The present invention relates to compounds useful for inhibiting retinoic acid receptor-related orphan receptor gamma-t (RORyt), pharmaceutical compositions, and methods for treating diseases related to RORy activity.

The retinoic acid receptor-related orphan receptors (RORs) are members of the nuclear receptor (NR) superfamily identified as important pathological regulators in many diseases. The ROR subfamily consists of RORa, ROR , and RORy. The mouse and human RORy gene generates two isoforms, γΐ and j2, the latter most commonly referred to as yt. RORyt signaling, often in response to IL-23/IL-23 receptor signaling, is required for the differentiation of naive CD4+ T-cells into a subset of T-cells designated Thl7, which are distinct from the classical Thl and Th2 cells, and supports their maintenance. Thl7 cells produce interleukin-17A (IL-17) and IL-17F. In addition, Thl7 cells produce a range of other factors known to drive inflammatory responses, including tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), GM-CSF, CXCL1 and CCL20. NK cells and innate lymphoid cells such as lymphoid tissue inducer (LTi)-like cells express IL-23 receptor and RORyt and produce IL-17 in response to stimulation and IL-23. There is substantial evidence that IL-23 -responsive, RORyt, and IL-17-expressing cells are associated with autoimmune diseases (AI), inflammatory diseases, and cancer. Thus, targeted inhibition of RORyt may be important to reducing the pathogenesis of those diseases.

AI diseases are chronic conditions for which no cure currently exists. Treatment of AI diseases typically involves an attempt to control the process of the disease and decrease the symptoms by administering anti-inflammatory, anti-pain, or

immunosuppressant medications. Unfortunately, the use of anti-inflammatory and anti-pain medications is sometimes ineffective and the use of immunosuppressants often leads to devastating long-term side effects. The most significant side effects of

immunosuppressant drugs are an increased risk of infection and a higher risk of cancer.

Natural and synthetic ligands to RORyt have been identified. Small molecule inhibitors against RORyt have been reported in the literature for AI. See WO

2015/017335 and WO 2014/179564. However, the prevalence of AI diseases coupled with the ineffectiveness or devastating side effects of current treatments necessitate that more treatment choices be available to patients. Targeting RORyt may present an advantage over current AI therapies by maximizing the therapeutic benefit by targeting pathogenic immune cells while minimizing the risk of suppression of host defenses.

The present invention provides novel compounds that are RORyt inhibitors. Such new compounds could address the need for potent, effective treatment of uveitis, multiple sclerosis, rheumatoid arthritis, graft versus host disease, Crohn's disease, other inflammatory bowel diseases, cancer, psoriasis, and seronegative spondylarthropathies, such as axial spondylarthritis, ankylosing spondylitis, and psoriatic arthritis.

The present invention rovides a compound of formula

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for the treatment of psoriasis in a patient comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method for the treatment of seronegative spondylarthropathies in a patient comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt thereof. In said embodiment, seronegative spondylarthropathies are axial spondyloarthritis, ankylosing spondylitis, or psoriatic arthritis.

The present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. In a further embodiment, the composition further comprises one or more other therapeutic agents. In a further embodiment, the present invention provides a pharmaceutical composition for the treatment of psoriasis comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with one or more

pharmaceutically acceptable carriers, diluents, or excipients. In yet a further

embodiment, the present invention provides a pharmaceutical composition for the treatment of seronegative spondylarthropathies comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. In said embodiment, seronegative spondylarthropathies are axial spondylarthritis, ankylosing spondylitis, or psoriatic arthritis.

Further, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular for the treatment of psoriasis. Even further, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In a further embodiment, the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of psoriasis.

Further, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular for the treatment of seronegative spondylarthropathies. Even further, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of seronegative spondylarthropathies. In a further embodiment, the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of seronegative spondylarthropathies. In said embodiments, seronegative

spondylarthropathies are of axial spondylarthritis, ankylosing spondylitis, or psoriatic arthritis.

The present invention also encompasses intermediates and processes useful for the synthesis of a compound of the present invention.

The term "treating" (or "treat" or "treatment") as used herein refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, condition or disorder.

The term "spondylarthropathies" refers to a number of chronic joint diseases that generally involve the vertebral column and the areas where ligaments and tendons attach to bone. Spondylarthropathies are sometimes also called spondyloarthropathies or spondylarthritis .

The term "seronegative" refers to a disease which is negative for reheumatoid factor.

A compound of the present invention may react to form pharmaceutically acceptable salts. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al. Handbook of

Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley- VCH, 2011); S.M. Berge, et al. , "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

The skilled artisan will appreciate that a compound of the invention, as shown in (I), or pharmaceutically acceptable salt thereof, is comprised of a core that contains at least two chiral centers, as re resented by * below:

Although the present invention contemplates all individual enantiomers, as well as mixtures of the enantiomers of said compounds including racemates, the preferred compounds of the invention are represented by (II) below:

or pharmaceutically acceptable salts thereof.

The skilled artisan will also appreciate that the Cahn-Ingold-Prelog (R) or (S) designations for all chiral centers will vary depending upon the substitution patterns of the particular compound. The single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographic or crystallization techniques at any convenient point in the synthesis of compounds of the invention. Single enantiomers of compounds of the invention are a preferred embodiment of the invention.

A compound of the present invention is preferably formulated as pharmaceutical compositions administered by a variety of routes. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g. , Remington: The Science and Practice of Pharmacy (A. Gennaro, et al. , eds., 21st ed., Mack Publishing Co., 2005). More particularly preferred, is a pharmaceutical composition comprising a compound of the formula,

or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or diluents.

An especially preferred embodiment of the present invention relates to the compound, (5 ' S)-N- { [5 -(ethylsulfonyl)pyridin-2-yl]methyl } -5 ' -methyl- 1 - { ( 1 R)- 1 - [2-trifluoromethyl)pyrimidin-5-yl]ethyl} -4' ,5 '-dihydrospiro[piperidine-4,7' -thieno[2,3,c]pyran]-2'-carboxamide:

or a pharmaceutically acceptable salt thereof.

Another especially preferred embodiment of the present invention relates to the compound,

The compounds of the present invention are generally effective over a wide dosage range. For example, dosages per day fall within the range of about 1 mg to 1 g. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed while maintaining a favorable benefit/risk profile, and therefore the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of Formula I, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,"

Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The designations "isomer 1" and "isomer 2" refer to the compounds that elute from chiral chromatography first and second, respectively, and if chiral chromatography is initiated early in the synthesis, the same designation is applied to subsequent intermediates and examples.

Additionally, certain intermediates described herein may contain one or more protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular

transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene 's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

Certain abbreviations are defined as follows: "AUC" refers to area under the curve; "BSA" refers to Bovine Serum Albumin; "CFA" refers to complete Freund's adjuvant; "DBA" refers to dilute brown non-Agouti; " "DCM" refers to dichloromethane; DPBS" refers to Dulbecco's phosphate-buffered saline; "DMEM" refers to Dulbecco's Modified Eagle's Medium; "DMSO" refers to dimethyl sulfoxide; "EC50" refers to the effective concentration at half the maximal response; "EtOAc" refers to ethyl acetate; "Et20" refers to ethyl ether; "EtOH" refers to ethyl alcohol or ethanol; "ee" refers to enantiomeric excess; "Ex" refers to example; "FBS" refers to Fetal Bovine Serum; "G" refers to gravitational force; "GAL" refers to beta-galactosidase DNA binding domain; "GPI" refers to glucose -6-phosphate isomerase; "HEC" refers to hydroxy ethyl cellulose; "HEK" refers to human embryonic kidney; "HEPES" refers to 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; "IC50" refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent; "IL" refers to interleukin; "IP A" refers to isopropyl alcohol or isopropanol; "Kd" refers to constant of dissociation; "Ki" refers to inhibition constant; "MeOH" refers to methyl alcohol or methanol; "MEM" refers to Minimum Essential Medium; "PBMC" refers to peripheral blood mononuclear cells; "PBS" refers to phosphate buffered saline; "Prep" refers to preparation; "RAR refers to retinoic acid receptor; and "RPMI" refers to Roswell Park Memorial Institute. "R " refers to retention time; "SCX" refers to strong cation exchange; "SFC" refers to supercritical fluid chromatography; and "THF" refers to tetrahydrofuran.

The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways to prepare compounds of the invention, or salts thereof. The products of each step below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

The following preparations and examples further illustrate the invention and represent typical synthesis of the compounds of the present invention.

Preparations and Examples

Preparation 1

1 -(3 -Thienyl)propan-2-one

Suspend 2-(3-thienyl)acetic acid (26.5 g, 146.5 mmol) in acetic anhydride (87.9 mL, 913 mmol,) and add 1-methylimidazole (7.57 g, 91.3 mmol). Stir the reaction mixture for 4 hours at room temperature under nitrogen. Cool the reaction mixture to 0 °C, add water (150 mL), and stir for 1 hour. Dilute the solution with EtOAc (300 mL) and wash successively with 2 M NaOH (2x200 ml), water (200 mL) and brine (200 mL). Separate the organic extracts phase, dry over sodium sulfate, filter, and concentrate to dryness to obtain the title compound (28.16 g, 77%) as a yellow oil. H NMR (400.13 MHz, CDC13) δ 2.14 (s 3H), 3.7 (s, 2H), 6.94 (d, J= 5.1 Hz, 1H), 7.08 (bs, 1H), 7.29-7.26

(M, 1H).

Preparation 2

1 -(3 -Thienyl)propan-2-ol

Add dry MeOH (63 mL) to sodium borohydride (1.61 g, 41.67 mmol) and cool the reaction mixture to -10 °C while adding the MeOH. Cool further to -20 °C and add a solution of l-(3-thienyl)propan-2-one (4.92 g, 33.34 mmol) in dry MeOH (26.7 mL) drop wise over 40 minutes and stir for 1.5 hours at -20 °C then at room temperature for 17 hours. Cool the solution to -5 °C (internal temperature) and quench with a saturated solution of ammonium chloride (15 ml) then with 1 N HC1 (15 mL). Add water (30 mL) and EtOAc (100 mL). Concentrate the mixture under reduced pressure to 1/3 of total volume. Extract the mixture with EtOAc (2x100 mL). Combine the organic extracts and

dry over magnesium sulfate, filter, and concentrate to dryness to give the title compound (4.74 g, 100%). Mass spectrum (m/z): 125 (M-OH+H), 164.8 (M+Na).

Alternate Preparation 2a

Add sodium borohydride (7.06 g, 182.8 mmol) portion wise over 30 minutes at 0

°C to a solution of l-(3-thienyl)propan-2-one (28.16 g, 140.6 mmol) in MeOH (282 mL) and stir at room temperature overnight. Concentrate to dryness, dilute with EtOAc (200 mL) and wash with a saturated solution of ammonium chloride (150 mL). Extract the aqueous layer with EtOAc (2x200 mL). Combine the organic extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel flash chromatography eluting with MeOH: DCM (0:100 to 5:95) to give the title compound (12.85 g, 64%) as a pale red oil. Mass spectrum (m/z): 125 (M-OH+H).

Preparation 3

(2S) -l- (3-Thien l) propan-2-ol

Dissolve 3-bromothiophene (6.88 g, 42.2 mmol) in anhydrous THF (10 mL) and toluene (100 mL). Cool to -78 °C. To this add via syringe sec-butyllithium (1.3 mol/L in cyclohexane, 34 mL, 44 mmol) over 15 minutes. Maintain the temperature at < -60 °C, stir 10 minutes, then add (2S)-2-methyloxirane (4.9 g, 84.4 mmol) dropwise. After 5 minutes, add boron trifluoride diethyl etherate (5.3 mL, 42 mmol) over 15 minutes via dropping funnel. Maintain the temperature at < -55 °C. After the addition is complete, stir at -78 °C for 2 hours. Quench at -78 °C with saturated sodium bicarbonate, add Et20, and warm to ambient temperature. Wash with saturated sodium bicarbonate (2x) followed by saturated brine. Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel flash chromatography eluting with 15% EtOAc/hexanes to give the title compound (3.85 g, 64.2%). Repurify the mixed fractions to give a total amount of the title compound (4.29 g, 71.5%) as a colorless liquid. H NMR (400.13 MHz, CDC13) δ 7.28-7.26 (dd, J=2.9, 5.0, 1H), 7.03-

7.01 (m, 1H), 6.96 (dd, J=1.2, 4.9, 1H), 4.04-3.95 (m, 1H), 2.83-2.68 (m, 2H), 1.63 (s, 1H), 1.22 (d, J= 6.2, 3H), OR [a]20D +25.50 (c 1.00, CHC13),

Preparation 4

(5'S)-5'-Methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]

Dissolve feri-butyl 4-oxopiperidine-l-carboxylate (6.50 g, 32.6 mmol) and (2S)-1-(3-thienyl)propan-2-ol (4.64g, 32.6 mmol) in DCM (100 mL). Add trifluoroacetic acid (20 mL, 264.5 mmol). Stir the mixture at ambient temperature 18 hours. Concentrate the mixture under reduced pressure, and then add water and Et20. Wash the organic layer with water, combine the aqueous washes, and then adjust pH to basic with solid sodium carbonate. Saturate the aqueous layer with solid sodium chloride, then wash aqueous layer with EtOAc (5x). Combine the EtOAc layers, wash with brine, dry with sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (4.61g, 63%) as a pale yellow oil. Mass spectrum (m/z): 224.2 (M+H).

Preparation 5

i