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WO2020176579A1 - Composés de thiényl cyclopropyl-amino-isoquinolinyle amide - Google Patents

Composés de thiényl cyclopropyl-amino-isoquinolinyle amide Download PDF

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Publication number
WO2020176579A1
WO2020176579A1 PCT/US2020/019822 US2020019822W WO2020176579A1 WO 2020176579 A1 WO2020176579 A1 WO 2020176579A1 US 2020019822 W US2020019822 W US 2020019822W WO 2020176579 A1 WO2020176579 A1 WO 2020176579A1
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Prior art keywords
compound
alkyl
pyridinyl
pharmaceutically acceptable
halogen
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Mitchell A. Delong
Jill M. STURDIVANT
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Aerie Pharmaceuticals Inc
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Aerie Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to amino isoquinolinyl amide compounds that affect the function of kinases and other proteins in a cel! and that are useful as therapeutic agents or with therapeutic agents.
  • these compounds are useful in the treatment of eye diseases such as glaucoma and retinal diseases, as anti-inflammatory agents, for the treatment of cardiovascular diseases, and for diseases characterized by abnormal growth, such as cancers.
  • G proteins guanine nucleotide-binding proteins
  • GPCRs G-protein coupled receptors
  • kinases play important roles in the regulation of various physiological functions.
  • kinases have been implicated in a number of disease states, including, but not limited to: cardiac indications such as angina pectoris, essential hypertension, myocardial Infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction, upper respiratory indications such as rhinitis, seasonal allergies, inflammatory disease, inflammation in response to injury, rheumatoid arthritis.
  • cardiac indications such as angina pectoris, essential hypertension, myocardial Infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes
  • respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction
  • upper respiratory indications such as
  • Other conditions include chronic inflammatory bowei disease, glaucoma, hypergastrinemia, gastrointestinal indications such as acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastrointestinal reflux, peptic ulcer, Zollinger-Eilison syndrome, pain, obesity, bulimia nervosa, depression, obsessive-compulsive disorder, organ malformations (e.g., cardiac malformations), neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease, multiple sclerosis, Epsiein-Barr infection and cancer ( Nature Reviews Drug Discovery 2002, 1 : 493-502). In other disease states, the role of kinases is only now becoming clear.
  • the retina is a complex tissue composed of multiple interconnected cell layers, highly specialized for transforming light and color into electrical signals that are perceived by the brain. Damage or death of the primary light-sensing cells, the photoreceptors, results in devastating effects on vision.
  • the cellular and molecular mechanisms leading from the primary mutations to photoreceptor apoptosis are not well understood, but may involve the wnt pathway (AS hacka “The Wnt Signaling Pathway in Retinal Degeneration” iUBMB Life Volume 57, Number 6 / June 2005).
  • the receptors when agonists are administered to treat a disease or condition by activation of certain receptors, the receptors relatively quickly become desensitized from the action of the GRKs such that agonist administration may no longer result in therapeutic activation of the appropriate receptors. At that point, administration of the agonist no longer enables sufficient or effective control of or influence on the disease or condition intended to be treated.
  • JAK Janus Kinases
  • JAK2, JAK3, and TYK2 The JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Specific cytokines are associated with specific JAK pairings. Each of the four members of the JAK family is implicated In the signaling of at least one of the cytokines associated with inflammation. Binding of cytokine to a JAK-dependeni cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation.
  • Pbosphory!ated JAKs in turn, bind and pbosphoryiate various STAT proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease.
  • n 0 or 1 ;
  • J is -S(0 2 j- or -C(Q)-;
  • R 1 is H, -Ci-s alkyl, ⁇ Ci_e haloalky!, aryl, -ary!-iCi-s alky!-N(R 3 )R 4 , -heteroaryi-(Ci- 6 aikyl)-N(R 3 )R 4 , - ⁇ C 1..6 aikyl)-beieroaryi-(Ci.. 6 alkyl), -(Ci- 6 aikyl)-aryi-(Ci..
  • R 2 is H, -C 1-6 alkyl, -Ci_s haloalkyi, aryl, -aryi-(Ci-e a!kyi)-N(R 3 )R 4 , heieroaryi (Ci_s alky!)-N(R 3 )R 4 , -(Ci- e aikyl)-heteroaryl ⁇ (Ci_ e alkyl), -(Ci_e alkyl)-aryl-(Gi-e alkyl), -NH-heteroaryl, -NH-aryl, -C 1-6 alkyl-CN, heteroaryi, -(Ci_s alkylVheieroaryi, -(C 1.6 a!kyi) ⁇ N(R 3 )R 4 , -(C 1-3 alkyl)-heterocyclyl or heterocycloaikyi;
  • R 1 and R 2 together with the nitrogen to which they are attached, form a -heterocycie;
  • R 3 is H, C 1-6 aikyl or -C 1-6 haloalkyi;
  • R 4 is H, C 1-6 alkyl or -Ci-s haloalkyi
  • X is H, Ci-e aikyl, -G I-6 haloalkyi, halogen or hydroxyl;
  • Y is H, C 1-6 alkyl, -Gi_e haloalkyi, halogen or hydroxyl;
  • Z is H, C1-6 alkyl, -Gi_e haloalkyi, halogen, hydroxyl, -(Ci-b alkyl)-N-[(Ci-e alkyl)]-(Ci-e alkyl), -Ci-@ alkyl-CIM, -C 1-6 alkyl-OH, -Ci-e alkyi 0(C0)-Ci ⁇ s aikyl, -Ci-g aikyl (COjO-Ci ⁇ 6 aikyl, - ⁇ CO)OH, or -(CO)0-Ci- 6 alky!.
  • R 2 is H, -Ci-s alkyl, -Ci-e haloaikyl, aryl, -aryl-(Ci_e alkyl)-N(R 3 )R 4 , ⁇ heteraaryi-(Ci- 8 a!kyl)-N ⁇ R 3 )R 4 , -(Ci_e aikyl)-heteroary!-(Ci_e alkyl), -(Ci_6 a!kyl)-aryi-(Ci_s alkyl), -NH-heteroaryl, -NH-aryl, -Ci_ s alkyl-CN, heteroaryl, -(Ci_ 6 alkyl)-heteroaryl, -(Ci- S aikyi)-N(R 3 )R 4 , -(Ci-s alkyl)-heterocyclyl or heterocycloaikyl;
  • R 1 and R 2 together with the nitrogen to which they are attached, form a -heterocycie;
  • R 3 is H, Ci-e alkyl or -Ci- S haloaikyl;
  • R 4 is H, Ci-s alkyl or -Ci_e haloaikyl
  • X is H, Ci-e alkyl, -Ci_e haloaikyl, halogen or hydroxyl;
  • Y is H, Ci-e alkyl, -Ci_e haloaikyl, halogen or hydroxyl;
  • Z is H, Ci-e alkyl, -Ci_ 8 haloaikyl, halogen or hydroxyl.
  • the present disclosure provides a pharmaceutical composition comprising a compound according to the present disclosure and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating an ocular disorder in a subject in need of treatment, comprising administering to the subject a compound or composition according to the present disclosure.
  • the present disclosure provides a method of reducing intraocular pressure in a subject in need thereof, comprising administering to an eye of the subject a compound or composition according to the present disclosure
  • the present disclosure provides a kit comprising a compound or composition of according to the present disclosure and instructions for use.
  • Alky!” refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.“Alkyl” may be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. Alkyl groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted.
  • the substituent group is preferably but not limited to C 1 -C 4 alkyl, aryl, heteroary!, amino, thioaikyi, cyano, halogen, a!koxy or hydroxyl.“C 1 -C 4 alkyl’’ refers to alkyl groups containing one to four carbon atoms.
  • Alkenyl refers to an unsaturated aliphatic hydrocarbon moiety including straight chain and branched chain groups. Alkenyl moieties must contain at least one aikene.“Alkenyl” may be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-buienyl and the like. Alkenyl groups may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituent group is preferably alkyl, halogen or aikoxy. Substituents may also be themselves substituted.
  • C2-C4 alkenyl refers to alkenyl groups containing two to four carbon atoms.
  • “Aikynyl” refers to an unsaturaied aliphatic hydrocarbon moiety including straight chain and branched chain groups. Aikynyl moieties must contain at least one a!kyne.“Aikynyl” may be exemplified by groups such as eihynyi, propynyl, n-butynyl and the like. Aikynyl groups may be substituted or unsubstituted. More than one substituent may be present. Substituents are not on the a!kyne itself but on the adjacent member atoms of the aikynyl moiety.
  • substituent group I When substituted, the substituent group Is preferably alkyl, amino, cyano, halogen, alkoxyl or hydroxyl. Substituents may also be themselves substituted.
  • C2-C4 aikynyl refers to aikynyl groups containing two to four carbon atoms.
  • “Acyl” or“carbonyl” refers to the group -C(0)R wherein R is hydrogen, alkyl, alkenyl, aikynyl, aryl, heteroary!, carbocyclic, heterocarbocyc!ic, C 1 -C 4 alkyl aryl or C 1 -C 4 alky! heteroary!.
  • C 1 -C 4 alky!carbonyl refers to a group wherein the carbonyl moiety is preceded by an alkyl chain of 1-4 carbon atoms.
  • “Aikoxy” refers to the group -O-R wherein R is alkyl, alkenyl, acyl, alkyl alkenyl, alkyl aikynyl, aryl, carbocyclic, heierocarbocyclic, heieroaryl, C 1 -C 4 alkyl aryl or Ci-C 4 alkyl heteroaryl.
  • “Amino” refers to the group -NR’R’ wherein each R’ is. independently, hydrogen, amino, hydroxyl, aikoxyl, alkyl, aryl, cycloalky!, heterocycloalkyl, heieroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroary!.
  • the two R’ groups may themselves be linked to form a ring.
  • the R’ groups may themselves be further substituted, In which case the group also known as guanidinyl is specifically contemplated under the term‘amino”.
  • “Aryl” refers to an aromatic carbocyclic group.“Aryl” may be exemplified by phenyi.
  • the ary! group may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. When substituted, the substituent group is preferably but not limited to aikyi, aikenyi, heteroaryi, acyl, carboxyl, sulfony!, su!fony!amino, tbicalkyi, trifluoromethyi, carbonylamino, amino, cyano, halogen, or hydroxyl.
  • Carbonyl refers to the group -C(0)R wherein each R is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryl, C1-C 4 alkyl aryl or Ci-C4 alky! heteroaryl.
  • “Carbonylamino” refers to the group -C(0)NR'R' wherein each R' is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryi, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryi.
  • the two R' groups may themselves be linked to form a ring.
  • “C1-C4 alkyl aryl” refers to C1-C4 aikyi groups having an aryl substituent such that the aryl substituent is bonded through an aikyi group.“C1-C4 alkyl aryl” may be exemplified by benzyl.
  • C1-C4 alkyl heteroaryi refers to C1-C4 alkyl groups having a heteroaryi substituent such that the heteroaryi substituent is bonded through an alkyl group.
  • Carbocyciic group” or“cycloalkyl” means a saturated or unsaturated hydrocarbon ring
  • Carbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyciic ring systems.
  • Monocyclic carbocyclic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
  • Bicyciic carbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring.
  • Carbocyclic groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted.
  • Suitable substituents include halogen, cyano, aikoxyl, amino, trifluoromethyi, and trifluoromethoxyl.
  • Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. The most preferred carbocyclic groups are cyclohexyl and cyclopentyl. Carbocyclic groups are not aromatic.
  • Halogen refers to fluoro, chloro, bromo or iodo moieties.
  • the halogen is fiuoro, chloro, or bromo.
  • Heteroaryi or“heteroaromatic” refers to a monocyclic or bicyciic aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring. Heteroaryi may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituents may themselves be substituted. Preferred but non limiting substituents are halogen, cyano, aikoxyl, amino, trifluoromethyi, trifluoromethoxyi, aryl, C 1 -C 4 aikyiaryl, hydroxyl, carboxyl, carbonylamino, or C 1 -C 4 alkyl.
  • Preferred beieroaromatic groups include benzo[b]thiophenyi, pyrrolidy!, benzofuranyl, isoquinoilnyi, imidazolyl, quinoiiny!, cinnolinyl, tetrazoy!, triazoiyl, thienyl, thiazolyl, purinyl, pyrimidyl, pyridyi, and furany!.
  • More preferred heteroaromatic groups include isoquinoiinyi, benzo[b] ⁇ hiophenyl; thienyl, furanyi, tetrazoyi, triazoiyl, and pyridyi.
  • “Heieroaiom” means a polyvalent atom other than carbon in the ring of a heterocyclic group or a heteroaromatic group or the chain of a heterogeneous group.
  • beieroaioms are selected from the group consisting of nitrogen, sulfur, and oxygen atoms.
  • Groups containing more than one heteroatom may contain different heteroatoms.
  • Halogens are monovalent and thus are not considered heteroatoms in this sense, but have their own category.
  • Heterocarbocydic group’ or“heterocydoalkyi” or “heterocyclic” means a saturated or unsaturated hydrocarbon ring containing at least one heteroatom.
  • Heterocarbocydic groups are monocyclic, or are fused, spiro, or bridged bicyciic ring systems.
  • Monocyclic heterocarbocydic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
  • Bicyciic heterocarbocydic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring.
  • Heterocarbocydic groups may be substituted or unsubsiituied.
  • substituents may be present. Substituents may also be themselves substituted. Suitable substituents include halogen, nitrile, hydroxyl, alkoxyl, amino, trifluoromethyi, and trifluoromeihoxyi.
  • Preferred heterocarbocydic groups include epoxy, tetrahydrofuranyi, azacyciopentyl (or pyrrolidyl), azacyciohexyi, piperidy!, and homopiperidyl. More preferred heterocarbocydic groups include pyrrolidyl, piperidyl, and homopiperidyl. The most preferred heterocarbocydic group is piperidyl. Heterocarbocydic groups are not aromatic.
  • “Hydroxy” or“hydroxyl” means a chemical entity that consists of -OH. Alcohols contain hydroxy groups. Hydroxy groups may be free or protected. An alternative name for hydroxy is hydroxyl.
  • “Linker” means a linear chain of n member atoms where n is an integer from 1 to 4.
  • “Member atom” means a carbon, nitrogen, oxygen or sulfur atom. Member atoms may be substituted up to their normal valence. If more than one stable valence is available for a member atom, e.g , sulfur, then all stable valences are contemplated. If substitution is not completely specified, the unspecified substituents required for valency are hydrogen.
  • Rings means a collection of member atoms that are cyclic. Rings may be carbocyclic, aromatic, or heterocyclic or heteroaromatic, and may be substituted or unsubstituted, and may be saturated or unsaturated. More than one substituent may be present. Ring junctions with the main chain may be fused or spirocyc!ic. Rings may be monocyclic or bicyciic. Rings contain at least 3 member atoms and at most 10 member atoms. Monocyclic rings may contain 3 to 7 member atoms and bicyciic rings may contain from 8 to 12 member atoms. Bicyciic rings themselves may be fused or spirocyciic
  • “Thioalkyi” refers to the group -S-aikyl.
  • “Suifonyl” refers to the ⁇ S(0) 2 ‘ group wherein R‘ is a!koxy, aikyl, aryl, carbocyclic, heterocarbocydic; heteroaryi, Ci-C alkyl aryl or CrC 4 alkyl heteroaryl.
  • “Su!fonylamino” refers to the -S(0) 2 NR'R’ group wherein each R' is independently alkyl, aryl, heteroaryl, Ci-C 4 alkyl aryl or Ci-C 4 alkyl heteroaryl.
  • “Pharmaceutically acceptable carrier” means a carrier that is useful for the preparation of a pharmaceutical composition that is: generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable.
  • “A pharmaceutically acceptable carrier” includes both one and more than one carrier. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal intramuscular, sublingual, nasal and ora! administration.“Pharmaceutically acceptable carrier” also includes agents for preparation of aqueous dispersions and sterile powders for injection or dispersions.
  • “Excipient” as used herein includes physiologically compatible additives useful In preparation of a pharmaceutical composition.
  • Examples of pharmaceutically acceptable carriers and excipients can for example be found in Remington Pharmaceutical Science, 16 s Ed.
  • “Therapeutically effective amount” as used herein refers to a dosage of the compounds or compositions effective for influencing, reducing or inhibiting the activity of or preventing activation of a kinase. This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, preferably, a human, such as reduction in intraocular pressure.
  • “Eye disease” as used herein includes, but is not limited to, glaucoma, allergy, cancers of the eye, neurodegenerative diseases of the eye, such as diabetic eye disease, macuiar degeneration (AMD), inflammation, and dry eye.
  • AMD macuiar degeneration
  • the term“disease or condition associated with kinase activity” is used to mean a disease or condition treatable, in whole or in part, by inhibition of one or more kinases.
  • controlling the disease or condition is used to mean changing the activity of one or more kinases to affect the disease or condition.
  • contacting a cell is used to mean contacting a cell in vitro or in vivo i.e. in a subject, such as a mammal, including humans, rabbits, cats and dogs.
  • n 0 or 1 ;
  • J is -S(0 2 )- or -C(O)-;
  • R 1 is H, -Ci_ 6 alkyl, -Ci_ 6 haloalkyl, aryl, -aryl-(Ci_e alkyl)-N(R 3 )R 4 , -heieroaryi-(C;-s alkyi)-N(R 3 )R 4 , -(Ci-$ aikyl)-beteroaryi ⁇ (Ci-.e alkyl), - ⁇ Ch-e aikyi)-aryi ⁇ (Ci-s
  • R 1 and R 2 together with the nitrogen to which they are attached, form a -heterocycle;
  • R 3 Is H, Ci-e alkyl or -Ci- 8 haioaikyi;
  • R 4 is H, Ci_e alkyl or -Ci_e haioaikyi;
  • X is H, Ci ⁇ s alkyl, -Ci_e haioaikyi, halogen or hydroxyl;
  • Y is H, C alkyl, -Ci- 6 haioaikyi, halogen or hydroxyl;
  • Z is H, Ci-e a!ky!, -Ci_e haioaikyi, halogen, hydroxyl, -(Ci-e alkyl)-N-[(Ci-e alkyl)]-(Ci-e alkyl), -Ci-e alkyl-CN, -Ci-e alkyl-OH, -Ci-e alkyl 0(C0)-Ci_g alkyl, -Ci ⁇ 6 alkyl-(COjO-C _6 alkyl, - ⁇ CO)OH, or -(CO)0-Ci-e alky!
  • Z is H, Ci.. 3 alkyl, -Ci_e haioaikyi, halogen or hydroxyl.
  • n is 1
  • Z is H, Ci- e alkyl, -Ci-s haioaikyi, halogen or hydroxyl.
  • n is i .
  • n 0.
  • R 1 is H, -Ci-e alkyl, -Ci_e haioaikyi, aryl, heteroaryl, -(Ci-e alky!)-heteroaryi, -(Ci-e alkyl)-N(R 3 )R 4 , -(Ci-e al ky I)- h ete ro cycly I or heterocycloalkyi; and
  • R 2 is H, -Ci-e alkyl, -Ci_s haioaikyi, aryl, heteroaryl, -(Ci_e alkyl)-heteroaryl, -(Ci-s alkyi)-N(R 3 )R 4 , -(Ci- 6 alkyl)-heterocyclyl or heterocycloalkyi.
  • R 1 is H, -Ci-s alkyl, -Ci-s haioaikyi, aryl, heteroaryl, ⁇ (Ci-s alkyi)-pyridinyl, -(Ci-s aikyi)-N(R 3 )R , -(Ci. 8 aikyl)-heferocyclyl or heterocycloalkyi;
  • R 2 is H, -Ci-s alkyl, -Ci-e haioaikyi, aryl, heteroaryi, -(Ci_e alkyl)-pyridinyl, -(Ci-e a!kyl)-N(R 3 )R 4 , -(Ci- 6 al ky I)- h ete ro cycly I or heterocycloalkyi;
  • n 0;
  • Z is H, Ci-e alkyl, -Ci-e haioaikyi, halogen, hydroxyl, -(Ci-e aikyl)-N-[(Ci-e alkyl)]-(Ci- 8 alkyl), -Ci_e alkyl-CN, -Ci_e alkyl-OH, ⁇ Ci- 6 alkyl-0(C0)-Ci-e alkyl, -(CO)OH, or - ⁇ C0)0-Ci- S alkyl.
  • n 0;
  • Z is hydroxyl, -Ci_ 6 a!kyl-OH, -Ci- 6 alkyi-0(C0)-Ci_ 6 alkyl, -(CO)OH, or -(CO)0-Ci- S alkyl.
  • n 0;
  • Z is H, Ci-6 alkyl, -Ci_e haloalkyl, halogen, -(Ci-e alkyi)-N-[(Ci-e aikyl)]-(Ci.s alkyl), or -Ci_e alkyi-CN
  • -Ci ⁇ e alkyl is methyl or ethyl.
  • -Ci-s haloalkyl is trihalomethanyl or trihaloethanyl.
  • the compound of Formula (I) is a compound of Formula (l-A):
  • the compound of Formula (I) is a compound of Formula (I-A1):
  • the compound of Formula (I) is a compound of Formula (i-A1-a):
  • the compound of Formula (I) is a compound of Formula (i-A1-b):
  • the compound of Formula (i) is a compound of Formula (I-A1-C):
  • the compound of Formula (I) is a compound of Formula (l-A1-d):
  • the compound of Formula (i) is a compound of Formula (I-A2):
  • the compound of Formula (!) is a compound of Formula (i-A2-a):
  • the compound of Formula (I) is a compound of Formula (i-A2-b):
  • the compound of Formula (i) is a compound of Formula (I-A2-C):
  • the compound of Formula (!) is a compound of Formula (l-A2-d):
  • the compound of Formula (!) is a compound of Formula (I-A3):
  • the compound of Formula (I) is a compound of Formula (l-B):
  • the compound of Formula (I) is a compound of Formula (I-B1):
  • the compound of Formula (i) is a compound of Formula (l-B1-a):
  • the compound of Formula (!) is a compound of Formula (l-B1-b):
  • the compound of Formula (!) is a compound of Formula (l-B1-c):
  • the compound of Formula (!) is a compound of Formula (l-B1-d):
  • the compound of Formula (i) is a compound of Formula (I-B2):
  • the compound of Formula (I) is a compound of Formula (!-B2 ⁇ a):
  • the compound of Formula (I) Is a compound of Formula (l-B2-b):
  • the compound of Formula (!) is a compound of Formula (l-B2-c):
  • the compound of Formula (I) is a compound of Formula (l-B2-d):
  • the compound of Formula (I) is a compound of Formula (I-B3):
  • the compound of Formula (i) is a compound of Formula (l-C):
  • Z is .
  • X, Y and Z are H.
  • X and Z are H.
  • Y and Z are H.
  • X is H.
  • R 1 is H, -Ci- 6 alkyl, -Ci_e haloaikyl, aryl, heteroaryi, -(Ci_e a!kyl)-pyridinyl, -(Ci-e alkyl) ⁇ M(R 3 )R 4 , -(Cm a!kyl)-heierocyciyi or heterocycloalkyl; and
  • R 2 is H, -Ci alkyl, -Ci-e haloaikyl, aryl, heteroaryi, -(Ci ⁇ s alkyl)-pyridinyl, -(Cm a!ky!-N(R 3 )R 4 , -(Ci-e alkyl)-heteroeyclyl or heterocycloalkyl
  • R 1 is H, -Ci- ® alkyl, aryl, heteroaryi, -(Ci_e alkyl)-pyridinyl, -(Cm alkyl)-N(R 3 )R 4 , -(Cm aikyl)-heterocycly! or heterocycloalkyl;
  • R 2 is H, -Ci-s alkyl, aryl, heteroaryi, -(Ci_e alkyl)-pyridinyl, -(Ci-e alkyl)-N(R 3 )R 4 , -(Cm a ! kyl)- heterocy cly I or heterocycloalkyl;
  • R 3 is H or Ci-e alkyl
  • R 4 is H or C 1—6 alkyl
  • X is H, Ci ⁇ s alkyl, halogen or hydroxyl
  • Y is H, Ci-e alkyl, halogen or hydroxyl
  • Z is H, Ci ⁇ 6 alkyl, halogen or hydroxyl.
  • R 1 is H, -Ci-4 alkyl, aryl, heteroaryi, -(Ci_ alkyl)-pyridinyl, -(Cm alkyl)-N(R 3 )R 4 , -(Cm alkyl)-heterocyclyl or heterocycloalkyl;
  • R 2 is H, -C i_4 alkyl, aryl, heteroaryi, -fCi- 4 alkyl)-pyridinyl. -(Cm a!ky!-N(R 3 )R 4 , -(C 1.4
  • R 3 is H or C 1...4 alkyl
  • R 4 is H or C1-4 alkyl
  • X is H, C 1-4 alkyl, halogen or hydroxyl
  • Y is H, C 1-4 alkyl, halogen or hydroxyl
  • Z is H, C 1-4 alkyl, halogen or hydroxyl.
  • R 1 is H, phenyl, pyridinyl, -(Ci_e alkyl)-pyridinyl, -(Ci-s aiky!)-N(R 3 )R 4 , -(C1-8 aikyl)-heterocyclyl or heterocycloaikyl;
  • R 2 is H, phenyl, pyridinyl, -(Ci- 6 a!kyl)-pyridinyi, -(Ci-s alkyl)-N(R 3 )R 4 , -(C1-6 a I kyi)- heterocycly I or heterocycloaikyl.
  • R 1 is H
  • R 2 is H, phenyl, pyridinyl, -(Ci_e aikyi)-pyridinyi, -(Ci-e aikyl)-N(R 3 )R 4 , -(Ci-e a I kyl)-- heterocycly I or heterocycloaikyl.
  • R 1 is H or -Ci- S alkyl.
  • R 1 is -Ci_e alkyl.
  • R 1 is H.
  • R 2 is phenyl, pyridinyi, -(Ci.. s aiky!)-pyridiny!, -(Ci-e aiky!-N(R 3 )R , -(Ci-s a!kyi)-heieroeyc!yi or heterocycloaikyl.
  • pyridinyl I 2-pyridinyi.
  • pyridinyi is 3-pyridinyi
  • pyridinyi is 4-pyridinyl.
  • R 2 is phenyl, pyridinyl, -(Ci_s aikyl) ⁇ pyridinyl, -(Ci- 6 a!ky!)-heterocycly! or heterocycloaikyl.
  • R 2 is -(C1-6 alky!)-N(R 3 )R 4 , -(C1-6 alky!)-beterocyc!y! or heterocycloaikyl;
  • R 2 is phenyl, pyridinyi, -(Ci_e alkyi)-pyridinyl.
  • R 2 is pyridinyl
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms, wherein one or two of the ring atoms are, independently, 0, S or N
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocydyi containing six ring atoms, wherein one or two of the ring atoms are N.
  • R 3 and R 4 are H.
  • R 3 and R 4 are, independently, Ci ⁇ s alkyl.
  • R 3 is H
  • R 4 is Ci_e alkyl
  • X is C l-® alkyl, halogen or hydroxyl:
  • Y and Z are H.
  • X is halogen
  • Y and Z are H.
  • X is Ci_e alkyl, halogen or hydroxyl
  • X is methyl, ethyl, CF3, CHF2 or CH 2 F.
  • Y is ethyl, ethyl, CF 3 , CHF 2 or
  • Z is methyl, ethyl, CF 3 , CHF 2 or CHzF.
  • X is halogen
  • X is F or CL
  • X is Cl.
  • X is methyl or halogen
  • Z is methyl or halogen.
  • X is methyl, F or Cl
  • Y is methyl, F or Cl
  • Z is methyl, F or Cl.
  • X is halogen
  • Y is hydroxyl
  • Y is hydroxyl
  • Z is H or F.
  • aryl is phenyl.
  • heteroaryi is pyridiny!, pyridaziny!, pyrimidinyl, pyraziny!, triaziny!, ieiraziny!, pyrazo!y!, or imidazo!y!.
  • the compound is a compound provided in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the compound is a compound provided in Table 2, below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound provided in Table 3, below, or a pharmaceutically acceptable salt thereof.
  • Compounds described herein may exist in one or more particular geometric, optical, enantiomeric, diasiereomerie, epimerie, atropic, stereoisomer, tautomeric, conformational, or anomeric forms, including but not limited to, c/s- and frans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1 -forms; (+) and (-) forms; keto ⁇ , eno! ⁇ , and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and b-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as“isomers” (or“isomeric forms
  • a compound described herein may be an enantiomerically enriched isomer of a stereoisomer described herein
  • the compound may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Enantiomer when used herein, refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other.
  • a preparation of a compound disclosed herein is enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter.
  • the compound has a purity corresponding to a compound having a selected stereochemistry of a selected siereocenier of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • a composition described herein includes a preparation of a compound disclosed herein that is enriched for a structure or structures having a selected stereochemistry, e.g., R or S, at a selected stereocenter.
  • a selected stereochemistry e.g., R or S
  • Exemplary R/S configurations can be those provided in an example described herein.
  • An“enriched preparation,” as used herein, is enriched for a selected stereoconfiguration of one, two, three or more selected stereocenters within the subject compound.
  • Exemplary selected stereocenters and exemplary stereoconfigurations thereof can be selected from those provided herein, e.g., in an example described herein.
  • enriched is meant at least 60%, e.g., of the molecules of compound in the preparation have a selected stereochemistry of a selected stereocenter in an embodiment it is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Enriched refers to the level of a subject oiecule(s) and does not connote a process limitation unless specified.
  • Compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution.
  • the compounds may, for example, be resolved info their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of ihe free acid.
  • the compounds may also be resolved by formation of siereolsomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral chromatography column.
  • the enantiomers also may be obtained from kinetic resolution of the racemate of corresponding esters using iipase enzymes
  • isomers are structural (or constitutional) isomers (i.e , isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a meihoxy group, -QCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH.
  • a reference to ortho-chiorophenyi is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms failing within that class (e.g., Cs-aiky! or propyl includes n-propyi and iso-propyl; C h alky! or butyl includes n-, iso-, sec-, and fe/f-butyl; methoxyphenyl includes ortho-, meia-, and para-methoxy phenyl).
  • keto-, enol-, and enolate-for s does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-for s, as in, for example, the following tautomeric pairs: keto/enol, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, ihiokeione/eneihioi, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 G, and 14 C; 0 may be in any isotopic form, including ,6 0 and i8 0; and the like.
  • a compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt Includes salts of the active compounds that are prepared with relatively nonioxic acids or bases, depending on the particular substituents found on the compounds described herein. Neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.
  • the compound is present in mono-salt form in embodiments, the compound is present in di-salt form.
  • the compound is anionic, or has a functional group which may be anionic
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2 ’, and other cations.
  • suitable organic cations include, but are not limited to, ammonium ion (i e., NHT) and substituted ammonium ions (e.g., NHsFV, NH2FV, NHFV, NRT).
  • substituted ammonium ions are those derived from: ethy!amine, dietbyiamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzyiamine, phenylbenzylamlne, choline, meglumine, and tromethamine, as wei! as dibasic amino acids, such as lysine and arginine.
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-aeetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, eihanesuifonic, fumaric, glucohepionic, gluconic, glutamic, glycolic, hydroxymaleic, bydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, iauric, maleic, malic, meibanesuifonie, mucie, oleic, oxalic, palmitic, pamoic, pantothenic, pheny!aceiic, phenylsu!fomc, propionic, pyruvic, salicylic, stearic, succinic, su!faniiic, tartaric, p-i
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
  • a wide variety of such“protecting,”“blocking,” or“masking” methods are wideiy used and well known in organic synthesis.
  • a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions may be derivatized to render one of the functional groups“protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group.
  • the protected group may be“deprotecied” to return it to its original functionality.
  • a hydroxyl group may be protected as an ether (-OR) or an ester (-OC(O)R), for example, as: a f- butyl ether; a benzyl, benzhydryl (diphenylmethyi), or trityl (triphenylmethyl) ether; a irimeihyisilyi or i-buty!dimethyisiiy! ether; or an acetyl ester (-0C(0)CH 3 , -OAc).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • An amine group may be protected, for example, as an amide (-NRC(O)R) or a urethane (-NRC(G)OR), for example, as: a methyl amide (-NHC(0)CH 3 ); a benzyioxy amide (-NHC(0)0CH 2 C e H5, -NH-Cbz); as a tert- buioxy amide (-NHC(0)0C(CH 3 )3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHC0(0)C(CH 3 ) 2 CeH 4 C 6 H 5 , -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH- Teoc), as a 2,2,2-irichioroethyioxy amide (-NRC(
  • a carboxylic acid group may be protected as an ester, for example, as: an alkyl ester (e.g., a methyl ester; a i-buty! ester); a ha!oalkyl ester (e.g., a ha!oalkyi ester); a trialkyisilyialky! ester; or an arylalkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an alkyl ester e.g., a methyl ester; a i-buty! ester
  • a ha!oalkyl ester e.g., a ha!oalkyi ester
  • a trialkyisilyialky! ester e.g., a benzyl ester; a nitrobenzyl ester
  • an amide for example, as a methyl amide.
  • a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an aceiamidomethyi ether (-S-CH 2 NHC(0)CH 3 )
  • the present disclosure may also provide compounds that are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds described herein.
  • Prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a iransdermal patch reservoir with or without a suitable enzyme or chemical reagent.
  • a compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, centra! nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatizatson with pivolates or fatty acid substituents, conversion to carbamates, hydroxyiation of aromatic rings, and heieroaiom substitution in aromatic rings.
  • Fieser, Fieser and Fieser are Reagents for Organic Synthesis, John Wiley and Sons (1994); and L Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
  • the compounds as disclosed herein and compositions including them have kinase inhibitory activity and are thus useful in modulating the action of kinases, and In treatment and/or prevention of diseases or conditions influenced by kinases.
  • the above compounds and compositions may be used to modulate (e.g., influence or inhibit) the action of kinases either in a cell in vitro or in a cell in a living body in vivo.
  • a method is provided of inhibiting the action of a kinase comprising applying to a medium such as an assay medium or contacting with a cell either in a cell in vitro or in a ceil in a living body in vivo an effective inhibitory amount of a compound as disclosed herein.
  • the kinase inhibited is a rho kinase (e.g , ROCK1 or ROCK2).
  • the kinase inhibited is a JAK (e.g., JAK2) kinase.
  • JAK inhibitors are useful in treating various JAK-associated diseases or disorders.
  • JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease).
  • organ transplant rejection e.g., allograft rejection and graft versus host disease.
  • JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, autoimmune thyroid disorders, chronic obstructive pulmonary disease (CORD), and the like.
  • the autoimmune disease is arthritis.
  • JAK-assodated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atropic eczema), and rhinitis.
  • JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1 , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
  • EBV Epstein Barr Virus
  • Hepatitis B Hepatitis C
  • HIV HTLV 1
  • VZV Varicella-Zoster Virus
  • HPV Human Papilloma Virus
  • JAK-associated diseases or conditions include those characterized by solid tumors (e.g , prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman’s disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
  • CTCLs include Sezary syndrome and mycosis fungoides.
  • Other examples of JAK-associated diseases or conditions include pulmonary arterial hypertension.
  • JAK-associated diseases or conditions include inflammation-associated cancers.
  • the cancer is associated with inflammatory bowel disease.
  • the inflammatory bowel disease Is ulcerative colitis.
  • the inflammatory bowel disease Is Crohn's disease.
  • the inflammation-associated cancer is colitis-associated cancer.
  • the inflammation-associated cancer is colon cancer or colorectal cancer.
  • the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stroma! tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.
  • the compounds of the present disclosure are used in methods of inhibiting kinases in a cell, a tissue or a subject such as a human comprising contacting the cel! with an amount of one or more of the compounds of the present disclosure effective to inhibit the kinase.
  • the compounds are administered in a pharmaceutically acceptable composition, such as In or with a pharmaceutically acceptable carrier.
  • the compounds of the present disclosure are used in methods for modulating the aci-on of a kinase in a ceil comprising contacting the cell with amount of one or more compounds of the present disclosure effective to modulate the action of a kinase in a ceil.
  • the compounds of the present disclosure are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.
  • Treatment or prevention of diseases or conditions for which the compounds of ihe present disclosure may be useful includes any of the diseases or conditions associated with kinase activity or diseases or conditions affected by kinases.
  • diseases or conditions include Alzheimer’s; ocular diseases, such as diabetic eye diseases, wet age-related macular degeneration, or dry age-related macular degeneration, inflammatory eye diseases, retinal degradation and glaucoma; cardiovascular diseases; and cancer.
  • Additional examples include bone disorder, obesity, hepatic disease, renal disease, pancreatitis, gastric disturbance, hypertension, fertility control, disorders of hair growth, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, dermatological disorder, and respiratory indications.
  • the compounds of the present disclosure will be administered in conjunction with one or more additional therapeutic agents.
  • additional therapeutic agents include, but are not limited to, beta blockers, alpha-agonists, carbonic anhydrase inhibitors, prosiaglandin-like compounds, miotic or cholinergic agents, epinephrine compounds, or neuroprotective or anti-inflammatory compounds.
  • Beta blockers These compounds are thought to lower intraocular pressure (iOR) by reducing the production of aqueous humor. Examples include levobunolol (BETAGANTM), timolol (BET!MOLTM, T!MOPT!CTM), betaxo!o! (BETOPT!CTM) and metipranoiol (OPTIPRANOLOLTM) [0166] Alpha-agonists These compounds are thought to lower IOP by reducing the production of aqueous humor and increasing drainage. Examples include apraclonidine (!GPIDINETM) and brimonidine (AIPHAGANTM)
  • Carbonic anhydrase inhibitors are thought to lower IOP by also reducing the production of aqueous humor. Examples include dorzo!amide (TRUSOPTTM) and brinzGiamide (AZOPTTM).
  • Prostaglandin-like compounds are thought to lower IOP by increasing the outflow of aqueous humor by the uveoscleral pathway. Examples include AR-102, latanoprost (XALATANTM), bi atoprost (LUMIGANTM), tafluprost (ZiGPTANTM), and travoprost (TRAVATANTM)
  • Miotic or cholinergic agents are thought to function by causing the pupil to constrict, which opens drainage channels in the eye.
  • Examples include pilocarpine (iSGPTQ CARPINETM, PILGPINETM) and carbachol (ISOPTO CARBACHOLTM)
  • Epinephrine compounds are thought to function by both decreasing the outflow of aqueous humor, as well as increasing fluid drainage.
  • Neuroprotective or anti-inflammatory compounds are treatments for conditions of the retina such as Macular Degeneration, and are designed as anti-VEGF treatments or have similar types of anti-growth or anti-inflammatory activity.
  • EYLEATM Af!ibercept
  • methods of treating an ocular disorder in a subject in need thereof comprising administering to the subject a compound, a composition, or a pharmaceutical composition provided herein.
  • A!so provided herein are methods of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound, a composition, or a pharmaceutical composition provided herein.
  • kits for treating an ocular disorder in a subject in need thereof comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, provided herein.
  • the ocular disorder is glaucoma.
  • kits for reducing intraocular pressure in a subject in need thereof comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, provided herein.
  • the compound is administered topically to an eye of the subject.
  • provided herein are methods of treating an ocular disorder in a subject in need thereof, comprising administering to the subject a compound of one of the Formulae provided herein, or a pharmaceutically acceptable salt thereof.
  • provided herein are methods of treating an ocular disorder In a subject in need thereof, comprising administering to the subject a compound provided in Table 1 , or a pharmaceutically acceptable salt thereof.
  • provided herein are methods of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound of one of the Formulae provided herein, or a pharmaceutically acceptable salt thereof.
  • kits for reducing intraocular pressure in a subject in need thereof comprising administering to the subject a compound provided in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering one or more additional therapeutic agents.
  • the one or more additional therapeutic agents is a beta blocker, an alpha-agonist, a carbonic anhydrase inhibitor, a prostaglandin or a prostaglandin-like compound, a miotic or cholinergic agent, an epinephrine compound, or a neuroprotective or anti-inflammatory compound.
  • the one or more additional therapeutic agents is a prostaglandin or a prostaglandin-like compound.
  • the prostaglandin-like compound is AR-102, latanoprost, bimatoprost, tafluprost, or travoprosi
  • provided herein are methods of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound of one of the Formulae provided herein, or a pharmaceutically acceptable salt thereof.
  • provided herein are methods of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound provided in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease is multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type ! diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, autoimmune thyroid disorders, or chronic obstructive pulmonary disease.
  • the additional therapeutic agent or agents can be administered simultaneously or sequentially with the compounds of the present disclosure. Sequential administration includes administration before or after the compounds of the present disclosure. In some embodiments, the additional therapeutic agent or agents can be administered In the same composition as the compounds of the present disclosure. In other embodiments, there can be an interval of time between administration of the additional therapeutic agent and the compounds of the present disclosure.
  • an additional therapeutic agent with a compound of the present disclosure will enable lower doses of the other therapeutic agents to be administered for a longer period of time.
  • compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the compositions provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
  • compositions for use in accordance with the present disclosure may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
  • the compounds and their physioiogicaiiy acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection (including injection of a drug-eluting device either into the body as a whole, or into specific tissues of the eye), inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral or rectal administration.
  • Techniques and formulations may generally be found in“Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, PA).
  • composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral, or by ocular injection into one of the chambers of the eye, such as intravitreai injection, intracameral injection, or injection into the aqueous humour.) or topical administration (e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis).
  • systemic administration e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral, or by ocular injection into one of the chambers of the eye, such as intravitreai injection, intracameral injection, or injection into the aqueous humour.
  • topical administration e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis.
  • Carriers for systemic administration typically comprise at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, t) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, combinations thereof, and others. All carriers are optional in the systemic compositions.
  • Ingredient a) is a diluent.
  • Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol.
  • the amount of ingredient a) in the systemic or topical composition is typically about 50 to about 90%.
  • Ingredient b) is a lubricant.
  • Suitable lubricants for solid dosage forms are exemplified by solid lubricants including silica, taic, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oii, cottonseed oil, sesame oil, olive oil, com oil and oil of Theobroma.
  • the amount of ingredient b) in the systemic or topical composition is typically about 5 to about 10%.
  • Ingredient c) is a binder.
  • Suitable binders for solid dosage forms include polyvinyl pyrro!idone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethyiceiluiose, ethyl cellulose, methylcellulose, microcrystai!ine cellulose, and sodium carboxymethyiceiluiose.
  • the amount of ingredient c) in the systemic composition is typically about 5 to about 50%, and in ocular solid dosing forms up to 99%.
  • Ingredient d) is a disintegrant.
  • Suitable disintegrants for solid dosage forms include agar, aiglnic acid and the sodium salt thereof, effervescent mixtures, croscarmeiose, crospovidone, sodium carboxymethyl starch, sodium starch g!ycolate, clays, and ion exchange resins.
  • the amount of ingredient d) in the systemic or topical composition is typically about 0.1 to about 10%.
  • Ingredient e) for solid dosage forms is a colorant such as an FD&C dye.
  • the amount of ingredient e) in the systemic or topical composition is typically about 0.005 to about 0.1 %.
  • Ingredient f) for solid dosage forms is a flavor such as menthol, peppermint, and fruit flavors.
  • the amount of ingredient f), when used, in the systemic or topical composition is typically about 0.1 to about 1.0%.
  • Ingredient g) for solid dosage forms is a sweetener such as aspartame and saccharin.
  • the amount of ingredient g) in the systemic or topical composition is typically about 0.001 to about 1%.
  • Ingredient h) is an antioxidant such as butyiated hydroxyanisole (“BHA”), butyiated hydroxyto!uene (“BHT”), and vitamin E.
  • BHA butyiated hydroxyanisole
  • BHT butyiated hydroxyto!uene
  • the amount of ingredient h) in the systemic or topical composition is typically about 0.1 to about 5%.
  • Ingredient j) is a preservative such as benzalkonium chloride, methyl paraben and sodium benzoate.
  • the amount of ingredient j) in the systemic or topical composition is typically about 0.01 to about 5%.
  • Ingredient k) for solid dosage forms is a glidant such as silicon dioxide.
  • the amount of ingredient k) in the systemic or topical composition is typically about 1 to about 5%.
  • Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions.
  • the amount of ingredient m) in the systemic or topical composition is typically from about 0 to about 100%.
  • Ingredient n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of ingredient n) in the systemic or topical composition is typically about 1 to about 8%.
  • Ingredient o) is a surfactant such as lecithin, Poiysorbaie 80, and sodium lauryl sulfate, and the TWEENS® from Atlas Powder Company of Wilmington, Delaware.
  • Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1 Emulsifiers & Detergents, 1994, North American Edition, pp. 238-239.
  • the amount of ingredient o) in the systemic or topical composition is typically about 0.1 % to about 5%.
  • system compositions comprise 0 01 % to 50% of component A and 50 to 99.99% of component B.
  • compositions for parenteral administration typically comprise A) 0.1 to 10% of the compounds of the present disclosure and B) 90 to 99.9% of a carrier comprising a) a diluent and m) a solvent.
  • component a) comprises propylene glycol and m) comprises ethanol or ethyl oleate.
  • compositions for oral administration can have various dosage forms.
  • solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms comprise a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of component A).
  • the oral dosage compositions further comprise about 50 to about 95% of component B), and more particularly, from about 50 to about 75%.
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multipie-compressed. Tablets typically comprise component A, and component B a carrier comprising ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disiniegrants, e) colorants, f) flavors, g) sweeteners, k) giidanis, and combinations thereof.
  • Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.
  • Specific binders include starch, gelatin, and sucrose.
  • Specific disintegrants include aiginic acid and croscarmeiose.
  • Specific lubricants include magnesium stearate, stearic acid, and talc.
  • Specific colorants are the FD&C dyes, which can be added for appearance.
  • Chewabie tablets preferably contain g) sweeteners such as aspartame and saccharin, or f) flavors such as menthol, peppermint, fruit flavors, or a combination thereof.
  • Capsules typically comprise component A, and a carrier comprising one or more a) diluents disclosed above in a capsule comprising gelatin.
  • Granules typically comprise component A, and preferably further comprise k) giidanis such as silicon dioxide to improve flow characteristics implants can be of the biodegradable or the non-biodegradab!e type. Implants may be prepared using any known biocompatibie formulation.
  • the solid compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that component A is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action.
  • the coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthaiate, polyvinyl acetate pbtbalaie, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAG!T® coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.
  • compositions for ora! administration can also have liquid forms.
  • suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervesceni granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like.
  • Liquid orally administered compositions typically comprise component A and component B, namely, a carrier comprising ingredients selected from the group consisting of a) diluents, e) colorants, f) flavors, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants.
  • Peroral liquid compositions preferably comprise one or more ingredients selected from the group consisting of e) colorants, f) flavors, and g) sweeteners
  • compositions useful for attaining systemic delivery of the subject compounds include injection, sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as a) diluents including sucrose, sorbitol and mannitol; and c) binders such as acacia, microcrystaliine cellulose, carboxymetby! cellulose, and hydroxypropyl methyicellulose
  • Such compositions may further comprise b) lubricants, e) colorants, flavors, g) sweeteners, h) antioxidants, and k) glidants.
  • Topical compositions that can be applied locally to the eye may be in any form known in the art, non-limiting Examples of which include solids, gelable drops, sprays, ointments, or a sustained or non-sustained release unit placed in the conjunctival cul-du-sac of the eye or another appropriate location.
  • Topicai compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
  • Topical compositions comprise: component A, the compounds described above, and component B, a carrier.
  • the carrier of the topicai composition preferably aids penetration of the compounds into the eye.
  • Component B may further comprise one or more optional components.
  • an effective amount of a compound according to the present disclosure will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the route of administration, the particular pharmaceuticaily-acceptabie carrier utilized, and like factors within the knowledge and expertise of the atending physician.
  • an effective amount of the compounds of the present disclosure for systemic administration is from about 0.01 to about 1000 pg/kg body weight, preferably from about 0.1 to about 100 pg/kg per body weight, most preferably form about 1 to about 50 pg/kg body weight per day.
  • the transdermal dosages will be designed to attain similar serum or plasma levels, based upon techniques known to those skilled in the art of pharmacokinetics and transdermal formulations.
  • Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 ng/ml, more preferably from 0.05 to 50 ng/ml and most preferably from 0.1 to 10 ng/mL. While these dosages are based upon a daily administration rate, the compounds of the present disclosure may also be administered at other intervals, such as twice per day, twice weekly, once weekly, or once a month.
  • One of ordinary skill in the art would be able to calculate suitable effective amounts for other intervals of administration.
  • the compounds of the present disclosure are useful in a method of reducing or decreasing intraocular pressure.
  • the compounds of the present disclosure may be administered to a subject in need of treatment in an amount effective to reduce intraocular pressure.
  • these compounds are useful in the treatment of glaucoma.
  • the preferred route of administration for treating glaucoma is topically.
  • each component in the topical composition depends on various factors.
  • the amount of component A added to the topicai composition is dependent on the ICso of component A, typically expressed in nanomoiar (nM) units. For example, if the IC 5 o of the medicament is 1 nM, the amount of component A will be from about 0 001 to about 0.3% If the IC 50 of the medicament is 10 nM, the amount of component A) will be from about 0.01 to about 1 %. if the IC 50 of the medicament is 100 nM, the amount of component A will be from about 0.1 to about 10%. If the amount of component A is outside the ranges specified above (i.e., lower), efficacy of the treatment may be reduced.
  • IC 50 - The remainder of the composition, up to 100%, is component B.
  • the amount of the carrier employed in conjunction with component A is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament.
  • Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modem Pharmaceutics , Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et a ., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2 nd Ed., (1976).
  • Component B may comprise a single ingredient or a combination of two or more ingredients.
  • component B comprises a topical carrier.
  • Suitable topical carriers comprise one or more ingredients selected from the group consisting of phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, ailanioin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.
  • the carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humeciants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.
  • Ingredient q) is an emollient.
  • the amount of ingredient q) in a skin-based topical composition is typically about 5 to about 95%.
  • Suitable emollients include sieary! alcohol, glyceryl monorlcinoleate, glyceryl monostearate, propane-1 ,2-diol, butane-1 , 3-diol, mink oil, cetyl alcohol, isopropyl isosiearate, stearic add, isobuiy!
  • paimitaie isocetyl stearate, oieyi alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl paimitate, di-n-butyl sebacate, isopropyl myristate, isopropyl paimitaie, isopropyl stearate, butyl stearate, polyethylene glycol, triethyiene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylaied lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl lino!eaie, iauryi lactate, myristyl lactate, decyi oleate, myristyl myristate, and combinations thereof.
  • Ingredient r) is a propellant.
  • the amount of ingredient r) in the topical composition is typically about 0 to about 95%.
  • Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.
  • Ingredient s) is a solvent.
  • the amount of ingredient s) in the topical composition is typically about 0 to about 95%.
  • Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycoi monobutyl ether, diethyiene glycol monoeihyi ether, dimethyisulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof.
  • Specific solvents include ethyl alcohol and homotopic alcohols.
  • Ingredient t) is a humectani.
  • the amount of ingredient t) in the topical composition is typically 0 to 95%.
  • Suitable humectants include glycerin, sorbitol, sodium 2-pyrroiidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
  • Specific humectants include glycerin.
  • Ingredient u) is a thickener.
  • the amount of ingredient u) in the topical composition is typically about 0 to about 95%.
  • Ingredient v) is a powder.
  • the amount of ingredient v) in the topical composition is typically 0 to 95%.
  • Suitable powders include befa-cydodextrins, hydroxypropyl cyclodexirins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified Montmorillonite day, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.
  • specific powders include ftefa-cyciodextrin, hydroxypropyl cyclodextrin, and sodium polyacry!ate.
  • sodium polyacrylaie may be used for gel dosing ocular formulations.
  • Ingredient w) is a fragrance.
  • the amount of ingredient w) in the topical composition is typically about 0 to about 0.5%, particularly, about 0.001 to about 0.1 %. For ocular applications a fragrance is not typically used.
  • Ingredient x) is a pigment.
  • Suitable pigments for skin applications include inorganic pigments, organic lake pigments, pearlesceni pigments, and mixtures thereof.
  • Inorganic pigments useful In this disclosure include those selected from the group consisting of rutile or anaiase titanium dioxide, coded in the Color Index under the reference Cl 77,891 ; black, yellow, red and brown iron oxides, coded under references Cl 77,499, 77,492 and, 77,491 ; manganese violet (Cl 77,742); ultramarine blue (Cl 77,007); chromium oxide (Cl 77,288); chromium hydrate (Cl 77,289); and ferric blue (Cl 77,510) and mixtures thereof.
  • organic pigments and lakes useful in this disclosure include those selected from the group consisting of D&C Red No. 19 (Cl 45,170), D&C Red No. 9 (Cl 15,585), D&C Red No. 21
  • the pearlescent pigments useful in this disclosure include those selected from the group consisting of the white pearlescent pigments such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments such as titanium mica with iron oxides, titanium mica with ferric blue, chromium oxide and the like, titanium mica with an organic pigment of the above-mentioned type as well as those based on bismuth oxychloride and mixtures thereof.
  • the amount of pigment in the topical composition is typically about 0 to about 10%. For ocular applications a pigment is generally not used
  • topical pharmaceutical compositions for ocular administration are prepared typically comprising component A and B (a carrier), such as purified water, and one or more ingredients selected from the group consisting of y) sugars or sugar alcohols such as dextrans, particularly mannitol and dextran 70, z) cellulose or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pH adjusting additive.
  • a carrier such as purified water
  • y sugars or sugar alcohols
  • dextrans particularly mannitol and dextran 70, z
  • cellulose or a derivative thereof aa salt
  • bb) disodium EDTA Edetate disodium
  • cc a pH adjusting additive
  • Examples of z) cellulose derivatives suitable for use in the topical pharmaceutical composition for ocular administration include sodium carboxymethylcelluiose, ethylcellulose, methylcellulose, and hydroxypropy!-meihylcellu!ose, particularly, bydroxypropyi-methyiceliu!ose.
  • Examples of aa) salts suitable for use in the topical pharmaceutical composition for ocular administration include mono-, dl- and trisodium phosphate, sodium chloride, potassium chloride, and combinations thereof.
  • pH adjusting additives include MCI or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition for ocular administration to the range of 4.5-7.5 pH units.
  • Component A may be included in kits comprising a compound as described herein, a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for cosmetic and medical conditions in mammals (particularly humans).
  • the information and instructions may be in the form of words, pictures, or both, and the like in addition or in the alternative, the kit may comprise the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing cosmetic and medical conditions in mammals (e.g., humans).
  • Example 1 ROCK and JAK assays.
  • the assay was performed in white 96-well, flat-bottom, ha!f-area, non-binding assay plate (Coming #3642) in assay buffer consisting of 20 m M HERBS (pH 7.5), 10 mM MgC! 2 * 6H 2 G, 100 mM sodium orthovanadate, 0.05% CHAPS and 0.1% bovine serum albumin.
  • a 10 m ⁇ aliquot of compound from each well of the intermediate dilution plate and 20 pL of a 2X substrate/enzyme solution containing acceptor substrate (800nM RSK2 peptide KRRRLSSLRA (SEG ID NO; 1)), ROCK2 enzyme (10 nM), or ROCK1 enzyme, and 1 ,4-Dithiothreitoi (DTT, 2uM) were added to ail wells.
  • the reaction was initiated by the addition of 10 pL of 4x stock solution ATP (2 mM) Reactions were thoroughly mixed manually, covered and allowed to incubate at room temperature for 75 min.
  • ATP concentrations remaining in Test wells following the termination of the enzymatic reaction were compared against control wells containing equivalent amounts of DMSO containing no inhibitor (CTRL).
  • CTRL DMSO containing no inhibitor
  • ATP concentrations in both Test wells and CTRL wells were normalized against background (BKG) ATP concentrations in welis containing concentrations of inhibitor that completely inhibited the protein kinase under investigation (i.e. a concentration that prevented any consumption of ATP over the course of the incubation).
  • JAK 2X substrate/enzyme solution consisted of acceptor substrate (800nM Abi peptide EAiYAAPFAKKK (SEQ ID NO:2)), JAK2 or
  • Porcine Trabecular Meshwork cells were isolated from freshly obtained enucleated porcine eyes. Immortalized Human Trabecular Meshwork cells (TM-1) were obtained through a kind gift from Donna Peters in the Department of Ophthalmology and Visual Sciences at the University of Wisconsin. Ceils were plated onto fibronectin coated glass-bottom 96-weli plates and allowed to attach overnight. Media was removed and replaced with test compound in media with 1 % fetal bovine serum and incubated for various times. After incubation, cells were formaldehyde fixed, triton solubilized, and stained.
  • PTM cells were stained with Alexa Fluor® 488 phalloidin (F-aciin) and Hoechst 33342 (nuclei) TM-1 cells were stained with anti-paxillin followed by Alexa Fluor® 488 goat-anti-mouse IgG (focal adhesions) and Hoechst 33342 (nuclei).
  • Ail staining reagents were obtained through invitrogen. Images were collected on an !NCe!l 2200 imager with a 20X objective. The actin fiber length and total area of focal adhesions were analyzed using custom algorithms developed in the !NCe!i Developer Toolbox, v1 .9.3. Data collected were converted to percent of control (untreated cells). Curves were fit to data in GraphPad Prizm using sigmoidal dose-response and constraining fop and bottom to 100% and 0%, respectively. Results are shown below in Table 3. able 3.
  • topical pharmaceutical compositions for lowering intraocular pressure comprising the compounds provided herein are prepared by conventional methods and formulated as shown in Table 4.
  • a compound according to this disclosure is used as the ihieny!cyclopropy! amino acid isoqulnoiyi amide.
  • the above composition decreases intraocular pressure in a subject suffering from glaucoma.
  • Pharmacological activity for glaucoma can also be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein by reference: C. Liljebris, G. Selen, B. Resul, J. Sternschantz, and Uhacksell, “Derivatives of 17 ⁇ phenyM 8, 19, 20-trinorprostaglandin F2 a isopropyl Ester: Potential Anti-glaucoma Agents”, Journal of Medicinal Chemistry b, 38 (2): 289-304.
  • a compound or composition provided herein is prepared and placed in a container for storage at ambient or elevated temperature.
  • a polyolefin plastic container as compared to a polyvinyl chloride plastic container, discoloration of the compound or composition is reduced, whether dissolved or suspended in a liquid composition (e.g., an aqueous or organic liquid solution), or as a solid.
  • the container reduces exposure of the container’s contents to electromagnetic radiation, whether visible light (e.g , having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV-B light) or about 320-380 nm (UV-A light)).
  • visible light e.g , having a wavelength of about 380-780 nm
  • UV light e.g., having a wavelength of about 190-320 nm (UV-B light) or about 320-380 nm (UV-A light).
  • Some containers also include the capacity to reduce exposure of the container’s contents to infrared light, or a second component with such a capacity
  • the containers used include those made from a polyolefin such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, poiymethylpentene, polybutene, or a combination thereof, especially polyethylene, polypropylene, or a combination thereof.
  • the container may further be disposed within a second container, for example, a paper, cardboard, paperboard, metallic film, or foil, or a combination thereof, container to further reduce exposure of the containers contents to UV, visibie, or infrared light.
  • Eye drop solutions or implants that include a compound or composition thereof provided herein.
  • Eye drop solutions or implants may need storage lasting up to, or longer than, three months; In some cases up to, or longer than one year.
  • the containers described herein may be eye drop or implant containers.
  • the containers may be in any form suitable to contain the contents; for example, a bag, a bottle, or a box.
  • Compositions disposed within the containers described may include: boric acid, D-mannitol, benzaikonium chloride, polyoxy! 40 stearate, polyethylene glycol 400, ethylenediamine tetraacetlc acid, or a combination thereof; and water or another suitable solvent vehicle or excipient.
  • the vehicle is an aqueous vehicle. In other cases, the vehicle is a non-aqueous vehicle.

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Abstract

La présente invention concerne des composés de thiényl cyclopropyl-amino-isoquinoline amide. En particulier, l'invention concerne des composés qui affectent la fonction de kinases dans une cellule et qui sont utiles en tant qu'agents thérapeutiques ou avec des agents thérapeutiques. Les composés de la présente invention sont utiles dans le traitement d'une série de maladies et d'états comprenant des maladies oculaires telles que le glaucome, des maladies cardiovasculaires, des maladies caractérisées par une croissance anormale, telles que des cancers, et des maladies inflammatoires. L'invention concerne également des compositions comprenant des composés de thiényl cyclopropyl-amino-isoquinoline amide.
PCT/US2020/019822 2019-02-26 2020-02-26 Composés de thiényl cyclopropyl-amino-isoquinolinyle amide Ceased WO2020176579A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100168102A9 (en) * 2005-07-11 2010-07-01 Devgen Nv Amide Derivatives as Kinase Inhibitors
US20170319559A1 (en) * 2007-07-17 2017-11-09 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20180186746A1 (en) * 2007-01-10 2018-07-05 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US20180327381A1 (en) * 2017-03-31 2018-11-15 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100168102A9 (en) * 2005-07-11 2010-07-01 Devgen Nv Amide Derivatives as Kinase Inhibitors
US20180186746A1 (en) * 2007-01-10 2018-07-05 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US20170319559A1 (en) * 2007-07-17 2017-11-09 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20180327381A1 (en) * 2017-03-31 2018-11-15 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

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