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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems

Definitions

• the invention is directed to substituted thiazole compo unds, which are modulators of the nuclear receptor RORyt, pharmaceutical compositions, and methods for use thereof. More particularly, the RORyt modulators are useful for preventing, treating or ameliorating an RORyt mediated inflammatory syndrome, disorder or disease,
• Retinoic acid-related nuclear receptor gamma t is a nuclear receptor, exclusively expressed in cells of the immu e system, and a key transcription factor driving Thl7 cell differentiation
• Thl7 cells are a subset of CD4 + T cells, expressing CCR6 on their surface to mediate their migration to sites of inflammation, and dependent, on IL-23 stimulation, through the IL-23 receptor, for their maintenance and expansion.
• Thl7 cells produce several proinflammatory cytokines including IL- 17A, IL-17F, IL-21 , and IL-22 (Korn, T., E. Bettelli, et al. (2009).
• Interleukin- 17 the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis
• Thl 7 cells have been shown to be the major pathogenic population in several models of autoimmune inflammation, including collagen- induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) (Dong, C. (2006). "Diversification of T-helper-cell lineages: finding the family root of IL- 17-producmg cells.” Nat Rev Immunol 6(4): 329-33; McKenzie, B. S., R. A. Kastelein, et al. (2006).
• mice Understanding the IL-23-IL-17 immune pathway.” Trends Immunol 27(1): 17-23.). RORyt- deficient mice are healthy and reproduce normally, but have shown impaired ThI7 cell differentiation in vitro, a significantly reduced ThI7 cell population in vivo, and decreased susceptibility to EAE (Ivanov, II, B. S, McKenzie, et al. (2006). "The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells," Cell 126(6): 1 121 -33.).
• mice deficient for IL-23 a cytokine required for ThI 7 cell survival, fail to produce Thl7 cells and are resistant to EAE, CIA, and inflammatory bowel disease (IBD)
• IBD inflammatory bowel disease
• IL-23 is essential for T cell- mediated colitis and promotes inflammation via IL-17 and IL-6," J Clin Invest 116(5): 1310-6.). Consistent with these findings, an anti-IL23-specific monoclonal antibody blocks development of psoriasis-like inflammation in a murine disease model (Tonel, G., C, Conrad, et al. "Cutting edge: A critical functional role for IL-23 in psoriasis.” J Immunol 185(10): 5688-91).
• IL-17 the key cytokine produced by Thl7 ceils, is expressed at elevated levels in a variety of allergic and autoimmune diseases (Barczyk, A., W. Pierzchaia, et al, (2003). "Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine.” Respir Med 97(6): 726-33.; Fujino, 8., A. Andoh, et al. (2003). "Increased expression of interieukin 17 in inflammatory bowel disease.” Gut 52(1): 65-70.: Lock, C, G. Hermans, et al. (2002).
• Ustekinumab (Stelara®), an anti-p40 monoclonal antibody blocking both IL-12 and IL-23, is approved for the treatment of adult patients (18 years or older), with moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy.
• monoclonal antibodies specifically targeting only IL-23, to more selectively inhibit the Thl7 subset are also in clinical development for psoriasis (Garber , (201 1), "Psoriasis: from bed to bench and back" Nat Biotech 29, 563-566), further implicating the important role of the IL-23- and RORyt-driven Thl 7 pathway in this disease.
• Anti-IL-17 antibodies have also demonstrated clinically relevant responses in early trials in RA and uveitis (Hueber, W., Patel, D.D., Dryja, T., Wright, A.M., Koroleva, L, Bruin, G., Antoni, C, Draelos, Z,, Gold, M.H., Durez, P., Tak, P.P., Gomez-Reino, J.J,, Foster, C.S., Kim, R.Y., Samson, CM,, Falk, N.S., Chu, D.S., Callanan, D., Nguyen, Q.D., Rose, K., Haider, A., Di Padova, F. (2010) Effects of AIN457, a fully human antibody to interleukin- 17 A, on psoriasis, rheumatoid arthritis, and uveitis, Sci Transl Med 2,
• the resent invention comprises a compound of Formula ⁇ .
• X is CH, CR', or N
• A is C( j-2 ) alkyl;
• A" is cyclobutyl, or C ( t- )alkyl, wherein said C(i-4 ) alkyl is optionally substituted with OCH 3 or up to three fluorine atoms;
• azetidinyl piperidinyl, pyrrolidinyl, ; wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of F, CF 3 , CFI 3 , -CN, and CH 2 OH;
• R 1 is CL C(CFi 3 ) 3 , CH 2 CH 3 , OCF 3 , CF 3 , OCF!(CH 3 ) 2 , CFIF 2 , OCHF 2 , OCI3 ⁇ 4, F, CH 3 , or -CN;
• R 2 is H, F, or CI;
• R 1 and R 2 may be taken together with their attached phenyl to form a naphthalenyl, or quinoliny! group;
• R is CF 3 , or CFJ 2 CH 3 ;
• C ( i-s ) alkyl is optionally substituted with one to two substituents independently selected from COOH, CON3 ⁇ 4 -CN, and OH;
• a J and A 4 may be taken together with their attached nitrogen to make a ring selected
• resent invention comprises a compound of Formula ⁇ .
• X is CH, CR 3 , or N
• a 3 is Q j- 2) alkyl
• a 2 is cyclobutyl, or wherein said C(3 ⁇ 4_4 ) alkyl is optionally substituted with OCH 3 or to three fluorine atoms:
• azetidiny! consisting of piperidinyl, pyrrolidinyl a d 3 ⁇ 4 ; wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of F, CF 3 , CI3 ⁇ 4, -CN, and CH 2 OH;
• R 1 is CI, ⁇ ( ⁇ ⁇ ⁇ . CH2CH3, OCF 3 , CF 3 , OCH(CH 3 ) 2 , CHF 2 , OCI !F.-. OCH3, F, CFI 3 , or -CN;
• R 2 is H, F, or CI;
• R 3 and R" may be taken together with their attached phenyl to form a naphthaienyl, or quinolinyl group;
• R 3 is CF 3 , or CH 2 CH 3 ;
• a 3 is H
• i-s j alkyl is optionally substituted with one to two substituents independently selected from.
• COOFL CONFI 2 , -CN, and OH; or A 3 and A 4 may be taken together with their attached nitrogen to make a ring selected
• X is CH, CR 3 , or N
• a 3 is C ( i-2 ) alkyl
• A" is cyclo butyl, or Chalky!, wherein said ⁇ alkyl is optionally substituted with OCH 3 or to three fluorine atoms;
• ring consisting of azetidinyl, piperidinyl, pyrrolidinyl, l ⁇ - x ⁇ 7 N group , and ; wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of F, CF 3 , CH 3 , -CN, and CH 2 OH;
• R ] is CI, C(CH 3 ) 3 , CH 2 CH 3 , OCF 3 , CF 3 , OCH(CH 3 ) 2 , CHF 2 , OCHF 2 , OCH 3 , F, or CH 3 ;
• R is H, F, or CI
• R 3 and R z may be taken together with their attached phenyl to fonn a naphthalenyl, or quinolinyl group;
• R 3 is CF 3 , or CH 2 CH 3 ;
• a 3 is FI , or ; wherein said j-sjalkyl is optionally substituted with one to two substituents independently selected from CONH 2 , -CN, and OH;
• a 3 and A 4 may be taken together with their attached nitrogen to make a ring selected
• X is CH, CR ! , or N;
• a 1 is C ( ] .2)alkyl
• A" is cyclobutyl, or C( 1 - 4 ) alkyl, wherein said Cf 1-4) alkyl is optionally substituted with OCH 3 or up to three fluorine atoms; or A J and A" are taken together with their attached nitrogen to form a ring selected the
• azetidinyl piperidinyl, pyrrolidinyl, ; where said ring is optionally substituted with up to three substituents independently selected from the group consisting of F, CF 3 , CH 3 , -CN, and CH 2 OH;
• R ! is CL C(CH 3 )3, CH -Cl k OCF 3 , CF 3 , ⁇ ⁇ ⁇ . ⁇ . CFIF 2 , (H i I! ⁇ . OCH 3 , F, or CFI 3 ;
• R 2 is H, F, or CI
• R 1 and R 2 may be taken together with their attached phenyl to form a naphthalenyl, or quinoliny! group;
• R is CF 3 , or CH 2 CH 3 ;
• a J and A 4 may be taken together with their attached nitrogen to make a ring selected
• Another embodiment of the invention comprises a compound of Formula ⁇ and a
• the present invention also provides a method for preventing, treating or ameliorating an RORyt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, ankylosing spondylitis, nephritis, organ allograft rejection, fibroid lung, systic fibrosis, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphylococcia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, systemic lup
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstmctive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound of Formula. ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament, thereof.
• the present, invention provides a method of treating or ameliorating a syndrome, disorder or disease, in a subject, in need thereof comprising administering to the subject an effective amount, of the compound of Formula ⁇ or composition or medicament thereof in a combination therapy with one or more anti -inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is psoriasis comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is chronic obstructive pulmonary disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is psoriatic arthritis comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is ankylosing spondylitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form., composition or medicament thereof.
• the present invention provides a method of treating or ameliorating an inflammatory bowel disease, wherein said inflammatory bowel disease is Crohn's disease comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating an inflammatory bowel disease, wherein said inflammatory bowel disease is ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is neutrophilic asthma comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is steroid resistant asthma comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof
• the present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is multiple sclerosis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.
• the present, invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form., composition or medicament thereof.
• the invention also relates to methods of modulating RORyt activity in a mammal by administration of an effective amount of at least one compound of Formula.
• administering means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula I or a form, composition or medicament thereof.
• Such methods include administering an effective amount of said compound, compound form, composition or medicament at different times during the course of a therapy or concurrently in a combination form.
• the methods of the invention are to be understood as embracing all known therapeutic treatment regimens.
• subject refers to a patient, which may be an animal, typically a mammal, typically a human, which has been the object of treatment, observation or experiment and is at risk of (or susceptible to) developing a syndrome, disorder or disease that is associated with abberant RORyt expression or RORyt overexpression, or a patient with an inflammatory condition that accompanies syndromes, disorders or diseases associated with abberant RORyt expression or RORyt overexpression.
• an effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
• alky refers to both linear and branched chain radicals of up to 52 carbon atoms, preferably up to 6 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyi, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Any alkyl group may be optionally substituted with one OCI 1 one OH, or up to two fluorine atoms.
• C ( « _a,/' (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, aikoxy or cycloaikyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to h carbon atoms inclusive.
• Ca- denotes a radical containing 1, 2, 3 or 4 carbon atoms.
• cycloaikyl refers to a saturated or partially unsaturated monocyclic or bicyciic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single ring carbon atom.
• Typical cycloaikyl radicals include cyelopropyl, eyclobutyi, cyelopentyl, cyelopentenyl, cyciohexyl, cyclohexenyl, cyeioheptyl and cyciooctyl.
• Any cycloaikyl group may be optionally substituted with one OCH 3 , one OH, or up to two fluorine atoms.
• the term " ' thiophenyl" is intended to describe the radical formed by removing a hydrogen atom from the molecule with the structure:
• Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, ⁇ hydrochloride, edetate, edisyiate, estolate, esyiate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/ diphosphate, polygalacturon
• Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, niethanesulfonic, hydroxyethanesulfonic, oxalic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trif uoroacetic acid.
• Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2- amino-2-hydroxymethyl-propane- 1 ,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or "TRIS”), ammonia, benzathine, i-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclobexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, N3 ⁇ 4, NH 4 OH, N-methyl-D-glucamine, piperidine, potassium, potassium-t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.
• TMS tris(hydroxymethyl)aminomethane
• the present invention is directed to a method for preventing, treating or ameliorating a. RORyt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula ⁇ or a form, composition or medicament thereof.
• RORyt is an N-terminal isoform of RORy, it is recognized that compounds of the present invention which are modulators of RORyt are likely to be modulators of RORy as well. Therefore the mechanistic description "RORyt modulators" is intended to encompass RORy modulators as well.
• the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 0 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses.
• the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.
• the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition, in addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.
• the above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
• the compounds of Formula. ⁇ may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
• exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
• exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
• the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
• acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecy .sulfate, hydrochloride, hydro bromide, lactate, nialeate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
• Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine.
• the basic nitrogen- containing groups may be quaternized with, for example, alkyl halides.
• compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
• suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose- water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
• the present invention also encompasses a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. Additionally, the present invention includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.
• the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention.
• the compounds may form solvates, for example with water (i.e., hydrates) or common organic solvents.
• solvate means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• the term "solvate” is intended to encompass both solution-phase and isolatable solvates.
• suitable solvates include ethanolates, methanolates, and the like.
• the present invention include within its scope polymorphs and solvates of the compounds of the present invention.
• the term "administering” shall encompass the means for treating, ameliorating or preventing a syndrome, disorder or disease described herein with the compounds of the present invention or a polymorph or solvate thereof, which would obviously be included within the scope of the invention albeit not specifically disclosed.
• the invention relates to a compound as described in Formula I for use as a medicament.
• the invention relates to the use of a compound as described in Formula ⁇ for the preparation of a medicament for the treatment of a disease associated with an elevated or aberrant RORyt activity.
• the present invention includes within its scope prodrugs of the compounds of this invention.
• prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
• the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", Ed. H. Bundgaard, Elsevier, 1985.
• any element in particular when mentioned in relation to a compound of Formula ⁇ , shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
• a reference to hydrogen includes within its scope 3 ⁇ 4 H, Z H (D), and ⁇ (T).
• references to carbon and oxygen include within their scope respectively ,2 C, °C and i4 C and f 6 0 and i8 0.
• the isotopes may be radioactive or non-radioactive.
• Radiolabelled compounds of Formula ⁇ may comprise a radioactive isotope selected from the group of 3 ⁇ 4, C, !
• the radioactive isotope is selected from the group of ⁇ , f *C and i 8 F.
• Some compounds of the present invention may exist as atropisomers.
• Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. It is to be understood that all such conformers and mixtures thereof are encompassed within the scope of the present invention.
• the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
• these isomers may be separated by conventional techniques such as preparative chromatography.
• the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
• the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (-f)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
• the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
• it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. MeOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
• the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
• DIPEA Human's base
• IP A isopropylalcohol
• the compounds of the present invention can be prepared according to schemes 1 to 5. Coupling of an aryl group to the thiazole ring of compounds of Formula ⁇ can be accomplished by coupling the bromo-aryl/heteroaryl building blocks E-I/II or F-I to the thiazole derivates A-I-V in the presence of palladium catalysis, using appropriate ligands, solvents, additives and temperatures to form the 5-aryl/heteroaryl-substituted thiazoles B-I to B-VII (Scheme 1),
• the thiazole reactants can be 2- and 4-substituted either by an ester group (A-I, ⁇ - ⁇ , A-TV), an amide group (A-I-III, A-V) or an alky! group (A-IV-V).
• A-I and A-II1 can be prepared by standard methods for amide bond formation and ester hydrolysis starting from 2- (a]koxycarbony ⁇ )thiazole-4-carboxylic acid.
• intermediates A-I can undergo a direct aminolysis with amines in appropriate solvents and temperatures to afford ⁇ - ⁇ ⁇ ⁇ .
• the thiazole esters ⁇ - ⁇ can either be prepared by first amide coupling of 2-carboxy-bromo-fhiazole O l, followed by a carbonyiation to afford the thiazole methyl ester A-IIa or by formation of tert-biityl ester OIV from OI which is followed by a selective ester hydrolysis at the 2-position of the thiazole ring and a final amide coupling reaction to provide A-IIb.
• Thiazole derivative A- IV can be prepared in a cyclocondensation step from l -bromo-3-hydroxypropan-2-one and a Iky I 2-amino-2-thioxoacetate C-V. Ester hydrolysis of A-IV followed by amide coupling provides intermediate A- V (Scheme 2).
• the metallated species can react with hexafluoroactoiie to directly form trifluoroacetone alcohols E-I where R 3 is a CF 3 group.
• the trifiuoromethyl alcohols E-I can be formed by reaction of D-II with TMSCF 3 in the presence of a fluoride source or by reaction with an alkyl Grignard reagent.
• the intermediates D-II can also be formed by a reaction of 1-bromo- 4-a!koxycarbonyl aromatics, which can be prepared from the corresponding 4-bromobenzoic acids (D-III) via esterificataion using reagents such as thionyl chloride and methanol, with TMSCF 3 in the presence of a fluoride source.
• intermediate D-II can be formed from 1 -bromo-4-formyl aromatics by reaction with TMSCF 3 in the presence of a fluoride source and subsequent, oxidation (Scheme 3).
• 5-Bromo-2-iodopyridines (D-VI) can be used as reactants for a metallation reaction, e.g.
• a lithiation with n-butyl-lithiurn and the metallated species can react with the ethyl trifluoroacetate to form 5-bromo-2-trifiuoroacetylpyridine derivates D-VII.
• the trifiuoromethyl alcohols E-II can be formed by reaction of D-II with T SCF 3 in the presence of a fluoride source.
• 1 ,3-Dibromoaryl derivatives F-II can be metallated, e.g.
• the trifiuoromethyl alcohols F-I can be formed by reaction of F-III with TMSCF 3 in the presence of a fluoride source or by reaction with an alkyl Grignard reagent.
• Compo unds of the present invention can be prepared by methods known to those who are skilled in the art.
• the following examples are only meant to represent examples of the in vention and are in no way meant to be a limit of the in vention.
• step a To a flask was added l-(4-bromo-2,3-dichlorophenyi)-2,2,2-trifluoroethanone (10.0 g, 31.1 mmol, Intermediate 2, step a), THF (10 mL) and TMSCF3 (22.1 g, 155 mmol). This mixture stirred and was cooled to -15-— 10 °C, and TBAF (14.3 g, 46.6 mmol) in THF (40 mL) was added dropwise. Then the reaction was quenched with 2 N aqueous HQ (78 mL), diluted with EtOAc (50 mL), and separated.
• step a To a solution of l-(4-bronio-3-ethylphenyl)-2,2,2 rifluoroethanone (1.63 g, 4.11 mmol, Intermediate 3, step a) and TMSCF 3 (901 mg, 6.17 mmol) in anhydrous THF (10 mL) was slowly added TBAF (65.3 mg, 0.25 mmol) at 0 °C, and the solution was stirred at rt for 5 h. The resulting solution was quenched with 1 N aqueous HCl and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na 2 S()4, filtered, concentrated to dryness and purified by FCC on silica gel (PE) to give the title compound as a yellow oil.
• TBAF 65.3 mg, 0.25 mmol
• Tetrabutylammonium fluoride (32 mL, 1 M in THF, 32 mm.ol) was added drop-wise to a solution of l-(4-bromo-3-ethylphenyl)-2,2,2-trifluoroethanone (6,0 g, 21 mmol, Intermediate 3, step cc), tximethyl(trifluorometbyl)silane (15.2 g, 107 mmol), and anhydrous THF (100 mL) at -15 °C. The resultant mixture was stirred for 16 h with gradual warming to room temperature before pouring it into water (100 mL) and extracting with EtOAc (200 mL x 2).
• step a To a solution of (2S,4R)-tert ⁇ but l 4-b.ydroxy-2-methylpiperidme- 1 -carboxylate (200 mg, 0.930 rnrnol, Intermediate 13, step a) in DCM (5 mL) was slowly added DAST (225 mg, 1.40 rnmol) at -78 °C and the solution was stirred at -78 °C for 1 h, then slowly warmed to rt and stirred at rt overnight, quenched with saturated aqueous NaHC(3 ⁇ 4 at 0 °C, and extracted with DCM.
• DCM To a solution of (2S,4R)-tert ⁇ but l 4-b.ydroxy-2-methylpiperidme- 1 -carboxylate (200 mg, 0.930 rnrnol, Intermediate 13, step a) in DCM (5 mL) was slowly added DAST (225 mg, 1.40 rnmol) at -78 °C and the
• Tetrabutylammonium fluoride (470 mL, 1 M in THF, 470 mmol) was added drop-wise to a solution of l-(4-bromo-3-(difiuoromethyi)phenyl)-2,2,2-trifluoroethanone (95.0 g, 313 mmol, Intermediate 18, step b), trimethyl(trifluoromethyl)silane (223 g, 1.6 mol), and anhydrous THF (100 mL) at - 15 °C.
• step a To a solution of 4-iert-butyl 2-ethyl thiazole-2,4 ⁇ dicarboxylate (1 5 mg, 0.64 mmol, Intermediate 10, step a) in EtOH (5 mL) was added aqueous LiOH (1 mL, 0.5 N) and the solution was stirred at rt overnight. Then the solvent was removed, the residue adjusted to pH ⁇ 2 with 2 N aqueous HC1 and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated to dryness to give the title compound as a yellow solid.
• Difluoromethyl trifluoromethanesulfonate (40 g, 200 mmol) was added drop-wise to a solution of 2-bromo-5-iodophenol (29.0 g, 97.0 mmol, Intermediate 24, step a), aqueous KOH (228 mL, 8 M, 1.82 mol), and MeCN (250 mL). The resultant mixture was stirred at room temperature for 1 h before pouring it into water (1 L) and extracting with DCM (800 mL x 3). The combined organic extracts were dried over anhydrous filtered, and concentrated to dryness to afford the title compound.
• the resultant mixture was stirred at -78 °C for 4 h before quenching with MeOH (5 mL) at - 10 °C to 5 °C. Then the resultant mixture was stirred at 20 °C for 5 minutes before pouring it into saturated aqueous NH 4 C1 (200 mL) solution and extracting with EtOAc (250 mL x 3). The combined organic extracts were dried over anhydrous a 2 S0 4 , filtered, and concentrated to dryness to afford the cnide product, which was used in the next step without further purification.
• Tetrabutylammonium fluoride (94 mL, 1 M in THF, 94 mmol) was added drop-wise to a solution of l-(4-bromo-3-(difluofomethoxy)phenyl)-2,2,2-trifiuoroethanone (20 g, 63 mmol, Intermediate 24, step e), trimethyl(trifluoromethyl)silane (44.6 g, 314 mmol), and anhydrous THF (100 mL) at -15 °C.
• Tetrabutylammonixim fluoride (37 mL, 1 M in THF, 37 mmol) was added drop-wise to a solution of l ⁇ (4 ⁇ bromo ⁇ 3 ⁇ methoxyphenyl)-2,2,2 ⁇ trifiuoroethanone (7.0 g, 25 mmol, Intermediate 25, step a), trimethyl(trifluoromethyl)silane (17.6 g, 124 mmol), and anhydrous THF (100 mL) at -15 °C. The resultant mixture was stirred for 1.5 h with gradual warming to room temperature before quenching with 2 N aqueous HC1 (150 mL) and extracting with EtOAc (150 mL x 3).
• Tetrabutylammonium fluoride (83,5 mL, 1 M in THF, 83,5 mmol) was added drop-wise to a solution of l-(4-bromo-2-chloro-3-fluorophenyl)-2,2,2-trifiuoroethanone (17 g, 56 mmol.
• Intermediate 26, step c) trimethyl(trifluoi methyl)silane (39.6 g, 278 mmol), and anhydrous THF (100 mL) at - 15 °C.
• NBS 3-(difluoromethyl)-2-fluoroaniline (30.5 g, 155 mmol, Intermediate 27, step b) and DMF (150 mL) at 0 °C.
• the resultant mixture was stirred at room temperature for 16 h before pouring it into water (300 mL) and extracting with DCM (300 mL x 4).
• the resultant mixture was stirred at -78 °C for 10 minutes and then treated with 2,2,2-trifluoiO-iV-methoxy-A-methylaeetamide (1.4 g, 8.9 mmol).
• the resultant mixture was stirred at -78 °C for 1 h and for 2 h with gradual warming to room temperature under N 2 before quenching with saturated aqueous NH 4 Ci solution (50 mL) and extracting with EtOAc (60 mL x 3).
• Tetrabutylarnmonium fluoride (7 mL, 5 in THF, 7 mmol) was added drop-wise to a solution of l-(4-bromo-3-(difluoromethyi)-2-f j .uorophenyl)-2,2,2-trifluoroetiianone (5.5 g, 4.7 mmol, Intermediate 27, step e), trimethyl(trifluoromethyl)silane (3.4 g, 24 mmol), and anhydrous TFIF (20 mL) at -15 °C.
• t-BuO (13.8 g, 123 mmol) was added to a solution consisting of S)-ethyl 4 ⁇ (2 ⁇ methylpyrrolidine- 1 -carbonyl)thiazole-2-carbox late (30.0 g, 1 12 mmol, Intermediate 15/1 , step a), THF (1 60 mL) and H 2 0 (40 niL). The resultant mixture was stirred at 60 °C for 2 h. THF was removed under reduced pressure and the residue was diluted with !3 ⁇ 4() (100 mL) and extracted with dichlorom ethane (50 mL x 2). The aqueous layer was frozen using dry ice/acetone and then lyophilized to dryness to afford the title compound.
• EDCl (4.9 g, 26 mmol) was added to a solution consisting of l-(aminomefhy[)cyclobutanol (1.3 g, 13 mmol), potassium (S ⁇ -4-(2-methylpyrrolidine-l-carbonyl)thiazole-2-carboxylate (3.6 g, 13 mmol, Intermediate 28, step a), HOBt (3.5 g, 26 mmol), DIPEA (6.9 mL, 39 mmol), and THF (100 mL). The resultant mixture was stirred at room temperature for 16 h before diluting with ethyl acetate (200 mL).
• Example 2/3 a, Example 2/3b and Example 2/3 c 5-(2,3-DichIoro-4-(l,1 i 3.3*3-hexafluoro-2- hydroxypropan ⁇ 2 ⁇ yI)phenyI)-4-(3-fluoro-3-meth ⁇
• Example 2/3a The title compound, Example 2/3a, was prepared as described in Example 2 using 3-f!uoro-3- methylpyrrolidine in place of 7-aza-bicyclo[2.2. l jheptane hydrochloride.
• the first eluting isomer was Example 2/3b: ⁇ NMR (CDCI 3 , 300 MHz, mixture of rotamers): ⁇ ppm 7.74-7.47 (m, 3H), 3.82-3.41 (rn, 6H), 2.33-2.21 (m, 1 H), 2.05-1.51 (m, 5H), 1.32 (s, 6H). MS: m/z 640.1 [M+H] " .
• the second eluting isomer was Example 2/3c: 5 H NMR (CDCI 3 , 300 MHz, mixture of rotamers): ⁇ ppm 7.74-7.47 (m, 3H), 3.82-3.41 (m, 6H), 2.33-2.21 (m, 1 H), 2.05-1.51 (m, 5H), 1.32 (s, 6H).
• Example 2/4 4-(2-AzabicycIo
• Example 2/5 5-(2,3-DichIoro-4-(l ,lil ? 3,3 ? 3-' i exafIiioro-2-hydroxypropaii-2-yl)phenyl)-A' 4 - ethyI-N 2 -(2-hydroxy-2-methyIpropyl)-/V 4 -(2,2,2-trifliioroethyl)thiazole-2,4-dicarboxam
• Example 2/9 5-(2,3-DichIoro-4-(l,l,l ? 3 ? 3,3-hexafInoro-2-hydroxypropan-2-yl)phenyr)-/V-(2- hydroxy-2-methylpropyl)-4-(3-(trifluoromethyI)azetidme-l-carbonyi)thiazole-2- carboxamide
• Example 2/13 j -Cyclobut l-S-i -S-dichloro ⁇ -iljljl ⁇ iS ⁇ -he afluoro- -h drosj- ro aii- - yl)phenyl)-N 2 -(2-hydrQxy-2-methylpropyl)- ⁇
• Example 2/14 S-i ⁇ -Dichloro ⁇ -iljl SiSjS-he afliioro- -h dro y ro aii- -yrj hen l)-/ ⁇ - ethyI-N 2 -(2-hydroxy-2-methyIpropyl)-7V-(2-methoxyethyl)thiazole-2,4-dicarboxamide
• Example 3/1 A r2 ⁇ (2-Cyaiio ⁇ 2-methy1propyI)-5-(2 ⁇ dkMoro ⁇
• Example 3/2 A '2 ⁇ (3 ⁇ AmiraQ ⁇ 2,2-dimethyI ⁇ 3- ⁇
• Example 3/3a and Example 3/3b 5-(2,3-DichIoro-4-(l ,l 5 l ? 3i3,3-' i exafIuoro-2- hydroxypropara ⁇ 2 ⁇ y!pheoyl) ⁇ iV ⁇
• the racemic title compound was prepared as described i Example 3 using 6-oxaspiro[2.5]octan- 1 -amine in place of 1 -amino-2-methyl-propan-2-ol.
• Example 3/5 5-(2,3-DichIoro-4-(l ,l 5 l ? 3i3,3-' i exafIuoro-2-liydroxypropaii-2-yl)p en.y])- y ⁇ - ⁇ - ieth l- ⁇ -iiS-h dro oxetan-S- meth ⁇ thiazoIe- ⁇ -dicarbo aniide
• Tlie title compound was prepared as described in Example 3 using ( ?)-l-aminopropan-2-ol in place of l-amino-2-methyl-propan-2-ol.
• the title compound was prepared from lithium 4-(7 ⁇ azahieyck>[2.2.1 ]heptane ⁇ 7 ⁇ carbQnyI)-5- (2,3-dichloro-4-(l ,l ,]. ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazole-2-carboxylate (Intermediate 19) using a procedure as described for Example 3, using piperazine-2,6 ⁇ dione in place of 1 -amino- 2-methyl-propan-2-ol.
• Example 6/1 5-(2,3-Dichloro-4-(l,1 i3 ? 3i3-hexafluoro-2-hydroxypropaii-2- )pheiiyl)-iV- -dioxidothietaQ-3-yl)-4-(4-fluoropiperidine-l-carbonyl)thiazole-2-carboxamid
• the title compound was prepared using a procedure as described for Example 10, using 1 -amino- 3-methylbutane-2,3-diol in place of (.?/?,5>S)-piperidine-3,5-diol hydrochloride.
• the title compound was prepared using a procedure as described for Example 10, starting from S)-ethyl 5-(4-(l ,1 ,1 ,3,3,3-hexafiuoro-2-hydroxypropan-2-yl)-2-(tTifluorome ⁇ l)ph£nyl)-4-(2- methylpyrrolidine- 1 -carbonyl)thiazole-2-carbox late (Intermediate 16/2), using l-amino-2- methyipropan-2-ol in place of (3i?,55) ⁇ piperidine-3,5-diol hydrochloride. !
• step a To a solution of l-(4-bromo-2,3-dichIorophenyl)-2,2,2-trifluoroethanone (2.0 g, 6.2 mniol, Intermediate 2, step a) in THF (20 mL) was added ethylmagnesiuni chloride (4.50 ml., 2.8 M in THF, 12.6 mniol) dropwise at -30 °C under a N2 atmosphere and the mixture was stirred at rt for 5 h. The solution was diluted with aqueous NH 4 CI at 0 °C and extracted with EtOAc (x 2).

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• Nitrogen Condensed Heterocyclic Rings (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

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