WO2013067131A1 - Treatment methods - Google Patents

Treatment methods Download PDF

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Publication number
WO2013067131A1
WO2013067131A1 PCT/US2012/062980 US2012062980W WO2013067131A1 WO 2013067131 A1 WO2013067131 A1 WO 2013067131A1 US 2012062980 W US2012062980 W US 2012062980W WO 2013067131 A1 WO2013067131 A1 WO 2013067131A1
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Prior art keywords
alkyl
substituted
compound
formula
taken together
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PCT/US2012/062980
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French (fr)
Inventor
Andrew A. Protter
David T. Hung
Sarvajit Chakravarty
Sebastian Bernales
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Medivation Technologies, Inc.
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Publication of WO2013067131A1 publication Critical patent/WO2013067131A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • TECHNICAL FIELD The technical field is treatment of disorders or conditions involving androgen, estrogen, and/or progesterone receptors.
  • Alkyl refers to and includes saturated linear, branched, or cyclic hydrocarbon structures and combinations thereof. Particular alkyl groups are those having I to 12 carbon atoms (a “C1-C12 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “Ci-Cg alkyl”).
  • alkyl group having a specific number of carbons When an alkyl group having a specific number of carbons is named, ail geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, "butyl” is meant to include n-butyl, sec-butyl, /so-butyl, /en-butyl and cyclo butyl; "propyl” includes /i-propyl, /sopropyl and cyclopropyl. This term is exemplified by groups such as methyl, /-butyl, «-beptyl, octyl, cyclohexylmethyi, cyclopropyl and the like.
  • Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
  • a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • cycloalkyl has from 3 to 12 annular carbon atoms (a "C 3 -C 12 cycloalkyl").
  • cycloalkyl has from 3 to 7 annular carbon atoms (a "C3-O7 cycloalkyl").
  • "Alkynyl” refers to an unsaturated linear, branched, or cyclic hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and In some embodiments, having from 2 to 10 carbon atoms and more In some embodiments, 3 to 8 carbon atoms.
  • “Substituted alkyl” refers to an alkyi group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyi, acyloxy,
  • Substituted alkenyl refers to an alkenyl group having from 1 to 5 substituents
  • substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, amiiioacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino , aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alky], substituted or unsubstituted alkynyl, substituted or unsubstituted heterocvclyl, substituted or unsubstituted aralkyi, aminosulfonyl, sulfonylamino, sulfonyl, oxo,
  • Substituted aikynyl refers to an aikynyl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonvlaikoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioaikyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyi, aminosulfonyl, sulfonyl,
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
  • the aryl group contains from 6 to 14 annular carbon atoms.
  • Heteroaryl refers to an unsaturated aromatic carbocyclic group having from 2 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • a heteroaryl group may have a. single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indoiizinyl, benzothienyl).
  • Substituted aryl or “substituted arene” refers to an aryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carboiiylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioaikyl, substituted or unsubstituted alky] , substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyi, aminos
  • Substituted heteroaryl or “substituted heteroarene” refers to a heteroaryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted aikoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonyiamino,
  • Alkyl refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. In some embodiments, an aralkyl is connected to the parent structure via the alkyl moiety.
  • Alkenyl refers to a. residue in which an aryl moiety is attached to an alkenvl residue and wherein the aralkenyl group may be attached to the parent structure at either the aryl or the aikenyl residue.
  • an aralkenyl is connected to the parent structure via the alkenvl moiety
  • “Aralkynyl” refers to a residue in which an aryl moiety is attached to an alkynyl residue and wherein the aralkynyl group may be attached to the parent stmcture at either the aryl or the alkynyl residue.
  • an aralkynyl is connected to the parent structure via the alkynyl moiety.
  • Heteroaralkyl refers to a residue in which a.
  • heteroaryl moiety is attached to an alkyl residue and wherein the heroaralkyl group may be attached to the parent structure at either the heroaryl or the alkyl residue.
  • a heteroaralkyl is connected to the parent structure via the alkyl moiety.
  • Heterocycle refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen.
  • a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof.
  • Substituted heterocyclic or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryi, substituted aryl, heteroaryi, substituted heteroaryi, aryloxy, substituted aryloxy, cyano, halo, hydroxy 1, nitro, carboxyl, thiol, thioaikyL substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted araikyl, amino sulf
  • Halo or halogen refers to elements of the Group 17 series having atomic number 9 to 85.
  • halo groups include the radicals of fluorine, chlorine, bromine and iodine.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, tribaloaryl etc. refer to aryl and alkyl substituted, with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fiuorophenyl is within the scope of dihaloaryl.
  • haloalkenyl or “haloalkynyl” indicates an alkenyl or alkynyl moiety respectively in which at least one H is replaced with a halo group.
  • An alkyl group in which each H is replaced with a halo group is referred to as a "perhaloalkyl.”
  • a perhaloalkyl group is tri fluoro methyl (-C F 3 ) .
  • a “substituted” group similarly refers to a group which is substituted with from I. to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryi, heteroaryi, substituted heteroaryi, aryloxy, substituted aryloxy, cyano, halo, hydroxy!, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,
  • the compound is a substituted di-arylhydantoin or substituted di- arylfhiohydantoin compound.
  • Useful compounds and their syntheses are disclosed, for example, in WO 2010/1 18354.
  • the compound is a compound of Formula I:
  • W 3 is CN, N0 2 or S0 2 R 4 ;
  • W is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
  • Y and Y 1 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, aryl alken l, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyi, substituted cycloalkyl;
  • T is carbon or nitrogen and can be at any position in the ring;
  • ⁇ V is -C]-C 8 alkyl-NR a R b , 0- ⁇ V ⁇ ⁇ »ik> l- ⁇ in ⁇ " or -C(0)NR e R f , where:
  • R a is a C 2 -C 12 alkyl and R b is H or a C C ⁇ aLkyl or R a and R b are taken together with the N to which they are attached to form a. heterocyclic ring;
  • R° is a C f -Ci 2 alkyl and R e is H or a Ci-Cj 2 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
  • R e is a C 2 -Ci 2 alkyl and R 1 is H or a Cj-Coalkyl, or
  • R e is a CrCi 2 ,alkyl and R f is CrC ⁇ alkyl, or
  • R and R 1 are taken together with the N to which they are attached to form a heterocyclic ring;
  • R 2 is hydrogen, halogen, nitro, alky] and substituted alkyl
  • R 4 is independently H, alky] , or aryl.
  • W is CN, In some embodiments, W is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments, W 2 is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen. W In some embodiments, is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. W In some embodiments, is a substituted alkyl. In some embodiments, W 2 is substituted alkyl where the alkyl is substituted with a halogen.
  • W is a haloalkyl or perhaloalkyl. In some embodiments, W is a perhaloalkyl.
  • the perhaloalkyl In some embodiments, is a Ci-Cs perhaloalkyl, such as tribal omethyl. In some embodiments, W 2 is trifSuoromethyl. In some
  • W 1 is CN and W 2 is perhaloalkyl. In some embodiments, W 1 is CN and W 2 is CF 3 .
  • Y 1 and Y 2 are both a Ci-Cg alkyl.
  • Y ! and Y 2 are the same Ci-Cg alkyl, such as when both Y 1 and Y are methyl, ethyl, propyl or butyl.
  • Y 1 and Y ⁇ are both methyl or are taken together with the carbon to which they are attached to form a C4-C5 cycloalkyl .
  • Y ! and Y 2 are both methyl.
  • at least one of Y 1 and Y is alkyl where the alkyl is a cycloalkyl.
  • At least one of Y 5 and Y J' is substituted alkyl where the substituted alkyl is a substituted cycloalkyl.
  • one or both of Y ! and Y z are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen.
  • at least one of Y 3 and Y 2 is a haloalkyl, haloalkenyl or haioalkynyl.
  • both Y f and Y 2 are a haloalkyl, haloalkenyl or haioalkynyl.
  • Y 3 and Y 2 are taken together with the carbon to which they are attached to form a C4-C5 cyeloalkyl. In some embodiments, Y ! and Y are taken together to form a cyclobutyl moiety. In some embodiments, Y 3 and Y 2 are both methyl, W 3 is CN. In some embodiments, Y ! and Y are both methyl and W is a. perhaloalkyl such as CF 3 . In some embodiments, Y and Y are both methyl, W 1 is CN and W 2 is a perhaloalkyl such as CF 3 . ] In some embodiments, Z f and Z 2 are independently S or O.
  • Z 3 is S and Z 2 is O.
  • Z f and Z l are independently S or O and Y f and Y" are both a Ci -Cg alkyl.
  • Z 1 is S
  • Z z is O
  • Y 1 and Y z are the same C ⁇ - Cg alkyl.
  • Z 3 and Z 2 are independently S or O and Y 3 and Y 2 are both methyl or are taken together with the carbon to which they are attached to form a C4-C5 cyeloalkyl .
  • Z 1 is S
  • Z 2 is O and the compound is further defined by one or more of the following structural features: (i) Y 1 and Y ⁇ are both a Cj- Cg alkyl; (ii) W is CN; (iii) W 2 is perhaloalkyl.
  • Z 3 is S, Z 2 is O, Y 3 and Y 2 are the same Ci-Cg alkyl, W 1 is CN and W ⁇ is CF 3 .
  • T is C.
  • T is N.
  • a compound of formula (III) may be further defined by T being C.
  • a compound of formula (III) may be further defined by T being N.
  • T is N.
  • the compound may be further defined by T being C or by T being N.
  • R 3 is -Ci-Cg alkyl ⁇ NR d R b where R a is a C2-C12 alkyl and R b is H or a Ci ⁇ Ci2 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring.
  • the -Q-Cg alkyl moiety of -Ci ⁇ Cg alkyl- NR a R b is a -(CH 2 ) n moiety where n is an integer from. 1 to 8. In some embodiments, n is less than 4. In some embodiments, n is 1.
  • R e is a C2-C12 alkyl and R b is H.
  • R 3 is ethyl, propyl, butyl or pen yl and R b is H.
  • R d is a C 2 -C 8 alkyl and R b is H.
  • R a is a C3-C6 alkyl and R° is H.
  • R a is a C2-Q2 alkyl and R b is a Cj-Cj 2 alkyl.
  • R a is a C 3 -C 12 cycioalkyl and R b is a CrC 12 alkyl (e.g.., methyl).
  • R a and R b are independently a C 2 -C 8 alkyl.
  • R* and R b are the same C 2 -C 12 alkyl, e.g., when both R a and R b are ethyl.
  • R a and R b are independently a C 3 -C 6 alkyl.
  • R a and R b are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R a and R b are taken together to form a heterocyclic ring, the ring is a C4-C7 heterocyclic ring.
  • the heterocyclic ring formed by K ' , R b and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R a and R b are taken together with the N to which they are attached.
  • R a and R b are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R 1 is - -Cgalkyl-NRfc k
  • the Ci-Cg alkyl moiety of -Ci-Cg alkyl-NR a R b is a -(CH 2 ) n moiety where n is 1.
  • R 1 is -CH 2 R a R b where R a and R may be as defined herein.
  • R ! is:
  • the compound is further defined by any one or more of the following structural features: (i) W 1 is CN; (ii) W is perha!oalkyi (e.g., CF 3 ); (iii) Z ! is S; (II) 7 is O; (III) Y 1 and Y 2 are both methyl and (Illi) T is C,
  • R 3 is -O-Cj-Cs alky l-NR c R d where R c is a C1-C32 alkyl and R d is
  • the -Ci-Cg alkyl moiety of-O-Cj-Cs alkyl-NR R d is a -(CH 2 ) n moiety where n is an integer from 1 to 8.
  • n is less than 4. In some embodiments, n is 2. In some embodiments, " is a Ci-Ci 2 alkyl and R d is H.
  • R In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R° is H. In some embodiments, R° is a C-.-Cg alkyl and R d is H. in some embodiments, R c is a C 1 -C 4 alkyl and R d is H.
  • R° and R d are independently a d-C alkyl. in some of these embodiments R° and R d are the same Ct-Ci 2 alkyl, e.g., when both R c and R d are methyl. In some embodiments, R° and R d are independently a Cj-Cg alkyl. In some embodiments, R° and R d are independently a C 1 -C 4 alkyl. In some embodiments, R c and R d are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R c and R d are taken together to form a heterocyclic ring, the ring is a C 4 -C7 heterocyclic ring.
  • the heterocyclic ring formed by R ⁇ R d and the N to which they are attached contains only C and N as annular atoms.
  • the heterocvcle contains as annular atoms only C and the N provided when R c and R d are taken together with the N to which they are attached.
  • R c and R d are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R 1 is -O-Ci-Cg alkyl-NR c R d
  • the C 3 -C 3 alkyl moiety of-O-Ci-Cg alkyl-NR c R d is a -(CH 2 ) n moiety where n is 2.
  • R 3 In some embodiments, is -OCFbCF ⁇ NR ⁇ R: 3 where R c and R a may be as defined herein.
  • R 1 is:
  • the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W ri is perhaloalkyl (e.g. , CF 3 ); (iii) Z 1 is S; (II) Z 2 is O; (III) Y 1 and Y 2 are both methyl; (mi) R 2 is H, and (Illii) T is C.
  • R ! is -C(Q)NR R f
  • R e and R f are as defined in provisions (i) or (ii) or (iii): (i) R e is a C 2 -Ci 2 alkyl and R f is H or a C]-C] ?alkyl; (ii) R e is a CrC ⁇ alkyl and R 1 is C] -Cj?alkyl; or (iii) R c and R 1 are taken together with the N to which they are attached to form a heterocyclic ring.
  • R 1 is -C(0)NR e R f and R e is a C 2 -C 12 alkyl and R* is H or a Ci ⁇ Cj 2 alkyl .
  • R 1 is -C(0)NR e R I and R e is a Ci-C] 2 alkyl and R 1 is Ci ⁇ Cj 2 alkyI.
  • R 1 is
  • R e and R 1 are taken together with the N to which they are attached to form a heterocyclic ring.
  • R e is a C 2 -C 12 alkyl and R 1 is H.
  • R e is ethyl, propyl, butyl, pentyl or hexyl and R is H.
  • R e is a Cs-Cj 2 cycloalkyl (e.g., cyclopentyl) and R* is H.
  • R s is a C3-C 12 branched alkyl (e.g., ie/f-butyl) and R 1 is H.
  • R e is a C 2 -C8 alkyl and R f is H.
  • R e is a (V( ' . : , alkyl and R 1 is H.
  • K ⁇ is a C 2 -C 12 alkyl and R f is a C 1 -C 12 alkyl (e.g., where R e is ethyl and R f is methyl).
  • W and R ! are independently a C Ci 2 alkyl (e.g., where both R s and R f are methyl).
  • R e and R* are independently a C 2 -C 12 alkyl.
  • R s and R f are the same C 2 -C f 2 alkyl, e.g., when both R e and R f are ethyl.
  • R and R' are independently a C 2 - alkyl.
  • R e and R 1 are independently a C3-C6 alkyl.
  • at least one of R e and R f is a Cj-Ce cycloalkyl.
  • R e and R f are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R e and R* are taken together to form a heterocyclic ring, the ring is a C4-C7 heterocyclic ring.
  • the heterocyclic ring formed by R e , R 1 and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycie contains as annular atoms only C and the N provided when R e and R 1 are taken together with the N to which they are attached.
  • R e and R 1 are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R 3 is:
  • the compound is further defined by any one or more of the following structural features: (i) W 1 is CN; (ii) W ⁇ is perhaloalkyl (e.g., CF 3 ); (iii) Z ! is S; (I I) Z ⁇ is (); ⁇ : ⁇ ⁇ ) Y 1 and Y 2 are both methyl and (Illi) T is C. ]
  • R ⁇ is halo (e.g., F).
  • R" is H.
  • R 2 is halo when R* is -Ci-Cgalkyl-NR a R b or -C(0)NR e R f .
  • R 2 is H when R ! is -0-CrCsalkyl-NR L R d .
  • the compound is a compound of Formula I- A:
  • the compound is a compound of Formula I-B:
  • the compound is a compound of Formula I-C:
  • T, R 1 and R "? are as defined in formula ( ⁇ ) or any embodiment thereof.
  • the compound is a compound of Formula I-D:
  • the compound is a compound of Formula 1-E:
  • the compound is a compound of Formula I-F:
  • n is an integer from 1 to 8 and W 3 , W 2 , Z ! , Z ⁇ , Y , Y 1 , R a and R b are as defined in formula (I) or any embodiment thereof.
  • the compound is a compound of Formula I-G:
  • n is an integer from 1 to 8 and W , VV " , Z , Z y" , Y , Y , R c and R 1" are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula I-H:
  • W ⁇ W, Z ⁇ Z , Y " , Y , R e and ⁇ are as defined in formula (I) or any embodiment thereof.
  • the compound is a substituted phenylcarbamoyl alkylamino aren or an ⁇ , ⁇ '-bis-arylurea compound.
  • Other useful compounds and their syntheses are disclosed in WO 201 1 /044327.
  • a compound is a compound of Formula 11:
  • W 1 is CN, N0 2 or S0 2 R 4 ;
  • W ' is alkyl, substituted alkyl, aikenyi, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
  • Z is S, O or NR 5 ;
  • Y 5 and Y J' are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarailvvl, heterocyclyl, substituted heterocyclyl or Y ! and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycioalkyl;
  • T is carbon or nitrogen and can be at any position in the ring
  • R ! is -Ci-Cs alkyl-NR a R b , -0-C C 8 a!kyl-NR c R d or -C(0)NR e R f , where:
  • R a is a Ci-Ci 2 alkyl and R° is H or a Ci-C 12 alkyl or R a and R° are taken together with the N to which they are attached to form a heterocyclic ring;
  • R° is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R and R d are taken together with the N to which they are attached to form a heterocyclic ring;
  • R e is a C1-C12 alkyl and R f is H or a C1-C12 alkyl, or e and R 1 are taken together with the N to which they are attached to form a heterocyclic ring;
  • R 2 is hydrogen, halogen, nitro, alkyl or substituted alkyl; R ⁇ * is H, alkyl, substituted alkyl, aryl or substituted aryl; and is H, alkyl, substituted alkyl, aryl or substituted aryl.
  • the salt is a pharmaceutically acceptable salt.
  • the compound is of the formula (II) where W ! is CN.
  • W 2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl.
  • W z is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens.
  • W 2 In some embodiments, is a haioalkyl, haloalkenyl, haloalkynyl or perhaloalkyl, W 2 In some embodiments, is a substituted alkyl. In some embodiments, W 2 is substituted alkyl where the alkyl is substituted with one or more halogens. In some embodiments, W 2 is a haioalkyl or perhaloalkyl. In some embodiments, W 2 is a perhaloalkyl.
  • the perhaloalkyl in some embodiments, is a Cj-Cg perhaloalkyl, such as trihalomethyl.
  • W 2 is trif!uoromethyl.
  • W 1 is CN and W 2 is perhaloalkyl.
  • W ! is CN and W 2 is CF 3 .
  • Y 1 and Y are both a C t -Cg alkyl.
  • Y and Y 2 are the same Cj-Cg alkyl, such as when both Y 1 and Y z are methyl, ethyl, propyl or butyl.
  • Y 1 and Y" are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl.
  • Y 1 and Y ⁇ are both methyl.
  • one ofY ] or Y" is hydrogen and the other of Y 1 or Y 2 is C3 alkyl.
  • one of Y 1 or Y 2 is hydrogen and the other of Y ! or Y 2 is methyl, ethyl, propyl or butyl .
  • at, least one of Y 1 and Y is alkyl where the alkyl is a cycloalkyl.
  • at least, one of Y 1 and Y 2 is substituted alkyl where the substituted alky! is a substituted cycloalkyl.
  • one or both of Y 1 and Y are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens.
  • At least one of Y 1 and Y ⁇ is a haioalkyl, haloalkenyl or haloalkynyl.
  • both Y 3 and Y 2 are a haioalkyl, haloalkenyl or haloalkynyl.
  • Y 1 and Y are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl.
  • Y ! and Y are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl moiety.
  • Y 1 and Y" are both methyl and W 3 is CN.
  • Y 3 and Y are both methyl and W 2 is a perhaloalkyl such as CF 3 .
  • Y ! and Y are both methyl, W 1 is CN and W is a perhaloalkyi such as CF .
  • Y 3 is isopropyl, is H, W ! is CN and is a perhaloalkyi such as CF 3 .
  • Y and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl, W J is CN.
  • formula (II) Y !
  • Z is substituted N (e.g., NR. 5 ), S or O, In some embodiments, Z is O. In a particular , Z is S or O and Y J and Y" are both a C3 ⁇ 4-Cg alkyl. In some
  • Z is O and Y s and Y 2 are the same C f -C 8 alkyl.
  • Z is S or O and Y 1 and Y" 6 are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl.
  • Z is O and the compound is further defined by one or more of the following structural features: (i) Y 1 and Y" are both a Ci-Cg alkyl; (ii) W 3 is CN; (iii) W 2 is perhaloalkyi.
  • Z is O, Y 1 and Y z are the same Ci-Cg alkyl, W is CN and W 2 is CF 3 .
  • Z is O, Y 1 and Y" are each methyl, W 3 is CN and W 2 is CF .
  • the compounds of formula (II) are provided where Z is O and the compound is further defined by one or more of the following structural features: (i) Y 3 and Y are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W 3 is CN; (iii) W 2 is perhaloalkyi.
  • Z is O, Y 3 and Y 2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl, W is CN and W is CF .
  • Z is (), Y 1 and Y are taken together with the carbon to which they are attached to form a cyclopropyl, W 3 is CN and W 2 is CF 3 .
  • T is CI
  • T is N. It is understood that where applicable, a compound may be further defined by T being C. It is understood that where applicable, a compound may be further defined by T being N. For example, the embodiments described herein may in some cases be further defined by T being C or by T being N.
  • Compounds of formula (11) are provided where R !
  • n is -Ci-Cs alk l-NR a R b where R a is a C
  • the -Cj-Cg alkyl moiety of -C3 ⁇ 4-Cg alkyl-NR a R b is a -(CH 2 ) n moiety where n is an integer from I to 8, In some embodiments, n is less than 4. In some embodiments, n is 1. In some
  • R a is a C 1 -C 12 alkyl and R b is H.
  • R a In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R D is H.
  • R a is a Cj-Cg alkyl and R b is H, In some embodiments, R a is a C3-G5 alkyl and R° is H.
  • Compounds of formula (II) are also provided where R d is a C]-Cj 2 aikyl and R b is a Cj-Cj 2 alkyl.
  • R a is a C 3 -C 12 cycloalkyl and R b is a C C 12 aikyl (e.g., methyl).
  • R a and R b are independently a Ci-Cg alkyl.
  • R a and R b are the same C1-C12 alkyl, e.g., when both R a and R b are ethyl.
  • R a and R° are independently a C 3 -C6 alkyl.
  • R d and R b are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R d and R 'J are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered. heterocyclic ring.
  • the heterocyclic ring formed by R a , R° and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R a and R b are taken together with the N to which they are attached.
  • R a and R b are taken together with the N to which they are attached to form a pyrroiidinyl or piperidinyl ring.
  • R 1 is - Ci-Cg alkyl-NR a R
  • the C C 8 alkyl moiety of -C C 8 aikyl-NR a R b is a moiety where n is 1.
  • I is -CH 2 NR a R° where R a and R° may be as defined herein.
  • R 1 is:
  • the compound is further defined by any one or more of the following structural features: (i) W ! is CN; (ii) W 2 is perhaloalkyl (e.g., CFi); (iii) Z is O: (II) ⁇ ' and Y 2 are both methyl and (III) T is C.
  • the compound is further defined by any one or more of the following structural features: (i) W 3 ⁇ 4 is CN; (ii) W 2 is perhaloalkyl (e.g., CF 3 ); (iii) Z is O; (II) Y 3 ⁇ 4 and Y 2 are both methyl, (III) R" is halogen (e.g. , F) and (Illi) T is C.
  • R ! is -O-Ct-Cg alkyl- NR ; R d where R c is a Cj-Cj 2 alkyl and R d is H or a C3 ⁇ 4-C3 ⁇ 4 ? alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring.
  • the -C j-Cs alkyl moiety of -O-Ci-Cs a.lkyl-NR c R d is a -(CH 2 ) n moiety where n is an integer from 1 to 8. In some embodiments, n is less than 4. In some embodiments, n is 2.
  • W is a Cj-Cj ? . alkyl and R d is H.
  • R c In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R d is H.
  • R c is a Cj-Cg alkyl and R° is H
  • R c is a C 1 -C4 alkyl and R d is H.
  • Compounds of formula (II) are also provided where L and R d are independently a Cj-Cj ? alkyl. In some embodiments, R° and R d are the same Cj-Cj ? alkyl, e.g.
  • R c and R d are independently a Cj-Cg alkyl. In some embodiments, R c and R d are independently a C 1 -C4 alkyl. In still some embodiments R c and R d are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when R and R d are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring.
  • the heterocyclic ring formed by R ⁇ R d and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R" and R d are taken together with the N to which they are attached.
  • R° and R d are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R ! is -O-Cj-Cs alkyl-NR°R d
  • the Cj-C 8 alkyl moiety of-O-Cj-Cg alkyl- NR c R is a -(CH 2 ) n moiety where n is 2.
  • R ! In some embodiments, is - OCH 2 CH 2 NR c R d where R c and R d may be as defined herein.
  • R is:
  • the compound is further defined by any one or more of the following structural features: (i) W ! is CN; (if) W is perhaloalkyl (e.g., CF 3 ); (iii) Z is O;
  • R 3 is -C(0)NR " R f where R e and R f are as defined in provisions (i) or (ii) or (iii) or (II): (i) R e and R 1 are independently H or a ( ' ⁇ ⁇ -( ⁇ alkyl; (ii) R e is a Ci ⁇ C
  • R 1 is -C(0)NR " R f and R e and R f are
  • R 1 is -C(0)NR " R f and R e is a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl.
  • R 1 is -C(0)NR e R f and R e is a Ci-Cj 2 alkyl and R' is C 1 -C 12 alkyl.
  • R f is -C(0)NR e R' and R e and R f are taken together with the N to which they are attached to form a heterocyclic ring.
  • R e is a C 1 -C 12 alkyl and R 1 is H.
  • R e is methyl, ethyl, propyl, butyl, pentyl or hexyl and R f is H.
  • R e is a C3-C 12 cycloalkyl (e.g., cyclopentyl) and R 1 is H.
  • K ⁇ is a C 3 -C 12 branched alkyl (e.g., ieri-butyi) and R f is H.
  • R e is a Ci-Cg alkyl and R* is H (e.g., where R is methyl and R 1 is H).
  • R e is a C 3 -C 6 alkyl and R 1 is H (e.g., where R e is propyl or butyl and R f is H). In some embodiments, R e is a C 1 -C 12 alkyl and R f is a C 3 ⁇ 4 -C] ? alkyl (e.g., where R e is ethyl and R 1 is methyl). In some embodiments, R e and R f are independently a C]-Ci 2 alky] (e.g., where both R and R f are methyl). In some embodiments, R e and R f are independently a alkyl.
  • R and R' are the same C 1 -C 12 alkyl, e.g., when both R e and R f are ethyl. In some embodiments, R and R' are independently a Cj-C alkyl. In some embodiments, R fc and R 1 are independently a C3-C6 alkyl. In some embodiments, at least one of R e and R 1 is a C3-C6 cycloalkyl. In still some embodiments R e and R 1 are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R e and R* are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring.
  • the heterocyclic ring formed by R e , R ! and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R e and R f are taken together with the N to which they are attached.
  • K ⁇ and R f are taken together with the N to which they are attached to form a pyrroiidinyl or piperidinyl ring.
  • R 3 ⁇ 4 is:
  • the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W is perhaloalkyl (e.g., CF 3 ); (iii) Z is O; (II) Y 1 and are both methyl and (Illi) T is C.
  • R 1 is as defined above and the compound is further defined by any one or more of the following structural features: (i) W !
  • W 2 is perhaloalkyl (e.g., CF 3 );
  • Z is O;
  • Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl and (l l li) T is C.
  • R 2 is halo (e.g., F).
  • R 2 is H.
  • R 2 is halo when R 1 is -Ci-Cg alky1-NR a R b or -C(0)NR e R f .
  • R 2 is H when R 1 is ( )-(>( alkyl-NR c R d .
  • the compound is a compound of Formula II- A:
  • the compound is a compound of Formula II ⁇ B:
  • T, R and R z are as defined in formula ( ⁇ ) or anv embodiment thereof.
  • the compound is a compound of Formula II-C:
  • T, R and " are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula II ⁇ D;
  • R and R are as defined in formula (II) or any embodiment thereof
  • the compound is a compound of Formula II ⁇ E:
  • R is as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula II-F:
  • n is an integer from 5 to 8 and R a and R° are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula II-G:
  • n is an integer from 1 to 8 and R and R are as defined in formula (II) or any embodiment thereof,
  • the compound is a compound of Formula II-H:
  • n is an integer from 1 to 8 and R c and R are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula II-J:
  • n 0 to 3
  • R fc and R 1 are as defined in formula (IT) or any embodiment thereof.
  • Y ' is thiocarboxyl, carboxyl, aminocarbonyi, N-alkyl aminocarbonyi, N,N-dia.lkyl
  • Y ⁇ is carboxyl.
  • Y J is aikoxy carbonyl.
  • Y° is aminocarbonyi.
  • the compound is a compound of Formula ⁇ :
  • W J isCN,N0 2 or S0 2 R 4 ;
  • W ' is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
  • Z is S, G or NR 5 ;
  • Y f and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryialkyl, aryialkenyl, arylalkynyl, heteroaralkyl, heterocyciyl, substituted heterocyciyl or Y ! and Y" are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
  • Y 3 is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, aryialkyl carbonyl, aryialkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyciyl carbonyl, substituted heterocyciyl carbonyl, cyano, ammocarbonyl, N-alkyl aminocarbonyl, N,N- di alkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N ⁇ bis ⁇ substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl
  • heteroaryl carbonyl substituted heteroaryl carbonyl, aryialkyl carbonyl, aryialkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyciyl carbonyl, substituted heterocyciyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyi
  • aminocarbonyl N-substituted alkyl aminocarbonyl, NN-bis-suhstituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;
  • T is carbon or nitrogen and can be at any position in the ring;
  • R 1 is hydrogen, -Ci-Cg alkyl-NR a R b , -0-C]-C 8 alkyl-NR c R d , -C(0) R e R f or -NR s R h , where:
  • R a is a C1-C12 alkyl and R b is H or a Cj-Q ? alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
  • R c is a C3 ⁇ 4-Ci? alkyl and R d is H or a C ⁇ -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
  • R e is H or a C3 ⁇ 4-Ci? alkyl and R f is H or a Ci-C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
  • R s is H or a Q-C12 alkyl and R u is H or a Ci-Ci2 alkyl, or R g and R h are taken together with the N to which they are attached to form a heterocyclic ring;
  • R 2 is hydrogen, halogen, nitro, alky! or substituted alkyl
  • R 4 is H, alkyl, substituted alkyl, aryl or substituted aryl;
  • R 5 is H, alkyl, substituted alkyl, aryl or substituted aryl.
  • the compo und is of the formula ⁇ I I I ⁇ where T is nitrogen when R 4 and R J are both hydrogen.
  • the compo und is of the formula ⁇ I I I ) where W 1 is CN.
  • W is hydrogen, alkyl, substituted alkyl, alkenvl, substituted alkenyl, aikynyl or substituted aikynyl.
  • W ⁇ is substituted alkyl, substituted alkenyl or substituted aikynyl where the alkyl, alkenyl or aikynyl is substituted with one or more halogens.
  • W J' In some embodiments, is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl.
  • w' In some embodiments, is a substituted alkyl.
  • W is substituted alky] where the alkyl is substituted with one or more halogens.
  • W is a haloalkyl or perhaloalkyl.
  • W 2 is a perhaloalkyl.
  • the perhaloalkyl in some embodiments, is a Ci-Cs perhaloalkyl, such as trihalomethyl. In some embodiments, is trifluoromefhyl. n a particular , W 3 is CN and W z is perhaloalkyl. In another particular , W 3 is CN and W 2 is CF 3 . In some embodiments, W is hydrogen. In a particular , W* is CN and W 2 is hydrogen.
  • Y ' and Y 2 are both a Ct-Cs aikyl.
  • Y 1 and Y 2 are the same Ci-Cs aikyl, such as when both Y ! and Y z are methyl, ethyl, propyl or butyl.
  • ⁇ ⁇ and Y ⁇ are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloaikyl.
  • the compounds of formula (III) are provided where Y 3 and Y 2 are both methyl.
  • the compounds of formula (III) are provided where one of Y J or Y 2 is hydrogen and the other of Y 3 or Y 2 is Cj-Cg aikyl. In some embodiments, one of Y 1 or Y 2 is hydrogen and the other of Y 3 or Y 2 is methyl, ethyl, propyl or butyl. In some embodiments, the compounds of formula (III) are provided where at least one of Y 1 and Y 2 is aikyl where the aikyl is a cycloaikyl.
  • the compounds of formula (III) are provided where at least one of Y 1 and Y" is substituted aikyl where the substituted aikyl is a substituted cycloaikyl. In some embodiments, the compounds of formula (III) are provided where one or both of Y 1 and Y 2 are substituted alky] , substituted alkenyl or substituted alkynyl where the aikyl, alkenyl or alkynyl is substituted with one or more halogens. In some embodiments, at, least one of Y 3 and Y 2 is a haloalkyl, haloalkenyl or haioa!kynyl .
  • both Y 1 and Y are a haloalkyl, haloalkenyl or haloalkynyl.
  • the compounds of formula (III) are provided where Y 3 and Y 2 are taken together with the carbon to which they are attached to form a C3-C5 cycloaikyl.
  • Y 1 and Y' are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyi or cyclopentyi moiety.
  • Y 3 and Y are both methyl
  • W 1 is CN.
  • Y 3 and Y' are both methyl and W is a perhaloalkyl such as CF 3 .
  • Y and Y " are both methyl, W is CN and W ' is a perhaloalkyl such as CF 3 .
  • Y 1 is isopropyl
  • Y J is H
  • W 3 is CN
  • W 2 is a perhaloalkyl such as CF 3 .
  • Y 3 and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl
  • W 3 is CN.
  • Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl and W z is a perhaloalkyl such as CF 3 .
  • W ! and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl, W ! is CN and W "' is a perhaloalkyl such as CF 3 .
  • Y J is carboxyl, carbonyl or derivative thereof, such as carboxyl, formyl, alkyi carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl.
  • Y 3 is thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyi thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, ⁇ , ⁇ -dialkyl thio carbamyl,
  • Y J is thiocarboxyl or carboxyl.
  • Y 3 is carboxyl.
  • Y 3 is arnmoearbonyl, N-alkyl aminocarbonyl, ⁇ , ⁇ -dialkyl
  • Y 3 is aminocarbonyl.
  • Y 3 is formyl, alkyl carbonyl or alkoxy carbonyl. In a particular , Y 3 is alkoxycarhonyl.
  • Y 3 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
  • the compounds of formula (SIS) are provided where Z is substituted N (e.g., NR J ), S or O. In some embodiments, Z is O. In some embodiments, Z is S, In a particular , Z is S or O and Y ! and Y 2 are both a Q-Cg alkyl. In some embodiments, Z is S or O and Y 3 and Y "6 are the same Ci-Cg alkyl. In some embodiments, Z is S or O and Y ! and Y z are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl.
  • Z is substituted N (e.g., NR J ), S or O. In some embodiments, Z is O. In some embodiments, Z is S, In a particular , Z is S or O and Y ! and Y 2 are both a Q-Cg alkyl. In some embodiments, Z is S or O and Y 3 and Y "6 are
  • the compounds of formula. (Ill) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y 3 ⁇ 4 and Y 2 are both a Ci-Cg alkyl; (ii) W ! is CN; (iii) W z is perhaloalkyl.
  • Z is S, Y f and Y" are the same Cj-Cg alkyl, W 3 is CN and W ' is CF .
  • Z is S, Y 1 and Y 2 are each methyl, W 3 is CN and W * is CF 3 .
  • Z is S, Y and Y' are each methyl, Y is carboxyl, W 1 is CN and W 2 is CF : 3 ⁇ 4.
  • the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y ⁇ 3 and Y 2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W ! is CN; (iii) W 2 is perhaloalkyl, (II) Y 3 is carboxyl.
  • Z is S, Y 1 and Y" are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl, W 1 is CN and W 2 is CF 3 .
  • Z is O, Y * and Y are taken together with the carbon to which they are attached to form a cyclopropyl, Y 3 is carboxyl, W 1 is CN and W is CF 3 .
  • the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y ⁇ 3 and Y 2 are both a Ci-Cg alkyl; (ii) W 1 is CN; (iii) W 2 is perhaloalkyl; (II) Y 3 is selected from the group consisting of thiocarboxvl, aminocarbonyl, N-alkyl aminocarbonyl, N,N- dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxycarbonyl. In one particular such embodiment Y J is alkoxycarbonyl or aminocarbonyl. In one particular such embodiment
  • Z is S, Y * and Y 2 are each methyl, Y 3 is alkoxycarbonyl or aminocarbonyl, W is CN and w' is CF 3 .
  • the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y ' and Y ' are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W ! is CN; (iii) W z is perhaioalkyl, (II) Y is alkoxycarbonyl or aminocarbonyl.
  • Z is S, Y !
  • Y 1 and Y 2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl
  • W 1 is CN and W "' is CF 3
  • Z is O
  • Y 1 and Y" 6 are taken together with the carbon to which they are attached to form a. cyclopropyl
  • Y 3 is alkoxycarbonyl or aminocarbonyl
  • W* is CN and W 2 is CF 3 .
  • T is C. In some embodiments, T is N. It is understood that where applicable, any embodiment may In some embodiments, be further defined by T being C. It is understood that where applicable, any embodiment may In some embodiments, be further defined by T being N. For example, the embodiments described herein may In some embodiments, be further defined by T being C, Additionally, it is understood that the embodiments described herein may In some embodiments, be further defined by T being N.
  • R 1 is -Ci-Cg alkyl-NR a R b where R a is a Ci-C3 ⁇ 4 2 alkyl and R b is H or a C3 ⁇ 4-C]? alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ⁇ C3 ⁇ 4-Cg alkyl moiety of -Cj-Cs alkyl-NR a R b is a (Ci I ⁇ ) ⁇ . ⁇ . moiety where n is an integer from 1 to 8. In some embodiments, n is less than 4, In some embodiments, n is 1. In some
  • R a is a C1-C12 alkyl and R° is H.
  • R a In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R b is H.
  • R a is a . ⁇ ( alky] and R b is H.
  • R e is a C 3 -C6 alkyl and R° is H.
  • Compounds of formula (III) are also provided where R a is a C 1 -C 12 alkyl and R b is a Ci-Ci 2 alkyl.
  • R d is a C 3 -C 12 cycloalkyl and R° is a Ci-C 12 alkyl (e.g., methyl).
  • R a and R are independently a Ci-Cg alkyl.
  • R a and R are the same C 1 -C 12 alkyl, e.g., when both R a and R° are ethyl.
  • and R b are independently a C 3 -C 6 alkyl.
  • R a and R are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring when R a and R b are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring.
  • the heterocyclic ring formed by R a , R and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R a and D are taken together with the N to which they are attached.
  • R a and R b are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R 1 is -Ci-Cg alkyl ⁇ NR a R b
  • the Cj-Cg aikyl moiety of -d-d aikyl-NR a R b is a -(03 ⁇ 4) ⁇ moiety where n is 1.
  • R f In some embodiments, is -CH2,NR a R b where R a and R b may be as defined herein.
  • R J is:
  • the compound is further defined by any one or more of the following structural features: (i) W 1 is CN; (ii) W 2 is perhaloalkyl (e.g., CF 3 ); (iii) Z is S; (IS) Y 1 and Y " are both methyl and (III) T is C.
  • IV is as defined above and the compound is further defined by any one or more of the following structural features: (i) W !
  • W 2 is perhaloalkyl (e.g., CF 3 );
  • Z is S;
  • Y f and Y 2 are both methyl,
  • R 2 is halogen (e.g., F) and
  • Mi) T is C.
  • R 3 is -O-d-Cs aikyl-NR c R d where R c is a d-C 12 alkvl and R d is H or a C1-C12 alkyl or R° and R d are taken together with the N to which they are attached to form a heterocyclic ring.
  • the -C-. -Cg alkyl moiety of -O-d-Cs aikyl-NR R d is a --((3 ⁇ 4>) ⁇ moiet where n is an integer from 1 to 8.
  • n is less than 4. In some embodiments, n is 2. In some embodiments, R° is a d-d? alkyl and R d is H.
  • R c In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R d is H. In some embodiments, R c is a d-C 8 alkyl and R d is H. In some embodiments, R' is a d -C 4 alkyl and R d is H.
  • Compounds of formula (III) are also provided where R c and R d are independently a d-C 12 alkyl. In some
  • R c and R d are the same d-Ci 2 alkyl, e.g. , when both R c and R d are methyl.
  • R L and R d are independently a Cj-Cs alkyl.
  • R c and R d are independently a d- alkyl.
  • R L and R d are taken together with the N to which they are attached to form a heterocyclic ring.
  • the ring is a 4- to 7-membered heterocyclic ring.
  • the heterocyclic ring formed by R' ⁇ R d and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R c and R d are taken together with the N to which they are attached.
  • R c and R° are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
  • R 1 is -G-Cj -Cg alkyl-NR c R a
  • the Cj-Cg alkyl moiety of -O-Ci-Cs alkyl- NR c R d is a -(03 ⁇ 4) ⁇ moiety where n is 2.
  • R 1 is - OCH 2 CH 2 R c R a where R c and R d may be as defined herein.
  • R 1 is:
  • the compound is further defined by any one or more of the following structural features: (i) W is CN: (ii) W 2 is perhaloalkyl (e.g., CFj); (iii) Z is S;
  • Y 1 and Y 2 are both methyl: (III) R 2 is H, and (Illi) T is C.
  • R 1 is -C(0)NR s R f where R e and R f are as defined in provisions (i) or (ii) or (iii) or (II): (i) R e and R 1 are independently H or a Ci-C 12 alkyl: (ii) R c is a Cj- Cj 2 alkyl and R f is H or a C]-Cj 2 alkyl; (iii) R e is a C3 ⁇ 4-C]? alkyl and R* is C]-Cj 2 alkyl; or ) R e and R f are taken together with the N to which they are attached to form a.
  • the compound is of the formula (III) where R ! is - ⁇ (0) ⁇ 3 ⁇ 43 ⁇ 4* and R e and R* are independently H or a C 3 ⁇ 4 -C] 2 alkyl .
  • the compound is of the formula (III) where R 1 is -C(0)NR e R ! and R e is a C i ⁇ Ci 2 alkyl and iV is II or a Ci-C !2 alkyl.
  • the compound is of the formula (III) where R 1 is -C(0)NR s R f and R e is a C3-C12 alkyl and R' is C 1 -C 12 alkyl.
  • the compound is of the formula (III) where R ! is -C(0) R e R* and R s and R are taken together with the N to which they are attached to form a heterocyclic ring.
  • R fc is a Q-C 12 alkyl and R 1 is H.
  • R e In some embodiments,
  • R e is methyl, ethyl, propyl, butyl, pentyl or hexyl and R 1 is H.
  • R e is a C- ? -C 12 cycloalkyl (e.g., cyciopentyl) and R l is H.
  • R ⁇ is a ( ' : ⁇ ( " ⁇ . - branched alkyl (e.g., tert-bu yi) and R f is H.
  • R e is a C-.-Cg alkyl and R* is H (e.g., where R s is methyl and R' is H).
  • R e is a C Ce alkyl and R 1 is H (e.g., where R e is propyl or butyl and R f is H).
  • R e is a C3 ⁇ 4 -Cj ? alkyl and R* is a Cj-Cj 2 alkyl (e.g., where R e is ethyl and R 1 is methyl).
  • Compounds of formula (III) are also provided where R e and R f are independently a Ci-C3 ⁇ 42 alkyl (e.g., where both R e and R* are methyl).
  • the compounds of formula (III) are provided where R e and R 1 are independently a C3 ⁇ 4 -Cj ?
  • R e and R 1 are the same Cj -Cj 2 alkyl, e.g. , when both R e and R f are ethyl .
  • R e and R 1 are independently a Cj-Cg alkyl.
  • R e and R f are independently a Cj-Ce alkyl.
  • at least one of R e and R 1 is a C3-C6 cycloalkyl .
  • R e and R* are taken together with the N to which they are attached to form, a heterocyclic ring.
  • the ring when R e and R 1 are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring.
  • the heterocyclic ring formed by R e , R 1 and the N to which they are attached contains only C and N as annular atoms.
  • the heterocycle contains as annular atoms only C and the N provided when R e and R f are taken together with the N to which they are attached.
  • R e and R f are taken together with the N to which they are attached to form a yrrolidinyl or piperidinyl ring.
  • R 1 is:
  • the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W " is perhaloalkyl (e.g., CF 3 ) or hydrogen; (iii) Z is S; (Ii) Y 5 and ⁇ are both methyl and (Illi) T is C. In some embodiments, R !
  • W 1 is CN;
  • W 2 is perhaloalkyl (e.g., CF 3 ) or hydrogen;
  • Z is S;
  • Y 5 and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl and
  • (llli) T is C.
  • R 2 is halo (e.g., F).
  • R 2 is H.
  • R 2 is halo when R 1 is -Ci-Cs alkyl-NR a R or -C(0)NR e R f .
  • R 2 is H when R 1 is -O-Ci-Cg alkyl-NR c R d .
  • Y ' is thiocarboxyl, carboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxy carbonyl.
  • Y " ' is carboxyl.
  • Y ' is alkoxycarbonyl.
  • Y 3 is aminocarbonyl.
  • the compound is a compound of Formula III ⁇ A
  • the compound is a compound of Formula III-B:
  • W 1 , W 2 , Y ' T, R 1 and R" are as defined in formula (II) or any embodiment thereof.
  • the compound is a compo und of Formula III-C:
  • the compound is a compound of Formula III-
  • the compound is a compound of Formula III-E:
  • the compound is a compound of Formula III-F:
  • n is an integer from 5 to 8 and Y R d and R b are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula III-G:
  • n is an integer from 1 to 8 and Y J , R c and R d are as defined in formula (I ) or any embodiment thereof.
  • the compound is a compound of Formula III-H:
  • the compound is a compound of Formula III- J:
  • n 0 to 3
  • Y 0 to 3
  • R e and R are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula 111- :
  • the compound is a compound of Formula III ⁇ L:
  • n is 0 to 3
  • Y Y "' , Y J , R e and R f are as defined in formula (II) or any embodiment thereof.
  • the compound is a compound of Formula III-M:
  • the compound is an antagonist of an androgen, progesterone, and/or estrogen receptor.
  • Compounds include, but are not limited to, Bicalutamide (e.g., CASODEX ® ), Cyproterone Acetate ⁇ e.g., ANDROCUR ® , CYPROSTAT ® ,
  • CYPROTERON ® PROCUR ® , CYPRONE ® , CYPROI IHXA! .
  • Dienogest e.g., VIS ANNE ®
  • Flutamide e.g., EULEXIN*
  • Galeterone TOK-001
  • Nilutamide e.g.,
  • NILANDRON ® Spironolactone
  • ALDACTONE ® Abiraterone
  • ZYTIGA* radium-223 chloride e.g., ALPH ARADI ®
  • TA 700 OGX 1 1 1 1
  • Cabozantinib e.g. , SPRYCEL ®
  • an mTOR inhibitor e.g., Everolimus,
  • Ridaforolimus, Rapamycin, Temsirolimus an HDAC inhibitor
  • an HDAC inhibitor e.g., Vorinostat, CI- 994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXDI OI
  • Sipuleucel-T e.g., PROVENGE "
  • Fulvestrant e.g., FASLODEX "'
  • Tamoxifen Raloxifene
  • Raloxifene Raloxifene
  • Toremifene an HDAC inhibitor
  • HDAC inhibitor e.g., Vorinostat, CI- 994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXDI OI
  • Sipuleucel-T e.g., PROVENGE "
  • Fulvestrant e.g., FASLODEX "'
  • Salts Salts of compounds described above can be used in the disclosed methods. If a compound has, for example, at least one basic center, it can form an acid addition salt. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohaiic acid, with strong organic carboxylic acids, such as alkanecarboxyiic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxy carboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such
  • Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine.
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts
  • salts with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, ter
  • Corresponding internal salts can furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds or their pharmaceutically acceptable salts, are also included.
  • salts of compounds which contain a basic group include monohydroch!oride, hydrogensulfate, methanesulfonate, phosphate or nitrate, in some embodiments, salts of compounds which contain an acid group include sodium, potassium and magnesium salts and
  • the salts are pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salts.
  • Pharmaceutically acceptable salts retain at least some of the biological activity of the free (non-salt ) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum, hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et ah , Pharmaceutical Salts, J. Pharm. Sci. 1977
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing
  • Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical 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.
  • Treating is an approach for obtaining a beneficial or desired result, including, but not limited to, relief from a symptom, lessening of a symptom, and preventing a worsening of a symptom associated with the disease being treated.
  • treatment also includes, but is not limited to, any one or more of enhancing survival time, enhancing progression-free survival time, and reducing tumor size.
  • disorders that can be treated include, but are not limited to:
  • neurodegenerative disorders including, but not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, hereditary spastic paraparesis, spinocerebellar atrophies, Friedreich's ataxia, amyloidosis, metabolic disease-related neurodegeneration, toxin-related neurodegeneration, multiple sclerosis, Charcot Marie Tooth syndrome;
  • cancer including, but not limited to, prostate cancer, bladder cancer, non- Hodgkin lymphoma, leukemia., thyroid cancer, breast cancer, ovarian cancer, glioblastoma, neuroblastoma, renal cancer, Wilms' tumor
  • nephroblastoma retinoblastoma
  • pancreatic cancer endometrial cancer
  • hepatocellular carcinoma desmoplastic small-round-cell tumor
  • colorectal cancer esophageal cancer
  • head and neck cancer esophageal cancer
  • lung cancer melanoma
  • systemic hyperandrogenism seborrhea, hirsuitism, precocious puberty, polycystic ovary syndrome, acne, alopecia, benign prostatic hyperplasia, intrauterine fibroids, endometriosis, glaucoma, meningiomas, Kennedy's disease (KD) or X-linked spinal and bulbar muscular atrophy.
  • disclosed compounds can be used for medical termination of intrauterine pregnancies .
  • disclosed compounds can be used as adjuvants to vaccines.
  • Yersinia enterocolitica Yersinia pseudotuberculosis, Mycobacterium tuberculosis, Legionella pneumophila, Rickettsia, E. coli, Vibrio cholera, Salmonella typhi.
  • Microsporum gypsum Microsporum nanum, Trichophyton concentricum, Trichophyton equinum, Trichophyton gallinae, Trichophyton gypseum, Trichophyton megnini, Trichophyton mentagrophytes , Trichophyton quinckeanum. Trichophyton riibrum, Trichophyton schoenleinii, Trichophyton tonsurans. Trichophyton verrucosum, T.
  • Compounds can be formulated in any type of pharmaceutical composition known in the art, including, but not limited to, tablets, troches, pills, capsules, syrups, elixirs, injectable solutions, and the like.
  • a pharmaceutical composition typically includes a pharmaceutically or
  • pharmacologically acceptable excipient or carrier a material that is not biologically or otherwise undesirable, e.g. , the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable carriers or excipients have met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound as an acti ve ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Binders include, e.g., carbomers, povidone, xanthan gum, etc.
  • coatings include, e.g. , cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.;
  • Tablets, troches, pills, capsules, and the like can also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fractose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • V arious other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosa ge form.
  • tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • a diarylhydantoin compound can be incorporated into sustained-release preparations and devices.
  • a compound can be incorporated into time release capsules, time release tablets, and time release pills.
  • compositions suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising a compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form typically is sterile, fluid, and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents are included, for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating a compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • methods of preparation include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticles or microparticles.
  • Useful liquid carriers include water, alcohols or glycols or water/a] cohol/glycol blends, in which a compound can be dissolved or dispersed at effective le vels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • useful dermatologicai compositions which can be used to deliver a compound to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,(508,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • the pharmaceutical composition is a unit dosage form.
  • unit dosage form is a physically discrete unit containing a predetermined quantity of active. Dosages
  • an effective amount intends such amount of a compound which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, i.e., a single close or multiple closes may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • Useful dosages of compounds can be determined by comparing their in vitro activity and/or in vivo acti vity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949,
  • the concentration of a compound in a liquid composition can be from about 0.1-25% by weight, or from about 0.5- 10% by weight.
  • the concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1-5% by weight, or about 0.5-2.5% by weight.
  • the amount of a compound required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • Effective dosages and routes of administration of compounds are conventional.
  • the exact amount (effective dose) of the agent will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like,
  • a therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art. See, e.g.. The Pharmacological Basis of Therapeutics, Goodman and Oilman, eds,, Macmillan Publishing Co., New York.
  • an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model can also be used to determine the appropriate concentration ranges and routes of administration.
  • a therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents.
  • the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years.
  • a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight of the recipient per day.
  • a suitable dose can be about, 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day.
  • a compound is conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of active ingredient per unit dosage form.
  • a compound can be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 ⁇ , about 1 to 50 ⁇ , about 2 to about 30 uM, or about 5 to about 25 ⁇ .
  • Exemplar ⁇ ' desirable plasma concentrations include at least or no more than 0.25, 0.5, 5 , 5, 10, 25, 50, 75, 100 or 200 uM.
  • plasma levels can be from about 1 to 500 micromolar or from about 10 to about 25 micrornolar.
  • Desirable blood levels can be maintained by continuous infusion to provide about 0.00005-5 mg per kg body weight per hour, for example at least or no more than 0.00005, 0.0005, 0.005, 0.05, 0.5, or 5 mg/kg/hr.
  • such levels can be obtained by intermittent infusions containing about 0.0002-20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0,02, 0.2, 2, 20, or 50 mg of a compound per kg of body weight.
  • a compound can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself can be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
  • a compound can be administered using pharmaceutical compositions comprising a therapeutically effec tive amount of the compound and a pharmaceutically acceptable carrier or diluent, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperito eally, or parenteral ly, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue.
  • a compound can be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation.
  • a compound can be combined with one or more excipients and used in the form of an ingestible tablet, a buccal tablet, troche, capsule, elixir, suspension, syrup, wafer, and the like.
  • a compound can be combined with a fine inert powdered carrier and inhaled by the subject or insufflated. In some embodiments, such compositions and preparations contain at least 0.1%
  • diarylhydantoin or hydantoin compound can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of a given unit dosage form.
  • the amount of diarylhydantoin or hydantoin compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • a compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of a compound can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetm, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
  • Combination Therapies In some embodiments, combinations of one or more compounds are used.
  • “combination” compounds includes one or more compounds administered substantially simultaneously, whether or not in the same pharmaceutical composition, or sequentially, compounds can, but need not be, chemically similar (i.e., two compounds of Formula I, one compound of Formula II and one compound of Formula III, etc.). ] In some embodiments, one or more of Bicalutamide (e.g., CASODEX*), Cyproterone Acetate (e.g., ANDROCUR ® , CYPRQSTAT ® , CYPROTERON ® , PROCUR ® ,
  • Bicalutamide e.g., CASODEX*
  • Cyproterone Acetate e.g., ANDROCUR ® , CYPRQSTAT ® , CYPROTERON ® , PROCUR ®
  • CYPRONE ® CYPROHEXAL ® , CIPROTERONA ® , CYPROTERONUM ® ,
  • NEOPRQXIL ® e.g., NEOPRQXIL ® , SITERONE ® ), Dienogest (e.g., VIS ANNE ® ), Flutamide (e.g.,
  • EULEXIN ® Galeterone (TOK-001), Nilutamide (e.g., NILANDRQN ® ), Spironolactone (e.g., ALDACTO E*), Abiraterone (e.g., ZYTIGA * ), radium-223 chloride (e.g., ALPHA ADIN ® ) , TAK.
  • TOK-001 Galeterone
  • Nilutamide e.g., NILANDRQN ®
  • Spironolactone e.g., ALDACTO E*
  • Abiraterone e.g., ZYTIGA *
  • radium-223 chloride e.g., ALPHA ADIN ®
  • OGX 1 1 1 Cabozantinib (XLl 84), Dasatinib (e.g., SPRYCEL ® ), an mTOR inhibitor (e.g., Everolimus, Ridaforolimus, Rapamycin, Temsirolimus), an HDAC inhibitor (e.g., Vorinostat, CI-994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXD101), Sipuleucel-T (e.g. , PROVENGE*), Fulvestrant (e.g., FASLODEX*), Tamoxifen, Raloxifene, and
  • Toremifene is used in combination with one or more compounds of Formula I, I I. or III, in some embodiments, use of one or more compounds is combined other cancer therapies, such as internal or external radiation, surgery, and chemotherapies, including:
  • anthracyclines such as doxorubicin (e.g., ADRIAMYCIN ® , DQXIL ® ), including liposomal doxorubicin, epirubicm (e.g., ELLEN CE” ), and daunorubicin (e.g., CERUBIDINE ® , DAUNOXOME ® );
  • taxanes such as tamoxifen (e.g., NOLVADEX ® , SOLTAMOX ® , ISTUBAL C VALODEX ® ), docetaxel (e.g., TAXOTERE ® ), paclitaxel (e.g., TAXOL ® , ABRAXANE ® ), and protein-bound paclitaxel (e.g., ABRAXANE ® );
  • tamoxifen e.g., NOLVADEX ® , SOLTAMOX ® , ISTUBAL C VALODEX ®
  • docetaxel e.g., TAXOTERE ®
  • paclitaxel e.g., TAXOL ® , ABRAXANE ®
  • protein-bound paclitaxel e.g., ABRAXANE ®
  • cyclophosphamide e.g., CYTOXAN*
  • capecitabine e.g., XELQDA ®
  • 5-fIuorouracil or 5 FU e.g., ADRUCIL ®
  • vino elbine e.g., NAVELS INE ®
  • gemcitabine e.g., GEMZAR ®
  • trastuzumab e.g., HERCEFTIN ® .
  • carboplatin e.g., PARAPLATIN ®
  • methotrexate e.g., AMETHOPTERIN ® , MEXATE ® , FOLEX ® );
  • mutamycin e.g., MITOMYCIN ®
  • niitoxantrone e.g., NOVANTRONE ®
  • thiotepa e.g., THIOPLEX ®
  • vincristine e.g., ONCOVIN ® , VINCASAR PES ® , VINCREX ®
  • aromatase inhibitors such as anastrozole (e.g., ARIMIDEX), exemestane (AROMASIN), and letrozole (FEMARA);
  • raloxifene e.g., E VISTA*
  • toremifene e.g., FARESTON ®
  • fulvestrant e.g., FASLODEX ®
  • lapatinib e.g., TYKERB*
  • metformin Use of one or more compounds also can be used in conjunction with combinations of chemical therapies, such as:
  • doxorubicin and docetaxel e.g., "AT,” ADRIAMYCIN ® and TAXOTERE ® );
  • doxorubicin and cyclophosphamide with or without paclitaxel or docetaxel (e.g. "AC ⁇ T,” ADRIAMYCIN ® and CYTOXAN ® , with or without TAXQL ® or TAXOTERE ® );
  • CYTOXAN ® methotrexate, and fluorouracii
  • cyclophosphamide, epirubicin, and fluorouracii e.g., "CEF,” CYTOXAN*, ELLENCE*, and fluorouracii
  • fluorouracii doxorubicin, and cyclophosphamide (e.g., "FAC,” fluorouracii, ADRIAMYCIN ® , and CYTOXAN ® or "CAF,” CYTOXAN ® ,
  • ADRIAMYCIN ® ADRIAMYCIN ® , and fluorouracii
  • docetaxel, doxorubicin, and cyclopho9sphamide e.g., "TAG,” TAXOTERE*, ADRIAMYCIN ® , and CYTOXAN ®
  • gemcitabine, epirubicin, and paclitaxel e.g., "GET,” GEMZAR
  • EXAMPLE 1 Androgen receptor-expressing human urothelial carcinoma UM-UC-3 cells are purchased from the American Type Culture Collection, Manassas, VA, USA) and maintained in MEM medium (Gibco, 51200) supplemented with glutamine, non-essential amino acids, and 50% fetal bovine serum (FBS) at 37°C in a humidified atmosphere of 5% C0 2 .
  • Cells are cultured in phenol red- free medium supplemented with 5% charcoal -stripped FBS (CSS) at least 24 h before experimental treatment with DHT (dihydrotestosterone) or a compound disclosed herein.
  • Cells (3xl0 3 ) are seeded in 96-well tissue culture plates and incubated for 3 or 6 days with medium supplemented with 5% CSS containing different treatments: a compound disclosed herein at 0 (control), 1 , 10, or 30 ⁇ or DHT at 0 (control), 0.1 , 1 or lOnM).
  • An MTS assay is used to determine cell viability.

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Abstract

The disclosure describes compounds useful for treating disorders involving androgen, estrogen, and/or progesterone receptors.

Description

TREATMENT METHODS ] This application claims the benefit of Serial No. 61/554,919 filed on November 2, 2011.
Serial No. 61/554,919 and ail other documents cited in this disclosure are incorporated herein by reference in their entireties.
TECHNICAL FIELD ] The technical field is treatment of disorders or conditions involving androgen, estrogen, and/or progesterone receptors.
DETAILED DESCRIPTION ] This disclosure describes the use of one or more compounds that, fall within the scope of one or more of structural formulae I, II, and III and compounds which are antagonists of androgen, estrogen, and/or progesterone receptors.
L Definitions ] "Alkyl" refers to and includes saturated linear, branched, or cyclic hydrocarbon structures and combinations thereof. Particular alkyl groups are those having I to 12 carbon atoms (a "C1-C12 alkyl"). More particular alkyl groups are those having 1 to 8 carbon atoms (a "Ci-Cg alkyl"). When an alkyl group having a specific number of carbons is named, ail geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, /so-butyl, /en-butyl and cyclo butyl; "propyl" includes /i-propyl, /sopropyl and cyclopropyl. This term is exemplified by groups such as methyl, /-butyl, «-beptyl, octyl, cyclohexylmethyi, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. In some embodiments, cycloalkyl has from 3 to 12 annular carbon atoms (a "C3-C12 cycloalkyl"). In some embodiments, cycloalkyl has from 3 to 7 annular carbon atoms (a "C3-O7 cycloalkyl"). Examples of cyeloalkyi groups include adamantyl, decahydronaphthalenyl, cyclopropvl, cyclobutyl, cyclopentyl and the like. ] "Alkenyl" refers to an unsaturated linear, branched, or cyclic hydrocarbon group having at least one site of olefinie unsaturation (i.e., having at least one moiety of the formula C=C) and In some embodiments, having from 2 to 10 carbon atoms and more In some embodiments, 2 to 8 carbon atoms. Examples of alkenyl groups include but are not limited to ~CH?-CH=CH~CH3 and -CH2-CH2-cyclohexenyl, where the ethyl group of the later example can be attached to the cyclohexenyi moiety at any available position on the ring. | "Alkynyl" refers to an unsaturated linear, branched, or cyclic hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and In some embodiments, having from 2 to 10 carbon atoms and more In some embodiments, 3 to 8 carbon atoms. | "Substituted alkyl" refers to an alkyi group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyi, acyloxy,
carbonylalkoxy, acylamino, substituted or unsubstituted amino, amiiioacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, amiiiocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, fhioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyciyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,
earbonylalkylenealkoxy and the like. ] "Substituted alkenyl" refers to an alkenyl group having from 1 to 5 substituents
including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, amiiioacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino , aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alky], substituted or unsubstituted alkynyl, substituted or unsubstituted heterocvclyl, substituted or unsubstituted aralkyi, aminosulfonyl, sulfonylamino, sulfonyl, oxo,
carbonylalkylenealkoxy and the like.
"■Substituted aikynyl" refers to an aikynyl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonvlaikoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioaikyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyi, aminosulfonyl, sulfonylamino, sulfonyl, oxo,
carbonylalkylenealkoxy and the like.
"Aryl," "arene" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains from 6 to 14 annular carbon atoms.
"Heteroaryl," "heteroarene" or "HetAr" refers to an unsaturated aromatic carbocyclic group having from 2 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a. single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indoiizinyl, benzothienyl).
"Substituted aryl" or "substituted arene" refers to an aryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carboiiylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioaikyl, substituted or unsubstituted alky] , substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyi, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. ] "■Substituted heteroaryl" or "substituted heteroarene" refers to a heteroaryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted aikoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonyiamino,
aniinocarbonyioxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxvl, thiol, thioaikyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenvl, substituted or unsubstituted alkynyL substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonyialkylenealkoxy and the like. ] "Aralkyl" refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. In some embodiments, an aralkyl is connected to the parent structure via the alkyl moiety. ] "Aralkenyl" refers to a. residue in which an aryl moiety is attached to an alkenvl residue and wherein the aralkenyl group may be attached to the parent structure at either the aryl or the aikenyl residue. In some embodiments, an aralkenyl is connected to the parent structure via the alkenvl moiety, ] "Aralkynyl" refers to a residue in which an aryl moiety is attached to an alkynyl residue and wherein the aralkynyl group may be attached to the parent stmcture at either the aryl or the alkynyl residue. In some embodiments, an aralkynyl is connected to the parent structure via the alkynyl moiety. ] "Heteroaralkyl" refers to a residue in which a. heteroaryl moiety is attached to an alkyl residue and wherein the heroaralkyl group may be attached to the parent structure at either the heroaryl or the alkyl residue. In some embodiments, a heteroaralkyl is connected to the parent structure via the alkyl moiety. ] "Heterocycle", "heterocyclic", or "heterocyclyl" refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof.
"■Substituted heterocyclic" or "substituted heterocyclyl" refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryi, substituted aryl, heteroaryi, substituted heteroaryi, aryloxy, substituted aryloxy, cyano, halo, hydroxy 1, nitro, carboxyl, thiol, thioaikyL substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted araikyl, amino sulfonyL sulfouylamino, suifonyl, oxo, carbonylalkylenealkoxy and the like. In some embodiments, a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.
"Halo" or "halogen" refers to elements of the Group 17 series having atomic number 9 to 85. In some embodiments, halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, tribaloaryl etc. refer to aryl and alkyl substituted, with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fiuorophenyl is within the scope of dihaloaryl. Similarly, a "haloalkenyl" or "haloalkynyl" indicates an alkenyl or alkynyl moiety respectively in which at least one H is replaced with a halo group. An alkyl group in which each H is replaced with a halo group is referred to as a "perhaloalkyl." In some embodiments, a perhaloalkyl group is tri fluoro methyl (-C F3) .
A "substituted" group similarly refers to a group which is substituted with from I. to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryi, heteroaryi, substituted heteroaryi, aryloxy, substituted aryloxy, cyano, halo, hydroxy!, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,
carbonylalkyienealkoxy and the like.
2. Formula (I)
In some embodiments, the compound is a substituted di-arylhydantoin or substituted di- arylfhiohydantoin compound. Useful compounds and their syntheses are disclosed, for example, in WO 2010/1 18354.
In some embodiments, the compound is a compound of Formula I:
Figure imgf000007_0001
wherein;
W3 is CN, N02 or S02R4;
W is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
/ ' is S or O
// is 8, 0 or NR4;
Y and Y1 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, aryl alken l, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y1 and are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyi, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring; \V is -C]-C8alkyl-NRaRb, 0- < V< \»ik> l-\ in<" or -C(0)NReRf, where:
Ra is a C2-C12alkyl and Rb is H or a C C^aLkyl or Ra and Rb are taken together with the N to which they are attached to form a. heterocyclic ring;
R° is a Cf-Ci2alkyl and Re is H or a Ci-Cj2alkyl or Rc and Rd are taken together with the N to which they are attached to form a heterocyclic ring;
Re is a C2-Ci2alkyl and R1 is H or a Cj-Coalkyl, or
Re is a CrCi2,alkyl and Rf is CrC^alkyl, or
R and R1 are taken together with the N to which they are attached to form a heterocyclic ring;
R2 is hydrogen, halogen, nitro, alky] and substituted alkyl; and
R4 is independently H, alky] , or aryl.
] In some embodiments, W is CN, In some embodiments, W is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments, W2 is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen. W In some embodiments, is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. W In some embodiments, is a substituted alkyl. In some embodiments, W2 is substituted alkyl where the alkyl is substituted with a halogen. In some embodiments, W is a haloalkyl or perhaloalkyl. In some embodiments, W is a perhaloalkyl. The perhaloalkyl In some embodiments, is a Ci-Cs perhaloalkyl, such as tribal omethyl. In some embodiments, W2 is trifSuoromethyl. In some
embodiments, W1 is CN and W2 is perhaloalkyl. In some embodiments, W1 is CN and W2 is CF3.
] In some embodiments, Y1 and Y2 are both a Ci-Cg alkyl. In some embodiments, Y! and Y2 are the same Ci-Cg alkyl, such as when both Y1 and Y are methyl, ethyl, propyl or butyl. In some embodiments, Y1 and Y~ are both methyl or are taken together with the carbon to which they are attached to form a C4-C5 cycloalkyl . In some embodiments, Y! and Y2 are both methyl. In some embodiments, at least one of Y1 and Y is alkyl where the alkyl is a cycloalkyl. In some embodiments, at least one of Y5 and YJ' is substituted alkyl where the substituted alkyl is a substituted cycloalkyl. In some embodiments, one or both of Y! and Yz are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen. In some embodiments, at least one of Y3 and Y2 is a haloalkyl, haloalkenyl or haioalkynyl. In some embodiments, both Yf and Y2 are a haloalkyl, haloalkenyl or haioalkynyl. In some embodiments, Y 3 and Y2 are taken together with the carbon to which they are attached to form a C4-C5 cyeloalkyl. In some embodiments, Y ! and Y are taken together to form a cyclobutyl moiety. In some embodiments, Y3 and Y2 are both methyl, W3 is CN. In some embodiments, Y ! and Y are both methyl and W is a. perhaloalkyl such as CF3. In some embodiments, Y and Y are both methyl, W1 is CN and W2 is a perhaloalkyl such as CF3. ] In some embodiments, Zf and Z2 are independently S or O. In some embodiments, Z3 is S and Z2 is O. In some embodiments, Zf and Zl are independently S or O and Yf and Y" are both a Ci -Cg alkyl. In some embodiments, Z1 is S, Zz is O and Y1 and Yz are the same C\- Cg alkyl. In some embodiments, Z3 and Z2 are independently S or O and Y3 and Y2 are both methyl or are taken together with the carbon to which they are attached to form a C4-C5 cyeloalkyl . In some embodiments, Z1 is S, Z2 is O and the compound is further defined by one or more of the following structural features: (i) Y1 and Y~ are both a Cj- Cg alkyl; (ii) W is CN; (iii) W2 is perhaloalkyl. In some embodiments, Z3 is S, Z2 is O, Y3 and Y2 are the same Ci-Cg alkyl, W1 is CN and W~ is CF3. ] In some embodiments, T is C. In some embodiments, T is N. In some embodiments, a compound of formula (III) may be further defined by T being C. In some embodiments, a compound of formula (III) may be further defined by T being N. For example. In some embodiments, the compound may be further defined by T being C or by T being N. ] In some embodiments, R3 is -Ci-Cg alkyl~NRdRb where Ra is a C2-C12 alkyl and Rb is H or a Ci~Ci2 alkyl or Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the -Q-Cg alkyl moiety of -Ci~Cg alkyl- NRaRb is a -(CH2)n moiety where n is an integer from. 1 to 8. In some embodiments, n is less than 4. In some embodiments, n is 1. In some embodiments, Re is a C2-C12 alkyl and Rb is H. For example, R3 In some embodiments, is ethyl, propyl, butyl or pen yl and Rb is H. In some embodiments, Rd is a C2-C8 alkyl and Rb is H. In some embodiments, Ra is a C3-C6 alkyl and R° is H. In some embodiments, Ra is a C2-Q2 alkyl and Rb is a Cj-Cj2 alkyl. In some embodiments, Ra is a C3-C12 cycioalkyl and Rb is a CrC12 alkyl (e.g.., methyl). In some embodiments, Ra and Rb are independently a C2-C8 alkyl. In some embodiments, R* and Rb are the same C2-C12 alkyl, e.g., when both Ra and Rb are ethyl. In some embodiments, Ra and Rb are independently a C3-C6 alkyl. In some embodiments, Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Ra and Rb are taken together to form a heterocyclic ring, the ring is a C4-C7 heterocyclic ring. The heterocyclic ring formed by K', Rb and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Ra and Rb are taken together with the N to which they are attached. In some embodiments, Ra and Rb are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
Where applicable, for any detailed herein wherein R1 is - -Cgalkyl-NRfck, the Ci-Cg alkyl moiety of -Ci-Cg alkyl-NRaRb is a -(CH2)n moiety where n is 1. Thus, R1 In some embodiments, is -CH2 RaRb where Ra and R may be as defined herein. In some embodiments, R! is:
Figure imgf000010_0001
In some of these
embodiments, the compound is further defined by any one or more of the following structural features: (i) W1 is CN; (ii) W is perha!oalkyi (e.g., CF3); (iii) Z! is S; (II) 7 is O; (III) Y1 and Y2 are both methyl and (Illi) T is C,
In some embodiments, R3 is -O-Cj-Cs alky l-NRcRd where Rc is a C1-C32 alkyl and Rd is
H or a C1-C12 alky] or R" and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the -Ci-Cg alkyl moiety of-O-Cj-Cs alkyl-NR Rd is a -(CH2)n moiety where n is an integer from 1 to 8. In some
embodiments, n is less than 4. In some embodiments, n is 2. In some embodiments, " is a Ci-Ci2alkyl and Rd is H. For example, R In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and R° is H. In some embodiments, R° is a C-.-Cg alkyl and Rd is H. in some embodiments, Rc is a C1-C4 alkyl and Rd is H.
In some embodiments, R° and Rd are independently a d-C alkyl. in some of these embodiments R° and Rd are the same Ct-Ci2 alkyl, e.g., when both Rc and Rd are methyl. In some embodiments, R° and Rd are independently a Cj-Cg alkyl. In some embodiments, R° and Rd are independently a C1-C4 alkyl. In some embodiments, Rc and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Rc and Rd are taken together to form a heterocyclic ring, the ring is a C4-C7 heterocyclic ring. The heterocyclic ring formed by R\ Rd and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocvcle contains as annular atoms only C and the N provided when Rc and Rd are taken together with the N to which they are attached. In some
embodiments, Rc and Rd are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R1 is -O-Ci-Cg alkyl-NRcRd, the C3-C3 alkyl moiety of-O-Ci-Cg alkyl-NRcRd is a -(CH2)n moiety where n is 2. Thus, R3 In some embodiments, is -OCFbCF^NR^R:3 where Rc and Ra may be as defined herein. In some embodiments, R1 is:
Figure imgf000011_0001
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) Wri is perhaloalkyl (e.g. , CF3); (iii) Z1 is S; (II) Z2 is O; (III) Y1 and Y2 are both methyl; (mi) R2 is H, and (Illii) T is C.
In some embodiments, R! is -C(Q)NR Rf where Re and Rf are as defined in provisions (i) or (ii) or (iii): (i) Re is a C2-Ci2alkyl and Rf is H or a C]-C] ?alkyl; (ii) Re is a CrC^alkyl and R1 is C] -Cj?alkyl; or (iii) Rc and R1 are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, R1 is -C(0)NReRf and Re is a C2-C12alkyl and R* is H or a Ci~Cj2alkyl . In some embodiments, R1 is -C(0)NReRI and Re is a Ci-C]2alkyl and R1 is Ci~Cj2alkyI. In some embodiments, R1 is
Figure imgf000011_0002
Re and R1 are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, Re is a C2-C12 alkyl and R1 is H. For example, Re In some embodiments, is ethyl, propyl, butyl, pentyl or hexyl and R is H. In some embodiments, Re is a Cs-Cj2 cycloalkyl (e.g., cyclopentyl) and R* is H. In some embodiments, Rs is a C3-C12 branched alkyl (e.g., ie/f-butyl) and R1 is H. I some embodiments, Re is a C2-C8 alkyl and Rf is H. In some embodiments, Re is a (V( '.:, alkyl and R1 is H. In some embodiments, K~ is a C2-C12 alkyl and Rf is a C1-C12 alkyl (e.g., where Re is ethyl and Rf is methyl). In some embodiments, W and R! are independently a C Ci2 alkyl (e.g., where both Rs and Rf are methyl). In some embodiments, Re and R* are independently a C2-C12 alkyl. In some embodiments, Rs and Rf are the same C2-Cf 2alkyl, e.g., when both Re and Rf are ethyl. In some embodiments, R and R' are independently a C2- alkyl. In some embodiments, Re and R1 are independently a C3-C6 alkyl. In some embodiments, at least one of Re and Rf is a Cj-Ce cycloalkyl. In some embodiments, Re and Rf are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Re and R* are taken together to form a heterocyclic ring, the ring is a C4-C7 heterocyclic ring. The heterocyclic ring formed by Re, R1 and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycie contains as annular atoms only C and the N provided when Re and R1 are taken together with the N to which they are attached. In some
embodiments, Re and R1 are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. In some embodiments, R3 is:
Figure imgf000012_0001
these embodiments, the compound is further defined by any one or more of the following structural features: (i) W1 is CN; (ii) W~ is perhaloalkyl (e.g., CF3); (iii) Z! is S; (I I) Z~ is (); ·: Ι Π ) Y1 and Y2 are both methyl and (Illi) T is C. ] In some embodiments, R~ is halo (e.g., F). In some embodiments, R" is H. In some embodiments, R2 is halo when R* is -Ci-Cgalkyl-NRaRb or -C(0)NReRf. In some embodiments, R2 is H when R! is -0-CrCsalkyl-NRLRd. ] In some embodiments, the compound is a compound of Formula I- A:
Figure imgf000013_0001
(I-A) where Z!, , Y\ Y T, R* and R* are as defined in formula (I) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula I-B:
Figure imgf000013_0002
where T, R and Rz are as defined in formula (I) or any embodiment thereof. In some embodiments, the compound is a compound of Formula I-C:
Figure imgf000014_0001
where T, R1 and R"? are as defined in formula (Γ) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula I-D:
Figure imgf000014_0002
(I-D) where R1 and R2 are as defined in formula (I) or any embodiment thereof. In some embodiments, the compound is a compound of Formula 1-E:
Figure imgf000014_0003
where R1 is as defined in formula (Γ) or any embodiment thereof. In some embodiments, the compound is a compound of Formula I-F:
Figure imgf000015_0001
where n is an integer from 1 to 8 and W3, W2, Z!, Z~, Y , Y1, Ra and Rb are as defined in formula (I) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula I-G:
Figure imgf000015_0002
where n is an integer from 1 to 8 and W , VV", Z , Zy", Y , Y , Rc and R1" are as defined in formula (II) or any embodiment thereof. In some embodiments, the compound is a compound of Formula I-H:
Figure imgf000016_0001
where W\ W, Z\ Z , Y", Y , Re and † are as defined in formula (I) or any embodiment thereof.
Examples of compounds according to Formula I are depicted in Table 1. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan, it is thus understood that pharmaceutically acceptable salts of compounds are intended.
Table 1. Representative Compounds of Formula I.
Figure imgf000017_0001
Figure imgf000018_0001
3. Formula (ΪΙ)
In some embodiments, the compound is a substituted phenylcarbamoyl alkylamino aren or an Ν,Ν'-bis-arylurea compound. Other useful compounds and their syntheses are disclosed in WO 201 1 /044327. In some embodiments, a compound is a compound of Formula 11:
Figure imgf000018_0002
(II) wherein:
W1 is CN, N02 or S02R4; W ' is alkyl, substituted alkyl, aikenyi, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR5;
Y5 and YJ' are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarailvvl, heterocyclyl, substituted heterocyclyl or Y! and Y2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycioalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R! is -Ci-Cs alkyl-NRaRb, -0-C C8 a!kyl-NRcRdor -C(0)NReRf, where:
Ra is a Ci-Ci2 alkyl and R° is H or a Ci-C12 alkyl or Ra and R° are taken together with the N to which they are attached to form a heterocyclic ring;
R° is a C1-C12 alkyl and Rd is H or a C1-C12 alkyl or R and Rd are taken together with the N to which they are attached to form a heterocyclic ring;
Re is a C1-C12 alkyl and Rf is H or a C1-C12 alkyl, or e and R1 are taken together with the N to which they are attached to form a heterocyclic ring;
R2 is hydrogen, halogen, nitro, alkyl or substituted alkyl; R~* is H, alkyl, substituted alkyl, aryl or substituted aryl; and is H, alkyl, substituted alkyl, aryl or substituted aryl. [47 In some embodiments, the salt is a pharmaceutically acceptable salt. ] In some embodiments, the compound is of the formula (II) where W! is CN. In some embodiments, W2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments, Wz is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. W2 In some embodiments, is a haioalkyl, haloalkenyl, haloalkynyl or perhaloalkyl, W2 In some embodiments, is a substituted alkyl. In some embodiments, W2 is substituted alkyl where the alkyl is substituted with one or more halogens. In some embodiments, W2 is a haioalkyl or perhaloalkyl. In some embodiments, W2 is a perhaloalkyl. The perhaloalkyl In some embodiments, is a Cj-Cg perhaloalkyl, such as trihalomethyl. In some embodiments, W2 is trif!uoromethyl. In a particular , W1 is CN and W2 is perhaloalkyl. In another particular , W! is CN and W2 is CF3.
] In some embodiments, Y1 and Y are both a Ct-Cg alkyl. In some embodiments, Y and Y2 are the same Cj-Cg alkyl, such as when both Y1 and Yz are methyl, ethyl, propyl or butyl. In some embodiments, Y1 and Y" are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl. In some embodiments, Y1 and Y~ are both methyl. In some embodiments, one ofY] or Y" is hydrogen and the other of Y1 or Y2 is C3 alkyl. I some embodiments, one of Y1 or Y2 is hydrogen and the other of Y! or Y2 is methyl, ethyl, propyl or butyl . In some embodiments, at, least one of Y1 and Y is alkyl where the alkyl is a cycloalkyl. In some embodiments, at least, one of Y1 and Y2 is substituted alkyl where the substituted alky! is a substituted cycloalkyl. In some embodiments, one or both of Y1 and Y are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. In some embodiments, at least one of Y1 and Y~ is a haioalkyl, haloalkenyl or haloalkynyl. In some embodiments, both Y3 and Y2 are a haioalkyl, haloalkenyl or haloalkynyl. In some embodiments, Y1 and Y are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl. In some embodiments, Y! and Y are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl moiety. In some embodiments, Y 1 and Y" are both methyl and W3 is CN. In some embodiments, Y3 and Y are both methyl and W2 is a perhaloalkyl such as CF3. In some embodiments, Y! and Y are both methyl, W1 is CN and W is a perhaloalkyi such as CF . In some embodiments, Y3 is isopropyl, is H, W! is CN and is a perhaloalkyi such as CF3. In a particular , Y and Y2 are taken together with the carbon to which they are attached to form a cyclopropyl, WJ is CN. In another particular of formula (II), Y! and Yz are taken together with the carbon to which they are attached to form a cyclopropyl and W is a perhaloalkyi such as CF3. In some embodiments, Y! and Y" are taken together with the carbon to which they are attached to form a cyclopropyl, W3 is CN and W2 is a perhaloalkyi such as CF3. ] In some embodiments, Z is substituted N (e.g., NR.5), S or O, In some embodiments, Z is O. In a particular , Z is S or O and YJ and Y" are both a C¾-Cg alkyl. In some
embodiments, Z is O and Ys and Y2 are the same Cf-C8 alkyl. In some embodiments, Z is S or O and Y1 and Y"6 are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl. In some embodiments, Z is O and the compound is further defined by one or more of the following structural features: (i) Y1 and Y" are both a Ci-Cg alkyl; (ii) W3 is CN; (iii) W2 is perhaloalkyi. In some embodiments, Z is O, Y1 and Yz are the same Ci-Cg alkyl, W is CN and W2 is CF3. In one particular such embodiment Z is O, Y1 and Y" are each methyl, W3 is CN and W2 is CF . In some embodiments, the compounds of formula (II) are provided where Z is O and the compound is further defined by one or more of the following structural features: (i) Y3 and Y are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W3 is CN; (iii) W2 is perhaloalkyi. In some embodiments, Z is O, Y3 and Y2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl, W is CN and W is CF . In one particular embodiment Z is (), Y1 and Y are taken together with the carbon to which they are attached to form a cyclopropyl, W3 is CN and W2 is CF3. ] In some embodiments, T is CI In some embodiments, T is N. It is understood that where applicable, a compound may be further defined by T being C. It is understood that where applicable, a compound may be further defined by T being N. For example, the embodiments described herein may in some cases be further defined by T being C or by T being N. Compounds of formula (11) are provided where R! is -Ci-Cs alk l-NRaRb where Ra is a C|-Ci2 alkyi and RD is H or a C\-Cn alkyl or Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the -Cj-Cg alkyl moiety of -C¾-Cg alkyl-NRaRb is a -(CH2)n moiety where n is an integer from I to 8, In some embodiments, n is less than 4. In some embodiments, n is 1. In some
embodiments, Ra is a C1-C12 alkyl and Rb is H. For example, Ra In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and RD is H. In some embodiments, Ra is a Cj-Cg alkyl and Rb is H, In some embodiments, Ra is a C3-G5 alkyl and R° is H. Compounds of formula (II) are also provided where Rd is a C]-Cj2 aikyl and Rb is a Cj-Cj 2 alkyl. In some embodiments, Ra is a C3-C12 cycloalkyl and Rb is a C C12 aikyl (e.g., methyl). In some embodiments, Ra and Rb are independently a Ci-Cg alkyl. In some embodiments, Ra and Rb are the same C1-C12 alkyl, e.g., when both Ra and Rb are ethyl. In some embodiments, Ra and R° are independently a C3-C6 alkyl. In still some embodiments Rd and Rb are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Rd and R'J are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered. heterocyclic ring. The heterocyclic ring formed by Ra, R° and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Ra and Rb are taken together with the N to which they are attached. In a particular , Ra and Rb are taken together with the N to which they are attached to form a pyrroiidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R1 is - Ci-Cg alkyl-NRaR , In some embodiments, the C C8 alkyl moiety of -C C8 aikyl-NRaRb is a moiety where n is 1. Thus, I In some embodiments, is -CH2NRaR° where Ra and R° may be as defined herein. In some embodiments, R1 is:
Figure imgf000022_0001
In some of these embodiments, the compound is further defined by any one or more of the following structural features: (i) W! is CN; (ii) W2 is perhaloalkyl (e.g., CFi); (iii) Z is O: (II) Υ' and Y2 are both methyl and (III) T is C. In some embodiments, the compound is further defined by any one or more of the following structural features: (i) W¾ is CN; (ii) W2 is perhaloalkyl (e.g., CF3); (iii) Z is O; (II) Y¾ and Y2 are both methyl, (III) R" is halogen (e.g. , F) and (Illi) T is C.
Compounds of formula (II) are provided where R! is -O-Ct-Cg alkyl- NR;Rd where Rc is a Cj-Cj2 alkyl and Rd is H or a C¾-C¾ ? alkyl or Rc and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the -C j-Cs alkyl moiety of -O-Ci-Cs a.lkyl-NRcRd is a -(CH2)n moiety where n is an integer from 1 to 8. In some embodiments, n is less than 4. In some embodiments, n is 2. In some embodiments, W is a Cj-Cj?. alkyl and Rd is H. For example, Rc In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and Rd is H. In some embodiments, Rc is a Cj-Cg alkyl and R° is H, In some embodiments, Rc is a C1-C4 alkyl and Rd is H. Compounds of formula (II) are also provided where L and Rd are independently a Cj-Cj? alkyl. In some embodiments, R° and Rd are the same Cj-Cj? alkyl, e.g. , when both R" and Rd are methyl. In some embodiments, Rc and Rd are independently a Cj-Cg alkyl. In some embodiments, Rc and Rd are independently a C1-C4 alkyl. In still some embodiments Rc and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when R and Rd are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R\ Rd and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when R" and Rd are taken together with the N to which they are attached. In a particular , R° and Rd are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R! is -O-Cj-Cs alkyl-NR°Rd, In some embodiments, the Cj-C8 alkyl moiety of-O-Cj-Cg alkyl- NRcR is a -(CH2)n moiety where n is 2. Thus, R! In some embodiments, is - OCH2CH2NRcRd where Rc and Rd may be as defined herein. In some embodiments, R is:
Figure imgf000024_0001
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W! is CN; (if) W is perhaloalkyl (e.g., CF3); (iii) Z is O;
Y¾ and Y2 are both methyl; (III) R2 is H, and (IUi) T is C. In some embodiments, R3 is -C(0)NR"Rf where Re and Rf are as defined in provisions (i) or (ii) or (iii) or (II): (i) Re and R1 are independently H or a ('■■-( ·■■ alkyl; (ii) Re is a Ci~ C|2 alkyl and Rf is H or a Ci-C12 alkyl; (iii) Re is a (■■( }■ alkyl and 1 is Ci-Cn alkyl; or (II) Re and Rf are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, R1 is -C(0)NR"Rf and Re and Rf are
independently H or a CrC12 alkyl. In some embodiments, R1 is -C(0)NR"Rf and Re is a C1-C12 alkyl and Rf is H or a C1-C12 alkyl. In some embodiments, R1 is -C(0)NReRf and Re is a Ci-Cj2 alkyl and R' is C1-C12 alkyl. In some embodiments, Rf is -C(0)NReR' and Re and Rf are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, Re is a C1-C12 alkyl and R1 is H. For example, Re In some embodiments, is methyl, ethyl, propyl, butyl, pentyl or hexyl and Rf is H. In some embodiments, Re is a C3-C12 cycloalkyl (e.g., cyclopentyl) and R1 is H. In some embodiments, K~ is a C3-C12 branched alkyl (e.g., ieri-butyi) and Rf is H. In some embodiments, Re is a Ci-Cg alkyl and R* is H (e.g., where R is methyl and R1 is H). In some embodiments, Re is a C3-C6 alkyl and R1 is H (e.g., where Re is propyl or butyl and Rf is H). In some embodiments, Re is a C1-C12 alkyl and Rf is a C¾ -C] ? alkyl (e.g., where Re is ethyl and R1 is methyl). In some embodiments, Re and Rf are independently a C]-Ci2 alky] (e.g., where both R and Rf are methyl). In some embodiments, Re and Rf are independently a
Figure imgf000024_0002
alkyl. In some embodiments, R and R' are the same C1-C12 alkyl, e.g., when both Re and Rf are ethyl. In some embodiments, R and R' are independently a Cj-C alkyl. In some embodiments, Rfc and R1 are independently a C3-C6 alkyl. In some embodiments, at least one of Re and R1 is a C3-C6 cycloalkyl. In still some embodiments Re and R1 are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Re and R* are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by Re, R! and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Re and Rf are taken together with the N to which they are attached. In a. particular , K~ and Rf are taken together with the N to which they are attached to form a pyrroiidinyl or piperidinyl ring. In some embodiments, R¾ is:
Figure imgf000025_0001
In some embodiments, the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W is perhaloalkyl (e.g., CF3); (iii) Z is O; (II) Y1 and are both methyl and (Illi) T is C. In some embodiments, R1 is as defined above and the compound is further defined by any one or more of the following structural features: (i) W! is CN; (ii) W2 is perhaloalkyl (e.g., CF3); (iii) Z is O; (II) Y1 and Y2 are taken together with the carbon to which they are attached to form a cyclopropyl and (l l li) T is C.
In any embodiment detailed herein, " In some embodiments, is halo (e.g., F). In some embodiments, R2 is H. In some embodiments, R2 is halo when R1 is -Ci-Cg alky1-NRaRb or -C(0)NReRf. In some embodiments, R2 is H when R1 is ( )-(>( alkyl-NRcRd.
In some embodiments, the compound is a compound of Formula II- A:
Figure imgf000025_0002
where Z, Y ', Y , T, 3 and RJ are as defined in formula (II) or any embodiment thereof.
[58] In some embodiments, the compound is a compound of Formula II~B:
Figure imgf000026_0001
2 j
where T, R and Rz are as defined in formula (Π) or anv embodiment thereof.
[59] In some embodiments, the compound is a compound of Formula II-C:
Figure imgf000026_0002
where T, R and " are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula II~D;
Figure imgf000026_0003
where R and R are as defined in formula (II) or any embodiment thereof
In some embodiments, the compound is a compound of Formula II~E:
Figure imgf000027_0001
where R is as defined in formula (II) or any embodiment thereof.
[62] In some embodiments, the compound is a compound of Formula II-F:
Figure imgf000027_0002
where n is an integer from 5 to 8 and Ra and R° are as defined in formula (II) or any embodiment thereof.
63] In some embodiments, the compound is a compound of Formula II-G:
Figure imgf000028_0001
where n is an integer from 1 to 8 and R and R are as defined in formula (II) or any embodiment thereof,
[64] In some embodiments, the compound is a compound of Formula II-H:
Figure imgf000028_0002
where n is an integer from 1 to 8 and Rc and R are as defined in formula (II) or any embodiment thereof.
65] In some embodiments, the compound is a compound of Formula II-J:
Figure imgf000029_0001
where n is 0 to 3, and Rfc and R1 are as defined in formula (IT) or any embodiment thereof.
[66] In a variation of any one of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II- H), (II-J), (II-K), (II-L) to (II-M) detailed herein, in particular embodiments Y ' is thiocarboxyl, carboxyl, aminocarbonyi, N-alkyl aminocarbonyi, N,N-dia.lkyl
aminocarbonyi, formyi, aikyl carbonyi or aikoxy carbonyl. In a particular variation of any one of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II- L) to (II-M) detailed herein, Y~ is carboxyl. In another particular variation of any one of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), i !!-H). (II-J), (II-K), (II-L) to (II-M) detailed herein, YJ is aikoxy carbonyl. In another particular variation of any one of formula (II-A), (Il-B), (II-C), (II-D), (II-E), (II-F), (II-G), i !!-H). (II-J), (II-K), (II-L) to (II-M) detailed herein, Y° is aminocarbonyi.
[67] Examples of compounds according to Formula (II) are depicted in Table 2. The
compounds depicted may be present as salts even if salts are not depicted and it is understood that this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form, of the compound, as is well understood by the skilled artisan. It is thus understood that pharmaceutically acceptable salts of compounds are intended. Table 2, Representative Compounds of Formula U.
Figure imgf000030_0001
Figure imgf000031_0001
[68] In some embodiments, the compound is a compound of Formula ΪΪΪ:
Figure imgf000031_0002
(III) wherein:
WJ isCN,N02or S02R4; W ' is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, G or NR5;
Yf and Y2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryialkyl, aryialkenyl, arylalkynyl, heteroaralkyl, heterocyciyl, substituted heterocyciyl or Y ! and Y" are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
Y3 is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, aryialkyl carbonyl, aryialkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyciyl carbonyl, substituted heterocyciyl carbonyl, cyano, ammocarbonyl, N-alkyl aminocarbonyl, N,N- di alkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N~bis~substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, aikylhydroxymethyl, substituted alkoxymethyl,
thiocarboxyl, thioforrnyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, aryialkyl thiocarbonyl, aryialkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyciyl thiocarbonyl, substituted heterocyciyl thiocarbonyl, tliiocarbamyl, N-alkyl tliiocarbamyl, N,N-dialkyl tliiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl;
heteroaryl carbonyl, substituted heteroaryl carbonyl, aryialkyl carbonyl, aryialkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyciyl carbonyl, substituted heterocyciyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyi
aminocarbonyl, N-substituted alkyl aminocarbonyl, NN-bis-suhstituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;
T is carbon or nitrogen and can be at any position in the ring; R1 is hydrogen, -Ci-Cg alkyl-NRaRb, -0-C]-C8 alkyl-NRcRd, -C(0) ReRf or -NRsRh, where:
Ra is a C1-C12 alkyl and Rb is H or a Cj-Q ? alkyl or Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring;
Rc is a C¾-Ci? alkyl and Rd is H or a C}-C12 alkyl or Rc and Rd are taken together with the N to which they are attached to form a heterocyclic ring;
Re is H or a C¾-Ci? alkyl and Rf is H or a Ci-C12 alkyl, or Re and Rf are taken together with the N to which they are attached to form a heterocyclic ring;
Rs is H or a Q-C12 alkyl and Ru is H or a Ci-Ci2 alkyl, or Rg and Rh are taken together with the N to which they are attached to form a heterocyclic ring;
R2 is hydrogen, halogen, nitro, alky! or substituted alkyl;
R4 is H, alkyl, substituted alkyl, aryl or substituted aryl;
R5 is H, alkyl, substituted alkyl, aryl or substituted aryl. ] In some embodiments, the compo und is of the formula { I I I } where T is nitrogen when R4 and RJ are both hydrogen. ] In some embodiments, the compo und is of the formula { I I I ) where W1 is CN. In some embodiments, W is hydrogen, alkyl, substituted alkyl, alkenvl, substituted alkenyl, aikynyl or substituted aikynyl. In some embodiments, W~ is substituted alkyl, substituted alkenyl or substituted aikynyl where the alkyl, alkenyl or aikynyl is substituted with one or more halogens. WJ' In some embodiments, is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. w' In some embodiments, is a substituted alkyl. In some embodiments, W is substituted alky] where the alkyl is substituted with one or more halogens. In some embodiments, W is a haloalkyl or perhaloalkyl. In some embodiments, W2 is a perhaloalkyl. The perhaloalkyl In some embodiments, is a Ci-Cs perhaloalkyl, such as trihalomethyl. In some embodiments, is trifluoromefhyl. n a particular , W3 is CN and Wz is perhaloalkyl. In another particular , W3 is CN and W2 is CF3. In some embodiments, W is hydrogen. In a particular , W* is CN and W2 is hydrogen.
In some embodiments, Y ' and Y2 are both a Ct-Cs aikyl. In some embodiments, Y1 and Y2 are the same Ci-Cs aikyl, such as when both Y! and Yz are methyl, ethyl, propyl or butyl. In some embodiments, ΥΛ and Y ~ are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloaikyl. In some embodiments, the compounds of formula (III) are provided where Y3 and Y2 are both methyl. In some embodiments, the compounds of formula (III) are provided where one of YJ or Y2 is hydrogen and the other of Y3 or Y2 is Cj-Cg aikyl. In some embodiments, one of Y1 or Y2 is hydrogen and the other of Y3 or Y 2 is methyl, ethyl, propyl or butyl. In some embodiments, the compounds of formula (III) are provided where at least one of Y1 and Y2 is aikyl where the aikyl is a cycloaikyl. In some embodiments, the compounds of formula (III) are provided where at least one of Y1 and Y" is substituted aikyl where the substituted aikyl is a substituted cycloaikyl. In some embodiments, the compounds of formula (III) are provided where one or both of Y1 and Y2 are substituted alky] , substituted alkenyl or substituted alkynyl where the aikyl, alkenyl or alkynyl is substituted with one or more halogens. In some embodiments, at, least one of Y3 and Y2 is a haloalkyl, haloalkenyl or haioa!kynyl . In another such embodiment both Y1 and Y are a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments, the compounds of formula (III) are provided where Y3 and Y2 are taken together with the carbon to which they are attached to form a C3-C5 cycloaikyl. In some embodiments, Y1 and Y' are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyi or cyclopentyi moiety. In a particular , Y3 and Y are both methyl, W1 is CN. In another particular , Y3 and Y' are both methyl and W is a perhaloalkyl such as CF3. In some embodiments, Y and Y " are both methyl, W is CN and W' is a perhaloalkyl such as CF3. In some embodiments, Y1 is isopropyl, YJ is H, W3 is CN and W2 is a perhaloalkyl such as CF3. In a particular , Y3 and Y2 are taken together with the carbon to which they are attached to form a cyclopropyl, W3 is CN. In another particular of formula (III), Y1 and Y 2 are taken together with the carbon to which they are attached to form a cyclopropyl and Wz is a perhaloalkyl such as CF3. In some embodiments, Y ! and Y2 are taken together with the carbon to which they are attached to form a cyclopropyl, W! is CN and W"' is a perhaloalkyl such as CF3.
[72] In a , YJ is carboxyl, carbonyl or derivative thereof, such as carboxyl, formyl, alkyi carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl. carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyi carbonyl, heterocyciyl carbonyl, substituted heterocyclyl carbonyl, cyaiio, carbamyl, N-alkyl carbamyl, Ν,Ν-dialkyl carbamyl, N- substituted alkyl carbamyl, N,N-bis-substituted alkyl carbamyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymefhyi or substituted alkoxymethyl. In a , Y3 is thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyi thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, Ν,Ν-dialkyl thio carbamyl, N-substituted alky] thiocarbamy!, N,N-bis-siibstituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl.
[73] In a particular , YJ is thiocarboxyl or carboxyl. In a particular , Y3 is carboxyl.
[74] In a particular , Y3 is arnmoearbonyl, N-alkyl aminocarbonyl, Ν,Ν-dialkyl
aminocarbonyl. In a particular , Y3 is aminocarbonyl.
[75] In another particular , Y3 is formyl, alkyl carbonyl or alkoxy carbonyl. In a particular , Y3 is alkoxycarhonyl.
[76] In a , Y 3 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyi, heterocyclyl, substituted heterocyclyl, In some embodiments, the compounds of formula (SIS) are provided where Z is substituted N (e.g., NRJ), S or O. In some embodiments, Z is O. In some embodiments, Z is S, In a particular , Z is S or O and Y! and Y2 are both a Q-Cg alkyl. In some embodiments, Z is S or O and Y3 and Y"6 are the same Ci-Cg alkyl. In some embodiments, Z is S or O and Y! and Yz are both methyl or are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl.
In some embodiments, the compounds of formula. (Ill) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y ¾ and Y2 are both a Ci-Cg alkyl; (ii) W! is CN; (iii) Wz is perhaloalkyl. In some
embodiments, Z is S, Yf and Y" are the same Cj-Cg alkyl, W3 is CN and W' is CF . In one particular such embodiment Z is S, Y1 and Y2 are each methyl, W3 is CN and W* is CF3. In one particular such embodiment Z is S, Y and Y' are each methyl, Y is carboxyl, W1 is CN and W2 is CF:¾. In some embodiments, the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y~3 and Y2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W! is CN; (iii) W2 is perhaloalkyl, (II) Y3 is carboxyl. In some embodiments, Z is S, Y1 and Y" are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl, W1 is CN and W2 is CF3. In one particular embodiment Z is O, Y* and Y are taken together with the carbon to which they are attached to form a cyclopropyl, Y3 is carboxyl, W1 is CN and W is CF3.
In some embodiments, the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y~3 and Y2 are both a Ci-Cg alkyl; (ii) W1 is CN; (iii) W2 is perhaloalkyl; (II) Y3 is selected from the group consisting of thiocarboxvl, aminocarbonyl, N-alkyl aminocarbonyl, N,N- dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxycarbonyl. In one particular such embodiment YJ is alkoxycarbonyl or aminocarbonyl. In one particular such embodiment
Z is S, Y* and Y2 are each methyl, Y3 is alkoxycarbonyl or aminocarbonyl, W is CN and w' is CF3. In some embodiments, the compounds of formula (III) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y' and Y ' are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl; (ii) W! is CN; (iii) Wz is perhaioalkyl, (II) Y is alkoxycarbonyl or aminocarbonyl. In some embodiments, Z is S, Y! and Y2 are taken together with the carbon to which they are attached to form a C3-C5 cycloalkyl, W1 is CN and W"' is CF3. In one particular embodiment Z is O, Y1 and Y"6 are taken together with the carbon to which they are attached to form a. cyclopropyl, Y3 is alkoxycarbonyl or aminocarbonyl, W* is CN and W2 is CF3.
In some embodiments, T is C. In some embodiments, T is N. It is understood that where applicable, any embodiment may In some embodiments, be further defined by T being C. It is understood that where applicable, any embodiment may In some embodiments, be further defined by T being N. For example, the embodiments described herein may In some embodiments, be further defined by T being C, Additionally, it is understood that the embodiments described herein may In some embodiments, be further defined by T being N.
Compounds of formula (III) are provided where R1 is -Ci-Cg alkyl-NRaRb where Ra is a Ci-C¾2 alkyl and Rb is H or a C¾-C]? alkyl or Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the ~C¾-Cg alkyl moiety of -Cj-Cs alkyl-NRaRb is a (Ci I■)■.·. moiety where n is an integer from 1 to 8. In some embodiments, n is less than 4, In some embodiments, n is 1. In some
embodiments, Ra is a C1-C12 alkyl and R° is H. For example, Ra In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and Rb is H. In some embodiments, Ra is a .~( alky] and Rb is H. In some embodiments, Re is a C3-C6 alkyl and R° is H. Compounds of formula (III) are also provided where Ra is a C1-C12 alkyl and Rb is a Ci-Ci2 alkyl. In some embodiments, Rd is a C3-C12 cycloalkyl and R° is a Ci-C12 alkyl (e.g., methyl). In some embodiments, Ra and R are independently a Ci-Cg alkyl. In some embodiments, Ra and R are the same C1-C12 alkyl, e.g., when both Ra and R° are ethyl. In some embodiments, and Rb are independently a C3-C6 alkyl. In still some embodiments Ra and R are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Ra and Rb are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by Ra, R and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Ra and D are taken together with the N to which they are attached. In a particular , Ra and Rb are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R1 is -Ci-Cg alkyl~NRaRb, In some embodiments, the Cj-Cg aikyl moiety of -d-d aikyl-NRaRb is a -(0¾)η moiety where n is 1. Thus, Rf In some embodiments, is -CH2,NRaRb where Ra and Rb may be as defined herein. In some embodiments, RJ is:
Figure imgf000038_0001
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W1 is CN; (ii) W2 is perhaloalkyl (e.g., CF3); (iii) Z is S; (IS) Y 1 and Y" are both methyl and (III) T is C. In some embodiments, IV is as defined above and the compound is further defined by any one or more of the following structural features: (i) W! is CN; (ii) W2 is perhaloalkyl (e.g., CF3); (iii) Z is S; (Π) Yf and Y2 are both methyl, (III) R2 is halogen (e.g., F) and (Mi) T is C.
In some embodiments, R3 is -O-d-Cs aikyl-NRcRd where Rc is a d-C12 alkvl and Rd is H or a C1-C12 alkyl or R° and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, the -C-. -Cg alkyl moiety of -O-d-Cs aikyl-NR Rd is a --((¾>)η moiet where n is an integer from 1 to 8. In some
embodiments, n is less than 4. In some embodiments, n is 2. In some embodiments, R° is a d-d? alkyl and Rd is H. For example, Rc In some embodiments, is methyl, ethyl, propyl, butyl or pentyl and Rd is H. In some embodiments, Rc is a d-C8 alkyl and Rd is H. In some embodiments, R' is a d -C4 alkyl and Rd is H. Compounds of formula (III) are also provided where Rc and Rd are independently a d-C12 alkyl. In some
embodiments, Rc and Rd are the same d-Ci2 alkyl, e.g. , when both Rc and Rd are methyl. In some embodiments, RL and Rd are independently a Cj-Cs alkyl. In some embodiments, Rc and Rd are independently a d- alkyl. In still some embodiments RL and Rd are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, when Rl and Rd are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R'\ Rd and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Rc and Rd are taken together with the N to which they are attached. In a particular , Rc and R° are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R! is -G-Cj -Cg alkyl-NRcRa, In some embodiments, the Cj-Cg alkyl moiety of -O-Ci-Cs alkyl- NRcRd is a -(0¾)η moiety where n is 2. Thus, R1 In some embodiments, is - OCH2CH2 RcRa where Rc and Rd may be as defined herein. In some embodiments, R1 is:
CH3
¾ O CH ·
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W is CN: (ii) W2 is perhaloalkyl (e.g., CFj); (iii) Z is S;
) Y1 and Y2 are both methyl: (III) R2 is H, and (Illi) T is C.
In some embodiments, R1 is -C(0)NRsRf where Re and Rf are as defined in provisions (i) or (ii) or (iii) or (II): (i) Re and R1 are independently H or a Ci-C12 alkyl: (ii) Rc is a Cj- Cj2 alkyl and Rf is H or a C]-Cj2 alkyl; (iii) Re is a C¾-C]? alkyl and R* is C]-Cj2 alkyl; or ) Re and Rf are taken together with the N to which they are attached to form a.
heterocyclic ring. In some embodiments, the compound is of the formula (III) where R! is -ϋ(0)^¾¾* and Re and R* are independently H or a C¾-C]2 alkyl . In some embodiments, the compound is of the formula (III) where R1 is -C(0)NReR! and Re is a C i~Ci2 alkyl and iV is II or a Ci-C!2 alkyl. In some embodiments, the compound is of the formula (III) where R1 is -C(0)NRsRf and Re is a C3-C12 alkyl and R' is C1-C12 alkyl. In some embodiments, the compound is of the formula (III) where R! is -C(0) ReR* and Rs and R are taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments, Rfc is a Q-C12 alkyl and R1 is H. For example, Re In some
embodiments, is methyl, ethyl, propyl, butyl, pentyl or hexyl and R1 is H. In another particular embodiment Re is a C-?-C12 cycloalkyl (e.g., cyciopentyl) and Rl is H. In some embodiments, R~ is a ( ' :··(" ·.- branched alkyl (e.g., tert-bu yi) and Rf is H. In some embodiments, Re is a C-.-Cg alkyl and R* is H (e.g., where Rs is methyl and R' is H). In some embodiments, Re is a C Ce alkyl and R1 is H (e.g., where Re is propyl or butyl and Rf is H). In another particular embodiment Re is a C¾ -Cj ? alkyl and R* is a Cj-Cj2 alkyl (e.g., where Re is ethyl and R1 is methyl). Compounds of formula (III) are also provided where Re and Rf are independently a Ci-C¾2 alkyl (e.g., where both Re and R* are methyl). In some embodiments, the compounds of formula (III) are provided where Re and R1 are independently a C¾ -Cj ? alkyl. In some embodiments, Re and R1 are the same Cj -Cj 2 alkyl, e.g. , when both Re and Rf are ethyl . In some embodiments, Re and R1 are independently a Cj-Cg alkyl. In some embodiments, Re and Rf are independently a Cj-Ce alkyl. In some embodiments, at least one of Re and R1 is a C3-C6 cycloalkyl . In still some embodiments Re and R* are taken together with the N to which they are attached to form, a heterocyclic ring. In some embodiments, when Re and R1 are taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by Re, R1 and the N to which they are attached In some embodiments, contains only C and N as annular atoms. In some embodiments, the heterocycle contains as annular atoms only C and the N provided when Re and Rf are taken together with the N to which they are attached. In a particular , Re and Rf are taken together with the N to which they are attached to form a yrrolidinyl or piperidinyl ring. In some embodiments, R1 is:
Figure imgf000040_0001
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W " is perhaloalkyl (e.g., CF3) or hydrogen; (iii) Z is S; (Ii) Y5 and Υ are both methyl and (Illi) T is C. In some embodiments, R! is as defined above and the compound is further defined by any one or more of the following structural features: (i) W1 is CN; (ii) W2 is perhaloalkyl (e.g., CF3) or hydrogen; (iii) Z is S; (11) Y 5 and Y2 are taken together with the carbon to which they are attached to form a cyclopropyl and (llli) T is C. 84] In any embodiment detailed herein, R2 In some embodiments, is halo (e.g., F). In some embodiments, R2 is H. In some embodiments, R2 is halo when R1 is -Ci-Cs alkyl-NRaR or -C(0)NReRf. In some embodiments, R2 is H when R1 is -O-Ci-Cg alkyl-NRcRd.
[85] In any embodiment detailed herein, Y ' is thiocarboxyl, carboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxy carbonyl. In a particular , Y"' is carboxyl. In another particular , Y ' is alkoxycarbonyl. In another particular , Y3 is aminocarbonyl.
[86] In some embodiments, the compound is a compound of Formula III~A;
Figure imgf000041_0001
where Y!, Y2, Y3, T, R1 and R2 are as defined in formula (II) or any embodiment thereof. 87] In some embodiments, the compound is a compound of Formula III-B:
Figure imgf000041_0002
where W1 , W2, Y' T, R1 and R" are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compo und of Formula III-C:
Figure imgf000042_0001
where YJ, T, R1 and R" are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III-
Figure imgf000042_0002
where YJ, R! and R are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III-E:
Figure imgf000043_0001
where Y3 and R! is as defined in formula (I) or any embodime t thereof.
In some embodiments, the compound is a compound of Formula III-F:
Figure imgf000043_0002
where n is an integer from 5 to 8 and Y Rd and Rb are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III-G:
Figure imgf000043_0003
where n is an integer from 1 to 8 and YJ, Rc and Rd are as defined in formula (I ) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III-H:
Figure imgf000044_0001
where Y3, Re and R1 are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III- J:
Figure imgf000044_0002
where n is 0 to 3, and Y", Re and R are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula 111- :
Figure imgf000045_0001
where Y], Y , Y\ R5 and Rz are as defined in formula (11) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III~L:
Figure imgf000045_0002
where n is 0 to 3, and Y Y"', YJ, Re and Rf are as defined in formula (II) or any embodiment thereof.
In some embodiments, the compound is a compound of Formula III-M:
Figure imgf000045_0003
(III- where Y , Y" and Y"' are as defined in formula (111) or any embodiment thereof.
[98] Examples of compounds according to Formula (III) are depicted in Table 3. The
compounds depicted may be present as salts even if salts are not depicted and it is understood that this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-sol vate form of the compound, as is well understood by the skilled artisan. It is thus understood that pharmaceutically acceptable salts of compounds are intended.
Table 3, Re resentative Compounds of Formula III.
Figure imgf000046_0001
Figure imgf000047_0001

Figure imgf000048_0001
5. Antagonists of Androgen, Progesterone, and/or Esirogeii Receptors
In some embodiments, the compound is an antagonist of an androgen, progesterone, and/or estrogen receptor. Compounds include, but are not limited to, Bicalutamide (e.g., CASODEX®), Cyproterone Acetate {e.g., ANDROCUR®, CYPROSTAT®,
CYPROTERON®, PROCUR®, CYPRONE®, CYPROI IHXA! . \ CIPROTERONA®, CYPROTERONUM®, NEOPROXIL®, SITERONE®), Dienogest (e.g., VIS ANNE®), Flutamide (e.g., EULEXIN*), Galeterone (TOK-001 ), Nilutamide (e.g.,
NILANDRON®), Spironolactone (e.g. , ALDACTONE®), Abiraterone (e.g. , ZYTIGA* radium-223 chloride (e.g., ALPH ARADI ® ) , TA 700, OGX 1 1 1 , Cabozantinib (XL 184), Dasatinib (e.g. , SPRYCEL®), an mTOR inhibitor (e.g., Everolimus,
Ridaforolimus, Rapamycin, Temsirolimus), an HDAC inhibitor (e.g., Vorinostat, CI- 994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXDI OI), Sipuleucel-T (e.g., PROVENGE"), Fulvestrant (e.g., FASLODEX"'), Tamoxifen, Raloxifene, and Toremifene.
6. Salts Salts of compounds described above can be used in the disclosed methods. If a compound has, for example, at least one basic center, it can form an acid addition salt. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohaiic acid, with strong organic carboxylic acids, such as alkanecarboxyiic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxy carboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
Compounds having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts can furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds or their pharmaceutically acceptable salts, are also included. In some embodiments, salts of compounds which contain a basic group include monohydroch!oride, hydrogensulfate, methanesulfonate, phosphate or nitrate, in some embodiments, salts of compounds which contain an acid group include sodium, potassium and magnesium salts and
pharmaceutically acceptable organic amines. In some embodiments, the salts are pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salts. Pharmaceutically acceptable salts retain at least some of the biological activity of the free (non-salt ) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum, hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et ah , Pharmaceutical Salts, J. Pharm. Sci. 1977
Jan;66(l): 1 -1 9. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing
arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical 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. Therapeutic Methods
[102 [ Compounds disclosed herein can be used to treat disorders in which modulation of
androgen, estrogen, and'or progesterone receptors would be beneficial. These disorders include indications discussed below and the therapeutic indications disclosed in U.S. Patent 7,709,517; US 201 1/0003839; WO 2010/118354; WO 2011/044327; and WO 2010/099238. Compounds disclosed herein and related compounds may also be useful as modulators of other nuclear receptors, such as glucocorticoid receptor and peroxisome proliferator-activated receptor, and as therapeutic agents for diseases in which nuclear receptors play a role, diabetes, cardiac diseases, and metabolism- related diseases.
[103 "Treating" or "treatment" as used herein is an approach for obtaining a beneficial or desired result, including, but not limited to, relief from a symptom, lessening of a symptom, and preventing a worsening of a symptom associated with the disease being treated. With respect to cancer, treatment also includes, but is not limited to, any one or more of enhancing survival time, enhancing progression-free survival time, and reducing tumor size.
[104] Disorders that can be treated include, but are not limited to:
1. neurodegenerative disorders, including, but not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, hereditary spastic paraparesis, spinocerebellar atrophies, Friedreich's ataxia, amyloidosis, metabolic disease-related neurodegeneration, toxin-related neurodegeneration, multiple sclerosis, Charcot Marie Tooth syndrome;
2. cancer, including, but not limited to, prostate cancer, bladder cancer, non- Hodgkin lymphoma, leukemia., thyroid cancer, breast cancer, ovarian cancer, glioblastoma, neuroblastoma, renal cancer, Wilms' tumor
(nephroblastoma), retinoblastoma, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, desmoplastic small-round-cell tumor, colorectal cancer, esophageal cancer, head and neck cancer, lung cancer, melanoma; and
3. other disorders, such as polyglutamate disease, rheumatoid arthritis,
systemic hyperandrogenism, seborrhea, hirsuitism, precocious puberty, polycystic ovary syndrome, acne, alopecia, benign prostatic hyperplasia, intrauterine fibroids, endometriosis, glaucoma, meningiomas, Kennedy's disease (KD) or X-linked spinal and bulbar muscular atrophy.
[105] In some embodiments, disclosed compounds can be used for medical termination of intrauterine pregnancies .
[106] In some embodiments, disclosed compounds can be used as adjuvants to vaccines,
including, but not limited to, vaccines for N. meningitides , Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Helicobacter pylori , Bordeteila pertussis. Staphylococcus aureus, Pseiidomonas aeruginosa, Staphylococcus epidermis, Staphylococcus saprophytics, Moraxella catarrhalis, Yersinia pestis. Yersinia enterocolitica, Yersinia pseudotuberculosis, Mycobacterium tuberculosis, Legionella pneumophila, Rickettsia, E. coli, Vibrio cholera, Salmonella typhi. Salmonella typhimurium, Listeria monocytogenes, Porphyromonas gingivalis, Tetanus, Borrelia burgdorferi, Haemophilus influenzae B, Klebsiella, Neiserria gonorrhoeae, Chlamydia pneumoniae, Chlamydia trachomatis, Treponema, Haemophilus ducreyi, Respiratory syncytial virus, Parainfluenza virus, Poliovirus, Measles, Mumps, Rubella, Rabies, Flaviviridae viruses, Caliciviridae, HIV, Rotavirus, Pestivirus, Parvovirus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Delta hepatitis virus, Hepatitis E virus, Hepatitis G virus, Varcicella roster virus, Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus, human Herpes virus, human papillomavirus, Trichophyton mentagrophytes, Epidermophytonfloccusum, Microsporum audouini, Microsporum canis, Microsporum distorlum, Microsporum equinum,
Microsporum gypsum, Microsporum nanum, Trichophyton concentricum, Trichophyton equinum, Trichophyton gallinae, Trichophyton gypseum, Trichophyton megnini, Trichophyton mentagrophytes , Trichophyton quinckeanum. Trichophyton riibrum, Trichophyton schoenleinii, Trichophyton tonsurans. Trichophyton verrucosum, T.
verrucosum var, album, var. discoides, var. ochraceum, Trichophyton violaceum, Trichoplyton faviforme, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, Aspergillus sydowi, Aspergillus flavatus, Aspergillus glaucus, Blastoschizomyces capitatus, Candida albicans, Candida enolase, Candida tropicalis, Candida glabrata, Candida krusei, Candida parapsilosis, Candida stellatoidea, Candida kusei, Candida parakwsei, Candida lusitaniae, Candida
pseudotropicaUs, Candida guilliermondi, Cladosporiimi carrionii, Coccidioides immitis, Blastomyces dermatidis, Cryptococcus neoformans, Geotrichum clavatum, Histoplasma capsulatum, Klebsiella pneumoniae, Paracoccidioides brasiliensis, Pneumocystis carinii, Pythiumn insidiosum, Pityrosporum ovale, Saccharomyces cerevisae, Saccharomyces boulardii, Saccharomyces pombe, Scedosporium apiosperum, Sporothrix schenckii, Trichosporon beigelii, Toxoplasma gondii, Penicillium marneffei Malassezia spp., Fonsecaea spp,, Wangiella spp., Sporothrix spp., Basidiobolus spp., Conidiobolus spp., Rhizopus spp, Mucor spp, Absidia spp, Mortierella spp, Cunninghamella spp, Saksenaea spp, Alternaria spp, Curvularia spp, Helminihosporium spp, Fusarium spp, Aspergillus spp, Penicillium spp, Monolinia spp, Rhizoctonia spp, Paecilomyces spp, Pithomyces spp, Cladosporium spp, Neiserria gonorrhoeae, Chlamydia pneumoniae. Chlamydia trachomatis, Treponema pallidum, Haemophilus ducreyi, and Bacillus anthracis.
Pharmaceutical Compositions
[107] Compounds can be formulated in any type of pharmaceutical composition known in the art, including, but not limited to, tablets, troches, pills, capsules, syrups, elixirs, injectable solutions, and the like.
] 108] A pharmaceutical composition typically includes a pharmaceutically or
pharmacologically acceptable excipient or carrier. As used herein, by "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, e.g. , the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. In some embodiments, pharmaceutically acceptable carriers or excipients have met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
[109] The term "excipient" as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound as an acti ve ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g. , cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.;
compression'' encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystailine cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystailine cellulose, etc.
[HO] Tablets, troches, pills, capsules, and the like can also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fractose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. V arious other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosa ge form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, a diarylhydantoin compound can be incorporated into sustained-release preparations and devices. For example, a compound can be incorporated into time release capsules, time release tablets, and time release pills.
[Ill] Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising a compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form typically is sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating a compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticles or microparticles. Useful liquid carriers include water, alcohols or glycols or water/a] cohol/glycol blends, in which a compound can be dissolved or dispersed at effective le vels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatologicai compositions which can be used to deliver a compound to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,(508,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508). In some embodiments, the pharmaceutical composition is a unit dosage form. As used herein, "unit dosage form" is a physically discrete unit containing a predetermined quantity of active. Dosages
117'i As used herein, the term "effective amount" intends such amount of a compound which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single close or multiple closes may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
118] Useful dosages of compounds can be determined by comparing their in vitro activity and/or in vivo acti vity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, For example, the concentration of a compound in a liquid composition, such as a lotion, can be from about 0.1-25% by weight, or from about 0.5- 10% by weight. The concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1-5% by weight, or about 0.5-2.5% by weight.
119] The amount of a compound required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
120] Effective dosages and routes of administration of compounds are conventional. The exact amount (effective dose) of the agent will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like, A therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art. See, e.g.. The Pharmacological Basis of Therapeutics, Goodman and Oilman, eds,, Macmillan Publishing Co., New York. For example, an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model can also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. A therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents. ] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years. ] In general, however, a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight of the recipient per day. For example, a suitable dose can be about, 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day. A compound is conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of active ingredient per unit dosage form. ] A compound can be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 μΜ, about 1 to 50 μΜ, about 2 to about 30 uM, or about 5 to about 25 μΜ. Exemplar}' desirable plasma concentrations include at least or no more than 0.25, 0.5, 5 , 5, 10, 25, 50, 75, 100 or 200 uM. For example, plasma levels can be from about 1 to 500 micromolar or from about 10 to about 25 micrornolar. This can be achieved, for example, by the intravenous injection of a 0,05 to 5% solution of a diarylhydantoin or hydantoin compound, optionally in saline, or orally administered as a bolus containing about 1-100 mg of a diarylhydantoin or hydantoin compound. Desirable blood levels can be maintained by continuous infusion to provide about 0.00005-5 mg per kg body weight per hour, for example at least or no more than 0.00005, 0.0005, 0.005, 0.05, 0.5, or 5 mg/kg/hr. Alternatively, such levels can be obtained by intermittent infusions containing about 0.0002-20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0,02, 0.2, 2, 20, or 50 mg of a compound per kg of body weight. A compound can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself can be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
Methods of Administration A compound can be administered using pharmaceutical compositions comprising a therapeutically effec tive amount of the compound and a pharmaceutically acceptable carrier or diluent, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperito eally, or parenteral ly, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue. A compound can be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation. It can be enclosed in hard or soft shell gelatin capsule, can be compressed into a tablet, or can be incorporated directly with the food of a patient's diet. For oral therapeutic administration, a compound can be combined with one or more excipients and used in the form of an ingestible tablet, a buccal tablet, troche, capsule, elixir, suspension, syrup, wafer, and the like. A compound can be combined with a fine inert powdered carrier and inhaled by the subject or insufflated. In some embodiments, such compositions and preparations contain at least 0.1%
diarylhydantoin or hydantoin compound. The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of diarylhydantoin or hydantoin compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. ] A compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of a compound can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetm, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
Combination Therapies ] In some embodiments, combinations of one or more compounds are used. A
"combination" compounds includes one or more compounds administered substantially simultaneously, whether or not in the same pharmaceutical composition, or sequentially, compounds can, but need not be, chemically similar (i.e., two compounds of Formula I, one compound of Formula II and one compound of Formula III, etc.). ] In some embodiments, one or more of Bicalutamide (e.g., CASODEX*), Cyproterone Acetate (e.g., ANDROCUR®, CYPRQSTAT®, CYPROTERON®, PROCUR®,
CYPRONE®, CYPROHEXAL®, CIPROTERONA®, CYPROTERONUM®,
NEOPRQXIL®, SITERONE®), Dienogest (e.g., VIS ANNE®), Flutamide (e.g.,
EULEXIN®), Galeterone (TOK-001), Nilutamide (e.g., NILANDRQN®), Spironolactone (e.g., ALDACTO E*), Abiraterone (e.g., ZYTIGA*), radium-223 chloride (e.g., ALPHA ADIN®) , TAK. 700, OGX 1 1 1 , Cabozantinib (XLl 84), Dasatinib (e.g., SPRYCEL®), an mTOR inhibitor (e.g., Everolimus, Ridaforolimus, Rapamycin, Temsirolimus), an HDAC inhibitor (e.g., Vorinostat, CI-994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXD101), Sipuleucel-T (e.g. , PROVENGE*), Fulvestrant (e.g., FASLODEX*), Tamoxifen, Raloxifene, and
Toremifene is used in combination with one or more compounds of Formula I, I I. or III, In some embodiments, use of one or more compounds is combined other cancer therapies, such as internal or external radiation, surgery, and chemotherapies, including:
1. anthracyclines, such as doxorubicin (e.g., ADRIAMYCIN®, DQXIL®), including liposomal doxorubicin, epirubicm (e.g., ELLEN CE" ), and daunorubicin (e.g., CERUBIDINE®, DAUNOXOME®);
2. taxanes, such as tamoxifen (e.g., NOLVADEX®, SOLTAMOX®, ISTUBALC VALODEX®), docetaxel (e.g., TAXOTERE®), paclitaxel (e.g., TAXOL®, ABRAXANE®), and protein-bound paclitaxel (e.g., ABRAXANE®);
3. cyclophosphamide (e.g., CYTOXAN*);
4. capecitabine (e.g., XELQDA®)
5. 5-fIuorouracil or 5 FU (e.g., ADRUCIL®);
6. vino elbine (e.g., NAVELS INE®);
7. gemcitabine (e.g., GEMZAR®);
8. trastuzumab (e.g., HERCEFTIN®);
9. carboplatin (e.g., PARAPLATIN®);
10. eribu!in (e.g., HALAVEN®);
11. ixabepilone (e.g., IXEMPRA®);
12. methotrexate (e.g., AMETHOPTERIN®, MEXATE®, FOLEX®);
13. mutamycin (e.g., MITOMYCIN®);
14. niitoxantrone (e.g., NOVANTRONE®);
15. thiotepa (e.g., THIOPLEX®); 16. vincristine (e.g., ONCOVIN®, VINCASAR PES®, VINCREX®);
17. aromatase inhibitors such as anastrozole (e.g., ARIMIDEX), exemestane (AROMASIN), and letrozole (FEMARA);
18. raloxifene (e.g., E VISTA*);
19. toremifene (e.g., FARESTON®);
20. fulvestrant (e.g., FASLODEX®);
21. lapatinib (e.g., TYKERB*); and
22. metformin. Use of one or more compounds also can be used in conjunction with combinations of chemical therapies, such as:
1. doxorubicin and docetaxel (e.g., "AT," ADRIAMYCIN® and TAXOTERE®);
2. doxorubicin and cyclophosphamide, with or without paclitaxel or docetaxel (e.g. "AC ± T," ADRIAMYCIN® and CYTOXAN®, with or without TAXQL® or TAXOTERE®);
3. cyclophosphamide, methotrexate, and fluorouracii (e.g., "CMF,"
CYTOXAN®, methotrexate, and fluorouracii);
4. cyclophosphamide, epirubicin, and fluorouracii (e.g., "CEF," CYTOXAN*, ELLENCE*, and fluorouracii);
5. fluorouracii, doxorubicin, and cyclophosphamide (e.g., "FAC," fluorouracii, ADRIAMYCIN®, and CYTOXAN® or "CAF," CYTOXAN®,
ADRIAMYCIN®, and fluorouracii);
6. docetaxel, doxorubicin, and cyclopho9sphamide (e.g., "TAG," TAXOTERE*, ADRIAMYCIN®, and CYTOXAN®); and 7. gemcitabine, epirubicin, and paclitaxel (e.g., "GET," GEMZAR
ELLENCE®, and TAXOL®). Nothing in this specification should be considered as limiting the scope of this disclosure. All examples presented are representative and non-limiting. The above-described embodiments can be modified or varied, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the embodiments disclosed herein can be practiced otherwise than as specifically described.
EXAMPLE 1 Androgen receptor-expressing human urothelial carcinoma UM-UC-3 cells are purchased from the American Type Culture Collection, Manassas, VA, USA) and maintained in MEM medium (Gibco, 51200) supplemented with glutamine, non-essential amino acids, and 50% fetal bovine serum (FBS) at 37°C in a humidified atmosphere of 5% C02. Cells are cultured in phenol red- free medium supplemented with 5% charcoal -stripped FBS (CSS) at least 24 h before experimental treatment with DHT (dihydrotestosterone) or a compound disclosed herein. Cells (3xl03) are seeded in 96-well tissue culture plates and incubated for 3 or 6 days with medium supplemented with 5% CSS containing different treatments: a compound disclosed herein at 0 (control), 1 , 10, or 30μΜ or DHT at 0 (control), 0.1 , 1 or lOnM). An MTS assay is used to determine cell viability.

Claims

1 , A method of treating a disorder involving an androgen, estrogen, and/or progesterone receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula I:
Figure imgf000064_0001
wherein:
W3 is CN, 'N02 or S02R4; w' is alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynvl, substituted alkynyl or halogen;
Z5 is S or O
Z2 is S, O or NR.4;
Y and Y1 are independently hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroary], arylalkyl, aryl alken i, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y1 and are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyi, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R1 is ~C rr,j!ky!~N!rR". -0-Ci-C8aiky]-NRcRd or -C(G)NReR.f, where:
(S3 Ra is a C2-Ci2alkyl and Rb is H or a Cj-Ci2alkyl or Ra and Rb are taken together with the N to which they are attached to form a heterocyclic ring;
Rc is a CrC12alkyl and Re is H or a d-C^alkyl or R1, and Rd are taken together with the N to which they are attached to form a. heterocyclic ring;
Re is a C2-C12alkyl and Rf is H or a d- 2alkyl, or
Re is a Cj-Cj2alkyl and R1 is Ci-Ci2alkyi, or
Re and Rf are taken together with the N to which they are attached to form a heterocyclic ring;
Rz is hydrogen, halogen, nitro, alkyl and substituted alkyl; and
R4 is independently H, alkyl, or aryl.
2. A method of treating a disorder involving an androgen, estrogen, and/or progesterone receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural Formula II:
Figure imgf000065_0001
wherein:
W3 is CN, N02 or SO..R 1:
W is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen; Z is S, O or NR5;
γ' and Y2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyL substituted alky yL arvi, substituted aryl, heteroarvi, substituted heteroaryl, arvialkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyelyl, substituted heterocyelyl or Y! and Y2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycioalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R1 is -Cj-Cs alkyl-NRaRb, -O-Ci-Cg alkyl-NRcRd or -C(0)NReRf,
where:
Ra is a Ci-Ci2 alkyl and R° is H or a Ci-C12 alkyl or Ra and R are taken together with the N to which they are attached to form a heterocyclic ring;
Rc is a Ci-Ci2 alkyl and Rd is H or a Ci-C12 alkyl or R° and Rd are taken together with the N to which they are attached to form a heterocyclic ring;
Re is a C1-C12 alkyl and Rf is H or a C1-Q2 alkyl, or Re and R1 are taken together with the N to which they are attached to form a heterocyclic ring;
R ' is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R* is H, alkyl, substituted alkyl, aryl or substituted aryl; and
Rs is H, alkyl, substituted alkyl, aryl or substituted aryl.
3. A method of treating a disorder involving an androgen, estrogen, and/or progesterone receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a selected from the group consisting of Bicalutamide, Cyproterone Acetate, Dienogest, Flutamide, Galeterone, Nilutamide, Spironolactone, Abiraterone, radium-223 chloride, TAK 700, OGX 111 , Cabozantinib, Dasatinib, an mTOR inhibitor, an HDAC inhibitor, Sipuleucel-T,
Fuivestrant, Tamoxifen, Raloxifene, and Toremifene.
4, The method of claim 1 , 2, or 3 wherein the disorder is selected from the group consisting of neurodegenerative disorders, cancer, polyglutamate disease, rheumatoid arthritis, systemic hyperandrogenism, seborrhea, hirsuitism, precocious puberty, polycystic ovary syndrome, acne, alopecia, benign prostatic hyperplasia, intrauterine fibroids, endometriosis, glaucoma, meningiomas, Kennedy's disease (KD) or X-linked spinal and bulbar muscular atrophy.
5, The method of claim 4 wherein the disorder is a neurodegenerative disorder and the neurodegenerative disorder is selected from, the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontoteniporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, hereditary spastic paraparesis, spinocerebellar atrophies, Friedreich's ataxia, amyloidosis, metabolic disease-related neurodegeneration, toxin- related neurodegeneration, multiple sclerosis, and Charcot Marie Tooth syndrome,
6. The method of claim 4 wherein the disorder is cancer and the cancer is selected from the group consisting of prostate cancer, bladder cancer, non-Hodgkin lymphoma, leukemia, thyroid cancer, breast cancer, ovarian cancer, glioblastoma, neuroblastoma, renal cancer, Wilms' tumor (nephroblastoma), retinoblastoma, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, desmoplastic small-round-cell tumor, colorectal cancer, esophageal cancer, head and neck cancer, lung cancer, and melanoma.
7. A vaccine composition comprising an androgen, estrogen, and/or progesterone receptor antagonist.
8. The vaccine composition of claim 7 which comprises a compound of Formula I, a compound of Formula II, a compound of Formula III, Bicalutamide, Cyproterone Acetate, Dienogest, Flutamide, Galeterone, Nilutamide, Spironolactone, Abiraterone, radium-223 chloride, TAK 700, OGX 111 , Cabozantinib, Dasatinib, an mTOR inhibitor, an HDAC inhibitor, Sipuleucei-T, Fulvestrant, Tamoxifen, Raloxifene, and Toremifene.
9. A method of vaccinating an individual, comprising administering to an individual in need thereof the vaccine composition of claim 7.
10. A method of terminating an intrauterine pregnancy, comprising administering to an individual in need thereof a compound of a structural formula selected from, the group consisting of Formula I, Formula II, and Formula III.
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