Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/08—Antiseborrheics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• RORs The retinoic acid related orphan nuclear receptors (RORs) have three members: RORa, RORP and RORy.
• RORP expression is mostly restricted to the brain and retina, while RORa and RORy expressions are wide spread.
• RORy also has a shorter isoform, RORyt, which is mostly expressed in the immune system.
• RORyt is essential for the development of secondary lymphoid tissues, in particular lymph nodes and Peyer's patches. Recent studies identified a critical role for RORyt in lineage specification of uncommitted CD4+ T helper cells into Thl7 cells as well as the development of Tel 7 (cytotoxic) T cells. Th l7 response has been implicated in a myriad of autoimmune diseases such as psoriasis, inflammatory bowel disease, arthritis and multiple scoliosis.
• Thl7 and Tcl7 response have also been shown to a mechanism for cancer cells to evade anti-tumor immunity in several experimental tumor models. These findings implicate both RORy agonists and inverse agonists as potential therapeutics for a variety of diseases.
• Described herein are compounds of Formula (I), (la), or (lb), pharmaceutical compositions that include such compounds, and methods of use thereof, for modulating RORy.
• Dermal diseases, disorders or conditions include, but are not limited to, skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, acne, or any other condition described herein.
• Dermal diseases or disorders also refer to pigmentary disorders including but not limited to vitiligo.
• Dermal diseases also refer to skin malignancies and cancer, including melanoma and metastatic forms of these diseases.
• a method for treating the epidermis of a mammalian subject suffering from a perturbed epidermal barrier function comprising topically administering to said epidermis a topical composition comprising an active ingredient that is a modulator of RORy, said active ingredient being present in a concentration that is effective in enhancing barrier development.
• a method for treating the epidermis or mucous membrane of a terrestrial mammalian subject suffering from a condition of disturbed differentiation or excess proliferation comprising topically administering to said epidermis or mucous membrane a topical composition comprising an active ingredient that is a modulator of RORy, said active ingredient being present in a concentration that is effective in enhancing barrier development.
• the modulator of RORy is a compound of Formula (I), (la), or (lb) as described herein. In some embodiments of the methods or compositions described above, the modulator of RORy is a compound of Formula (I), (la), or (lb) as described herein. In some embodiments of the methods or compositions described above, the concentration of said active ingredient in the topical composition is from about 0.1 ⁇ to 100 ⁇ .
• a RORy modulator in the manufacture of a topical formulation for use in the treatment of a dermal disease, disorder or condition in a mammal.
• an RORy modulator and a second therapeutic agent in the manufacture of a topical formulation for use in the treatment of a dermal disease, disorder or condition in a mammal.
• X is a bond, Ci-C 6 alkyl, or Ci-C 6 heteroalkyl
• each R 2 is independently halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy;
• each 5 is independently hydrogen, Ci-C 6 alkyl, or -Ci-C 6 alkyl-Y-R 9 ;
• each Y is independently -0-, -S-, or -N(R 10 )-;
• each R 7 is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl;
• each R 8 is independently Ci-C 6 alkyl or Ci-C 6 heteroalkyl
• each R 9 is independently hydrogen or Ci-C 6 alkyl
• each Rio is independently hydrogen or Ci-C 6 alkyl
• n O, 1, 2, 3, or 4;
• n O, 1, 2, 3, or 4;
• p 0, 1, 2, 3, or 4;
• q 0, 1, 2, or 3;
• a compound of Formula (I) wherein is phenyl or a 6- membered heteroar l rin .
• a com ound of Formula I wherein is phenyl.
• a compound of Formula (I) wherein is a 6- membered heteroar l rin .
• a com ound of Formula I wherein is pyridyl.
• a compound of Formula (I) wherein is phenyl o -membered heteroaryl ring.
• a compound of Formula (I) wherein is a 6-membered heteroaryl ring.
• a compound of Formula (I) wherein is pyridyl.
• a compound of Formula (I) wherein is phenyl or -membered heteroaryl ring.
• a compound of Formula (I) or (la) wherein Ri is -C( 0)OR 6 , R5 is -Ci-C 6 alkyl-Y-R 9 , Y is -0-, and R 9 is hydrogen.
• a compound of Formula (I) or (la) wherein Ri is -C( 0)OCH 2 CH 2 OH.
• a compound of Formula (I) or (la) wherein Ri is -C( 0)OR 5 , R 6 is -Ci-C 6 alkyl-Y-R 9 , Y is -0-, and R 9 is Ci-C 6 alkyl.
• a compound of Formula (I) or (la) wherein Ri is -C( 0)OR 5 , R 6 is -Ci-C 6 alkyl-Y-R 9 , Y is - N(Rio)-, and R 9 is hydrogen.
• a compound of Formula (I) or (la) wherein X is a bond.
• each R 3 , each R 4 , and each R 5 are each independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci- C 6 alkoxy.
• a compound of Formula (I) or (la) wherein m is 0 or 1, and n is 0 or 1.
• n is 0 or 1
• p is 0 or 1
• q is 0 or 1.
• m is 0, n is 0, p is 0, and q is 0.
• X is a bond, Ci-C 6 alkyl, or Ci-C 6 heteroalkyl
• each R 2 is independently halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy;
• R 4 is hydrogen or Ci-C 6 alkyl
• each 5 is independently hydrogen, Ci-C 6 alkyl, or -Ci-C 6 alkyl-Y-R 9 ;
• each Y is independently -0-, -S-, or -N(Rio)-;
• each R 7 is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl; each R 8 is independently Ci-C 6 alkyl or Ci-C 6 heteroalkyl;
• each R 9 is independently hydrogen or Ci-C 6 alkyl
• each Rio is independently hydrogen or Ci-C 6 alkyl
• n O, 1, 2, 3, or 4;
• n 0, 1, 2, 3, or 4;
• q 0, 1, 2, or 3;
• R 6 is Ci-C 6 alkyl.
• a compound of Formula (lb) wherein Ri is -C( 0)OR 6 and R 6 is -Ci-C 6 alkyl-Y-R9.
• R 6 is -Ci-C 6 alkyl-Y-R9.
• 5 is -Ci-C 6 alkyl-Y-R 9
• Y is -0-.
• 5 is -Ci-C 6 alkyl-Y-R 9
• Y is -0-
• R 9 is hydrogen.
• a compound of Formula (lb) wherein Ri is -C( 0)OR 6 , 5 is -Ci-C 6 alkyl-Y-R 9 , Y is -0-, and R 9 is Ci-C 6 alkyl.
• a compound of Formula (lb) wherein Ri is -C( 0)OR 6 , R5 is -Ci-C 6 alkyl-Y-R 9 , Y is -N(R 10 )-, and R 9 is hydrogen.
• a compound of Formula (lb) wherein X is a bond.
• a compound of Formula (lb) wherein X is -Ci-C 6 alkyl.
• each R 3 and each R 5 are each independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• R 4 is hydrogen.
• R 4 is -CH 3 .
• In another embodiment is a compound selected from: ; or a pharmaceutically acceptable salt or solvate thereof.
• composition comprising a pharmaceutically acceptable diluent, excipient, carrier or binder, and a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is selected from the group consisting of skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne.
• Figure 1 shows the inhibition of Thl7 cell differentiation with reduction of IL-17A+ cells in the presence of a compound of Formula (I) (Compound B).
• Figure 2 shows a pharmacokinetic plot of a compound of Formula (I) (Compound A) dosed in rats.
• Figure 3 shows the total psoriasis score for mice treated with a compound of Formula (I) (Compound A) in the imiquimod (EVIQ) induced mouse psoriasis model.
• Figure 4 shows the back skin thickness for mice treated with a compound of Formula (I)
• Figure 5 shows the ear thickness for mice treated with a compound of Formula (I)
• Figure 6 shows the total histopathology score for mice treated with a compound of
• Formula (I) (Compound A) in the imiquimod (EVIQ) induced mouse psoriasis model.
• compositions comprising RORy modulators as active ingredients in a formulation that is pharmaceutically acceptable for topical administration.
• Topical formulations containing RORy modulators described herein are applied to beneficial effect to skin and/or mucus membranes.
• the activators are formulated as lotions, solutions, gels, creams, emollient creams, unguents, sprays, or any other form that will permit topical application.
• the formulation may also contain one or more agents that promote the spreading of the formulation over the affected area, but are otherwise biologically inactive. Examples of these agents are surfactants, humectants, wetting agents, emulsifiers, or propellants.
• Amounts that are referred to herein as effective in enhancing barrier development are any amount that will cause a substantial relief of the symptoms of a disrupted or dysfunctional epidermal permeability barrier when applied repeatedly over time.
• the optimum amounts in any given instance will be readily apparent to those skilled in the art or are capable of determination by routine experimentation.
• Examples of skin conditions that are susceptible to topical treatment with RORy modulators are: atopic and seborrheic dermatitis; inflammation to mucous membranes, such as cheilitis, chapped lips, nasal irritation and vulvovaginitis; eczematous dermatitis resulting from allergic and irritant contact, eczema craquelee, radiation and stasis dermatitis; ulcers and erosions due to chemical or thermal burns, bullous disorders, or vascular compromise or ischemia including venous, arterial, embolic or diabetic ulcers; ichthyoses, with or without an associated barrier abnormality; epidermolysis bullosa; psoriasis; hypertrophic scars and keloids; intrinsic aging, photo aging and/or dermatoheliosus; melanoma and non-melanoma skin cancer, including lignin melanoma, basal cell carcinoma, squamous cell carcinoma, actinic
• compositions described herein are generally applicable to the treatment of mammalian skin including for example humans, domestic pets, and livestock and other farm animals.
• Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
• Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
• Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
• the foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
• Ci-C x includes C 1 -C 2 , C 1 -C3 . . . Ci-C x .
• Ci-C x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
• An "alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carbon-carbon triple bond). The alkyl group may also be an "unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
• the "alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., "1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
• the alkyl group of the compounds described herein may be designated as "Ci-C 6 alkyl" or similar designations.
• Ci-Cealkyl indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
• Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
• alkoxy refers to a "-O-alkyl” group, where alkyl is as defined herein.
• alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl" group).
• Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
• alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
• R refers to the remaining portions of the alkynyl group.
• Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 and -C ⁇ CCH 2 CH 2 CH 3 .
• the "R" portion of the alkynyl moiety may be branched, straight chain, or cyclic.
• An alkynyl group can have 2 to 6 carbons.
• Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group). [0045] "Amino" refers to a - H 2 group.
• “Dialkylamino” refers to a -N(alkyl) 2 group, where alkyl is as defined herein.
• aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
• aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
• Carboxy refers to -C0 2 H.
• carboxy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
• a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
• a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
• a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid roup.
• bioisosteres of a carboxylic acid include, but are not limited to,
• cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
• An N- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
• heterocycloalkyl refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur.
• the radicals may be fused with an aryl or heteroaryl.
• heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
• the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e.
• halo or, alternatively, "halogen” means fluoro, chloro, bromo and iodo.
• haloalkyl refers to an alkyl group that is substituted with one or more halogens.
• the halogens may the same or they may be different.
• Non-limiting examples of haloalkyls include -CH 2 C1, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
• fluoroalkyl and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms.
• fluoroalkyls include -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
• Non-limiting examples of fluoroalkoxy groups include -OCF 3 , -OCHF 2 , -OCH 2 F, - OCH 2 CF 3 , -OCF 2 CF 3 , -OCF 2 CF 2 CF 3 , -OCF(CH 3 ) 2 , and the like.
• heteroalkyl refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
• the heteroatom(s) may be placed at any interior position of the heteroalkyl group.
• heteroalkyl may have from 1 to 6 carbon atoms.
• bond or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• moiety refers to a specific segment or functional group of a molecule.
• Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• substituent "R" appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
• the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-C 6 alkylalkyne, halo, acyl, acyloxy, -C0 2 H, -C0 2 -alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g.
• the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
• a "therapeutically effective amount” as used herein refers to the amount of an
• RORy modulator that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent conditions related to skin aging.
• expression includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.
• modulate encompasses either a decrease or an increase in activity or expression depending on the target molecule.
• activator is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically.
• the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.
• mammal refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal.
• a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
• soft-drug refers to drug substance and/or a chemical compound that is biologically active in the desired target tissue and that is metabolized, after exerting its effect in the target tissue, to a compound that is inactive against the biological target.
• the soft-drug has no target biological activity in systemic circulation.
• skin aging includes conditions derived from intrinsic chronological aging (for example, deepened expression lines, reduction of skin thickness, inelasticity, and/or unblemished smooth surface), those derived from photoaging (for example, deep wrinkles, yellow and leathery surface, hardening of the skin, elastosis, roughness, dyspigmentations (age spots) and/or blotchy skin), and those derived from steroid-induced skin thinning.
• RQRy modulators contemplated for use in the compositions and methods described herein are compounds with RQRy modulator activities.
• the term "RORy modulator” includes RQRy and/or RORyt agonists and inverse agonists.
• X is a bond, Ci-C 6 alkyl, or Ci-C 6 heteroalkyl
• each R 2 is independently halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy;
• each 5 is independently hydrogen, Ci-C 6 alkyl, or -Ci-C 6 alkyl-Y-R 9 ;
• each Y is independently -0-, -S-, or -N(Rio)-;
• each R 7 is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl;
• each R 8 is independently Ci-C 6 alkyl or Ci-C 6 heteroalkyl
• each R 9 is independently hydrogen or Ci-C 6 alkyl
• each Rio is independently hydrogen or Ci-C 6 alkyl
• n O, 1, 2, 3, or 4;
• n O, 1, 2, 3, or 4;
• p 0, 1, 2, 3, or 4;
• q 0, 1, 2, or 3;
• X is a bond.
• X is Ci-C 6 alkyl.
• X is a compound of Formula (I) wherein X is -CH 2 -.
• X is Ci-C 6 heteroalkyl.
• a compound of Formula (I) wherein Ri is -C( 0)OR 5 and R 6 is -CH(CH 3 ) 2 .
• a compound of Formula (I) wherein Ri is -C( 0)OR 5 , R 6 is -Ci-C 6 alkyl-Y-R 9 , and Y is -S-.
• R 6 is -Ci-C 6 alkyl-Y-R9
• Y is -N(H)-.
• R 9 is hydrogen.
• R 9 is Ci-C 6 alkyl.
• R 9 is a compound of Formula (I) wherein R 9 is - CH 3 .
• a compound of Formula (I) wherein Ri is -C( 0)N(Re) 2 , and one R 6 is hydrogen and one 5 is -CH 2 CH 3 .
• a compound of Formula (I) wherein Ri is -C( 0)N(Re) 2 and each 5 is - CH 2 CH 3 .
• one 5 is hydrogen and one 5 is -Ci- C 6 alkyl-Y-R 9
• Y is -N(Ri 0 )-.
• one R 6 is hydrogen and one R 6 is -Ci-C 6 alkyl-Y-R 9
• Y is -N(H)-.
• R 9 is hydrogen.
• -X-Ri is -
• a compound of Formula (I) wherein m is 0, 1, 2, or 3. In some embodiments is a compound of Formula (I) wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (I) wherein m is 0 or 1. In some embodiments is a compound of Formula (I) wherein m is 0. In some embodiments is a compound of Formula (I) wherein m is 1. In some embodiments is a compound of Formula (I) wherein m is 2. In some embodiments is a compound of Formula (I) wherein m is 3. In some embodiments is a compound of Formula (I) wherein m is 4.
• n is 0, 1, 2, or 3.
• n is 0, 1, or 2.
• n is a compound of Formula (I) wherein n is 0 or 1.
• n is 0.
• n is 1.
• n is 2.
• n is 3.
• n is 4.
• n is 1, 2, or 3 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 or 2 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen. In some embodiments is a compound of Formula (I) wherein n is 1 and R 3 is -F. In some embodiments is a compound of Formula (I) wherein n is 1 and R 3 is -CI. In some embodiments is a compound of Formula (I) wherein n is 1 and R 3 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (I) wherein n is 1 and R 3 is -CH 3 . In some embodiments is a compound of Formula (I) wherein n is 1 and R 3 is Ci-C 6 haloalkyl.
• n is 1 and R 3 is -CF 3 .
• n is 1 and R 3 is Ci-C 6 alkoxy.
• n is 1 and R 3 is -OCH 3 .
• a compound of Formula (I) wherein p is 0, 1, 2, or 3.
• a compound of Formula (I) wherein p is 0, 1, or 2.
• a compound of Formula (I) wherein p is 0 or 1.
• a compound of Formula (I) wherein p is 0.
• a compound of Formula (I) wherein p is 1.
• a compound of Formula (I) wherein p is 2.
• a compound of Formula (I) wherein m is 0 or 1, n is 0 or 1, p is 0 or 1, and q is 0 or 1. In some embodiments is a compound of Formula (I) wherein m is 0, n is 0, p is 0, and q is 0. In some embodiments is a compound of Formula (I) wherein m is 1, n is 0, p is 0, q is 0 and R 2 is halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy.
• R 3 is halogen, Ci-C 6 alkyl, Ci- C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 0, p is 0, q is 1, and R5 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• a compound of For is pyridyl.
• a compound of Formula (I) wherein is pyrimidyl.
• a compound of Formul wherein is pyrazinyl.
• Formula is pyrrolyl. In another embodiment is a compound of Formula (I) wherein is imidazolyl. In another embodiment is a compound of Formula (I) wherein is oxazolyl. In another embodiment is a compound of Formula (I) wherein
• thiazolyl In another embodiment is a compound of Formula (I) whe is thiophenyl.
• a compound of For is pyridyl.
• a compound of Formula (I) wherein is pyrimidyl.
• a compound of Formul wherein is pyrazinyl.
• a compound of Formula (I) wherein is a 5-membered ring.
• a B is a B
• Formula is pyrrolyl. In another embodiment is a compound of Formula (I) wherein is imidazolyl. In another embodiment is a compound of Formula (I) wherein is oxazolyl. In another embodiment is a compound of Formula (I) wherein thiazolyl. In another embodiment is a compound of Formula (I) whe is thiophenyl.
• a compound of For is pyridyl.
• a compound of Formula (I) wherein is pyrimidyl.
• a compound of Formul wherein is pyrazinyl.
• a compound of Formula (I) wher is pyridizinyl.
• Formula erein is pyrrolyl.
• a compound of Formula (I) wherein is imidazolyl.
• a compound of Formula (I) wherein is oxazolyl.
• a compound of Formula (I) whe is thiophenyl.
• a compound of Formula (I) wherein are phenyl In another embodiment is a compound of Formula (I) wherein are phenyl.
• membered hetero diment is a compound of Form ula (I) wherein is py y , an ⁇ phenyl.
• compound of Formula (I) wherein is a 6-membered heteroaryl ring an are phenyl.
• a compound of Formula (I) wherein is pyridyl are phenyl.
• phenyl are phenyl.
• other embodiment is a compound of Formula (I) wherein yridyl, and ound of Formula (I) wherein and are a 6-membered heteroaryl ring is phenyl.
• 6-membered heteroaryl ring and is phenyl.
• another e mbodiment is a compound of Formula (I) wherein
• X is a bond, Ci-C 6 alkyl, or Ci-C 6 heteroalkyl
• each R 2 is independently halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy;
• each 5 is independently hydrogen, Ci-C 6 alkyl, or -Ci-C 6 alkyl-Y-R 9 ;
• each Y is independently -0-, -S-, or -N(R 10 )-;
• each R 7 is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl;
• each R 8 is independently Ci-C 6 alkyl or Ci-C 6 heteroalkyl
• each R 9 is independently hydrogen or Ci-C 6 alkyl
• each Rio is independently hydrogen or Ci-C 6 alkyl
• n O, 1, 2, 3, or 4;
• p 0, 1, 2, 3, or 4;
• q 0, 1, 2, or 3;
• X is a bond.
• X is Ci-C 6 alkyl.
• X is a compound of Formula (la) wherein X is -CH 2 -.
• X is Ci-C 6 heteroalkyl.
• a compound of Formula (la) wherein Ri is -C( 0)OR 5 .
• a compound of Formula (la) wherein Ri is -C( 0)OR 6 and R3 ⁇ 4 is hydrogen.
• a compound of Formula (la) wherein Ri is -C( 0)OR5 and R 6 is Ci-C 6 alkyl or -Ci-C 6 alkyl-Y-R 9 .
• a compound of Formula (la) wherein Ri is -C( 0)OR 6 and R 6 is Ci-C 6 alkyl.
• a compound of Formula (la) wherein Ri is -C( 0)ORe and R 6 is -CH 3, -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• a compound of Formula (la) wherein Ri is -C( 0)OR 6 , Rs is Ci-C 6 alkyl or -Ci-C 6 alkyl-Y-R9, Y is -0-, and R is hydrogen or Ci-C 6 alkyl.
• R 6 is -Ci- C 6 alkyl-Y-R 9
• Y is -0-.
• a compound of Formula (la) wherein Ri is -C( 0)OR 6 , R5 is -Ci-C 6 alkyl-Y-R 9 , and Y is -0-, and R 9 is hydrogen.
• a compound of Formula (la) wherein Ri is -C( 0)OR5, R 6 is -Ci-C 6 alkyl-Y-R 9 , and Y is -N(R 10 )-.
• R5 is -Ci-C 6 alkyl-Y-R 9
• Y is -N(H)-.
• R 9 is hydrogen.
• R 9 is Ci-C 6 alkyl.
• a compound of Formula (la) wherein Ri is -C( 0)N(Re) 2 , and one R 6 is hydrogen and one 5 is -CH 2 CH 3 .
• a compound of Formula (la) wherein Ri is -C( 0)N(R 6 ) 2 , and one 5 is hydrogen and one R 6 is -CH(CH 3 ) 2 .
• a compound of Formula (la) wherein Ri is -C( 0)N(Re) 2 and each R 6 is -CH 3 .
• a compound of Formula (la) wherein Ri is -C( 0)N(R 6 ) 2 and each 5 is -CH 2 CH 3 .
• a compound of Formula (la) wherein Ri is -C( 0)N(R 5 ) 2 , and one R 6 is hydrogen and R 6 is -Ci-C 6 alkyl-Y-R 9 .
• a compound of Formula (la) wherein Ri is -C( 0)N(R 6 ) 2 , one 5 is hydrogen and one 5 is -Ci-C 6 alkyl-Y-R9, and Y is -0-.
• a compound of Formula (la) wherein Ri is -C( 0)N(R 5 ) 2 , one 5 is hydrogen and one R 6 is -Ci-C 6 alkyl-Y-R9, and Y is -N(R 10 )-.
• R 9 is hydrogen.
• R 9 is Ci-C 6 alkyl.
• CH 2 C( 0)N(H)CH 2 CH 2 OCH 2 CH 3 .
• a compound of Formula (la) wherein m is 0, 1, 2, or 3.
• a compound of Formula (la) wherein m is 0, 1, or 2.
• a compound of Formula (la) wherein m is 0 or 1.
• a compound of Formula (la) wherein m is 0.
• a compound of Formula (la) wherein m is 1.
• a compound of Formula (la) wherein m is 2.
• embodiments is a compound of Formula (la) wherein m is 1 and R 2 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (la) wherein m is 1 and R 2 is -CH 3 . In some embodiments is a compound of Formula (la) wherein m is 1 and R 2 is Ci-C 6 alkoxy. In some embodiments is a compound of Formula (la) wherein m is 1 and R 2 is -OCH 3 .
• n is 0, 1, 2, or 3.
• n is 0, 1, or 2.
• n is 0 or 1.
• n is 0.
• n is 1.
• n is 2.
• n is 3.
• n is 4.
• n is 1, 2, or 3 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 or 2 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen. In some embodiments is a compound of Formula (la) wherein n is 1 and R 3 is -F. In some embodiments is a compound of Formula (la) wherein n is 1 and R 3 is -CI. In some embodiments is a compound of Formula (la) wherein n is 1 and R 3 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (la) wherein n is 1 and R 3 is -CH 3 . In some embodiments is a compound of Formula (la) wherein n is 1 and R 3 is Ci-C 6 haloalkyl.
• n is 1 and R 3 is -CF 3 .
• n is 1 and R 3 is Ci-C 6 alkoxy.
• n is 1 and R 3 is -OCH 3 .
• a compound of Formula (la) wherein m is 0 or 1, n is 0 or 1, p is 0 or 1, and q is 0 or 1. In some embodiments is a compound of Formula (la) wherein m is 0, n is 0, p is 0, and q is 0. In some embodiments is a compound of Formula (la) wherein m is 1, n is 0, p is 0, q is 0 and R 2 is halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy.
• R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 0, p is 0, q is 1, and R 5 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• X is a bond, Ci-C 6 alkyl, or Ci-C 6 heteroalkyl
• each R 2 is independently halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy;
• R 4 is hydrogen or Ci-C 6 alkyl
• each Y is independently -0-, -S-, or -N(R 10 )-;
• each R 7 is independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 heteroalkyl;
• each R 8 is independently Ci-C 6 alkyl or Ci-C 6 heteroalkyl
• each R 9 is independently hydrogen or Ci-C 6 alkyl
• each Rio is independently hydrogen or Ci-C 6 alkyl
• n O, 1, 2, 3, or 4;
• n 0, 1, 2, 3, or 4;
• q 0, 1, 2, or 3;
• X is a bond.
• X is Ci-C 6 alkyl.
• X is a compound of Formula (lb) wherein X is -CH 2 -.
• X is Ci-C 6 heteroalkyl.
• a compound of Formula (lb) wherein R x is -C( 0)OR 6 and R 6 is -CH 3; -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• Rs is Ci-C 6 alkyl or -Ci-C 6 alkyl-Y-R 9
• Y is -0-
• R 9 is hydrogen or Ci-C 6 alkyl.
• R is -Ci-C 6 alkyl-Y- R 9 .
• Rs is -Ci- C 6 alkyl-Y-R 9
• Y is -0-.
• Rs is -Ci-C 6 alkyl-Y-R 9
• Y is -0-
• R 9 is hydrogen.
• R is -Ci-C 6 alkyl-Y-R 9
• Y is -0-
• R 9 is Ci-C 6 alkyl.
• R 6 is -Ci-C 6 alkyl-Y-R 9
• Y is -S-.
• R 6 is -Ci-C 6 alkyl-Y-R 9
• Y is -N(Ri 0 )-.
• R is -Ci-C 6 alkyl-Y-R 9
• Y is -N(H)-.
• R 9 is hydrogen.
• R 9 is Ci-C 6 alkyl.
• each R 6 is hydrogen.
• a compound of Formula (lb) wherein Ri is -C( 0)N(R 6 ) 2 , and one 5 is hydrogen and one R 6 is Ci-C 6 alkyl.
• a compound of Formula (lb) wherein Ri is -C( 0)N(R 5 ) 2 , and one R 6 is hydrogen and one R 6 is -CH 2 CH 3 .
• one R 6 is hydrogen and one 5 is -Ci-C 6 alkyl-Y-R 9
• Y is - S-.
• a compound of Formula (lb) wherein Ri is -C( 0)N(R 6 ) 2 , one 5 is hydrogen and one R 6 is -Ci- C 6 alkyl-Y-R 9 , and Y is -N(H)-.
• R 9 is hydrogen.
• R 9 is Ci-C 6 alkyl.
• R 9 is a compound of Formula (lb) wherein R 9 is -CH 3 .
• a compound of Formula (lb) wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (lb) wherein m is 0 or 1. In some embodiments is a compound of Formula (lb) wherein m is 0. In some embodiments is a compound of Formula (lb) wherein m is 1. In some embodiments is a compound of Formula (lb) wherein m is 2. In some embodiments is a compound of Formula (lb) wherein m is 3. In some embodiments is a compound of Formula (lb) wherein m is 4.
• embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is halogen. In some embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is -CI. In some
• embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is -CH 3 . In some embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is Ci-C 6 alkoxy. In some embodiments is a compound of Formula (lb) wherein m is 1 and R 2 is -OCH 3 .
• n 0, 1, 2, or 3.
• n is 0, 1, or 2. In some embodiments is a compound of Formula (lb) wherein n is 0 or 1. In some embodiments is a compound of Formula (lb) wherein n is 0. In some embodiments is a compound of Formula (lb) wherein n is 1. In some embodiments is a compound of Formula (lb) wherein n is 2. In some embodiments is a compound of Formula (lb) wherein n is 3. In some embodiments is a compound of Formula (lb) wherein n is 4.
• n is 1, 2, or 3 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci- C 6 alkoxy.
• n is 1 or 2 and each R 3 is independently halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 1 and R 3 is halogen. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -F. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -CI. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -CH 3 . In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is Ci-C 6 haloalkyl. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -CF 3 . In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -CF 3 . In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -CF 3
• embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is Ci-C 6 alkoxy. In some embodiments is a compound of Formula (lb) wherein n is 1 and R 3 is -OCH 3 .
• R 4 is hydrogen. In some embodiments is a compound of Formula (lb) wherein R 4 is Ci-C 6 alkyl. In some embodiments is a compound of Formula (lb) wherein R 4 is CH 3 .
• R 4 is Ci-C 6 alkyl, and R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci- C 6 alkoxy.
• n is 0, q is 0, R 4 is -CH 3 , and R 3 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• embodiments is a compound of Formula (lb) wherein m is 0, n is 0, q is 1, R 4 is hydrogen, and R 5 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• R 4 is Ci-C 6 alkyl
• R 5 is halogen, Ci- C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 alkoxy.
• n is 0, q is 1, R4 is -CH 3 , and R5 is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci- C 6 alkoxy.
• 00110] is a compound selected from:
• the therapeutic agent(s) e.g. compound of Formula (I), (la), or (lb)
• the pharmaceutical composition is present in the pharmaceutical composition as a pharmaceutically acceptable salt.
• any compound described above is suitable for any method or composition described herein.
• the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration.
• the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
• Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral
• a compound of Formula (I), (la), or (lb) is used as a single enantiomer. In some embodiments, a compound of Formula (I), (la), or (lb) is used as a racemic mixture.
• the methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structures presented herein, as well as active metabolites of these compounds having the same type of activity.
• compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
• the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.
• the compounds of Formula (I), (la), or (lb) described herein include solvent addition forms thereof.
• Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
• sites on the compounds of Formula (I), (la), or (lb) disclosed herein are susceptible to various metabolic reactions. Therefore incorporation of appropriate substituents at the places of metabolic reactions will reduce, minimize or eliminate the metabolic pathways.
• the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium or an alkyl group.
• the compounds of Formula (I), (la), or (lb) disclosed herein are isotopically-labeled, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• one or more hydrogen atoms are replaced with deuterium.
• metabolic sites on the compounds described herein are deuterated.
• substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
• RQRy modulators which have been structurally modified to incorporate a carboxylic ester functional group to produce an RQRy soft-drug.
• the carboxylic ester RORy modulators described herein retain RORy activity.
• the corresponding carboxylic acids of the ester derivatives lack appreciable RORy activity.
• the carboxylic esters described herein provide an optimal delivery for a topically administered RORy modulator.
• the carboxylic esters are potent RORy modulators which induce the expression and/or protein levels of RORy in skin cells.
• the corresponding carboxylic acids are devoid of appreciable RORy activity.
• the carboxylic esters will have little or no systemic exposure as they are readily hydrolyzed upon entering the systemic circulation (Scheme A).
• the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
• the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science
• Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
• Groups such as trityl, dimethoxytrityl, acetal and t-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 and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
• 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.
• an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-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.
• blocking/protecting groups may be selected from:
• provided herein are methods for modulating of RORy activity in a cell by contacting the cell with an RORy modulator. Examples of such RORy modulators are described above.
• [00130] is a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition selected from the group consisting of skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is skin aging.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising
• a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof wherein the disease, disorder or condition is a dermal disease, disorder or condition is scarring.
• embodiments is a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is psoriasis.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is dermatitis.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is eczema.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is urticaria.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is rosacea.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is burns.
• a method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is acne.
• RORy modulators described herein are administered to subjects in a biologically compatible form suitable for topical administration to treat or prevent dermal diseases, disorders or conditions.
• biologically compatible form suitable for topical administration is meant a form of the RORy modulator to be administered in which any toxic effects are outweighed by the therapeutic effects of the modulator.
• Administration of RORy modulators as described herein can be in any pharmacological form including a therapeutically effective amount of an RORy modulator alone or in combination with a pharmaceutically acceptable carrier.
• Topical administration of an RORy modulator may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution.
• a semisolid composition is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.
• Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein.
• Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds.
• Patches can include those that control the rate of drug delivery to the skin.
• Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively.
• the reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin.
• the monolithic design typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing.
• This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.
• a therapeutically effective amount of an RORy modulator may vary according to factors such as the skin aging state, age, sex, and weight of the individual, and the ability of the RORy modulator to elicit a desired response in the individual. Dosage regime may be adjusted to provide the optimum cosmetic, response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the skin aging.
• RORy modulators can also be linked or conjugated with agents that provide desirable pharmaceutical or pharmacodynamic properties.
• RORy modulators can be stably linked to a polymer such as polyethylene glycol to obtain desirable properties of solubility, stability, half-life, and other pharmaceutically advantageous properties (see, e.g., Davis et al., Enzyme Eng. 4: 169-73 (1978); Burnham N L, Am. J. Hosp. Pharm. 51 :210-18 (1994)).
• RORy modulators can be in a composition which aids in delivery into the cytosol of a cell.
• an RORy modulator may be conjugated with a carrier moiety such as a liposome that is capable of delivering the modulator into the cytosol of a cell.
• a carrier moiety such as a liposome that is capable of delivering the modulator into the cytosol of a cell.
• RORy modulators can be employed in the form of pharmaceutical preparations. Such preparations are made in a manner well known in the pharmaceutical art. One preferred preparation utilizes a vehicle of physiological saline solution, but it is contemplated that other pharmaceutically acceptable carriers such as physiological concentrations of other non-toxic salts, five percent aqueous glucose solution, sterile water or the like may also be used. As used herein "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
• compositions can, if desired, be lyophilized and stored in a sterile ampoule ready for reconstitution by the addition of sterile water for ready injection.
• the primary solvent can be aqueous or alternatively non-aqueous.
• the anti-skin aging compositions disclosed herein can further comprise a retinoic acid receptor (RAR) ligand.
• RAR ligands include, for example, all- trans retinoic acid (tretinoin) and/or synthetic retinoic acid receptor ligands.
• tretinoin all- trans retinoic acid
• Tretinoin is sold under such trademarks as Atragen®, Avita®, Renova®, Retin-A®, Vesanoid®, and Vitinoin®.
• Exemplary synthetic retinoic acid receptor ligands include tazarotene (Avage®; ethyl 6-[2-(4,4- dimethylthiochroman-6-yl)ethynyl]pyridine-3-carboxylate) and Differin® (adapalene; 6-[3-(l- adamantyl)-4-methoxyphenyl]-2-naphthoic acid; CD271).
• Topical compositions can be prepared by combining the anti-skin aging composition with conventional pharmaceutically acceptable diluents and carriers commonly used in topical dry, liquid, cream, and aerosol formulations.
• Ointment and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• An exemplary base is water.
• Thickening agents which can be used according to the nature of the base include aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, hydrogenated lanolin, and the like.
• Lotions can be formulated with an aqueous base and will, in general, also include one or more of the following: stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like. Powders can be formed with the aid of any suitable powder base, for example, talc, lactose, starch, and the like. Drops can be formulated with an aqueous base or non-aqueous base, and can also include one or more dispersing agents, suspending agents, solubilizing agents, and the like.
• the topical composition may, for example, take the form of hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethyleneglycol (PEG) as the carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes.
• PEG polyethyleneglycol
• DAB 8 50% PEG 1500
• emulsion especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes.
• Suitable permeation accelerators include sulphoxide derivatives such as dimethylsulphoxide (DMSO) or decylmethylsulphoxide (decyl- MSO) and transcutol (diethyleneglycolmonoethylether) or cyclodextrin; as well as pyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or the biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3-diphenylurea; terpenes, for example D-limonene, menthone, a-terpinol, carvol, limonene oxide, or 1,8-cineol.
• DMSO dimethylsulphoxide
• Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof.
• Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals.
• such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice.
• Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• the carrier can also contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation.
• the anti-skin aging compositions can also further comprise antioxidants, sun screens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.
• Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.
• Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the RORy modulator and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
• the specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Such calculations can be made without undue experimentation by one skilled in the art in light of the RORy modulator activities disclosed herein in assay preparations of target cells. Exact dosages are determined in conjunction with standard dose-response studies.
• the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration.
• Toxicity and therapeutic efficacy of such RORy modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
• modulators that exhibit large therapeutic indices are preferred. While RORy modulators that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such modulators to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
• the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
• the dosage of such RORy modulators lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• the therapeutically effective dose can be estimated initially from cell culture assays.
• a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of RORy modulator that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
• IC 50 i.e., the concentration of RORy modulator that achieves a half-maximal inhibition of symptoms
• levels in plasma may be measured, for example, by high performance liquid chromatography.
• Step A To a solution of 1 (15 g, 1.0 eq) in DMF (120 mL) was added a solution of NaN0 2 (4.4 g, 1.1 eq) in water (30 mL). The mixture was cooled to 0 °C for 15 minutes and 6N HCl (29 mL, 3.0 eq) was added dropwise to the reaction mixture for over 15 minutes at 0 °C. The resulting mixture was stirred at 0 °C for lh. KI (10.1 g, 1.05 eq) was added with portions (over 15 minutes). The reaction mixture was stirred at 0 °C for lh, and then stirred at room temperature overnight.
• reaction mixture was diluted with water (-500 mL) and extracted with EtOAc/Hexane (2: 1, 3x150 mL). The combined organic phase was washed with NaHS0 3 , water, and brine. The crude mixture was purified on a silica gel column to afford 2 (18.85 g, 88%) as a pale yellow oil.
• Step B To 2 (6.6 g, 1.0 eq), 3 (3.21 g, 1.2 eq), Pd(PPh 3 ) 4 (2.05 g, 0.1 eq), and K 2 C0 3 (7.4 g, 3.0 eq) were combined in dioxane (150 mL) and water (40 mL). The mixture was flushed with N 2 for 5 minutes and then heated at 80 °C for 8h under N 2 . The reaction mixture was cooled and extracted with EtOAc (2x200 mL). The combined organic phase was washed with IN HCl and brine. The crude mixture was purified on a silica gel column to afford the title compound 4 (4.6 g, 74%) as a white solid.
• Boc-piperazine 5 (1.0 eq) and aldehyde 4 (1.0 eq) were dissolved in 1,2-DCE and TFA (0.2 eq) was added. The mixture was stirred at room temperature for 3h and NaBH(OAc) 3 (3.0 eq) was then added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and washed with saturated NaHC0 3 , water and brine. The crude mixture was purified on a silica gel column to afford compound 6.
• Step A Boc-piperazine 5 (1.0 eq) and 4-pyridine aldehyde (1.0 eq) were dissolved in 1,2-DCE and TFA (0.2 eq) was added. The mixture was stirred at room temperature for 3h and NaBH(OAc) 3 (3.0 eq) was then added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and washed with saturated NaHC0 3 , water, and brine. The crude mixture was purified on a silica gel column to afford compound 14. Compound 14 was dissolved in CH 2 CI 2 and TFA (1 : 1). The mixture was stirred at room temperature for 2h. The solvent was removed in vacuo. The residue was dissolved in CH 2 C1 2 and washed with saturated NaHC0 3 to afford compound 15.
• Step B Compound 4 (1.0 eq) and compound 15 (1.0 eq) were dissolved in 1,2-DCE and TFA (0.2 eq) was added. The mixture was stirred at room temperature for 3h. NaBH(OAc) 3 (3.0 eq) was then added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and washed with saturated NaHC0 3 , water, and brine. The crude mixture was purified on a silica gel column to afford compound 16.
• Example 16 Synthesis of 2-ethoxyethyl 2-(4-((4'-(l,1 ? 3 ? 3,3-hexafluoro-2-hydroxypropan- 2-yl)-[l,l'-biphenyl]-4-yl methyl)-l-(pyridin-4-ylmethyl)piperazin-2-yl)acetate (32)
• Step A The title compound 33 was prepared as described in Synthesis Protocol F wherein Compound 29 from Example 9 (1.0 eq) in DMF was the starting material to which was added EDCI (2.5 eq) and tert-butyl (2-hydroxyethyl)carbamate (10 eq). The mixture was stirred at room temperature overnight.
• Step B The ester was treated with 4N HC1 in dioxane to afford the title compound.
• Example 18 Synthesis of ethyl 2-(4-((4'-(l,l,l ? 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2- methyl-[l,l'-biphenyl]-4-yl)methyl)-l-(pyridin-4-ylmethyl)piperazin-2-yl)acetate (35)
• Step A The aldehyde intermediate 4'-(l,l, l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- 2-methyl-[l,l'-biphenyl]-4-carbaldehyde (compound 34) was synthesized as described in Step B of Example 1, but substituting (4-formyl-2-methylphenyl)boronic acid for compound 3.
• Step B The title compound was prepared as described in Synthesis Protocol C, but substituting 4'-(l , 1 , 1 ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[ 1 , 1 '-biphenyl]-4- carbaldehyde (compound 34) for compound 4 and wherein n is 1.
• (R)-(l,4-Dibenzylpiperazin-2-yl)methanol dihydrochloride 38 (17.3 g, 1.0 eq) was suspended in 120 mL SOCl 2 . The mixture was heated at 60° C for 4 h. The excess SOCl 2 was removed in vacuo, the residue was diluted with 200 mL ice water. To the mixture was added solid Na 2 C0 3 to adjust pH 9, then extracted with 3x50 mL DCM to afford pale yellow oil (R)- l,4-dibenzyl-2-(chloromethyl)piperazine 39 (13.6 g, 93%) which was used without purification.
• Ethyl (5)-2-(l,4-dibenzylpiperazin-2-yl)acetate 41 (14.6 g, 1.0 eq) was dissolved in 100 mL EtOH, added 2M HC1 in EtOH (75 mL) and Pd/C (2.5 g, 10%). The mixture was hydrogenated at 60PSI H 2 for 8 h. The catalyst was removed, and the mixture was concentrated in vacuo. The residue white solid was washed with EtOAC/Hexane (1 :5, 2x20 mL) to afford ethyl (,S)-2-(piperazin-2-yl)acetate 42 (9.2 g, 91%) as a dihydrochloride salt.
• Ethyl (5)-2-(piperazin-2-yl)acetate 42 (9.2 g, 1.0 eq) was dissolved in THF (50 mL) and water (50 mL). To the mixture was added 2M K 2 C0 3 to adjust pH 9-10 at 0 °C, then Boc- ON (2-(tert-butoxycarbonyloxyiraino)-2-phenyIacetoniianae) (9.4 g, 1.0 eq) was added. The resulting mixture was stirred at 0° C for 2 h, then rt. overnight. THF was removed in vacuo, then extracted with acetate (3x100 mL). The mixture was purified on silica gel column to provide oil tert-butyl (,S)-3-(2-ethoxy-2-oxoethyl)piperazine-l-carboxylate 43 (6.65 g, 59%)
• tert-Butyl (,S)-3-(2-ethoxy-2-oxoethyl)piperazine-l-carboxylate 43 (1.0 eq) and 4- pyridine aldehyde (1.0 eq) were dissolved in 1,2-DCE to which TFA (0.2 eq) was added. The mixture was stirred at room temperature for 3h after which NaBH(OAc) 3 (3.0 eq) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and washed with saturated NaHC0 3 , water, and brine.
• tert-Butyl (,S)-3-(2-ethoxy-2-oxoethyl)-4-(pyridin-4-ylmethyl)piperazine-l-carboxylate 44 was dissolved in CH 2 C1 2 and TFA (1 : 1). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was dissolved in CH 2 C1 2 and washed with saturated NaHC0 3 to afford ethyl (S)-2-(l-(pyridin-4-ylmethyl)piperazin-2-yl)acetate 45.
• Example 20 Synthesis of ethyl (S)-2-(4-((4'-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan-2- yl)-[l,l'-biphenyl]-4-yl)meth l)-l-(pyridin-4-ylmethyl)piperazin-2-yl)acetate (48)
• Table 1 shows additional compounds of Formula (I) that are prepared using the protocols and intermediates described above.
• [00193] Human RORy ligand binding assay was performed in 96-well format.
• the N-terminal DNA binding domains (DBD) of the native RORy and RORyt receptors have been substituted with that of the yeast GAL4-DBD and RORy is expressed constitutively in the cell line. Both agonist and inverse agonist activity can be detected.
• 10 mM compound stocks were diluted serially 1 :3 with DMSO and further diluted with provided media to generate 10 titration points from 60 ⁇ to 3 nM. These treatment conditions were added to the plates as 2x media in 100 ⁇ _, volume. Each plate includes a positive control with 10 titration points as well as 6 negative control wells with vehicle only.
• Reporter cells were rapidly thawed and added to the plates in 100 ⁇ _, volume. The plates were incubated for 24 hrs in a 37°C humidified 5% C0 2 incubator. Media was removed before the addition of room temperature Detection Substrate. After 5 minute incubation, the luminescence was quantified on a luminescence plate reader.
• RORyt inverse agonists TH17 cell differentiation is inhibited and reduction of IL-17A production is quantitatively correlated to the efficiency of RORyt inhibition.
• Plasma samples were collected at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hr (i.v.) and 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hr (p.o.) with K 2 EDTA as anticoagulant. Plasma samples were separated by centrifugation of whole blood and stored below -70 °C until bioanalysis. All samples were processed for analysis by protein precipitation using acetonitrile (ACN) and analyzed with fit for purpose LC/MS/MS method. Pharmacokinetic parameters were calculated using the non-compartmental analysis tool of Phoenix WinNonlin (Version 6.3).
• Figure 2 shows the pharmacokinetic plot of a compound of Formula (I) (Compound A).
• a daily topical dose of 62.5 mg of a cream preparation containing 5% Imiquimod: 47 mg on hair-free back of mice and 15.5 mg on right ear was administered to establish a model of EVIQ-induced psoriasis.
• Figures 3-6 show the in vivo efficacy results obtained from treatment with a compound of Formula (I) (Compound A) in this psoriasis model. All the animals treated with Compound A were found to be normal and active (no signs of skin irritation, no changes in posture, gait and response to handling behavior, no secretions and excretions, normal body movement display) during the treatment period. No morbidity or mortality was found. Vehicle control group treated with F Q showed significant increase in total psoriasis score with pronounced erythema, scaling and increased thickness. Histology sections of the back skin and ear showed massive immune infiltration, hyperkarotosis and pustule formation.
• Pre-treatment with clobetasol significantly decreased psoriasis score, ear and back skin thickness, as well as histopathology scoring.
• Pre- treatment with Compound A showed a dose dependent decrease of all three read-outs (1%> dose of Compound A not shown in figures).
• the responses from the high dose Compound A treated group (3%) dose of Compound A) is not statistically different from the responses from clobetasol treatment.
• contraceptives must continue using the same hormonal contraceptive as that was used in the past 3 months, with the same route of administration and the same dose during the study
• Topical anti -psoriasis treatment in 2 weeks e.g. corticosteroids, retinoids acid, anthranol, tars, keratolytics.
• Vitamin D analogues or local immune regulator treatment in 4 weeks Emollient or cosmetics in 24 hours; Any psoriasis vaccine, or have participated in any psoriasis vaccine trial; Biologies treatment in 12 weeks, e.g. Alefacept, Etanercept, Infliximab, Adalimumab, Ustekinumab, Efalizumab; Any phototherapy or systemic treatment in 4 weeks, e.g.
• corticosteroids methotrexate, retinoids acids, ciclosporin
• Long time exposure to natural light or artificial UV, or will have such exposure Use of drug known to harm certain organ in 12 weeks; Participated in any clinical trial in 4 weeks, or have plan to participate any trial during treatment period;
• ALT Alanine transaminase
• AST aspartate aminotransferase
• UPN Upper Limit Normal
• Hepatitis B Surface Antigen (HBsAg), hepatitis C or anti-HIV test • Positive for Hepatitis B Surface Antigen (HBsAg), hepatitis C or anti-HIV test
• AUC Area under the plasma concentration versus time curve(AUC) of a single-dose of a Compound of Formula (I), (la), or (lb) Cream from zero(0) hours to time (t) in patients with mild to moderate psoriasis [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
• AUC Area under the plasma concentration versus time curve(AUC) of a single-dose of a Compound of Formula (I), (la), or (lb) Cream from zero (0) hours to infinity ( ⁇ ) in patients with mild to moderate psoriasis [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
• AUC Area under the plasma concentration versus time curve(AUC) of a repeat-dose of a Compound of Formula (I), (la), or (lb) Cream from zero(0) hours to time (t) in patients with mild to moderate psoriasis [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• AUC Area under the plasma concentration versus time curve(AUC) of a repeat-dose of a Compound of Formula (I), (la), or (lb) Cream from zero (0) hours to infinity ( ⁇ ) in patients with mild to moderate psoriasis [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
• Placebo Comparator Cohort 3 -Placebo
• Formula (I), (la), or (lb) Cream applied twice Topical administration for twice daily

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