WO2017147161A1 - Traitement de troubles ou d'affections dermatologiques - Google Patents

Traitement de troubles ou d'affections dermatologiques Download PDF

Info

Publication number
WO2017147161A1
WO2017147161A1 PCT/US2017/018896 US2017018896W WO2017147161A1 WO 2017147161 A1 WO2017147161 A1 WO 2017147161A1 US 2017018896 W US2017018896 W US 2017018896W WO 2017147161 A1 WO2017147161 A1 WO 2017147161A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
sulfur
oxygen
nitrogen
ring
Prior art date
Application number
PCT/US2017/018896
Other languages
English (en)
Inventor
Raju Mohan
Original Assignee
Raju Mohan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Raju Mohan filed Critical Raju Mohan
Publication of WO2017147161A1 publication Critical patent/WO2017147161A1/fr

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • 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
    • A61P17/10—Anti-acne agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Described herein is a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X).
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII),
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X). Further provided herein are
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII),
  • the dermatological disorder or condition is selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • ACC Acetyl-CoA carboxylase
  • methods and compositions comprising topical administration of a Acetyl-CoA carboxylase (ACC) inhibitor for treatment of dermal diseases, disorders or conditions.
  • methods and compositions comprising topical administration of a Acetyl-CoA carboxylase (ACC) inhibitor for treatment of dermal disorders or conditions selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia,
  • Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • an ACC inhibitor in the manufacture of a topical formulation for use in the treatment of a dermal disease, disorder or condition in a mammal.
  • an ACC inhibitor 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.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma- type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound havin the structure of Formula (I):
  • X is -0-, -S-, or - R-;
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of L 1 and L 2 is independently a covalent bond, an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (II):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 are
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is an optionally substituted phenyl or naphthyl ring
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (II), wherein R 2 is Hy, or a pharmaceutically acceptable salt thereof.
  • R 2 is oxazolyl, or a pharmaceutically acceptable salt thereof.
  • R 3 is tetrazolyl, - C(0)OR, -C(0)N(R) 2 , or -OR, or a pharmaceutically acceptable salt thereof.
  • R 5 and R 5 ' are each -CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OR or -C(0)N(R) 2 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OH, or a pharmaceutically acceptable salt thereof.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (III):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicycl
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (IV):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (Va):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea,
  • Rhinophyma-type rosacea seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (Vb):
  • R 1 is hydrogen or Ci-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, -
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or
  • Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea,
  • Rhinophyma-type rosacea seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (VI):
  • W is oxygen or sulfur;
  • X is O, S, N or R;
  • each Y is independently C, N, or O;
  • each Z is independently C or N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (VII):
  • W is oxygen or sulfur
  • Q is C or N; wherein if Q is N, then R z is absent; X is -0-, -S-, or - R-;
  • each Z is independently C or N; provided that both Z are not N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (VIII):
  • W is -C(O)-, -C(S)-, or -S(0) 2 -;
  • Q is -C(O)-, -C(S)-, or -S(0) 2 -, or N;
  • X is -O-, -S-, - R-, or N;
  • Y is C or N;
  • Z is C or N;
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the m mmal a compound having the structure of Formula (IX):
  • W is -C(R Z )-, -C(O)-, or -C(S)-;
  • Q is -C(R Z )-, -C(O)-, or -C(S)-;
  • J is C or N; provided that when J is N, R 1 is absent;
  • X is CH or N
  • Y is CH or N
  • Z is C or N
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • R z is selected from hydrogen, halogen, Ci -3 alkyl, -CN;
  • n 0-5;
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is acne vulgaris.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is acne conglobata.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is choracne.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is rosacea.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is Rhinophyma-type rosacea.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is seborrhea.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is seborrheic dermatitis.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is sebaceous gland hyperplasia.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is Meibomian gland dysfunction of facial rosacea.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is mitogenic alopecia.
  • a method of treating a dermatological disorder or condition in a mammal comprising administering to the mammal a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the
  • dermatological disorder or condition is oily skin.
  • X is -0-, -S-, or - R-;
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of L 1 and L 2 is independently a covalent bond, an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • compositions for use in treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula II):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 are
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is an optionally substituted phenyl or naphthyl ring
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (II), wherein R 2 is Hy, or a pharmaceutically acceptable salt thereof.
  • R 2 is oxazolyl, or a pharmaceutically acceptable salt thereof.
  • R 3 is tetrazolyl, -C(0)OR, - C(0)N(R) 2 , or -OR, or a pharmaceutically acceptable salt thereof.
  • R 5 and R 5 ' are each -CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OR or -C(0)N(R) 2 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OH, or a pharmaceutically acceptable salt thereof.
  • compositions for use in treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula III):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • compositions for use in treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula IV):
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • compositions for use in treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula Va):
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • W is oxygen or sulfur
  • X is O, S, N or R
  • each Y is independently C, N, or O;
  • each Z is independently C or N;
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • W is oxygen or sulfur
  • Q is C or N; wherein if Q is N, then R z is absent;
  • X is -0-, -S-, or - R-;
  • each Z is independently C or N; provided that both Z are not N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • compositions for use in treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula VIII):
  • W is -C(O)-, -C(S)-, or -S(0) 2 -;
  • Q is -C(O)-, -C(S)-, or -S(0) 2 -, or N;
  • X is -O-, -S-, - R-, or N;
  • Y is C or N
  • Z is C or N
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • W is -C(R Z )-, -C(O)-, or -C(S)-;
  • Q is -C(R Z )-, -C(O)-, or -C(S)-;
  • J is C or N; provided that when J is N, R 1 is absent;
  • X is CH or N
  • Y is CH or N
  • Z is C or N
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • R z is selected from hydrogen, halogen, Ci -3 alkyl, -CN;
  • n 0-5;
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) wherein the dermatological disorder or condition is acne vulgaris.
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is acne conglobata.
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is choracne.
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is rosacea.
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is Rhinophyma-type rosacea.
  • compositions for use in treating a dermatological disorder or condition in a mammal wherein the composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is seborrhea.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is sebaceous gland hyperplasia.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is Meibomian gland dysfunction of facial rosacea.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is mitogenic alopecia.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), wherein the dermatological disorder or condition is oily skin.
  • sebum production due to sebaceous gland hyperactivity is one of several factors generally believed to be contributors to acne pathogenesis.
  • sebum there is stepwise differentiation of sebocytes, a specialized epithelial cell type, arising from basal progenitor cells leading to lipid-forming cells which as they progress toward the gland outlet. These enlarged cells ultimately rupture (holocrine secretion) releasing their lipid-rich content (sebum).
  • the overall makeup of sebum consists of squalene (12%), cholesterol (2%), wax esters (26%)), and diglycerides/triglycerides/free fatty acids (57%) (see, Zouboulis et al., "An oral 5- lipoxygenase inhibitor, directly reduces sebum production”. Dermatology. (2005) 210:36-38). Free fatty acid levels may be increased by bacterial degradation of the di- and triglycerides present within sebum (see, Thiboutot D. "Regulation of human sebaceous glands" J. Invest Dermatol. (2004) 123 : 1-12).
  • Free fatty acids may also promote the inflammatory aspects of acne by activating local immune cells and their release of a variety of pro-inflammatory factors.
  • Fatty acid synthesis starts with the carboxylation of acetyl CoA to malonyl CoA. This irreversible reaction is the committed step in fatty acid synthesis.
  • the synthesis of malonyl CoA is catalyzed by acetyl CoA carboxylase (ACC) (See, Brownsey, R. W. et al., "Regulation of acetyl-CoA carboxylase", Biochem Soc. Trans. (2006) 34: 223-227).
  • ACC acetyl CoA carboxylase
  • ACC and other fatty acid and cholesterol synthesis-regulating enzymes have been shown to be positively regulated by androgen, a key factor contributing to the increased sebum production at puberty as well as the expression of acne (see, Rosignoli, C. et al., "Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo", Exp. Dermatol. (2003) 12:480-489).
  • ACC also catalyzes the first committed and regulated step in fatty acid synthesis in bacteria. Since membrane lipid biogenesis is essential for bacterial growth, inhibition of ACC activity may potentially decrease the growth of bacteria normally present within a comedone.
  • 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).
  • 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-C 6 alkyl 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.
  • 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).
  • 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. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • cyclobutylenyl refers to a bivalent cyclobutyl group of the following structure:
  • oxetanyl refers to a bivalent oxetanyl group of the following structure:
  • 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.
  • Polycyclic heteroaryl groups may be fused or non-fused.
  • Illustrative examples of heteroaryl groups include the following moieties:
  • a “heterocycloalkyl” group or “heteroalicyclic” group 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.
  • heterocycloalkyl groups also referred to as non-aromatic heterocycles, include:
  • 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. It is understood that when referring to the number of carbon atoms in a
  • 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. skeletal atoms of the heterocycloalkyl ring).
  • 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 , -CF(CH 3 ) 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 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 "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 ACC inhibitor that, when administered to a mammal in need, is effective to at least partially ameliorate dermatological disorders or conditions described herein.
  • Dermatological disorders or conditions includes disorders involving hyperactive sebaceous gland activity including, for example, acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • Dermatologically acceptable excipient includes without limitation any adjuvant, carrier, vehicle, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, including those approved by the United States Food and Drug Administration as being acceptable for dermatological use on humans or domestic animals, or which are known, or are suitable for use in dermatological compositions.
  • Dermatologically effective amount refers to that amount of an active ingredient which, when administered dermatologically (i.e., systemically or locally, including, for example, topically, intradermally, intravenously, orally or by use of an implant, that afford administration to the sebaceous glands) to a human, is sufficient to effect the desired treatment, as defined below, of the disorder or condition of interest in the human.
  • the amount of an active ingredient which constitutes a “dermatologically effective amount” will vary depending on the active ingredient, the disorder or condition and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • 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.
  • compositions comprising these compounds are useful for the treatment of dermatological disorders and conditions.
  • the dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • the compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) has a structure selected from:
  • the therapeutic agent(s) e.g. compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X)
  • 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), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) is used as a single enantiomer.
  • a compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) is used as a racemic mixture.
  • the methods and formulations described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formulas (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), 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 can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), 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
  • the compounds of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) described herein include solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization 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), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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.
  • compounds described herein such as compounds of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X), are in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms.
  • compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy.
  • Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies.
  • Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry
  • X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources.
  • the various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and MR (liquid and solid state).
  • the various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.
  • the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof.
  • solvents, temperatures and other reaction conditions presented herein may vary.
  • the compounds described herein are prepared as described in WO 2013/071169, which is hereby incorporated by reference in its entirety.
  • 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
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma- type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a comp nd having the structure of Formula (I):
  • X is -0-, -S-, or - R-;
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring; each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of L 1 and L 2 is independently a covalent bond, an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is not hydrogen.
  • the group -L 2 -R 4 is not alkyl when R 2 is unsubstituted alkyl.
  • the group -I ⁇ -R 3 taken together is not unsubstituted alkyl.
  • R 1 is not the group -CH 2 C(0)N(R)V, where V is an aryl or heteroaryl ring, when -I ⁇ -R 3 taken together is unsubstituted alkyl.
  • X is -0-, -S-, or - R-. In certain embodiments, X is -0-. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is - R-. In some embodiments, X is - H-.
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -SO 2 R.
  • R 1 is hydrogen.
  • R 1 is C 1-4 aliphatic.
  • R 1 is methyl.
  • R 1 is trifluorom ethyl.
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 2 is halogen. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is trifluorom ethyl. In certain embodiments, R 2 is fluorine. In certain embodiments, R 2 is chlorine. In certain embodiments, R 2 is bromine. In certain embodiments, R 2 is iodine. In certain embodiments, R 2 is -C(0)OR or -C(0)N(R) 2 . In certain embodiments, R 2 is -C(0)OR. In some embodiments, R 2 is Hy.
  • Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Hy is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Hy is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Hy is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Hy is oxazolyl.
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclic ring. In some embodiments, R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , - N(R)C(0)R, -C(0)N(R) 2 , -C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 is -CN, - OR, -C(0)OR, -C(0)N(R) 2 , -S0 2 R, or an optionally substituted ring selected from phenyl or a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 is -OR.
  • R 3 is -C(0)OR.
  • R 3 is phenyl or tetrazolyl.
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, 3-8 membered unsaturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, each R is independently hydrogen or optionally substituted Ci -6 aliphatic.
  • each of L 1 and L 2 is independently a covalent bond or an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, or a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • L 1 is a Ci -3 straight or branched bivalent hydrocarbon chain.
  • L 1 is a straight or branched bivalent C 2 hydrocarbon chain.
  • L 1 is a straight or branched bivalent C 3 hydrocarbon chain.
  • L 1 is a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • L 2 is an optionally substituted Ci -3 straight or branched hydrocarbon chain. In some embodiments L 2 is an optionally substituted C 2 straight
  • L 2 is an optionally substituted C 3 straight or branched hydrocarbon chain.
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2
  • heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4
  • R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated ring. In some embodiments R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments R 4 is an optionally substituted 10 membered bicyclic aryl ring. In some embodiments, R 4 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated ring. In some embodiments R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In
  • R 4 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (II):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 are
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is an optionally substituted phenyl or naphthyl ring
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (II), wherein R 2 is Hy, or a pharmaceutically acceptable salt thereof.
  • R 2 is oxazolyl, or a pharmaceutically acceptable salt thereof.
  • R 3 is tetrazolyl, - C(0)OR, -C(0)N(R) 2 , or -OR, or a pharmaceutically acceptable salt thereof.
  • R 5 and R 5 ' are each -CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OR or -C(0)N(R) 2 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OH, or a pharmaceutically acceptable salt thereof.
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, - S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • each of R 5 and R 5 ' is -R, wherein -R is not hydrogen. In some embodiments, each of R 5 and R 5 ' is methyl. In some embodiments, R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group. In some embodiments, R 5 and R 5 ' are taken together to form a cyclobutylenyl group.
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, - SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • one of R 7 and R 7 ' is hydrogen, and the other is -OR. In some embodiments one of R 7 and R 7 ' is hydrogen, and the other is isopropoxy. In some embodiments R 7 and R 7 ' are taken together to form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments R 7 and R 7 ' are taken together to form a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2
  • R 7 and R 7 ' is hydrogen and the other is -OR, where R in this instance is a 4-7 membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 7 and R 7 ' is hydrogen and the other is -OR, where R in this instance is oxetane, tetrahydrofuran, or tetrahydropyran.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea,
  • Rhinophyma-type rosacea seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (III):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5; or a pharmaceutically acceptable salt thereof.
  • [00128] is a method of treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (III), wherein R 6 is hydrogen. In some embodiments, R 6 is isopropyl. In some embodiments, R 8 is halogen. In some embodiments, n is 0. In some embodiments, n is 1-2.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (IV):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • [00130] in another aspect is a method of treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (Va):
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea,
  • Rhinophyma-type rosacea seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (Vb):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea,
  • Rhinophyma-type rosacea seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (VI):
  • W is oxygen or sulfur
  • X is O, S, N or R
  • each Y is independently C, N, or O;
  • each Z is independently C or N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (VII):
  • W is oxygen or sulfur
  • Q is C or N; wherein if Q is N, then R z is absent;
  • X is -0-, -S-, or - R-;
  • each Z is independently C or N; provided that both Z are not N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a com ound having the structure of Formula (VIII):
  • W is -C(O)-, -C(S)-, or -S(0) 2 -;
  • Q is -C(O)-, -C(S)-, or -S(0) 2 -, or N;
  • X is -O-, -S-, - R-, or N;
  • Y is C or N
  • Z is C or N
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • I l l - R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • [00135] in another aspect is a method of treating a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (IX):
  • W is -C(R Z )-, -C(O)-, or -C(S)-;
  • Q is -C(R Z )-, -C(O)-, or -C(S)-;
  • J is C or N; provided that when J is N, R 1 is absent;
  • X is CH or N
  • Y is CH or N
  • Z is C or N
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; selected from hydrogen, halogen, C 1-3 alkyl, -CN; and
  • n 0-5;
  • a dermatological disorder or condition selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin in a mammal comprising administering to the mammal a compound having the structure of Formula (X):
  • R 11 is selected from the group consisting of -OH, halogen, and -OS0 2 R;
  • R 12 is selected from the group consisting of R 13 or -OR 13 ;
  • R 13 is straight or branched Ci -4 aliphatic
  • R 14 is hydrogen or halogen.
  • compositions and methods of administration are provided.
  • the therapeutic or pharmaceutical compositions described herein can be administered by any other suitable route known in the art including, for example, oral, intravenous, subcutaneous, intramuscular, topical, or transdermal, or administration to cells in ex vivo treatment protocols.
  • the therapeutic or pharmaceutical compositions described herein are administered orally.
  • compositions described herein are administered intravenously. In some embodiments, the therapeutic or pharmaceutical compositions described herein are administered subcutaneously. In some embodiments, the therapeutic or pharmaceutical compositions described herein are administered intramuscularly. In some embodiments, the therapeutic or pharmaceutical compositions described herein are administered topically. In some
  • the therapeutic or pharmaceutical compositions described herein are administered transdermally. Administration can be either rapid as by injection or over a period of time as by slow infusion or administration of slow release formulation.
  • Topical administration may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution.
  • a semi-solid composition is meant an ointment, cream, salve, gel, 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
  • 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 compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • Topical compositions can be prepared by combining a compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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 compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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. It will be understood that 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 mammal patient, the severity of the patient's symptoms, and the chosen route of administration.
  • Toxicity and therapeutic efficacy of such compounds and compositions of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for
  • LD 50 the dose lethal to 50% of the population
  • 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 .
  • 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 compounds and compositions of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 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.
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of Formula (I):
  • X is -0-, -S-, or - R-;
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of L 1 and L 2 is independently a covalent bond, an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is not hydrogen.
  • the group -L 2 -R 4 is not alkyl when R 2 is unsubstituted alkyl.
  • the group -I ⁇ -R 3 taken together is not unsubstituted alkyl.
  • R 1 is not the group -CH 2 C(0)N(R)V, where V is an aryl or heteroaryl ring, when -I ⁇ -R 3 taken together is unsubstituted alkyl.
  • X is -0-, -S-, or - R-. In certain embodiments, X is -0-. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is - R-. In some embodiments, X is - H-.
  • R 1 is hydrogen or Ci-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R.
  • R 1 is hydrogen.
  • R 1 is Ci -4 aliphatic.
  • R 1 is methyl.
  • R 1 is trifluorom ethyl.
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 2 is halogen. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is trifluorom ethyl. In certain embodiments, R 2 is fluorine. In certain embodiments, R 2 is chlorine. In certain embodiments, R 2 is bromine. In certain embodiments, R 2 is iodine. In certain embodiments, R 2 is -C(0)OR or -C(0)N(R) 2 . In certain embodiments, R 2 is -C(0)OR. In some embodiments, R 2 is Hy.
  • Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Hy is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Hy is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Hy is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Hy is oxazolyl.
  • R 1 and R 2 are taken together to form an optionally substituted
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , - N(R)C(0)R, -C(0)N(R) 2 , -C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 is -CN, - OR, -C(0)OR, -C(0)N(R) 2 , -S0 2 R, or an optionally substituted
  • R 3 is -OR. In some embodiments, R 3 is -C(0)OR. In some embodiments, R 3 is phenyl or tetrazolyl.
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4- 8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, 3-8 membered unsaturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, each R is independently hydrogen or optionally substituted Ci -6 aliphatic.
  • each of L 1 and L 2 is independently a covalent bond or an optionally substituted 1-6 membered straight or branched bivalent hydrocarbon chain, or a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • L 1 is a Ci -3 straight or branched bivalent hydrocarbon chain.
  • L 1 is a straight or branched bivalent C 2 hydrocarbon chain.
  • L 1 is a straight or branched bivalent C 3 hydrocarbon chain.
  • L 1 is a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • L 2 is an optionally substituted Ci -3 straight or branched hydrocarbon chain. In some embodiments L 2 is an optionally substituted C 2 straight
  • L 2 is an optionally substituted C 3 straight or branched hydrocarbon chain.
  • R 4 is hydrogen or an optionally substituted ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4
  • heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated ring. In some embodiments R 4 is an optionally substituted 5-6 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments R 4 is an optionally substituted 10 membered bicyclic aryl ring. In some embodiments, R 4 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some
  • R 4 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • [00163] is a pharmaceutical composition for use in treating a
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of Formula (II):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, -
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or
  • Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is an optionally substituted phenyl or naphthyl ring
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, - C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, - C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (II), wherein R 2 is Hy, or a pharmaceutically acceptable salt thereof.
  • R 2 is oxazolyl, or a pharmaceutically acceptable salt thereof.
  • R 3 is tetrazolyl, -C(0)OR, - C(0)N(R) 2 , or -OR, or a pharmaceutically acceptable salt thereof.
  • R 5 and R 5 ' are each -CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OR or -C(0)N(R) 2 , or a pharmaceutically acceptable salt thereof.
  • R 3 is -C(0)OH, or a pharmaceutically acceptable salt thereof.
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, - S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.
  • each of R 5 and R 5 ' is -R, wherein -R is not hydrogen. In some embodiments, each of R 5 and R 5 ' is methyl. In some embodiments, R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group. In some embodiments, R 5 and R 5 ' are taken together to form a cyclobutylenyl group.
  • each of R 7 and R 7 ' is independently hydrogen, -R, -OR, - SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • one of R 7 and R 7 ' is hydrogen, and the other is -OR. In some embodiments one of R 7 and R 7 ' is hydrogen, and the other is isopropoxy. In some embodiments R 7 and R 7 ' are taken together to form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments R 7 and R 7 ' are taken together to form a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2
  • R 7 and R 7 ' is hydrogen and the other is -OR, where R in this instance is a 4-7 membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 7 and R 7 ' is hydrogen and the other is -OR, where R in this instance is oxetane, tetrahydrofuran, or tetrahydropyran.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (III):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R; or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • [00170] is a pharmaceutical composition for use in treating a
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (III), wherein R 6 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • R 6 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • R 6 is isopropyl.
  • R 8 is halogen.
  • n is 0. In some embodiments, n is 1-2.
  • [00171] is a pharmaceutical composition for use in treating a
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of Formula (IV):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R; or R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group; and
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of Formula (Va):
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 and R 2 are
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • [00173] is a pharmaceutical composition for use in treating a
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of Formula (Vb):
  • R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, or -S0 2 R, or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;
  • each R is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - C(0)N(R)S(0) 2 R, -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , - C(0)R, -C(0)OR, -OC(0)R, -S(0)R, -S0 2 R, -B(OH) 2 , or an optionally substituted ring selected from phenyl and 5-6 membered heteroaryl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, or -S0 2 R or R 5 and R 5 ' are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;
  • each of R 1 , R 9 , and R 9 ' is independently CH 3 or CD 3 ;
  • each of X, Y, Z 1 , and Z 2 is independently H or D;
  • R 10 is CH 3 , CD 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CF 2 H, CH 2 CD 3 , CD 2 CH 3 , or CD 2 CD 3 ; or a pharmaceutically acceptable salt thereof.
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (VI):
  • W is oxygen or sulfur
  • X is O, S, N or R
  • each Y is independently C, N, or O;
  • each Z is independently C or N;
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5; or a pharmaceutically acceptable salt.
  • [00175] is a pharmaceutical composition for use in treating a
  • composition comprises a dermatologically acceptable excipient and a compound having the structure of Formula (VII):
  • W is oxygen or sulfur
  • Q is C or N; wherein if Q is N, then R z is absent;
  • X is -0-, -S-, or - R-;
  • each Z is independently C or N; provided that both Z are not N;
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • n 0-5; or a pharmaceutically acceptable salt.
  • composition comprises a dermatologically acceptable excipient and a compound havin the structure of (VIII):
  • W is -C(O)-, -C(S)-, or -S(0) 2 -;
  • Q is -C(O)-, -C(S)-, or -S(0) 2 -, or N;
  • X is -O-, -S-, - R-, or N;
  • Y is C or N
  • Z is C or N
  • R 1 is hydrogen or Ci -4 aliphatic, optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium; and n is 0-5;
  • W is -C(R Z )-, -C(O)-, or -C(S)-;
  • Q is -C(R Z )-, -C(O)-, or -C(S)-;
  • J is C or N; provided that when J is N, R 1 is absent;
  • X is CH or N
  • Y is CH or N
  • Z is C or N
  • R 1 is hydrogen or optionally substituted with one or more halogens, -OR, -SR, - N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , - N(R)S0 2 R, -S0 2 RN(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -C(0)OR, -S(0)R, or -S0 2 R;
  • R 2 is halogen, -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , -N(R)C(0)N(R) 2 , - N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, -OC(0)R, -S(0)R, - S0 2 R, -B(OR) 2 , or Hy, where Hy is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 and R 2 are taken together to form an optionally substituted 4-7 membered partially unsaturated carbocyclo-, heterocyclo-, benzo-, or 5-6 membered heteroarylo- fused ring;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci -6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 5 and R 5 ';
  • L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain optionally substituted with R 7 and R 7 ';
  • R 3 is halogen, -CN, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)RN(R) 2 , -C(0)N(R)S(0) 2 R, - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, -B(OR) 2 , or an optionally substituted ring selected from phenyl and 5- 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 4 is hydrogen or a ring selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- 10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with n instances of R 8 ; each of R 5 and R 5 ' is independently -R, -OR, -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC
  • each of R 7 and R 7 ' is independently, -R, -OR 6 , -SR, -N(R) 2 , -N(R)C(0)R, -C(0)N(R) 2 , - N(R)C(0)N(R) 2 , -N(R)C(0)OR, -OC(0)N(R) 2 , -N(R)S0 2 R, -S0 2 N(R) 2 , -C(0)R, -C(0)OR, - OC(0)R, -S(0)R, -S0 2 R, or -B(OR) 2 ; or R 7 and R 7 ' are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 is -R, -C(0)N(R) 2 , or -C(0)R;
  • each R 8 is independently selected from halogen, -R, -OR, -SR, -N(R) 2 or deuterium;
  • R z is selected from hydrogen, halogen, Ci -3 alkyl, -CN;
  • n 0-5;
  • R 11 is selected from the group consisting of -OH, halogen, and -OS0 2 R;
  • R 12 is selected from the group consisting of R 13 or -OR 13 ;
  • R 13 is straight or branched
  • R 14 is hydrogen or halogen.
  • Compounds of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) may be usefully combined with one or more other therapeutic agents in the treatment of dermatological disorders or conditions described herein.
  • Compounds of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to 1) topical/oral antibiotics, such as clindamycin, tetracycline, minoccline,
  • deoxycycline, erythromycin, trimethoprim, and azithromycin 2) retinoids, such as Accutane®, tretinion, tazarotene, and adapalene; 3) benzoyl peroxide; 4) blue/red light; 5) anti -androgenic compounds such as PSK 3841 ; 6) 5-alpha reductase type I inhibitors; and 7) comedolytics, such as salicylic acid, azelaic acid, sulfur and resorcinol.
  • retinoids such as Accutane®, tretinion, tazarotene, and adapalene
  • benzoyl peroxide 4) blue/red light; 5) anti -androgenic compounds such as PSK 3841 ; 6) 5-alpha reductase type I inhibitors; and 7) comedolytics, such as salicylic acid, azelaic acid, sulfur and resorcinol.
  • combination refers to any mixture or permutation of a compound of the invention and one or more additional therapeutic agents useful in the treatment of dermatological disorders or conditions. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the invention (e.g., dermatological or pharmaceutical compositions comprising a compound of the invention and a dermatological acceptable excipient) with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include compositions comprising a compound of the invention and another therapeutic agent. Dosage forms, routes of administration and dermatological and pharmaceutical compositions include, but are not limited to, those described herein.
  • Diethylene glycol monoethyl ether, glycerin and water are mixed. Polysorbate 80 and tocophersolan are added and mixed to dissolve. The compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) is added and mixed to dissolve. Edetate disodium, methylparaben, and propylparaben are added and mixed to dissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer are quickly dispersed with high-speed mixing until uniform mixture obtained. Trolamine is added with constant mixing to obtain a viscous gel at a pH of approximately 6.75 (when diluted 1 :9 with water).
  • Diethylene glycol monoethyl ether, glycerin alcohol and water are mixed.
  • Polysorbate 80 and tocophersolan are added and mixed to dissolve.
  • the compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) is added and mixed to dissolve.
  • Edetate disodium, methylparaben and propylparaben are added and mixed to dissolve.
  • Acrylates/ClO- C30 alkyl acrylate crosspolymer and hydroxypropyl cellulose are quickly dispersed with highspeed mixing until uniform mixture obtained.
  • Trolamine is added with constant mixing to obtain a viscous gel at a pH of approximately 6.75 (when diluted 1 :9 with water).
  • White petrolatum, cyclomethicone, isopropyl myristate and cetostearyl alcohol are combined in a separate vessel and melted completely at a temperature of between about 65°C and about 75°C and stirred.
  • Example 5 Phase II Clinical Trial - Safety and Efficacy of Compound of Formula (I), (II), (III), (IV), (Va), (Vb), (VI), (VII), (VIII), (IX), or (X) 1.25% and 2.5% Topical Acne Solutions in the Treatment of Acne Vulgaris
  • Eligible subjects will be men and women 18 years of age and older.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés, des compositions, et leurs méthodes d'utilisation pour le traitement de troubles ou d'affections dermatologiques.
PCT/US2017/018896 2016-02-23 2017-02-22 Traitement de troubles ou d'affections dermatologiques WO2017147161A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662298908P 2016-02-23 2016-02-23
US62/298,908 2016-02-23

Publications (1)

Publication Number Publication Date
WO2017147161A1 true WO2017147161A1 (fr) 2017-08-31

Family

ID=59685643

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/018896 WO2017147161A1 (fr) 2016-02-23 2017-02-22 Traitement de troubles ou d'affections dermatologiques

Country Status (1)

Country Link
WO (1) WO2017147161A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019233443A1 (fr) * 2018-06-05 2019-12-12 南京明德新药研发有限公司 Dérivé thiéno[2,3-c]pyridazin-4(1h)-one et son application
CN110950884A (zh) * 2018-09-27 2020-04-03 上海翰森生物医药科技有限公司 含二并环类衍生物抑制剂、其制备方法和应用
US10759812B2 (en) 2017-01-22 2020-09-01 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
WO2021110138A1 (fr) * 2019-12-05 2021-06-10 漳州片仔癀药业股份有限公司 Forme cristalline d'un composé thiéno[2,3-c]pyridazine-4(1h)-one, son procédé de préparation et son utilisation
WO2021110135A1 (fr) * 2019-12-05 2021-06-10 漳州片仔癀药业股份有限公司 Forme cristalline en tant qu'inhibiteur d'acc1 et d'acc2, son procédé de préparation et son utilisation
WO2022138812A1 (fr) 2020-12-24 2022-06-30 モジュラス株式会社 Composé de tétrahydrothiénopyridinesulfonamide

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050100621A1 (en) * 2003-11-07 2005-05-12 Popp Karl F. Dermatological compositions
US20110269689A1 (en) * 2008-12-04 2011-11-03 Chongxi Yu High penetration compositions and their applications
US20130123231A1 (en) * 2011-11-11 2013-05-16 Nimbus Apollo, Inc. Acc inhibitors and uses thereof
US20160220557A1 (en) * 2013-09-12 2016-08-04 Pfizer Inc. Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050100621A1 (en) * 2003-11-07 2005-05-12 Popp Karl F. Dermatological compositions
US20110269689A1 (en) * 2008-12-04 2011-11-03 Chongxi Yu High penetration compositions and their applications
US20130123231A1 (en) * 2011-11-11 2013-05-16 Nimbus Apollo, Inc. Acc inhibitors and uses thereof
US20160220557A1 (en) * 2013-09-12 2016-08-04 Pfizer Inc. Use of acetyl-coa carboxylase inhibitors for treating acne vulgaris

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10759812B2 (en) 2017-01-22 2020-09-01 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
JP7275444B2 (ja) 2018-06-05 2023-05-18 メッドシャイン ディスカバリー インコーポレイテッド チエノ［２，３－ｃ］ピリダジン－４（１Ｈ）－オン系誘導体及びその使用
CN112218871A (zh) * 2018-06-05 2021-01-12 南京明德新药研发有限公司 噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用
WO2019233443A1 (fr) * 2018-06-05 2019-12-12 南京明德新药研发有限公司 Dérivé thiéno[2,3-c]pyridazin-4(1h)-one et son application
US20210238190A1 (en) * 2018-06-05 2021-08-05 Medshine Discovery Inc. Thieno[2,3-c]pyridazin-4(1h)-one derivative and application thereof
JP2021525784A (ja) * 2018-06-05 2021-09-27 メッドシャイン ディスカバリー インコーポレイテッド チエノ［２，３−ｃ］ピリダジン−４（１Ｈ）−オン系誘導体及びその使用
US11680070B2 (en) * 2018-06-05 2023-06-20 Medshine Discovery Inc. Thieno[2,3-c]pyridazin-4(1H)-one derivative and application thereof
CN110950884A (zh) * 2018-09-27 2020-04-03 上海翰森生物医药科技有限公司 含二并环类衍生物抑制剂、其制备方法和应用
CN110950884B (zh) * 2018-09-27 2024-03-26 上海翰森生物医药科技有限公司 含二并环类衍生物抑制剂、其制备方法和应用
WO2021110135A1 (fr) * 2019-12-05 2021-06-10 漳州片仔癀药业股份有限公司 Forme cristalline en tant qu'inhibiteur d'acc1 et d'acc2, son procédé de préparation et son utilisation
CN114787166A (zh) * 2019-12-05 2022-07-22 漳州片仔癀药业股份有限公司 噻吩并[2,3-c]哒嗪-4(1H)-酮类化合物的晶型及其制备方法和应用
JP2022551014A (ja) * 2019-12-05 2022-12-06 ▲ザン▼州片仔▲ファン▼薬業股▲フン▼有限公司 Ａｃｃ１及びａｃｃ２阻害剤としての結晶形及びその製造方法並びに使用
US20230034132A1 (en) * 2019-12-05 2023-02-02 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. Crystal form as inhibitor of acc1 and acc2, and preparation method therefor and use thereof
US11578081B1 (en) 2019-12-05 2023-02-14 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. Crystal form as inhibitor of ACC1 and ACC2, and preparation method therefor and use thereof
JP7265681B2 (ja) 2019-12-05 2023-04-26 ▲ザン▼州片仔▲ファン▼薬業股▲フン▼有限公司 Ａｃｃ１及びａｃｃ２阻害剤としての結晶形及びその製造方法並びに使用
CN114746426A (zh) * 2019-12-05 2022-07-12 漳州片仔癀药业股份有限公司 作为acc1和acc2抑制剂的晶型及其制备方法和应用
US11673899B2 (en) 2019-12-05 2023-06-13 Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd. Crystal form of thieno[2,3-c]pyridazine-4(1H)-one compound, preparation method therefor and use thereof
CN114787166B (zh) * 2019-12-05 2023-09-19 漳州片仔癀药业股份有限公司 噻吩并[2,3-c]哒嗪-4(1H)-酮类化合物的晶型及其制备方法和应用
CN114746426B (zh) * 2019-12-05 2023-12-01 漳州片仔癀药业股份有限公司 作为acc1和acc2抑制剂的晶型及其制备方法和应用
WO2021110138A1 (fr) * 2019-12-05 2021-06-10 漳州片仔癀药业股份有限公司 Forme cristalline d'un composé thiéno[2,3-c]pyridazine-4(1h)-one, son procédé de préparation et son utilisation
WO2022138812A1 (fr) 2020-12-24 2022-06-30 モジュラス株式会社 Composé de tétrahydrothiénopyridinesulfonamide

Similar Documents

Publication Publication Date Title
WO2017147161A1 (fr) Traitement de troubles ou d'affections dermatologiques
AU2017348345B2 (en) ROR-gamma modulators
ES2691079T3 (es) Moduladores del receptor X hepático (LXR) para el tratamiento de enfermedades, trastornos y afecciones dérmicas
CA2971279C (fr) Synthese commercialement viable de la cantharidine et de derives bioactifs de la cantharidine
CA3185793A1 (fr) Composes d'isoquinoleine et leur utilisation dans le traitement d'un desequilibre du ahr
EP3750883B1 (fr) Composé aminoalkyle
ES2523037T3 (es) Ésteres de metronidazol para el tratamiento de la rosácea
CN105367438A (zh) AHU-377α-苯乙胺盐多晶型及其制备方法和应用
TW201811307A (zh) 2-(2-乙氧基-2-氧代乙基)(甲基)胺基-2-氧代乙基5-(十四烷氧基)呋喃-2-羧酸酯之皮膚調配物
CN110088108A (zh) 取代的吡唑并氮杂*-4-酮类及其作为磷酸二酯酶抑制剂的用途
US8796325B2 (en) Metronidazole esters for treating rosacea
US8802710B2 (en) Metronidazole esters for treating rosacea

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17757131

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17757131

Country of ref document: EP

Kind code of ref document: A1