoxybenzylsulfonyl)phenyl)propyl)acetamide as a colorless oil. Yield (0.46 g, 23%); 'H NMR (DMSO d 6 , 400 MHz) 8 9.46 (s, 1H), 7.41-7.39 (m, 31-1), 7.36 (s, 1 H), 7.27 (t, J = 7.2 Hz, 11-1), 7.18 (d, J = 7.6 Hz, 1H), 6.90 (t, J= 7.2 Hz, 1H), 6.82 (d, J= 8 Hz, 1H), 4.53 (s, 2H), 3.32 (s, 3$), 3.19-3.14 (m, 2H), 2.61 (t,J = 7.2 Hz, 2H), 1.71(quintet, J= 7.6 Hz, 2H). 30 100863] Step 4: 2,2,2-Trifluoro-N-(3-(3-(2-methoxybenzylsulfonyl)phenyl)propyl)acetamide was deprotected following the method used in Example 137 to give Example 138 as a colorless semi solid. Yield (0.12 g, 35%); 'H NMR (DMSO-d 6 , 400 MHz). 8 8.39 (s, 2H), 7.53 (d, J= 6.4 Hz, 1H), 7.47 (t, J= 7.6 Hz, IH), 7.42 (d, J= 7.6 Hz, 1H), 7.39 (s, I H), 7.32 (t, J= 7.6 Hz, 1H), 7.19 (d, J= 7.2 H z, 1H), 6.91 (t, J= 7.2 Hz, 1 H), 6.84 (d, J 8 Hz, 1H), 4.54 (s, 2H), 3.35 (s, 3H), 2.72-2.65 (m, 4H), 1.75 (quintet, 2H). RP-HPLC 35 purity 97.2% (AUC); ESI MS m/z 320.15 [M+H]l. EXAMPLE 139 40 PREPARATION OF 3-(3-(4-(BENZYLOXY)BUTYLTHO)PHENYL)PROPAN-1-AMINE N Q' O '-r. N NH 2 [00864] 3-(3-(4-(Benzyloxy)butylthio)phenyl)propan-1-amine is prepared following the method used in Example 198 WO 2010/028088 PCT/US2009/055785 5 137. [008651 Step 1: Alkylation of thiol 1 with ((4-bromobutoxy)methyl)benzene gives (4-(benzytoxy)butyl)(3 bromophenyl)sulfane. 100866] Step 2: Heck coupling between (4-(benzyloxy)butyl)(3-bromophenyl)sulfane and alkene 12 following the method used in Example 56 gives (E)-N-(3-(3-(4-(benzyloxy)butylthio)phenyl)allyl)-2,2,2 10 trifluoroacetamide. [00867] Step 3: Hydrogenation of (E)-N-(3-(3-(4-(benzyloxy)butylthio)phenyl)allyl)-2,2,2-trifluoroacetamide following the method used in Example 57 gives N-(3-(3-(4-(benzyloxy)butylthio)phenyl)propyl)-2,2,2 trifluoroacetamide, 1008681 Step 4: Deprotection of N-(3-(3-(4-(benzyloxy)butylthio)phenyl)propyl)-2,2,2-trifluoroacetanide gives 15 Example 139. EXAMPLE 140 PREPARATION OF 3-(3-(4-(BENZYLOXY)BUTYLSULFONYL)PHENYL)PROPAN-1-AMiNE O '..NH 2 20 0 [00869] 3-(3-(4-(Benzyloxy)butylsulfonyl)phenyl)propan-l-amine is prepared following the method used in Example 139 and 9. [00870] Step 1: Oxidation of N-(3-(3-(4-(benzyloxy)butylthio)phenyl)propyl)-2,2,2-trifluoroacetamide following the method used in Example 9 gives N-(3-(3-(4-(benzyloxy)butylsulfonyl)phenyl)propyl)-2,2,2 25 trifluoroacetamide, 100871] Step 2: Deprotection of N-(3-(3-(4-(benzyloxy)butylsulfonyl)phenyl)propyl)-2,2,2-trifluoroacetamide following the method used in Example 9 gives Example 140. EXAMPLE 141 30 PREPARATION OF 3-(3-AMINO-1-HYDROXYPROPYL)-5-(CYCLOHEXYLMETHYLTHIO)PHENOL OH S /

NH

2 K) OH 1008721 3-(3-Amino-1-hydroxypropyl)-5-(cyclohexylmethylthio)phenol is prepared following the method used in Examples 1 and 55. 35 (008731 Step 1: Methylation of 3-bromo-5-iodophenol with methyl iodide following the method used in Example 1 gives 1-bromo-3-iodo-5-methoxybenzene. [00874] Step 2: Reaction between 1-bromo-3-iodo-5-methoxybenzene and thiolbenzoic acid (56) following the method used in Example 55 gives S-3-bromo-5-methoxyphenyl benzothioate. [00875] Step 3: Reaction between S-3-bromo-5-methoxyphenyl benzothioate and bromide 2 in the presence of 40 Cs 2

CO

3 following the method used in Example 55 gives (3-bromo-5 199 WO 2010/028088 PCT/US2009/0557 8 5 5 methoxyphonyl)(cyclohexylmethyl)sulfane. 100876] Step 4: Formylation of (3-bromo-5-methoxyphenyl)(cyclohexylmethyl)sulfane following the method used in Example 55 gives 3-(cyclohexylmethylthio)-5-methoxybenzaldehyde. [00877] Step 5: To a cold (-78 *C) solution of 3-(cyclohexylmethylthio)-5-methoxybenzaldehyde in CH 2 Cl 2 under inert atmosphere is added BBr 3 . The reaction mixture is stirred until no starting material is seen by TLC. 10 The reaction mixture is partitioned between CH 2 Cl 2 and aqueous solution of NaHCO 3 . Organic layer is extracted with CH 2

CI

2 and combined organic layers is washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. Purification by flash chromatography gives 3 (cyclohexylmethylthio)-5-hydroxybenzaldehyde. (00878] Step 6: Acetonitrile addition to 3-(cyclohexylmethylthio)-5-hydroxybenzaldehyde following the method 15 used in Example 55 gives 3-(3-(cyclohexylmethylthio)-5-hydroxyphonyl)-3-hydroxypropanenitrile. 1008791 Step 7: Borane-DMS reduction of 3-(3-(cyclohexylmethylthio)-5-hydroxyphenyl)-3-hydroxypropanenitrile gives Example 141. EXAMPLE 142 20 PREPARATION OF 3-(3-AMINO--HYDROXYPROPYL)-5-(CYCLOEXYLMETHYLSULFONYL)PHENOL OH

NH

2 0 OH 1008801 3-(3-Amino-l-hydroxypropyl)-5-(cyclohexylmethylsulfonyl)pheno is prepared following the method used in Example 55. 25 [00881] Step 1: Protection of Example 141 with Boc 2 O followed by oxidation gives tert-butyl 3-(3 (cyclohexylmethylsulfonyl)-5-hydroxyphenyl)-3-hydroxypropylcarbamate. [00882] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-hydroxyphcny)-3 hydroxypropylcarbamate gives Example 142 hydrochloride. 30 EXAMPLE 143 PREPARATION oF 2-(3-AMNOo-1-HYDROxYPROPYL)-4-(CYCLOHEXYLMETHYLTHIO)PHENOL S NH 2 OH 100883] 2-(3- Amino- l-hydroxypropyl)-4-(cyclohexymethylthio)phenol is prepared from 5-(cyclohexylmethylthio) 35 2-hydroxybenzaldehyde. 5-(Cyclohexylmethylthio)-2-hydroxybenzaldehyde was prepared following the methods described below. 1008841 Step 1: Reaction between 2-bromo-4-iodo- 1-methoxybenzene and thiolbenzoic acid (56) following the method used in Example 141 gave S-3-bromo-4-methoxyphenyl benzothioate as a light yellow oil, Yield (1.3 g, 60%); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.94 (dd,J= 8.4, 1.2 Hz, 2H), 7.70-7.72 (m, 1H), 7.58 (t, J 40 = 8.0 Hz, 2H), 7.49 (dd, J= 8.4, 2.0 Hz, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.22 (d, J= 8.8 Hz, 1H), 3.90 200 WO 2010/028088 PCTIUS2009/055785 5 (s, 3H). 1008851 Step 2: Reaction between S-3-bromo-4-methoxyphenyl benzothioate and bromide 2 in the presence of Cs 2 C0 3 following the method used in Example 141 gave (3-bromo-4 metboxyphenyl)(cyclohexylmethyl)sulfane as an off-white solid. Yield (1.2 g, 94%); 'H NMR (400 MHz, DMS0-d 6 ) 8 7.51 (d, J= 2.4 Hz, 1H), 7.31 (dd, J= 8.8, 2.4 Hz, 1H), 7.03 (d, J= 8.8 Hz, 1H), 3.80 (s, 3H), 10 2.77 (d, J= 6.8 Hz, 2H), 1.75-1.78 (m, 2H), 1.53-1.67 (m, 3H), 1.31-1.42 (m, 1H), 1.05-1,20 (m, 3H), 0.88 1.02 (m, 2H). [00886] Step 3: Formylation of (3-bromo-4-methoxyphenyl)(cyclohexylmethyl)sulfane following the method used in Example 141 gave 5-(cyclohexylmethylthio)-2-methoxybenzaldehyde as a light yellow oil. Yield (0.29 g, 29%); 'H NMR (400 MHz, CD 3 0D) 8 10.30 (s, 1H), 7.70 (d, J= 2.8 Hz, 1H), 7.60 (dd, J= 8.8, 2.4 Hz, 15 1H), 7.12 (d, J= 8.8 Hz, 1H), 3.93 (s, 3H), 2.75 (d, J= 6.8 Hz, 2H), 1.85-1.88 (m, 2H), 1.61-1.74 (m, 3H), 1.38-1.48 (m, 1H), 1.15-1.26 (m, 3H), 0.94-1.04 (m, 2H). [00887] Step 4: Demethylation of 5-(cyclohexylmethylthio)-2-methoxybenzaldehyde following the method used in Example 141 gave 5-(cyclohexylmethylthio)-2-hydroxybenzaldehyde as a white solid. Yield (0.15 g, 54%); 'H NMR (400 MHz, CDC1 3 ) 8 10.30 (s, 1H), 9.85 (s, 1H), 7.53-7.57 (m, 2H), 6.93 (d, J= 8.8 Hz, 1H), 2.74 20 (d, J= 6.8 Hz, 2H), 1.82-1,92 (m, 211), 1.61-1.76 (n, 3H), 1.40-1.52 (m, IH), 1.10-1.32 (m, 3H), 0.92-1.04 (m, 2H). [008881 Step 5: Acetonitrile addition to 5-(cyclohexylmethylthio)-2-hydroxybenzaldehyde following the method used in Example 141 gives 3-(5-(cyclohexylmethylthio)-2-hydroxyphenyl)-3-hydroxypropanenitrile. [00889] Step 6: Borane-DMS reduction of 3-(5-(cyclohexylmethylthio)-2-hydroxyphenyl)-3-hydroxypropanenitrile 25 gives Example 143. EXAMPLE 144 PREPARATION OF 2-(3-AMNo- 1-HYDROXYPROPYL)-4-(CYCLOHEXYLMETHYLSULFONYL)PHENOL 30O NH 2 30 0r OH [00890] 2-(3-Amino- t-hydroxypropyl)-4-(cyclohexylmethylsulfonyl)phenol is prepared following the method used in Example 142. [00891] Step 1: Protection of Example 1431 with Boc20 followed by oxidation gives tert-butyl 3-(5 (cyclohexylimethylsulfonyl)-2-hydroxyphenyl)-3-hydroxypropylcarbamate. 35 [00892] Step 2: Deprotection of tert-butyl 3-(5-(cyclohexylmethylsulfonyl)-2-hydroxyphenyl)-3 hydroxypropylcarbamate gives Example 143 hydrochloride. EXAMPLE 145 40 PREPARATION OF 3-AMINO-1-(3-(CYCLOHEXYLMETHYLTHWO)-5-FLUOROPHENYL)PROPAN-1-OL 201 WO 2010/028088 PCT/US2009/055785 F S$ /

NH

2 5 OH [00893] 3-Amino-1-(3-(cyclohexylmethylthio)-5-fluorophenyl)propan-I-ol is prepared following the method used in Example 55. [00894] Step 1: Reaction between 1-bromo-3-fluoro-5-iodobenzene and tbiolbenzoic acid (56) gives S-3-bromo-5 fluorophenyl benzothioate, 10 [00895] Step 2: Reaction of S-3-bromo-5-fluorophenyl benzothioate with bromide 2 gives (3-bromo-5 fluorophenyl)(cyclohexylmethyl)sulfane. [00896] Step 3: Formylation of (3-bromo-5-fluorophenyl)(cyclohexylmethyl)sulfane gives 3 (cyclohexyhnethylthio)-5-fluorobenzaldehyde. [00897] Step 4: Acetonitrile addition to 3-(cyclohexylmethylthio)-5-fluorobenzaldehyde gives 3-(3 15 (cyclohexyhnethylthio)-5-fluorophenyl)-3-hydroxypropanenitrile. [00898] Step 5: Borane-DMS reduction of 3-(3-(cyclohexylmethylthio)-5-fluorophenyl)-3-hydroxypropanenitrile gives Example 145. EXAMPLE 146 20 PREPARATION OF 3-AMINO-I-(3-(cYcLoHEXYLMETHYLsuLoNYL)-5-FLUOROPHENYL)PROPAN-1-OL F 11

NH

2 O OH [00899] 3-Amino-1-(3-(cyclohexylmethylsulfonyl)-5-fluorophenyl)propan- 1 -ol is prepared following the method used in Example 55. 25 [00900] Step 1: Protection of Example 145 with Boc 2 O followed by oxidation gives tert-butyl 3-(3 (cyclohexylmethylsulfonyl)-5-fluorophenyl)-3-hydroxypropylcarbamate. [00901] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-fluorophenyl)-3 hydroxypropylcarbamate gives Example 146 hydrochloride. 30 EXAMPLE 147 PREPARATION OF 3-AMINo-1-(5-(CYCLOHEXYLMETHYLTIIO)-2-FLUOROPHENYL)PROPAN-1-OL 8 N H 2 OH [00902] 3-Amino-1-(5-(cyclohexylmethylthio)-2-fluorophenyl)propan-1-ol is prepared following the method used 35 in Example 145. [00903] Step 1: Reaction between 2-bromo- I -fluoro-4-iodobenzene and thiolbenzoic acid (56) gives S-3-bromo-4 fluorophenyl benzothioate. 202 WO 2010/028088 PCT/US2009/055785 5 [00904] Step 2: Reaction of S-3-bromo-4-fluorophenyl benzothioate with bromide 2 gives (3-bromo-4 fluorophenyl)(cyclohexylnethyl)sulfane. [00905] Step 3: Formylation of (3-bromo-4-fluorophenyl)(cyclobexylmethyl)sulfane gives 5 (cyclobexylmethylthio)-2-fluorobenzaldehyde. [00906] Step 4: Acetonitrile addition to 5-(cyclohexylmethylthio)-2-fluorobenzaldehyde gives 3-(5 10 (cyclohexylmethylthio)-2-fluorophenyl)-3-hydroxypropanenitrile. [009071 Step 5: Borane-DMS reduction of 3-(5-(cyclohexylmethylthio)-2-fluorophenyl)-3-hydroxypropanenitrile gives Example 147. EXAMPLE 148 15 PREPARATION OF 3-AMINo-I-(5-(CYCLOHEXYLMETHYLSULFONYL)-2-FLUOROPHENYL)PROPAN-I-OL 9 NH 2 S 0r OH [00908] 3-Amino-1-(5-(cyclohexylmethylsulfonyl)-2-fluorophenyl)propan-1-ol is prepared following the method used in Example 146, 20 [00909] Step 1: Protection of Example 147 with Boc 2 0 followed by oxidation gives tert-butyl 3-(5 (cyclohexylmethylsulfonyl)-2-fluorophenyl)-3-hydroxypropylcarbamate. 1009101 Step 2: Deprotection of tert-butyl 3-(5-(cyclohexyhnethylsulfonyl)-2-fluorophenyl)-3 hydroxypropylcarbamate gives Example 148 hydrochloride. 25 EXAMPLE 149 PREPARATION OF 1-(3-(CYCLOHEXYLMETHrYLSULFONYL)PHENYL)-3-(METHYLAMINO)PROPAN-1-OL H N NN I I O OH 100911] 1-(3-(Cyclohexylmethylsulfonyl)phenyl)-3-(methylamino)propan- 1-ol is prepared following the method 30 used in Examples 90, 51, and 3. 1009121 Step 1: tert-Butyl 3-(3-(cyclohexylmethylthio)phenyl)-3-hydroxypropylcarbamate is reduced with LiAlH 4 following the method used in Example 51 to give 1-(3-(cyclohexylmethylthio)phenyl)-3 (methylamino)propan-1 -ol. [00913] Step 2: 1-(3-(Cyclohexylmethylthio)phenyl)-3-(methylamino)propan-1-ol is oxidized following the method 35 used in Example 3 to give Example 149. EXAMPLE 150 PREPARATION OF 3-AMINo-I-(3-(CYCLOHEXYLMETHYLSULFONYL)PHENYL)-l -DEUTEROPROPAN-1-OL 203 WO 2010/028088 PCT/US2009/055785 0

NH

2 5 0 OH [00914] 3-Amino- 1-(3-(cyclohexylmethylsulfonyl)phenyl)-1-deuteropropan-1-ol is prepared following the method used in Example 10. [00915j Step 1: NaBD 4 reduction of ketone 11 following the method used in Example 10 gives tert-butyl 3-(3 (cyclohexylmethylsulfonyl)phenyl)-3-deutero-3-hydroxypropylcarbanate. 10 [00916] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)phenyl)-3-fluoro-3 hydroxypropylcarbamate following the method used in Example 10 gives Example 150 hydrochloride. EXAMPLE 151 15 PREPARATION OF 3-AMINo-1-(3-((PERDEUTEROCYCLOHEXYL)METHYLSULFONYL)PHBNYL)PROPAN-1-OL DD D D D NH2 D D O OH D D D [00917] 3-Amino-1-(3-((perdeuterocyclohexyl)methylsulfonyl)phenyl)propan-1-oI is prepared following the method used in Example 53. [00918] Step 1: Example 52 is protected with Boc 2 O following the method used in Example 53 to give tert-butyl 3 20 hydroxy-3-(3-((perdeuterocyclohexyl)methylsulfony)phenyl)propylcarbamate. [00919] Step 2; Oxidation of tert-butyl 3-hydroxy-3-(3 ((perdeuterocyclohexyl)methylsulfonyl)phenyl)propylcarbamate gives tert-butyl 3-oxo-3-(3 ((perdeuterocyclohexyl)methylsulfonyl)phenyl)propylcarbamate. [00920] Step 3: Deprotection of tert-butyl 3-hydroxy-3-(3 25 ((perdeuterocyclohexyl)methylsulfonyl)phenyl)propylcarbamate gives Example 151 hydrochloride. EXAMPLE 152 PREPARATION oF 3-AMINo-I-(3-(CYCLOHEXYLMETHYLTHIO)-5-DEUTEROPHENYL)PROPAN-1-OL D S0 /

NH

2 30 OH [00921] 3-Amino--(3-(cyclohexylmethylthio)-5-deuterophenyl)propan-1-ol is prepared from 3-(3 (cyclohexylmethylthio)-5-fluorophenyl)-3-hydroxypropanenitrile. 3-(3-(Cyclohexylmethylthio)-5 fluorophenyl)-3-hydroxypropanenitrile was prepared following the methods described below. 100922] Step 1: Reaction between thiolbenzoic acid (56) and 3-bromo-5-iodobenzaldehyde gave S-3-bromo-5 35 formylphenyl benzothioate. Yield (0.642 g, 92%); 'H NMR (400 MHz, CDCl,) 6 9.98 (s, 1H), 8.07 (t, J= 1.96 Hz, 1H), 7.98-8.02 (m, 2H), 7.94 (t, J= 1.6 Hz, IH), 7.91 (t, J= 1.8 Hz, 1H), 7.65 (tt, J= 1.4, 7.4 Hz, 11H), 7.48-7.54 (in, 2H). 204 WO 2010/028088 PCT/US2009/055785 5 [009231 Step 2: A solution of S-3-bromo-5-formylphenyl benzothioate (0.642 g, 2.00 mmol), bromide 2 (0.49 g, 2.77 mmol) in MeOH:THF (1:2) was degassed by applying vacuum/argon, Cs2CO3 (1.25 g, 3.84 mmol) was then added and the reaction mixture was stirred for 20 hrs at room temperature. NaBH 4 (0.20 g, 5.29 mmol) was added and the reaction mixture was stirred for an additional 20 min. EtOAc and brine were added to the reaction mixture, layers separated and aqueous layer was extracted with EtOAc. Combined 10 organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (5% to 20% EtOAc - haxanes gradient) gave (3-bromo-5 (cyclohexylmethylthio)phenyl)methanol as a colorless oil. Yield (0.40 g, 64%); 'H NMR (400 MHz,

CDC

3 ) 8 7.31 (t, J= 1.6 Hz, 1H), 7.25-7.27 (m, 1H), 7.18-7.19 (in, 1H), 4.63 (s, 2H), 2.81 (d, J= 6.85 Hz, 2H), 1,84-1.91 (m, 2H), 1.60-1.76 (m, 4H), 1.48-1.59 (m, IH), 1.09-1.30 (in, 3H), 0.94-1.05 (m, 2H). 15 [009241 Step 3: To a cold (-78 *C) soluion of (3-bromo-5-(cyclohexylmethylthio)phenyl)methanol (0.40 g, 1.27 mmol) in anhydrous THIF under argon was added a solution of n-BuLi (2.5M in hexanes, 1.5mL). The reaction mixture was stirred for 4 mins and quenched with CD 3 0D (0.75 mL) followed by D 2 0 (0.75 mL). The mixture was allowed to warm to room temperature and partitioned between aqueous NH 4 CI and EtOAc. Aqueous layer was extracted with EtOAc, combined organic layers were washed with brine, dried 20 over anhydrous MgSO 4 , and concentrated under reduced pressure to give (3-(cyclohexylmethylthio)-5 deuterophenyl)methanol as a colorless oil. Yield (0.32 g, quant.); 'H NMR (400 MHz, CDCl 3 ) 8 7,29-7.32 (in, 1H), 7.20-7.23 (in, 1H), 7.11-7.14 (in, 1H), 4.66 (s, 2H), 2.82 (d, J= 6.85 Hz, 2H), 1.84-1.92 (m, 2H), 1.60-1.76 (in, 4H), 1.48-1.59 (in, 1H), 1.09-1.28 (m, 3H), 0.94-1.05 (in, 2H). 100925] Step 4: Oxidation of (3-(cyclohexylmethylthio)-5-deuteropheny)methanol with Dess-Martin periodinane 25 following the method used in Example 17 gave 3-(cyclohexylmethylthio)-5-deuterobenzaldehyde. Yield (0.252 g, 79%); 'H NMR (400 MHz, CDC1 3 ) 8 10.03 (s, 1H), 7.76 (t, J= 1.96 Hz, 1H), 7.60-7.63 (M, 1H), 7.50-7.54 (m, 1H), 2.86 (d, J= 6.85 Hz, 2H), 1.85-1.94 (in, 211), 1.62-1.77 (m, 4H), 1.50-1.61 (in, 1H), 1.10-1.29 (m, 31), 0.95-1.07 (in, 2H). 1009261 Step 5: Acetonitrile addition to 3-(cyclohexylmethylthio)-5-deuterobenzaldehyde gave 3-(3 30 (cyclohexylmethylthio)-5-deuterophenyl)-3-hydroxypropanenitrile. Yield (0.161 g, 55%); 'H NMR (400 MHz, DMSO-d) 8 7.30-7.32 (m, 1H), 7.14-7.20 (in, 2H), 5.92 (d, J= 4.5 Hz, 1H), 4.84 (dt, J= 4.9, 6.3 Hz, 1H), 2.75-2.90 (m, 4H), 1.76-1.86 (m, 2$), 1.52-1.70 (in, 3H), 1.40-1.51 (m, 1H), 1.04-1.21 (m. 3H), 0.90-1.03 (m, 2H). [00927] Step 6: Borane-DMS reduction of 3-(3-(cyclohexylmethylthio)-5-fluoropbenyl)-3-hydroxypropanenitrile 35 gives Example 152, EXAMPLE 153 PREPARATION OF 3-AMINo--(3-(CYCLOHEXYLMETHYLSULFONYL)-5-DEUTEROPHENYL)PROPAN-1-OL D oKi "1 NH 2 40 0 OH 100928] 3-Amino-i.-(3-(cyclohexyhnethylsulfonyl)-5-deuterophenyl)propan-1-cl is prepared following the method used in Example 146. 205 WO 2010/028088 PCT/US2009/055785 5 [00929 Step 1: Protection of Example 152 with Boc 2 O followed by oxidation gives tert-butyl 3-(3 (cyclohexylmethylsulfonyl)-5-deuterophenyl)-3-hydroxypropylcarbamate. [00930J Step 2: Deprotection of ten-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-deuterophenyl)-3 hydroxypropylcarbamate gives Example 153 hydrochloride. 10 EXAMPLE 154 PREPARATION OF 3-AMINO-1-(5-(CYCLOHEXYLMETHYLTHIO)-2-DEUTEROPHENYL)PROPAN-1-OL S 1NH 2 OH [009311 3-Amino-1-(5-(cyclohexylmethylthio)-2-deuterophenyl)propan-1-o was prepared following the method 15 used in Example 8 and 141. 100932] Step 1: Reaction between thiolbenzoic acid (56) and 2-bromo-5-iodobenzaldehyde following the method used in Example 141 gave S-4-bromo-3-formylphenyl bcnzothioate as a yellow solid. Yield (1.8 g, 87%). 1009331 Step 2: Reaction between S-4-bromo-3-formylphenyl benzothioate and bromide 2 in the presence of Cs 2

CO

3 following the method used in Example 141 gave 2-bromo-5-(cyclohexylmethylthio)benzaldehyde 20 as an light yellow oil. Yield (0.85 g, 88%). 100934] Step 3: A mixture of 2-bromo-5-(cyclohexylmethylthio)benzaldehyde (0.85 g, 2.72 mmol) andp toluenesulphonic acid (0.5 g) in ethanol (20 ml) was stirred at 70 *C for 4 hr. The reaction mixture was concentrated and partitioned between ethyl acetate (80 nil) and NaHCO 3 (50 ml). Organic layer was seperated and dried, concentrated to give (4-bromo-3-(diethoxymethyl)phenyl)(cyclohexylmethyl)sulfane 25 that was directly used in next reaction without further purification. [00935] Step 4: To a solution of (4-bromo-3-(diethoxymethyl)phenyl)(cyclohexylmethyl)sulfane in THF was added n-BuLi (2.5 N in hexane, 1.3 ml, 3.25 mmol) at -78 *C. After stirring for 20 min at -78 *C, D 2 0 (0.7 ml) was added and the reaction mixture was allowed to room temperature. To the mixture was added 6N HCi, stirred for 2 hr, and extracted with ethyl acetate. Organic layer was dried over anhydrous Na 2

SO

4 and 30 concentrated under reduced pressure, Purification by flash chromatography (5% to 30% EtOAc - hexanes gradient) gave 2-deutero-5-(cyclohexylmethylthio)benzaldebyde as a light yellow oil. Yield (0.40 g, 63%); 'H NMR (400 MHz, CDCI 3 ) 8 10.31 (s, 1H), 7.76 (d, J= 2.4 Hz, I H), 7.50 (d, J= 8.8 Hz, I H), 7.32 (dd, J = 8.8, 2.4 Hz, 1H), 2.83 (d, J= 6.4 Hz, 2H), 1.84-1.92 (m, 2H), 1.60-1.76 (m, 3H), 1.48-1.60 (m, 1 H), 1.10 1.29 (m, 3H), 0,96-1.06 (m, 2H). 35 [00936] Step 5: Acetonitrile addition of 2-deutero-5-(cyclohexylmethylthio)benzaldehyde following the method used in Example 8 gave 3-(2-deutero-5-(cyclohexylmethylthio)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (0.22 g, 47%); 'H NMR (400 MHz, CD 3 OD) 8 7.62 (d, J= 2.4 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.13 (dd, J= 8.4, 2.8 Hz, 1H), 5.22 (dd, J= 6.0, 4.4 Hz, I H), 2.72-2.95 (m, 411), 1.84-1.94 (m, 2H), 1.60-1.76 (m, 3H), 1.46-1.58 (m, 1H), 1.16-1.29 (m, 3H), 0.96-1.06 (m, 2H). 40 [00937] Step 6: Borane-DMS reduction of 3-(2-deutero-5-(cyclohexylmethylthio)phenyl)-3-hydroxypropanenitrile gave Example 154 as a color less oil. Yield (0.20 g, 90%); 'H NMR (400 MHz, MeOD) 8 7.52 (d, J= 2.4 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.07 (dd, J= 8.4, 2.4 Hz, 1H), 5.03 (dd, J= 4.4, 3.2 Hz, 1H), 2.78-2.84 (m, 411), 1.85-1.94 (m, 2H), 1.45-1.76 (m, 6H), 1.16-1.29 (m, 3H), 0.96-1.07 (m, 211). 206 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 155 PREPARATION OF 3-AMINO-1-(5-(CYCLOHEXYLMETHYLSULFONYL)-2-DEUTEROPHENYL)PROPAN-1-OL

NH

2 10 I00938] 3-Amino-l-(5-(cyclohexylmethylsulfonyl)-2-deuterophenyl)propan-1-o is prepared following the method used in Example 153. 100939] Step 1: Protection of Example 154 with Boc 2 Q followed by oxidation gives tert-butyl 3-(5 (cyclohexylmethylsulfonyl)-2-deuterophenyl)-3-hydroxypropylcarbamate. 100940] Step 2: Deprotection of tert-butyl 3-(5-(cyclohexylmethylsulfonyl)-2-deuterophenyl)-3 15 hydroxypropylcarbamate gives Example 155 hydrochloride. EXAMPLE 156 PREPARATION OF 3-AMINo-1-(3-(2-ETHYLBUTYLTIO)PHENYL)PROPAN-1-OL SH NH2 20 100941] 3-Amino-1-(3-(2-ethylbutylthio)phenyl)propan- 1-ol is prepared following the methods used in Examples 8 and 22. EXAMPLE 157 25 PREPARATION OF 3-AMINO-1-(3-(2-ETHYLBUTYLSULFONYL)PHBNYL)PROPAN-1-OL

NH

2 0 0 OH [009421 3-Amino-1-(3-(2-ethylbutylsulfonyl)phenyl)propan-I-ol is prepared following the methods used in Examples 3 and 105. 30 EXAMPLE 158 PREPARATION OF 3-AMINO-1-(3-(CYCLOPENTYLMBTHYLSULFONYL)PHENYL)PROPAN-1-OL N H2 00 OH [00943] 3-Arnino-1-(3-(cyclopentylmethylsulfonyl)phenyl)propan-1-o is prepared following the methods used in 35 Examples 3 and 105. 207 WO 2010/028088 PCT/US2009/055785 5 EXAMPLE 159 PREPARATION OF 3-AMINo-1-(3-(CYCLOPENTYLMETHYLSULFONYL)PHENYL)PROPAN-1-ONE

NH

2 Cr00 0 [00944] 3-Amino-1-(3-(cyclopentylmethylsulfonyl)phenyl)propan-1 -one is prepared following the methods used in 10 Examples 3 and 108. EXAMPLE 160 PREPARATION OF 3-AMINO-1-(3-(2-ETHYLPENTYLSULFONYL)PHENYL)PROPAN-1-OL 5 __NH 2 15 00 OH 100945] 3-Amino-1-(3-(2-ethylpentylsulfonyl)phenyl)propan-1-ol is prepared following the methods described in Examples 22, 8 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by 2 ethylpentyl methanesulfonate, 20 EXAMPLE 161 PREPARATION OF (R)-3-AMINO-1-(3-((R)-2-ETHYLPBNTYLSULPONYL)PHENYL)PROPAN-1-OL

NH

2 0 0 OH 100946] (R)-3-Amino-1-(3-((R)-2-ethylpentylsulfonyl)phenyl)propan-1-ol is prepared following the methods 25 described in Examples 22, 8, 17 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by (R)-2-ethylpentyl methanesulfonate. The chiral mesylate is prepared by application of chiral alkylation methodology as described by Evans et al., J. Am. Chem. Soc. .112:5290-5313 (1990). EXAMPLE 162 30 PREPARATION OF 3-AMiNO-1-(3-(2-ETHYLHEXYLSULFONYL)PHENYL)PROPAN-1-OL

NH

2 0 0 OH [009471 3-Amino-l-(3-(2-ethylhexylsulfonyl)phenyl)propan-1-oI is prepared following the methods described in 35 Examples 22, 8 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by 2 ethylhexyl methanesulfonate. 208 WO 2010/028088 PCTIUS2009/055785 5 EXAMPLE 163 PREPARATION OF (R)-3-AMINo-1-(3-((S)-2-ETHYLHEXYLSULFONYL)PHENYL)PROPAN-1-OL N H 2 0 0 OH [009481 (R)-3-Amino-l-(3-((S)-2-ethylhexylsulfonyl)phenyl)propan-1-ol is prepared following the methods 10 described in Examples 22, 8, 17 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by (S)-2-ethylhexyl methanesulfonate, The chiral mesylate is prepared by application of chiral alkylation methodology as described by Evans et al., J. Am. Chem. Soc. 112:5290-5313 (1990). EXAMPLE 164 15 PREPARATION OF 3-AMNo-1-(3-(2-PROPYLHEXYLSULFONYL)PHENYL)PROPAN-1-OL

NH

2 00 OH [00949] 3-Amino-1-(3-(2-propylhexylsulfonyl)phenyl)propan-1-ol is prepared following the methods described in Examples 22, 8 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by 2 20 propylhexyl methanesulfonate. EXAMPLE 165 PREPARATION OF (R)-3-AMINo-1-(3-((S)-2-PRoPYLHExYLsuLFoNYL)PENYL)PROPAN-1-OL

NH

2 25 0 0 OH [00950] (R)-3-Amino-1-(3-((S)-2-propylhexylsulfonyl)phenyl)propan-I-ol is prepared following the methods described in Examples 22, 8, 17 and 9. In step 1 of Example 22, the 2-propylpentyl methanesulfonate is replaced by (S)-2-propylhexyl methanesulfonate, The chiral mesylate is prepared by application of chiral alkylation methodology as described by Evans et al., J. Am. Chem. Soc. 112:5290-5313 (1990). 30 EXAMPLE 166 PREPARATION OF 3-AMINO-i-(3-(CYCLOHEXYLMETHYLSULFONYL)-5-METHYLPHENYL)PROPAN-1-OL o | 'N NH 2 o OH 35 [00951] 3-Amino-I-(3-(cyclohexylmethylsulfonyl)-5-methylphenyl)propan-1-ol was prepared following the method used in Example 153. 209 WO 2010/028088 PCT/US2009/055785 5 [00952] Step 1: Protection of Example 100 with Boc 2 0 followed by oxidation gave, after flash chromatography purification (10% to 80% EtOAc - hexanes gradient) tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5 methyiphenyl)-3-hydroxypropylcarbamate as a colorless oil. Yield (0.300 g, 90%); 'H NMR (DMSO-d 6 , 400 MHz) 8 7.60-7.62 (in, 1H), 7.53-7.55 (m, 1H), 7.44-7.46 (m, 11), 6.77 (br.t, J= 5.1 Hz, 1H), 5.39 (d, J = 4.7 Hz, IH), 4.62 (dt, J= 6.3, 11.0 Hz, 1H), 3.11 (d, J= 5.9 Hz, 2H), 2.88-3.00 (m, 2H), 2.38 (s, 3H), 10 1.62-1.80 (m, 5H), 1.47-1.61 (m, 3H), 1.34 (s, 9H), 0.94-1.21 (m, 5H). [00953] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-methylphenyl)-3 hydroxypropylcarbamate gave Example 155 hydrochloride as a colorless oil which solidifies upon standing to white solid. Yield (0.044 g, 36%); 'H NMR (CD 3 0D, 400 MHz) S 7.73-7.75 (m, IH), 7.64-7.66 (m, IH), 7.53-7.55 (m, 1H), 4.91 (dd, J= 3.7, 8.8 Hz, 1I), 3.02-3.16 (m, 4H), 2.46 (s, 3H), 1.88-2.08 (m, 2H), 1.76 15 1.88 (m, 3H), 1.56-1.71 (m, 3H), 1.00-1.30 (m, 5H); RP-HPLC tR = 8.86 min; 94.8% (AUC); ESI MS m/z 326.8 [M+H]*. EXAMPLE 167 20 PREPARATION OF 3-AMINO-I -(3-(CYCLOHEXYLMEffHYLSULFONYL)-5-METHYLPHENYL)PROPAN-1 -ONE o 1

NH

2 o a [009541 3-Amino- 1-(3-(cyclohexylmethylsulfonyl)-5-methylphenyl)propan-1 -one was prepared following the method used in Examples 166 and 51. [00955] Step 1: Oxidation of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-methylphenyl)-3 25 hydroxypropylcarbamate following the method used in Example 51 gave tert-butyl 3-(3 (cyclohexylmethylsulfonyl)-5-methylphenyl)-3-oxopropylcarbamate as a white solid. Yield (0.105 g, 90%); 'H NMR (CDC1 3 , 400 MHz) 8 8.20-8.22 (m, 1H), 7.97-7.99 (m, 1H), 7.88-7.90 (m, 1H), 5.07 (br.s, 1), 3.52 (q, J 5.9 Hz, 2H), 3.20 (t, J= 5.7 Hz, 2H), 2.97 (d, J= 6.26 Hz, 2H), 2.49 (s, 3H), 1.94-2.05 (m, 1H), 1.82-1.90 (m, 2H), 1.55-1.70 (m, 3H), 1.40 (s, 9H), 1.18-1.31 (m, 2H), 1.00-1.18 (m, 3H). 30 [00956] Step 2: Deprotection of tert-butyl 3-(3-(cyclohexylmethylsulfonyl)-5-methylphenyl)-3 hydroxypropylcarbamate following the method used in Example 166 gave Example 167 hydrochloride as a white solid. Yield (0.054 g, 90%); 'H NMR (CD 3 0D, 400 MHz) S 8.27-8.29 (m, 1H), 8.15-8.17 (m, 1H), 8.01-8.03 (m, IH), 3.50 (t, J= 6.3 Hz, 2H), 3.35 (t, J= 5.9 Hz, 2H), 3.14 (d, J= 6.3 Hz, 2H), 2.54 (s, 3H), 1.80-1.94 (m, 3H), 1,58-1.72 (m, 3H), 1.14-1.32 (m, SH); "C NNR (CD 3 0D, 400 MHz) 8 196.3, 141.5, 35 141.2, 137.0, 133.5, 132.6, 124.2, 61.8, 35.5, 34.5, 33.1, 32.8, 25.7, 20.0. EXAMPLE 168 PREPARATION OF 3-(3-AMINo-l-HYDROXYPROPYL)-N-CYCLOHEXYLBBNZENESULPONAMIDE NH 2 40 NO OH 210 WO 2010/028088 PCTIUS2009/055785 5 [009571 3-(3-Amino-1-hydroxypropyl)-N-cyclohexylbenzenesulfonamide was prepared following the method shown in Scheme 29. SCHEME 29 NH Et 3 N PyHBrBr 2 + 84 0 CH 2 C1 2 O THF, CH2C12 84 85 N NaBH4 N> B N O HN QI< r Br 0 N, 0i-PrOH- K.'- 1 NB EtOH:H 2 0 H 0 86 H 0 87 OH N CN 1. BH 3 -Me 2 S, THF NH2 -HCI H 0 OH 2. HCI, MeOH H OH 88 H 0 O 10 [00958] Step 1: Sulphonation of cyclohexylamine with 3-acetylbenzene-1-sulfonyl chloride (84) following the method used in Example 15 gave crude 3-acetyl-N-cyclohexylbenzenesulfonamide (85) which was used in the next step without further purification. Yield (2.98 g, 93%). 1009591 Step 2: To a solution of 3-acetyl-N-cyclohexylbenzenesulfonamide (85) (2.98 g, 10.6 mmol) in anhydrous

CH

2 Cl 2 was added in portions pyridinium tribromide (3.765 g, 11.8 mnmol) and the reaction mixture was 15 stirred at room temperature for 3 hrs. The reaction mixture was partitioned between brine and EtOAc, layers were separated and the aqueous layer was extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. purification by column chromatography gave 3-(2-bromoacetyl)-N-cyclohexylbenzenesulfonamide (86) as a colorless oil which crystallized to white solid upon standing. Yield (0.893 g, 23.4%); 'H NMR (DMSO-d 6 , 400 MHz) 8 20 8.33 (t, J= 1.76 Hz, 1H), 8.19-8.23 (in, 1H), 8.03-8.07 (in, 1H), 7.79 (d, J= 7.4 Hz, 1H1), 7.75 (t, J= 7.8 Hz, 1H), 4.96 (s, 2H), 2.90-3.00 (in, 1H), 1.48-1.58 (in, 4H), 1.36-1.44 (in, 1H), 0.95-1.17 (in, 5H). [00960] Step 3: 3-(2-Bromoacetyl)-N-cyclohexylbenzenesulfonamide (86) was reduced with NaBH 4 following the method used in Example 53 with the exception that NH 4 CI was used instead of NaHCO 3 . Purification by colunm chromatography (30% EtOAc/hexane) gave 3-(2-bromo-I-hydroxyethyl)-N 25 cyclohexylbenzenesulfonamide (87) as a colorless oil. Yield (0.253 g, 58%); 'H NMR (DMSO-d 6 , 400 MHz) 8 7.83-7.86 (in, IH), 7.66-7.70 (in, IH), 7.55-7.60 (in, 2H), 7.51 (t, J= 7.8 Hz, IH), 5.95-6.02 (in, 1H), 4.85-4.95 (n, 1H), 3.57-3.70 (in, 2H), 2.80-2.92 (in, 1H), 1.46-1.58 (in, 4H), 1.36-1.44 (m, iH), 0.94 1. 10 (mn, 5H). [00961] Step 4: A mixture of 3-(2-bromo-1-hydroxyethyl)-N-cyclohexylbenzenesulfonamide (87) (0.226 g, 0.622 30 mmnol) and sodium cyanide (0.077 g, 1.571 mmol) inEtOH:H 2 0 (3:1) was stirred at room temperature for 3 days. Concentration under reduced pressure followed by column chromatography (30% to 50% EROAc hexanes gradient) gave 3-(2-cyano- 1 -hydroxyethyl)-N-cyclohexylbenzenesulfonamide (88) as a colorless oil. Yield (0.11 g, 57%); 'H NMR (CDCI 3 , 400 MHz) 8 7.95 (t, J= 1.6 Hz, 1H), 7.80 (dt, J= 1.4, 7,6 Hz, IH), 7.55-7.59 (in, 1H), 7.49 (t, J= 7.8 Hz, 1H), 5.08 (dt, J= 6.1, 5.7 Hz, 2H), 3.05-3.15 (in, 1H), 2.71 35 2.83 (m, 2H), 1.53-1.73 (in, 4H), 1.44-1.52 (in, 1H), 1.01-1.28 (in, 5H). 211 WO 2010/028088 PCT/US2009/055785 5 [00962] Step 5: Borane-DMS reduction of 3-(2-cyanD-1-hydroxyethyl)-N-cyclohexylbenzenesulfonamide (88) following the method used in Example 100 gave Example 168 hydrochloride as a colorless oil. Yield (0.11 g, quant.); 1H NMR (CD 3 0D, 400 MHz) 8 7.91 (t, J= 1.8 Hz, 1H), 7.77 (dt, J= 1.4, 7.8 Hz, 111), 7.59-7.66 (m, 111), 7.54 (t, J= 7.8 Hz, 1H), 4.92 (dd, J= 3.9,9.0 Hz, IH), 2.96-3.16 (m, 3H), 1.90-2.08 (m, 2H), 1.48-1.70 (in, 5H), 1.08-1.24 (m, 5H). 10 EXAMPLE 169 IN VITRO ISOMERASE INHIBrrION ASSAY 1009631 The capability of sulphur-linked compounds to inhibit the activity of a visual cycle isomerase was determined in vitro either in a human or bovine-based assay system. The isomerase inhibition reactions were performed essentially as described (Stecher et al., J. Biot, Chem, 274:8577-85 (1999); see also Golczak et al., Proc. Nat. Acad. Sci. USA 102:8162-67 (2005), reference 3), either using a human cell line 15 or a bovine retinal pigment epithelium (RPE) microsome membranes as the source of visual enzymes. Isolation of Human Apo Cellular Retinaldehyde-Binding Protein (CRALBP) [00964) Recombinant human apo cellular retinaldehyde-binding protein (CRALBP) was cloned and expressed according to standard methods in the molecular biology art (see Crabb et al., Protein Science 7:746-57 (1998); Crabb et al., J. Biol. Chem. 263:18688-92 (1988)). Briefly, total RNA was prepared from confluent ARPE1 9 cells (American Type Culture Collection, Manassas, VA), cDNA was synthesized using an 20 oligo(dT) 12 18 primer, and then DNA encoding CRALBP was amplified by two sequential polymerase chain reactions (see Crabb et al., J. Biol. Chem. 263:18688-92 (1988); Intres, et al., J. Biol. Chem, 269:25411-18 (1994); GenBank Accession No. L34219.1). The PCR product was sub-cloned into pTrcHis2-TOPO TA vector according to the manufacturer's protocol (Invitrogen Inc., Carlsbad, CA; catalog no. K4400-01), and then the sequence was confirmed according to standard nucleotide sequencing techniques. Recombinant 25 6xHis-tagged human CRALBP was expressed in One Shot TOP 10 chemically competent E. coli cells (Invitrogen), and the recombinant polypeptide was isolated from E. coli cell lysates by nickel affinity chromatography using nickel (Ni) Sepharose XK 16-20 columns for HPLC (Amersham Bioscience, Pittsburgh, PA; catalog no.17-5268-02). The purified 6xHis-tagged human CRALBP was dialyzed against 10 mM bis-tris-Propane (BTP) and analyzed by SDS-PAGE. The molecular weight of the recombinant 30 human CRALBP was approximately 39 kDal. Human In Vitro Isomerase Inhibition Reaction [00965] The concentration dependent effect of the compounds disclosed herein on the retinol isomerization reaction were evaluated with a recombinant human enzyme system. In particular, the in vitro isomerase assay was performed essentially as in Golczak et al. 2005, PNAS 102: 8162-8167, ref. 3). A homogenate of HEK293 cell clone expressing recombinant human RPE65 and LRAT were the source of the visual enzymes, and 35 exogenous all-trans-retinol (about 20pM) was used as the substrate. Recombinant human CRALBP (about 80ug/mL) was added to enhance the formation of 1 1-cis-retinal. The 200 pL Bis-Tris Phosphate buffer (10mM, pH 7.2) based reaction mixture also contains 0.5% BSA, and 1mM NaPPi. In this assay, the reaction was carried out at 37 *C in duplicates for one hour and was terminated by addition of 300 pL methanol. The amount of reaction product, 1 1-cis-retinol, was measured by HPLC analysis following 40 Heptane extraction of the reaction mixture. The Peak Area Units (PAUs) corresponding to 1 Icis-retinol in the HPLC chromatograms were recorded and concentration dependent curves analyzed by GraphPad Prism for IC5 0 values. The ability of the compounds disclosed herein to inhibit isomerization reaction is 212 WO 2010/028088 PCT/US2009/055785 5 quantified and the respective IC 50 value is determined. Table 2 summarizes the IC 50 values of all the compounds of the present disclosure. Figures 1-4 depict dose-dependent curves for the inhibition of human in vitro isomerase for Compounds 5, 11, 14, and 17 by. The production of 1 1-cis-retinol was measured at different doses of compound administration. TABLE2 HuMAN IN VITRO INHiBITiON DATA IC0 (pM) Compound/Example Number < 0.01 iM 3, 9, 10, 14, 17,18, 46,48, 51, 52,53, 54 > 0.01 to< 0.1 pM 1, 2, 4,5, 6,7, 8,11, 13,15,16,19, 20,21, 22,23, 24, 25, 26, 27, 28, 32, 33,34, 35, 36, 37, 38, 40, 42, 45, 47, 49, 50, 55, 56, 57, 60, 61, 62, 63, 64, 65, 66, 70, 71, 100 > 0.1 to < I pM 12, 29, 30, 39, 58, 59, 79, 81, 84 Bovine In Vitro Isomerase Inhibition Reaction [00966] Bovine RPE microsome membrane extracts are prepared according to methods described (Golczak et al., 10 Proc. Nall. Acad. Sci. USA 102:8162-67 (2005)) and stored at -80 *C. Crude RPE microsome extracts are thawed in a 37 *C water bath, and then immediately placed on ice. About 50 ml crude RPE microsomes are placed into a 50 ml Teflon-glass homogenizer (Fisher Scientific, catalog no. 0841416M) on ice, powered by a hand-held DeWalt drill, and homogenized ten times up and down on ice under maximum speed. This process is repeated until the crude RPE microsome solution is homogenized. The homogenate 15 is then subjected to centrifugation (50.2 Ti rotor (Beckman, Fullerton, CA), 13,000 RPM; 15360 Rcf) for about 15 minutes at 4 *C. The supernatant is collected and subjected to centrifugation at 42,000 RPM (160,000 Rcf; 50.2 Ti rotor) for about 1 hour at 4 *C. The supernatant is removed, and the pellets are suspended in 12 ml (final volume) cold 10 mM MOPS buffer, pH 7.0. The resuspended RPE membranes in about 5 ml aliquots are homogenized in a glass-to-glass homogenizer (Fisher Scientific, catalog 20 no.K885500-002 1) to high homogeneity. Protein concentration is quantified using the BCA protein assay according to the manufacturer's protocol (Pierce, Rockford, IL). The homogenized RPE preparations are stored at -80 *C. 1009671 Sulphur-tinked compounds and control compounds are reconstituted in ethanol to 0.1 M. Ten-fold serial dilutions (102, 100,1o 1- 106 M) in ethanol of each compound are prepared for analysis in the 25 isomerase assay. [00968] The isomerase assay is performed in about 10 mM bis-tris-propane (BTP) buffer, pH 7.5, 0.5% BSA (diluted in BTP buffer), about 1 mM sodium pyrophosphate, about 20 gM all-trans retinol (in ethanol), and about 6 pM apo-CRALBP. The test compounds (2 p1) (final 1/15 dilution of serial dilution stocks) are added to the above reaction mixture to which RPE microsomes are added. The same volume of ethanol is 30 added to the control reaction (absence of test compound). Bovine RPE microsomes (9 P1) (see above) are then added, and the mixtures transferred to 37 *C to initiate the reaction (total volume = 150 pl). The reactions are stopped after about 30 minutes by adding methanol (about 300 Il), Heptane is added (300 pl) and mixed into the reaction mixture by pipetting. Retinoid is extracted by agitating the reaction mixtures, followed by centrifugation in a microcentrifuge. The upper organic phase is transferred to HPLC vials and 35 then analyzed by HPLC using an Agilent 1100 HPLC system with normal phase column: SILICA (Agilent Technologies, dp 5p, 4.6mmX, 25CM; running method has a flow rate of 1.5 ml/min; injection volume 100 213 WO 2010/028088 PCT/US2009/055785 5 1). The solvent components are 20% of 2% isopropanol in EtOAc and 80% of 100% hexane. [00969] The area under the A.

31 mu curve represents the 1 1-cis-retinol peak, which is calculated by Agilent Chemstation software and recorded manually. The ICso values (concentration of compound that gives 50% inhibition of 11 -cis-retinol formation in vitro) are calculated using GraphPad Prism@ 4 Software (Irvine, CA). All tests are performed in duplicate and it is expected that the sulphur-linked compounds of the 10 present disclosure show concentration dependent effects on the retinol isomerization reaction, as compared to control compounds. EXAMPLE 170 IN VIvo MURINE ISOMERASE ASSAY [00970] The capability of sulphur-linked compounds to inhibit isomerase is determined by an in vivo murine isomerase assay. Brief exposure of the eye to intense light ("photobleaching" of the visual pigment or simply "bleaching") is known to photo-isomerize almost all 11-cis-retinal in the retina. The recovery of 15 1 l-cis-retinal after bleaching can be used to estimate the activity of isomerase in vivo. Delayed recovery, as represented by lower 11-cis-retinal oxime levels, indicates inhibition of isomerization reaction. Procedures are performed essentially as described by Golczak et al., Proc. Natl. A cad. Sci. USA 102:8162 67 (2005). See also Deigner et al., Science, 244: 968-71 (1989); Gollapalli et al., Biochim Biophys Aca. 1651: 93-101 (2003); Parish, et al., Proc. Nail. Acad. Sci. USA, 14609-13 (1998); Radu, et al., Proc Natl 20 Acad Sci USA 101: 5928-33 (2004). [00971] About six-week old dark-adapted CD-I (albino) male mice are orally gavaged with compound (0.01 - 25 mg/kg) dissolved in an appropriate amount of oil (about 100 pl corn oil containing 10% ethanol, at least five animals per group). Mice are gavaged with the sulphur-linked compounds described in the present disclosure. After about 2-24 hours in the dark, the mice are exposed to photobleaching of about 5,000 lux 25 of white light for 10 minutes. The mice are allowed to recover for about 2 hours in the dark. The animals are then sacrificed by carbon dioxide inhalation. Retinoids are extracted from the eye and the regeneration of 1 1-cis-retinal is assessed at various time intervals. Eye Retinoid Extraction [00972] All steps are performed in darkness with minimal redlight illumination (low light darkroom lights and red filtered flashlights for spot illumination as needed) (see, e.g., Maeda et al., J. Neurochem 85:944-956, 30 2003; Van Hooser et al., JBiol Chem 277:19173-82, 2002). After the mice are sacrificed, the eyes are immediately removed and placed in liquid nitrogen for storage. [00973] The eyes are placed in about 500 AL of bis-tris propane buffer (10 mM, pH -7.3) and about 20 IiL of 0.8M hydroxylamine (pH-7.3). The eyes are cut up into small pieces with small iris scissors and then thoroughly homogenized at 30000 rpm with a mechanical homogenizer (Polytron PT 1300 D) in the tube until no 35 visible tissue remains. About 500 pL of methanol and about 500 gL of heptane are added to each tube. The tubes are attached to a vortexer so that the contents are mixed thoroughly for about 15 minutes in room temperature. The organic phase is separated from the aqueous phase by centrifugation for about 10 min at 13K rpm, 4 *C. 240 pL of the solution from the top layer (organic phase) is removed and transferred to clean 300 pl glass inserts in HPLC vials using glass pipette and the vials are crimped shut tightly. 40 [00974j The samples are analyzed on an Agilent 1100 HPLC system with normal phase column: SILICA (Beckman Coutlier, dp 5 pm, 4.6 mM x 250 mM). The running method has a flow rate of 1.5 ml/min; solvent components are 15% solvent I (1% isopropanol in ethyl acetate), and 85% solvent 2 (100% hexanes). 214 WO 2010/028088 PCT/US2009/055785 5 Loading volume for each sample is about 100 pl; detection wavelength is 360 nm. The area under the curve for 1 1-cis-retinal oxime is calculated by Agilent Chemstation software and recorded manually, Data processing is performed using Prizm software. [009751 Positive control mice (no compound administered) are sacrificed fully dark-adapted and the eye retinoids analyzed. Light (bleached) control mice (no compound administered) are sacrificed and retinoids isolated 10 and analyzed immediately after light treatment. [00976] A dose response in vivo isomerase inhibition study is performed with the compounds of the present disclosure. Male or female mice (such as Balb/c mice) (at least about 8/group) are dosed orally with about 0.01 to 25 mg/kg of the compounds of HCl salts of the compounds in sterile water as solution, and photobleached about 4 hours after dosing. Recovery and retinoid analysis is performed as described above, 15 Dark control mice are vehicle-only treated, sacrificed fully dark adapted without light treatment, and analyzed. The concentration-dependent inhibition of isomerase activity at about 4 hours post dosing of the compounds, inhibition of I 1-cis-retinal (oxime) recovery for and estimates of ED50 (dose of compound that gives 50% inhibition of 1-cis-retinal (oxime) recovery) are calculated. It is expected that the compounds display a dose-dependent response. 20 [00977] A time course study is also performed to determine the isomerase inhibitory activity of compounds of the present disclosure. Female or male mice (such as Balb/c mice) (at least 4/group) receive 0 to about 5 mg of compounds (in water) per kg bodyweight orally, by gavage. The animals are then "photo-bleached" (about 5000 Lux white light for about 10 minutes) at about 2,4, 8, 16 and 24 hours after dosing, and returned to darkness to allow recovery of the I I-cis-retinal content of the eyes. Mice are sacrificed about 2 hours after 25 bleaching, eyes are enucleated, and retinoid content is analyzed by HPLC. [009781 A single dose study of any compound is also performed at various dosages, a various time points post dosing. The experiments can be carried out in CD1 male mice, by way of example. Results are analyzed by HPLC, It is expected that the compounds of the present disclosure will exhibit different profiles of activity at different times and dosages, with different compounds also exhibiting different recovery patterns. 30 TABLE3 IN Vivo INHlBITION DATA % Inibition % Inibition Example No. 0.3 mg/kg, 4 h 1.0 mg/kg, 4 h 5 1.1 -12.1 8 Not tested -14.2 9 3.7 20.3 10 Not tested 79,3 17 Not tested 33.4 18 Not tested 68.6 27 Not tested 14.8 45 Not tested 87.1 46 Not tested -12.5 49 Not tested -8.5 50 Not tested -1.6 53 Not tested -4.9 215 WO 2010/028088 PCT/US2009/055785 EXAMPLE 171 PREPARATION OF RETINAL NEURONAL CELL CULTURE SYSTEM 5 [009791 This example describes methods for preparing a long-term culture of retinal neuronal cells. All compounds and reagents can be obtained from Sigma Aldrich Chemical Corporation (St. Louis, MO) or other suitable vendors. Retinal Neuronal Cell Culture [00980] Porcine eyes are obtained from Kapowsin Meats, Inc. (Graham, WA). Eyes are enucleated, and muscle and tissue are cleaned away from the orbit. Eyes are out in half along their equator and the neural retina is 10 dissected from the anterior part of the eye in buffered saline solution, according to standard methods known in the art. Briefly, the retina, ciliary body, and vitreous are dissected away from the anterior half of the eye in one piece, and the retina is gently detached from the clear vitreous. Each retina is dissociated with papain (Worthington Biochemical Corporation, Lakewood, NJ), followed by inactivation with fetal bovine serum (FBS) and addition of 134 Kunitz units/mi of DNaseI. The enzymatically dissociated cells are 15 triturated and collected by centrifugation, resuspended in Dulbecco's modified Eagle's medium (DMEM)/F12 medium (Gibco BRL, Invitrogen Life Technologies, Carlsbad, CA) containing about 25 pg/ml of insulin, about 100 pg /ml of transferrin, about 60 pM putrescine, about 30 aM selenium, about 20 nM progesterone, about 100 U/ml of penicillin, about 100 pg/ml of streptomycin, about 0.05 M Hepes, and about 10% FBS. Dissociated primary retinal cells are plated onto Poly-D-lysine- and Matrigel- (BD, 20 Franklin Lakes, NJ) coated glass coverslips that are placed in 24-well tissue culture plates (Falcon Tissue Culture Plates, Fisher Scientific, Pittsburgh, PA). Cells are maintained in culture for 5 days to one month in 0.5 ml of media (as above, except with only 1% FBS) at 37 C and 5% CO 2 . Immunocytochemistry Analysis 100981] The retinal neuronal cells are cultured for about 1, 3, 6, and 8 weeks, and the cells are analyzed by immunohistochemistry at each time point. Immunocytochenistry analysis is performed according to 25 standard techniques known in the art. Rod photoreceptors are identified by labeling with a rhodopsin specific antibody (mouse monoclonal, diluted about 1:500; Chemicon, Temecula, CA). An antibody to mid-weight neurofilament (NFM rabbit polyclonal, diluted about 1:10,000, Chemicon) is used to identify ganglion cells; an antibody to 03-tubulin (G7121 mouse monoclonal, diluted about 1:1000, Promega, Madison, WI) is used to generally identify interneurons and ganglion cells, and antibodies to calbindin 30 (AB 1778 rabbit polyclonal, diluted about 1:250, Chemicon) and calretinin (AB5054 rabbit polyolonal, diluted about 1:5000, Chemicon) are used to identify subpopulations of calbindin- and calretinin-expressing interneurons in the inner nuclear layer. Briefly, the retinal cell cultures are fixed with 4% paraformaldehyde (Polysciences, Inc, Warrington, PA) and/or ethanol, rinsed in Dulbecco's phosphate buffered saline (DPBS), and incubated with primary antibody for about I hour at 37 "C. The cells are then 35 rinsed with DPBS, incubated with a secondary antibody (Alexa 488- or Alexa 568-conjugated secondary antibodies (Molecular Probes, Eugene, OR)), and rinsed with DPBS. Nuclei are stained with 4', 6 diamidino-2-phenylindole (DAPI, Molecular Probes), and the cultures are rinsed with DPBS before removing the glass coverslips and mounting them with Fluoromount-G (Southern Biotech, Birmingham, AL) on glass slides for viewing and analysis, 40 [00982] Survival of mature retinal neurons after varying times in culture is indicated by the histochemical analyses. Photoreceptor cells are identified using a rhodopsin antibody; ganglion cells are identified using an NFM antibody; and amacrine and horizontal cells are identified by staining with an antibody specific for 216 WO 2010/028088 PCT/US2009/055785 5 calretinin. [00983] Cultures are analyzed by counting rhodopsin-labeled photoreceptors and NFM-labeled ganglion cells using an Olympus IX81 or CZX41 microscope (Olympus, Tokyo, Japan). Twenty fields of view are counted per coverslip with a 20x objective lens. Six coverslips are analyzed by this method for each condition in each experiment. Cells that are not exposed to any stressor are counted, and cells exposed to a stressor are 10 normalized to the number of cells in the control. It is expected that compounds presented in this disclosure promote dose-dependent and time-dependent survival of mature retinal neurons. EXAMPLE 172 EFFECT OF SULPHUR-LINKED COMPOUNDS ON RETINAL CELL SURVIVAL 100984] This Example describes the use of the mature retinal cell culture system that comprises a cell stressor for determining the effects of a sulphur-linked compound on the viability of the retinal cells. [00985] Retinal cell cultures are prepared as described in Example 171. A2E is added as a retinal cell stressor, 15 After culturing the cells for 1 week, a chemical stress, A2E, is applied. A2E is diluted in ethanol and added to the retinal cell cultures at concentration of about 0, 10 pM, 20 RM, and 40 pM. Cultures are treated for about 24 and 48 hours. A2E is obtained from Dr. Koji Nakanishi (Columbia University, New York City, NY) or is synthesized according to the method of Parish et al. (Proc. Natt. A cad. Scl. USA 95:14602-13 (1998)). A sulphur-linked compound is then added to the culture. To other retinal cell cultures, a sulphur 20 linked compound is added before application of the stressor or is added at the same time that A2E is added to the retinal cell culture. The cultures are maintained in tissue culture incubators for the duration of the stress at 37 *C and 5% CO 2 . The cells are then analyzed by immunocytochemistry as described in Example 171. Apoptosis Analysis [009861 Retinal cell cultures are prepared as described in Example 171 and cultured for about 2 weeks and then 25 exposed to white light stress at about 6000 lux for about 24 hours followed by a 13-hour rest period. A device was built to uniformly deliver light of specified wavelengths to specified wells of the 24-well plates. The device contains a fluorescent cool white bulb (GE P/N FC12T9/CW) wired to an AC power supply. The bulb is mounted inside a standard tissue culture incubator. White light stress is applied by placing plates of cells directly underneath the fluorescent bulb. The CO 2 levels are maintained at about 5%, and the 30 temperature at the cell plate is maintained at 37 *C. The temperature is monitored by using thin thermocouples. The light intensities for all devices is measured and adjusted using a light meter from Extech Instruments Corporation (P/N 401025; Waltham, MA), Any sulphur-linked compound is added to wells of the culture plates prior to exposure of the cells to white light and is added to other wells of the cultures after exposure to white light. To assess apoptosis, TUNEL is performed as described herein. 35 [009871 Apoptosis analysis is also performed after exposing retinal cells to blue light. Retinal cell cultures are cultured as described in Example 171. After culturing the cells for about I week, a blue light stress is applied. Blue light is delivered by a custom-built light-source, which consists of two arrays of 24 (4X6) blue light-emitting diodes (Sunbrite LED P/N SSP-0 1 TWB7UWB 12), designed such that each LED is registered to a single well of a 24 well disposable plate. The first array is placed on top of a 24 well plate 40 full of cells, while the second one is placed underneath the plate of cells, allowing both arrays to provide a light stress to the plate of cells simultaneously. The entire apparatus is placed inside a standard tissue culture incubator. The CO 2 levels are maintained at about 5%, and the temperature at the cell plate is 217 WO 2010/028088 PCT/US2009/055785 5 maintained at about 37 "C. The temperature is monitored with thin thermocouples. Current to each LED is controlled individually by a separate potentiometer, allowing a uniform light output for all LEDs. Cell plates are exposed to about 2000 lux of blue light stress for either about 2 hours or 48 hours, followed by a about 14-hour rest period. A sulphur-linked compound is added to wells of the culture plates prior to exposure of the cells to blue light and is added to other wells of the cultures after exposure to blue light. To 10 assess apoptosis, TUNEL is performed as described herein. [009881 To assess apoptosis, TUNEL is performed according to standard techniques practiced in the art and according to the manufacturer's instructions. Briefly, the retinal cell cultures are first fixed with 4% paraformaldehyde and then ethanol, and then rinsed in DPBS. The fixed cells are incubated with TdT enzyme (0.2 units/li final concentration) in reaction buffer (Fermentas, Hanover, MD) combined with 15 Chroma-Tide Alexa568-5-dUTP (0.1 pM final concentration) (Molecular Probes) for about I hour at 37 *C. Cultures are rinsed with DPBS and incubated with primary antibody either overnight at 4 *C or for about I hour at 37 *C. The cells are then rinsed with DPBS, incubated with Alexa 488-conjugated secondary antibodies, and rinsed with DPBS. Nuclei are stained with DAPI, and the cultures are rinsed with DPBS before removing the glass coverslips and mounting them with Fluoromount-G on glass slides 20 for viewing and analysis. [00989] Cultures are analyzed by counting TUNEL-labeled nuclei using an Olympus IX81 or CZX41 microscope (Olympus, Tokyo, Japan). Twenty fields of view are counted per coverslip with a 20x objective lens. Six coverslips are analyzed by this method for each condition. Cells that are not exposed to a sulphur-linked compound are counted, and cells exposed to the antibody are normalized to the number of cells in the 25 control, Data are analyzed using the unpaired Student's t-test. It is expected that sulphur-linked compounds reduce A2E-induced apoptosis and cell death in retinal cell cultures in a dose-dependent and time-dependent mainer. EXAMPLE 173 IN Vivo LIGHT MOUSE MODEL 100990] This Example describes the effect of a sulphur-linked compound in an in vivo light damage mouse model. 1009911 Exposure of the eye to intense white light can cause photo-damage to the retina. The extent of damage 30 after light treatment can be evaluated by measuring cytoplasmic histone-associated-DNA-fragment (mono and oligonucleosomes) content in the eye (see, e.g., Wenzel et al., Prog. Retin. Eye Res. 24:275-306 (2005)). [00992] Dark adapted mice (for example, male Balb/c (albino, 10/group)) are gavaged with the sulphur-linked compounds of the present disclosure at various doses (about 0.01 - 25 mg/kg) or vehicle only is 35 administered. About six hours after dosing, the animals are subjected to light treatment (8,000 lux of white light for 1 hour). Mice are sacrificed after about 40 hours of recovery in dark, and retinas are dissected. A cell death detection ELISA assay is performed according to the manufacturer's instructions (ROCHE APPLIED SCIENCE, Cell Death Detection ELISA plus Kit). Contents of fragmented DNA in the retinas are measured to estimate the retinal-protective activity of the compounds. It is expected that compounds of 40 the present disclosure mitigate or inhibit photo-damage to the retina. EXAMPLE 174 ELEcTRoRETINOGRAPHIC (ERG) STUDY [009931 This example describes determining the effect of a sulphur-linked compound that is a visual cycle 218 WO 2010/028088 PCT/US2009/055785 5 modulator on the magnitude of the ERG response in the eyes of mice after oral dosing of the animals with the compound. The level of ERG response in the eyes is determined after administering the compound to the animals (for example at 18 and 66 hours post administration). 1009941 Three groups of about nine-week old mice (19-25 grams), both genders (strain C5 7BL6, Charles River Laboratories, Wilmington, MA) are housed at room temperature, 72 + 4 *F, and relative humidity of 10 approximately 25%. Animals are housed in a 12-hour light /dark cycle environment, have free access to feed and drinking water and are checked for general health and well-being prior to use and during the study. Body weights are determined for a representative sample of mice prior to initiation of dosing. The average weight determined from this sampling is used to establish the dose for all mice in the study. [009951 Each test compound is dissolved in the control solvent (EtOH), and diluted 1:10 (90 ml/900 ml) in the 15 appropriate oil (for example corn oil (Crisco Pure Corn Oil, J.M. Smucker Company, Orrville, OH)) to the desired dose (mg/kg) in the desired volume (about 0.1 mUanimal). The control vehicle is ethanol: oil (about 1:10 (0.9 ml/9 ml)). An example of treatment designations and animal assignments are described in Table 4. TABLE 4 Dose Group Route Treatment Animals (mg/kg) Test oral Sulphur-linked (0.01 - 25 mg/kg) >4 compound Control oral Vehicle None >4 [00996] Animals are dosed once orally by gavage, with the assigned vehicle control or test compounds during the 20 light cycle (between about 30mn and about 3 hours 30min after the beginning of the light cycle). The volume of the administered dose usually does not exceed about 10 mlkg. [00997] ERG recordings are made on dark-adapted and, subsequently (during the course of the same experiment), on light-adapted states. For the dark-adapted response, animals are housed in a dark-adapted environment for at least about I hour prior to the recording, commencing at least about 30 minutes after the start of the 25 light cycle. 100998] At about eighteen and about sixty six hours after dosing, the mice are anesthetized with a mixture of Ketamine and Xylazine (100 mg/kg and 20 mg/kg, respectively) and placed on a heating pad to maintain stable core body temperature during the course of the experiment. Pupils are dilated by placing a 5 microliter drop of mydriatic solution (tropicamide 0.5%) in the recorded eye. A mouse corneal monopolar 30 contact lens electrode (Mayo Corporation, Inazawa, Aichi, Japan) is placed on the cornea, and a subcutaneous reference low profile needle 12 mm electrode (Grass Telefactor, W Warwick, RI) is placed medial from the eye. A ground needle electrode is placed in the tail. Data collection is obtained using an Espion E 2 (Diagnosys LLC, Littleton, MA) ERG recording system with Color Dome Ganzfeld stimulator. Full dark-adapted intensity-response function is determined following a brief white flash stimuli of about 35 14 intensities ranging from about 0.0001 cd.s/m 2 to about 333 cd.s/m 2 . Subsequently, full light-adapted intensity-response function is determined following a brief white flash stimuli of about 9 intensities ranging from about 0.33 cd.s/m 2 to about 333 cd.s/m 2 . Analysis of the obtained responses is done off-line. Intensity-response function determination is done by fitting a sigmoid function to the data (Naka KI, 219 WO 2010/028088 PCT/US2009/055785 5 Rushton WA, 1966; Naka KI, Rushton WA, 1967). It is expected that sulphur-linked compounds of the present disclosure will depress or suppress the dark-adapted ERG responses (measured at about 0.01 cd.s/m) while minimally affecting the photopic, light-adapted V. values when compared to control compounds. EXAMPLE 175 EFFECT OF A SULPHUR-LINKED COMPOUND ON REDUCTION OF LPOFUSCN FLUOROPHORES 100999] This example describes testing the capability of a sulphur-linked compound to reduce the level of existing 10 bis-retinoid, N-retinylidene-N-retinylethanolaniine (A2E) and lipofuscin fluorophores in the retina of mice as well as prevention of the formation of A2E and lipofuscin fluorophores, A2E is the major fluorophore of toxic lipofuscin in ocular tissues. 10010001 The eyes of aboa4-null (abca4 -/-) mutant mice (see, e.g., Weng et al., Cell 98:13-23 (1999)) have an increased accumulation of lipofuscin fluorophores, such as A2E (see, e.g., Karan et al., Proc. Nat. 15 Acad. Sci. USA 102:4164-69 (2005)). Compounds (about 1 mg/kg) or vehicle are administered daily for about three months by oral gavage to abca4/ mice that are about 2 months old. Mice are sacrificed after about three months of treatment. Retinas and RPE are extracted for A2E analysis. [001001] A similar experiment is performed with aged balb/c mice (about 10 months old). The test mice are treated with about 1 mg/kg/day of compounds for about three months and the control mice are treated 20 with vehicle. 1001002] Briefly, under dim red light, each pair of eye balls are harvested, homogenized in a mixture of PBS buffer and methanol and the A2E extracted into chloroform. The samples are dried down and reconstituted in a water/acetonitrile mix for HPLC analysis. The amount of A2E present is determined by comparison of the area under the curve (AUC) of the A2E peak in the sample with an A2E 25 concentration/AUC curve for an A2E reference standard measuring at 440 nm. [001003] It is expected that A2E levels are reduced upon treatment with one or more sulphur-linked compounds disclosed herein. EXAMPLE 176 EFFECT OF A SULPHUR-LINKED COMPOUND ON RETINOID NUCLEAR RECEPTOR ACTIVITY [0010041 Retinoid nuclear receptor activity is associated with transduction of the non-visual physiologic, pharmacologic, and toxicologic retinoid signals that affect tissue and organ growth, development, 30 differentiation, and homeostasis. 1001005] The effect of one or more sulphur-linked compounds disclosed herein and the effect of a retinoic acid receptor (RAR) agonist (E-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)- I -propenyl] benzoic acid) (TTNPB), and of all-trans-retinoic acid (at-RA), which is an RAR and retinoid X receptor (RXR) agonist, are studied on RAR and RXR receptors essentially as described by Achkar et al. (Proc. 35 Natl Acad. Sci. USA 93:4879-84 (1996)). It is expected that the compounds of the present disclosure do not show significant effects on retinoid nuclear receptors (RAR and RXR). By contrast, TTNPB and at-RA activated the RXR, RAR 0 , RARp and RAR 7 receptors as expected (Table 5). Table 5 Compound RARa RARfi RARy RXRa ECs 0 (nM) EC 5 (nM) ECs 0 (nM) ECso (nM) 220 WO 2010/028088 PCTIUS2009/055785 TTNPB 5.5 +/- 4.5 0.3 +/- 0.1 0,065 +/- 0.005 N/A at-RA N/A N/A N/A 316 +/-57 N/A = Not applicable 5 [001006] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included, [001007] The various embodiments described herein can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent 10 applications, and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference in their entireties. [001008] From the foregoing it will be appreciated that, although specific embodiments have been described herein for purposes of illustration, various modifications may be made, Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the 15 specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. 20 [001009] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only, Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims 25 define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. 221

Claims (47)

1. A compound of Formula (I) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt thereof: (R 33 ), R X R 3 R 4 R6 R 12 Y Z N R1 Formula (I) wherein, Z is -C(R 9 )(R' 0 )-C(R')(R 2 )- or -X-C(R")(R")-; Y is -SO 2 NR 40 -, -S-C(R' 4 )(R")-, -S(=O)-C(R 14 )(R")-, or -S(=0)2-C(R14)(R )-; R' and R 2 are each independently selected from hydrogen, halogen, Cj-C 5 alkyl, fluoroalkyl, or -OR 6 ; or R' and R 2 together form an oxo; R 3 1 and R 32 are each independently selected from hydrogen, Cr-C 5 alkyl, or fluoroalkyl; R 40 is hydrogen; each R' 4 and R' 5 is independently selected from hydrogen or alkyl; R 3 and RW are each hydrogen; or R3 and R4 together form an imino; R 5 is C 2 -Ci 5 alkyl, carbocyclyalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl; X is -0-; R9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or -OR 6 ; or R9 and R' 0 form an oxo; or optionally, R 9 and R' together form a direct bond to provide a double bond; or optionally, RW and R' together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R" and R' are each independently selected from hydrogen, alkyl, -C(=0)R , or CO 2 R"; each R 13 is alkyl each R 6 and R 3 4 is independently hydrogen or alkyl; each R 33 is independently selected from halogen, OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1, or 2.

2. The compound of claim I having the structure of Formula (1a) (R 3 3 )n R R3 4- R 12 Y Z l R 11 Formula (Ia) wherein, Z is -C(R 9 )(R 0 )-C(R)(R 2 )- or -O-C(RM)(R3)-; Y is -S0 2 NR 40 -, -S-C(R1 4 )(R")-, -S(=O)-C(R' 4 )(R")-, or -S(=0)2-C(R'4)(R")-; R' is -C(R' 6 )(R)(R"); 222 R1 6 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R 16 and R", together with the carbon to which they are attached form a carbocyclyl; R1 8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; R' and R 2 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, or -OR 6 ; or R' and R 2 together form an oxo; R 3 1 and R 32 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl; R 3 and R 4 are each hydrogen; or R3 and R4 together form an imino; R9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or -OR 6 ; or R9 and R' 0 together form an oxo; R" and R" are each independently selected from hydrogen, alkyl, or -C(=0)R each R 13 is alkyl; each R 6 and R 34 are independently hydrogen or alkyl; each R 33 is independently selected from halogen, -OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1 or 2; and with the provision wherein R 6, R" and R are all hydrogen are excluded.

3. The compound of claim 2 having the structure of Formula (Ib): (R 33)n R 17 1 6 Rl\. R R 2 Ri1 Y 9 'R R 9 R10R 3 R 4 Formula (Ib) wherein, Y is -S-C(R1 4 )(R")-, -S(=O)-C(R 4 )(R")-, or -S(=0)rC(R14)(R")-; R' and R 2 are each independently selected from hydrogen, halogen, CI-Cs alkyl, fluoroalkyl, or -OR 6 ; or R' and R 2 together form an oxo; R 3 and R 4 are each hydrogen; or R3 and R 4 together form an imino; R9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or -OR 6 ; or R 9 and R' 0 together form an oxo; R" and R1 2 are each independently selected from hydrogen, alkyl, or -C(=O)R1 3 ; each R1 3 is alkyl; each R 6 and R 34 are independently hydrogen or alkyl; R' 4 and R1 5 are each independently selected from hydrogen or alkyl; R' 6 and R 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R", together with the carbon to which they are attached form a carbocyclyl; R1 8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 33 is independently selected from halogen, -OR 3 4 , alkyl, or fluoroalkyl; and n is 0, 1, or 2; and with the provision wherein R 16 , R1 7 , and R1 8 are all hydrogen is excluded.

4. The compound of claim 3 wherein n is 0 and each of R' and R 12 is hydrogen. 223

5. The compound of claim 4 wherein each of R 3 , R 4 , R" and R" is hydrogen.

6. The compound of claim 5 wherein, R' and R 2 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, -OR 6 ; R 9 and R' are each independently selected from hydrogen, halogen, alkyl, -OR 6 ; or R 9 and R' together form an oxo; each R 6 is independently hydrogen or alkyl; R 1 6 and R' 7 , together with the carbon to which they are attached, form a carbocyclyl; and R' 8 is selected from a hydrogen, alkoxy or hydroxy.

7. The compound of claim 6 wherein R' 6 and R 1 7 , together with the carbon to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R 18 is hydrogen or hydroxy.

8. The compound of claim 3, wherein R" is hydrogen and R" is -C(=0)R", wherein R 13 is alkyl.

9. The compound of claim 8, wherein R' and R 2 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, or -OR 6 ; R 9 and RIO are each independently selected from hydrogen, halogen, alkyl, or -OR 6 ; or R 9 and RIO together form an oxo; each R 6 is independently selected from hydrogen or alkyl; Ri 6 and R' 7 , together with the carbon atom to which they are attached, form a carbocyclyl; and Ri 8 is hydrogen, hydroxy or alkoxy.

10. The compound of claim 9 wherein n is 0; R' 6 and R' 7 , together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R1 8 is hydrogen or hydroxy.

11. The compound of claim 5, wherein R' and R 2 are each independently selected from hydrogen, halogen, Ci-C 5 alkyl or -OR 6 ; R 9 and R' are each independently selected from hydrogen, halogen, alkyl, or -OR 6 ; or R 9 and R' together form an oxo; each R 6 is independently hydrogen or alkyl; R 16 and R' 7 are each independently alkyl; and R' 8 is hydrogen, hydroxy or alkoxy.

12. The compound of claim 2 having the structure of Formula (Ic): (R 33 )n R 17 R 16 R31R32R R ' O3 11R12 R 3 R 4 Formula (Ic) wherein, Y is -S-C(R 4 )(R' 5 )-, -S(=O)-C(R 1 4 )(R" 5 )-, or -S(=0)2-C(R 4)(R")-; R 3 1 and R 32 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl; 224 R3 and R 4 are each hydrogen; or R3 and R4 together form an imino; R" and R 12 are each independently selected from hydrogen, alkyl, or -C(=O)R 3 ; R 3 is alkyl; R' 4 and R' 5 are each independently selected from hydrogen or alkyl; R' 6 and R' are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R, together with the carbon atom to which they are attached, form a carbocyclyl; R' 8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 33 is independently selected from halogen, -OR 34 , alkyl, or fluoroalkyl; R 3 4 is hydrogen or alkyl; and n is 0, 1, or 2.

13. The compound of claim 12 wherein n is 0 and each R" and R1 2 is hydrogen.

14. The compound of claim 13 wherein each R 3 , R 4 , R' 4 and R 5 is hydrogen.

15. The compound of claim 14 wherein, R 3 1 and R 32 are each independently hydrogen, or CI-C 5 alkyl; R' 6 and R 7 , together with the carbon atom to which they are attached, form a carbocyclyl; and R's is hydrogen, hydroxy, or alkoxy.

16. The compound of claim 15 wherein R' 6 and R", together with the carbon atom to which they are attached, form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; and R 18 is hydrogen or hydroxy.

17. The compound of claim 14 wherein, R 3 1 and R 32 are each independently selected from hydrogen, or C C 5 alkyl; and R1 8 is hydrogen, hydroxy or alkoxy.

18. The compound of claim 2 having the structure of Formula (le): (R 33)n R 40 R R 4 R 16 N 1 R 180 0 R Formula (le) wherein, Z is -C(R 9 )(R" 0 )-C(R')(R 2 )- or -O-C(R3)(R3)-; R' and R2 are each independently selected from hydrogen, halogen, CI-C 5 alkyl, fluoroalkyl, or -OR6; or R 1 and R2 together form an oxo; R3 and R 4 are each hydrogen; or R 3 and R 4 together form an imino; R 9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or -OR; or R' and R 10 form an oxo; or optionally, R9 and R' together form a direct bond to provide a double bond; or optionally, RW and R 1 together form a direct bond, and R' 0 and R 2 together form a direct bond to provide a triple bond; R 3 1 and R 32 are each independently selected from hydrogen, CI-C 5 alkyl, or fluoroalkyl; R" and R1 2 are each independently selected from hydrogen, alkyl, or -C(=0)R1; 225 each R1 3 is alkyl; each R 6 and R 3 4 are independently hydrogen or alkyl; R 1 6 and R' 7 are each independently selected from hydrogen, alkyl, halo or fluoroalkyl; or R' 6 and R 7 , together with the carbon to which they are attached form a carbocyclyl; R" is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 3 is independently selected from halogen, -OR 34 , alkyl, or fluoroalkyl; R 40 is hydrogen; and n is 0, 1, or 2; and with the provision wherein R1 6 , R1 7 , and R1 8 are all hydrogen excluded.

19. The compound of claim 2 having the structure of Formula (If): (R 33 )n R 14 R 1 5 NH 2 R180 0 R 9 R 1 0 Formula (If) wherein, R 9 and R' 0 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, or -OR 6 ; or R 9 and R 10 together form an oxo; each R 6 and R 3 4 are independently hydrogen or alkyl; R' 4 and R1 5 are each independently selected from hydrogen or alkyl; R' and R' 7 , together with the carbon to which they are attached form an optionally substituted cyclopentyl, an optionally substituted cyclohexyl or an optionally substituted cycloheptyl; R 8 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl; each R 3 3 is independently selected from halogen, -OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, or 2; and with the provision wherein R 16 , R1 7 , and R" are all hydrogen is excluded.

20. A compound selected from the group consisting of: S NH 2 II K NH 2 (1) 0 S NH2 NH 2 S NH 2 NH 2 K NH 2 0 0 SJN H 2 SN H 2 OH 226 NH2 NH2 0 0 OH 0 0 0 Sk NH2 (:: S) O N H2 , NH2 NH2 s 0 ~7 N 2 s -~ 0 N N 2 0 0 N NH2 NH2 0 - NH 2 NH 2 N H2 N H2 OH 0 H NH2 N Si 7 NH 2 cc J z> NH 2 2 00 0-~ i 'N N H 2 OH 7 H S NHc NH 2 H22 22 I I OH 0 OH NH 2 I'NH NH 2 sNH 2 (I I Sj), NH 2 OH OH " OH ' OH SA NH 2 sNH CF 3 - NH 2 OHN NH 2 OCF 3 QCF 3 NH1 NH 2 OH 0OH 0 s 'NNH 2 1 N NH 2 CrOH DD OHD NH 2 D NH OH OH 'NNH 2 0 N NH 2 OH C 0 OH D DD DN D DD 0 D~~ ~ 'N2 H DO DO 0 DsNH 2 0D D D OH 'NNH DD 0 DD r OH 228 OH 0 N 7 NH 2 0 NH_",~~N .' 7 NH 2 NH NH 2 I IH 00 NH 2 NH 2 10,, 0\ NH21 0 H HHO N, .7 NH 2 N., 'NH 2 H 0 s 7 NH SJ NH 2 N 10 NH 2 7OHII SJ N 7 ,, NH 2 < SJ N NH 2 O H S:)NH 2 11 ,, N H 2 0 0 O H NH 2 ,,,NH 229 H~ 0~ H NH 2 N I I 2I O0 0 OH S 'H2 NH 2 I'2 0 N , NH 2 N NH 2 0 0"'N ) ,,, NH 2 N l,7 N H 2 s 0 0 Ho 7 N" IN. I 3NH 2 isNa NH 2 O 0 OH NN NH 2 NNH 2 ( o 0 0 0 N 5 NNH 2 N 0 NH 2 7OH 0 OH 0 2 N " N NH N NH I I SOH 00 NH 2 11j NH 2 0 O H '..0 OH 7f 0 N 7 ja ,,NH 2 NNH 2 S 0 O H O OH 230 NH 2 NH 2 NH2N IIII OO0 0 0H S NH2 NH2 F NH 2 F NH 2 F F FFN NH 2 O N NH 2 0 0 F ONHNH2 HO S NH2 "N NH 2 SN HO*',- sNH2 S 0 NH2 II O O0 , OH NH 2 OH NH 2 SS O OH F OH S 0 0O0 NH 2 NH2 1123I N NH 2 I, ro OH 0 O OH sNH 2 SH N ::l r, NH 2 00 0 OH I2OH OH IOHO 0H NNH 2 I H O OH 0 OH OH OHO 0 H NH NHNH O0 0 O N NH 2 "NN 2 Ss 00 0 OH 0 O 0O 0 "'0 -~"'S17 01 NsNNH 2 11 b' NH 2 OH OH NH 2 111NH 2 OH 0 OH F F 01 NH 2 11 - NH 2 OH 0r OH s 'NH 2 H OH 0r OH N, I NH 2 0 OH 0 OH 232 D D DID D NH2N D SNH 2 N 0 DO OH2 NH 2 0 0 OH D 0 1 0 O1 NH 2 NH 2 S N NH2 H H OH OH S NH2 NH2 , n OH 0 N O NH 2 NH 2 S S2 0 0H OH SNH 2 NH 2 0 0 OH 00 OH 00 I N11 NH 2 NH S 0 OH 00 0 OHan R SINH 2 NH N , \\ /, \ 00 OH00 O S- _NH 2 NH OH 00O and S -- O- NH 2 H 0 OH

21. copoud sleced romthegrop cnsitin3of

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 1-21.

23. A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject the pharmaceutical composition of claim 22.

24. The method of claim 23 wherein the ophthalmic disease or disorder is a retinal disease or disorder.

25. The method of claim 24 wherein the retinal disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy.

26. A method of inhibiting at least one visual cycle trans-cis isomerase in a cell comprising contacting the cell with the compound of any one of claims 1-2 1, thereby inhibiting the at least one visual cycle trans-cis isomerase.

27. The method of claim 26 wherein the cell is a retinal pigment epithelial (RPE) cell.

28. A method of inhibiting at least one visual cycle trans-cis isomerase in a subject comprising administering to the subject the pharmaceutical composition of claim 22.

29. The method of either claim 23 or claim 28 wherein the subject is human.

30. The method according to either claim 23 or claim 28 wherein accumulation of lipofuscin pigment is inhibited in an eye of the subject.

31. The method according to claim 30 wherein the lipofuscin pigment is N-retinylidene-N-retinyl ethanolamine (A2E).

32. The method according to any one of claims 23-30 wherein degeneration of a retinal cell is inhibited.

33. The method according to claim 32 wherein the retinal cell is a retinal neuronal cell.

34. The method according to claim 33 wherein the retinal neuronal coil is a photoreceptor cell, an amacrine cell, a horizontal cell, a ganglion cell, or a bipolar cell.

35. The method according to claim 32 wherein the retinal cell is a retinal pigment epithelial (RPE) cell.

36. A method of modulating chromophore flux in a retinoid cycle comprising introducing into a subject a compound of any one of claims 1-21.

37. 37. The method according to claim 36 resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject.

38. The method according to claim 37 wherein the lipofuscin pigment is N-retinylidene-N-retinyl ethanolamine (A2E).

39. A method of inhibiting dark adaptation of a rod photoreceptor cell of the retina comprising contacting the retina with the compound of any one of claims of 1-2 1.

40. A method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of the retina comprising contacting the retina with the compound of any one of claims of 1-21.

41. A method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with the compound of any one of claims of 1-21.

42. The method of claim 41 wherein the retinal cell is a retinal neuronal cell.

43. The method of claim 42 wherein the retinal neuronal cell is a photoreceptor cell. 234

44. A method of reducing lipofuscin pigment accumulated in a subject's retina comprising administering to the subject the pharmaceutical composition of claim 22.

45. The method of claim 44 wherein the lipofuscin is N-retinylidene-N-retinyl-ethanolamine (A2E).

46. The compound of claim I wherein, the compound of Formula (1) has one, more than one or all of the non-exchangeable 'H atoms replaced with 2 H atoms.

47. The compound of claim 73 selected from the group consisting of: SNH201 NH2 NHH2g NH NH2 cc OH DD 0oH2D ) D S 'NSNH 2 NH 2 NH 2 OH OH OH D NH2 a NH 2 N23 S'N DH D 0 0 OH DOr O DO 0 s 0 0 0 0 OH DOf a N1120Q0O H2'0 NHD 'I 'N NH 2 Or OH 00 D 0 " NH 2 NH 2 OH 0 OHD 'D DIN sNH 2 11 NH 2 0"_OH ,and OH 235