THENYL CYCLQPROPYL-AiV!INO-!SOQUiNOLiNYL AMIDE COMPOUNDS

RELATED APPLICATIONS

[0001] This application ciaims priority to United States Provisional Patent Application No. 62/810,783, filed February 26, 2019, the entire content of which is herein incorporated by reference.

SEQUENCE LISTING

[0002] This application contains a sequence listing having the filename 1959002-00199_PCT_ST25.txt, which is 666 bytes in size, and was created on February 24, 2020. The entire content of this sequence listing is herein incorporated by reference.

FIELD OF THE INVENTION

[0003] 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. In particular, 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.

BACKGROUND

[0004] A variety of hormones, neuroiransmitters and biologically active substances control, regulate or adjust the functions of living bodies via specific receptors located in cel! membranes. Many of these receptors mediate the transmission of intracellular signals by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are generiea!!y referred to as G-protein coupled receptors (GPCRs) and include, among others, a-adrenergic receptors, b-adrenergic receptors, opioid receptors, cannabinoid receptors and prostaglandin receptors. The biological effects of activating or inhibiting these receptors is not direct, but is mediated by a host of intracellular proteins. The importance of these secondary proteins has been recognized and modulation of this class is now being investigated as intervention points in disease states. One of the most important classes of these downstream effectors is the“kinase” class.

[0005] The various kinases play important roles in the regulation of various physiological functions. For example, 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. The importance of p38 MARK inhibitors in particular as new drugs for rheumatoid arthritis is reflected by the large number of compounds that has been developed over the Iasi years (J. Westra and P.C. Limburg Mini-Reviews in Medicinal Chemistry Volume 6, Number 8, August 2006). 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. Despite the identification of numerous mutations that cause inherited retinal degenerations, 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).

[0006] The success of the tyrosine-kinase inhibitor STI571 (Gieevec) in the treatment of chronic myelogenous leukemia ( Nature Reviews Drug Discovery 2003, 2: 296-313) has spurred considerable efforts to develop other kinase inhibitors for the treatment of a wide range of other cancers ( Nature Reviews Cancer 2003, 3: 650-665). The balance between the initiation and the inactivation of intracellular signals determines the intensity and duration of the response of the receptors to stimuli such as agonists. When desensiiization occurs, the mediation or regulation of the physiological function mediated or regulated by the G proteins to which the receptors are coupled is reduced or prevented. For example, 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.

[0007] Janus Kinases (or JAK) are a family of cytoplasmic protein tyrosine kinases. The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. Currently, there are four JAK family members are known JAK1 ,

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.

[0008] In view of the role that kinases play in many disease states, there is an urgent and continuing need for small molecule ligands which inhibit or modulate the activity of kinases. Without wishing to be bound by theory, it is thought that modulation of the activity of kinases, in particular ROCK and JAK kinases, by the compounds of the present disclosure is, at least in part, responsible for their beneficial effects.

SUMMARY

[0009] in one aspect, provided herein are compounds of Formuia (I):

or a pharmaceutically acceptable salt thereof,

wherein,

n is 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.. ₈ alkyl), -NH-heteroaryl, -NH-ary!, -Ci_e a!kyl-CN, heteroaryi, -(Ci_ ₆ alky!Vheteraaryi, -(Ci. _s aikyi)~N(R ³ )R ⁴ , -(C _1-3 a!kyl)-heierocydyi or heterocycloaikyi;

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;

or 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; and

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!.

- 3 -

5UB5TITUTE SHEET (RULE 26) [0010] In one aspect, provided herein are compounds of Formula (i):

(I).

or a pharmaceutically acceptable salt thereof,

wherein,

C(O)-;

alkyl, -Ci-e haloaikyl, aryl, -aryl-(Ci_e a!ky!)-N(R ³ )R ⁴ , -heteroaryl-(Ci- ₆ Ci_e a!kyi)-heteroary!-(Ci_e alkyl), -(Ci_e al ky!)~a ry !- (C i_a alkyl), -NH-heteroaryi, -NH-aryl, -Ci- _S a!kyl-CN, heteroaryl, -(Ci_e alkyl)-heteroaryl, -(C|. _s alkyi)-N(R ³ )R ⁴ , -(Ci-s aikyl)-heterocyciyl or heterocycloalkyl;

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;

or 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; and

Z is H, Ci-e alkyl, -Ci_ ₈ haloaikyl, halogen or hydroxyl.

[0011] In an aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to the present disclosure and a pharmaceutically acceptable excipient.

[0012] In an aspect, 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.

[0013] In an aspect, 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

[0014] In an aspect, the present disclosure provides a kit comprising a compound or composition of according to the present disclosure and instructions for use.

DETAILED DESCRIPTION

[0015] Publications and patents are referred to throughout this disciosure. All U.S. Patents cited herein are hereby incorporated by reference. Ail percentages, ratios, and proportions used herein are percent by weight unless otherwise specified.

- 4 -

5UB5TITUTE SHEET (RULE 26) [0018] Ary!cyciopropyi amino-isoquinolinyl amides are provided.

[0017]“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. When 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.

[0018]“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. Substituents can be placed on the aikene itself and also on the adjacent member atoms or the aikynyl moiety.“C2-C4 alkenyl” refers to alkenyl groups containing two to four carbon atoms.

[0019]“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. 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.

[0020]“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.

[0021]“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.

[0022]“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”.

[0023]“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.

[0024]“Carboxyl” refers to the group -C(=0)0-Ci-C4 alkyl.

[0025]“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.

[0028]“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.

[0027]“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.

[0028]“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.

[0029]“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.

[0030]“Halogen" refers to fluoro, chloro, bromo or iodo moieties. Preferably, the halogen is fiuoro, chloro, or bromo.

[0031]“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.

[0032]“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. Preferably, 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.

[0033]“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. More than one substituent 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.

[0034]“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.

[0035]“Linker” means a linear chain of n member atoms where n is an integer from 1 to 4.

[0036]“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.

[0037]“Ring” 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

[0038]“Thioalkyi” refers to the group -S-aikyl.

[0039]“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.

[0040]“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.

[0041]“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.

[0042]“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.

[0043]“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.

[0044]“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.

[0045] 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.

[0046] The term“controlling the disease or condition” is used to mean changing the activity of one or more kinases to affect the disease or condition.

[0047] The term“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.

Compounds

[0048] In one aspect, provided herein are compounds of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

n is 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

8

5UB5TITUTE SHEET (RULE 26) alkyl) , -NH-aryl, -Ci- _S a!kyl-CN, heteroaryl, -(Ci_e alkyl)-heteroaryl, -(Ci_e alkyl) kyl)-heterocyclyl or heterocycloalkyl;

alkyl, -Ci_e haioaikyi, aryl, -aryl-(Ci-e aikyi)-N(R ³ )R ⁴ , -heteroaryl-(Ci_ ₆ alkyl) i_e alkyl)-heteroaryl-(Ci_e alkyl), -(Ci_e alky!)-aryl~(Ci_ ₆ alkyl), -NH-heteroaryl, -NH-aryi, -Ci.. ₆ alkyl-CN, heteroaryl, -(Ci- ₆ alkyl)-heteroaryl, -(Ci-s aikyi)-N(R ³ )R ⁴ , -(Ci-e al ky I)- h ete ro cycly I or heterocycloalkyl;

or 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; and

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!

[0049] In an embodiment of the Formulae provided herein, Z is H, Ci.. ₃ alkyl, -Ci_e haioaikyi, halogen or hydroxyl.

[0050] In an embodiment of the Formulae provided herein, n is 1 , and Z is H, Ci- _e alkyl, -Ci-s haioaikyi, halogen or hydroxyl.

[0051] In an embodiment of the Formulae provided herein, n is i .

[0052] In an embodiment of the Formulae provided herein, n is 0.

[0053] In an embodiment of the Formulae provided herein:

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.

[0054] In an embodiment of the Formulae provided herein;

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;

[0055] In an embodiment of the Formulae provided herein:

n is 0; and

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.

[0056] In an embodiment of the Formulae provided herein;

n is 0; and

Z is hydroxyl, -Ci_ ₆ a!kyl-OH, -Ci- ₆ alkyi-0(C0)-Ci_ ₆ alkyl, -(CO)OH, or -(CO)0-Ci- _S alkyl. [0057] In an embodiment of the Formulae provided herein:

n is 0; and

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

[0058] In an embodiment of the Formulae provided herein, -Ci _~e alkyl is methyl or ethyl.

[0059] In an embodiment of the Formulae provided herein, -Ci-s haloalkyl is trihalomethanyl or trihaloethanyl.

[0080] In an embodiment, the compound of Formula (I) is a compound of Formula (l-A):

(!-A),

or a pharmaceutically acceptable salt thereof.

[0081] In an embodiment, the compound of Formula (I) is a compound of Formula (I-A1):

( I -A 1 ) ,

or a pharmaceutically acceptable salt thereof.

[0082] In an embodiment, the compound of Formula (I) is a compound of Formula (i-A1-a):

(l-A1~a),

or a pharmaceutically acceptable salt thereof.

[0083] In an embodiment, the compound of Formula (I) is a compound of Formula (i-A1-b):

(!-A1~b),

or a pharmaceutically acceptable salt thereof. [0084] In an embodiment, the compound of Formula (i) is a compound of Formula (I-A1-C):

(I-A1-C),

or a pharmaceutically acceptable salt thereof.

[0085] In an embodiment, the compound of Formula (I) is a compound of Formula (l-A1-d):

(!-A1-d),

or a pharmaceutically acceptable salt thereof.

[0088] In an embodiment, the compound of Formula (i) is a compound of Formula (I-A2):

(I-A2),

or a pharmaceutically acceptable salt thereof.

[0087] In an embodiment, the compound of Formula (!) is a compound of Formula (i-A2-a):

(l-A2-a),

or a pharmaceutically acceptable salt thereof.

[0088] In an embodiment, the compound of Formula (I) is a compound of Formula (i-A2-b):

(l-A2-b),

or a pharmaceutically acceptable salt thereof. [0089] In an embodiment, the compound of Formula (i) is a compound of Formula (I-A2-C):

(I-A2-C),

or a pharmaceutically acceptable salt thereof.

[0070] In an embodiment, the compound of Formula (!) is a compound of Formula (l-A2-d):

(!-A2-d),

or a pharmaceutically acceptable salt thereof.

[0071] In an embodiment, the compound of Formula (!) is a compound of Formula (I-A3):

or a pharmaceutically acceptable salt thereof.

[0072] In an embodiment, the compound of Formula (I) is a compound of Formula (l-B):

(l-B),

or a pharmaceutically acceptable salt thereof.

[0073] In an embodiment, the compound of Formula (I) is a compound of Formula (I-B1):

(I-B1),

or a pharmaceutically acceptable salt thereof. [0074] In an embodiment, the compound of Formula (i) is a compound of Formula (l-B1-a):

(l-B1-a),

or a pharmaceutically acceptable salt thereof.

[0075] In an embodiment, the compound of Formula (!) is a compound of Formula (l-B1-b):

or a pharmaceutically acceptable salt thereof.

[0076] In an embodiment, the compound of Formula (!) is a compound of Formula (l-B1-c):

(I-B1-C),

or a pharmaceutically acceptable salt thereof.

[0077] In an embodiment, the compound of Formula (!) is a compound of Formula (l-B1-d):

(I-B1 -d).

or a pharmaceutically acceptable salt thereof. [0078] In an embodiment, the compound of Formula (i) is a compound of Formula (I-B2):

(I-B2),

or a pharmaceutically acceptable salt thereof.

[0079] In an embodiment, the compound of Formula (I) is a compound of Formula (!-B2~a):

(l-B2-a),

or a pharmaceutically acceptable salt thereof.

[0080] In an embodiment, the compound of Formula (I) Is a compound of Formula (l-B2-b):

(l~B2-b),

or a pharmaceutically acceptable salt thereof.

[0081] In an embodiment, the compound of Formula (!) is a compound of Formula (l-B2-c):

(I-B2-C),

or a pharmaceutically acceptable salt thereof.

[0082] In an embodiment, the compound of Formula (I) is a compound of Formula (l-B2-d):

(l-B2-d),

or a pharmaceutically acceptable salt thereof.

[0083] In an embodiment, the compound of Formula (I) is a compound of Formula (I-B3):

or a pharmaceutically acceptable salt thereof.

[0084] In an embodiment, the compound of Formula (i) is a compound of Formula (l-C):

or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments of the Formulae provided herein, Z is .

[0086] In some embodiments of the Formulae provided herein, X, Y and Z are H.

[0087] In some embodiments of the Formulae provided herein, X and Z are H.

[0088] in some embodiments of the Formulae provided herein, Y and Z are H.

[0089] In some embodiments of the Formulae provided herein, X is H.

[0090] In some embodiments of the Formulae provided herein:

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

[0091] In some embodiments of the Formulae provided herein:

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;

or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocycle;

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; and

Z is H, Ci _~6 alkyl, halogen or hydroxyl.

[6092] In some embodiments of the Formulae provided herein:

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

15

5UB5TITUTE SHEET (RULE 26) aikyi)-heterocycly! or heterocycloalky!;

or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocycie;

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; and

Z is H, C _1-4 alkyl, halogen or hydroxyl.

[0093] In some embodiments of the Formulae provided herein:

R ¹ is H, phenyl, pyridinyl, -(Ci_e alkyl)-pyridinyl, -(Ci-s aiky!)-N(R ³ )R ⁴ , -(C1-8 aikyl)-heterocyclyl or heterocycloaikyl; and

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.

[0094] In some embodiments of the Formulae provided herein:

R ¹ is H; and

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.

[0095] In some embodiments of the Formulae provided herein, R ¹ is H or -Ci- _S alkyl.

[0098] in some embodiments of the Formulae provided herein, R ¹ is -Ci_e alkyl.

[0097] In some embodiments of the Formulae provided herein, R ¹ is H.

[0098] In some embodiments of the Formulae provided herein, R ² is phenyl, pyridinyi, -(Ci.. _s aiky!)-pyridiny!, -(Ci-e aiky!)-N(R ³ )R , -(Ci-s a!kyi)-heieroeyc!yi or heterocycloaikyl.

[0099] In some embodiments of the Formulae provided herein, pyridinyl Is 2-pyridinyi.

[0100] In some embodiments of the Formulae provided herein, pyridinyi is 3-pyridinyi,

[0101] In some embodiments of the Formulae provided herein, pyridinyi is 4-pyridinyl.

[0102] In some embodiments of the Formulae provided herein, R ² is phenyl, pyridinyl, -(Ci_s aikyl)~pyridinyl, -(Ci- ₆ a!ky!)-heterocycly! or heterocycloaikyl.

[0103] In some embodiments of the Formulae provided herein, R ² is -(C1-6 alky!)-N(R ³ )R ⁴ , -(C1-6 alky!)-beterocyc!y! or heterocycloaikyl;

[0104] In some embodiments of the Formulae provided herein, R ² is phenyl, pyridinyi, -(Ci_e alkyi)-pyridinyl.

[0105] In some embodiments of the Formulae provided herein. R ² is pyridinyl.

[0108] In some embodiments of the Formulae provided herein, R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclyl containing six ring atoms.

[0107] In some embodiments of the Formulae provided herein, 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

[0108] In some embodiments of the Formulae provided herein, 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.

[0109] in some embodiments of the Formulae provided herein, R ³ and R ⁴ are H.

[0110] In some embodiments of the Formulae provided herein, R ³ and R ⁴ are, independently, Ci~s alkyl.

[0111] In some embodiments of the Formulae provided herein, R ³ is H, and R ⁴ is Ci_e alkyl.

[0112] In some embodiments of the Formulae provided herein:

X is C _l-® alkyl, halogen or hydroxyl: and

Y and Z are H.

[0113] In some embodiments of the Formulae provided herein:

X is halogen; and

Y and Z are H.

[0114] In some embodiments of the Formulae provided herein, X is Ci_e alkyl, halogen or hydroxyl

[0115] In some embodiments of the Formulae provided herein, X is methyl, ethyl, CF3, CHF2 or CH ₂ F.

[0116] In some embodiments of the Formulae provided herein, Y is ethyl, ethyl, CF ₃ , CHF ₂ or

CH ₂ F.

[0117] In some embodiments of the Formulae provided herein, Z is methyl, ethyl, CF ₃ , CHF ₂ or CHzF.

[0118] In some embodiments of the Formulae provided herein, X is halogen

[0119] In some embodiments of the Formulae provided herein, X is F or CL

[0120] In some embodiments of the Formulae provided herein, X is Cl.

[0121] In some embodiments of the Formulae provided herein:

X is methyl or halogen;

Y Is methyl or halogen; and

Z is methyl or halogen.

[0122] In some embodiments of the Formulae provided herein:

X is methyl, F or Cl;

Y is methyl, F or Cl; and

Z is methyl, F or Cl.

[0123] In some embodiments of the Formulae provided herein:

X is halogen; and

Y is hydroxyl.

[0124] In some embodiments of the Formulae provided herein, Y is hydroxyl.

[0125] In some embodiments of the Formulae provided herein, Z is H or F.

[0126] In some embodiments of the Formulae provided herein, aryl is phenyl. [0127] In some embodiments of the Formulae provided herein, heteroaryi is pyridiny!, pyridaziny!, pyrimidinyl, pyraziny!, triaziny!, ieiraziny!, pyrazo!y!, or imidazo!y!.

[0128] In some embodiments of the Formulae provided herein,

[0129] In some embodiments of the Formulae provided herein, the compound is a compound provided in Table 1 , or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments of the Formulae provided herein, the compound is a compound provided in Table 2, below, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments of the Formulae provided herein, the compound is a compound provided in Table 3, below, or a pharmaceutically acceptable salt thereof. Isomers

[0132] 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”).

[0133] In one embodiment, a compound described herein may be an enantiomerically enriched isomer of a stereoisomer described herein For example, 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.

[0134] in one embodiment, 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. For example, 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%.

[0135] In one embodiment, 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. Exemplary R/S configurations can be those provided in an example described herein.

[0138] 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. By 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.

[0137] 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

[0138] Except as discussed below for tautomeric forms, specifically excluded from the term “isomers,” as used herein, 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). For example, a reference to a meihoxy group, -QCH ₃ , is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chiorophenyi is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, 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).

[0139] The above exclusion 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.

[0140] Note that specifically included in the term“isomer” are compounds with one or more isotopic substitutions. For example, 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.

Saits

[0141] A compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt. The term “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. Examples of pharmaceutically acceptable salts are discussed in Berge et al, 1977, “Pharmaceutically Acceptable Saits.” J. Pharm. Sci. Voi. 66, pp. 1-19. in an embodiment, the compound is present in mono-salt form in embodiments, the compound is present in di-salt form.

[0142] For example, if the compound is anionic, or has a functional group which may be anionic

(e.g., -COOH may be -COO ), then a salt may be formed with a suitable cation. Examples of 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. Examples of suitable organic cations include, but are not limited to, ammonium ion (i e., NHT) and substituted ammonium ions (e.g., NHsFV, NH2FV, NHFV, NRT). Examples of some suitable 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.

[0143] If the compound is cationic, or has a functional group that may be cationic (e.g., -NH ₂ may be -NH ₃ ⁺ ), then a salt may be formed with a suitable anion. Examples of 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.

[0144] Examples of 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-ioluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0145] Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Chemically Protected Forms

[0146] It may be convenient or desirable to prepare, purify, and/or handle an active compound in a chemically protected form. The term “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

(e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, 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). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective

Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.

[0147] A wide variety of such“protecting,”“blocking,” or“masking” methods are wideiy used and well known in organic synthesis. For example, 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. After the desired reaction (involving the other functional group) is complete, the protected group may be“deprotecied” to return it to its original functionality.

[0148] 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).

[0149] An aldehyde or ketone group may be protected as an acetal (RCH(OR) ) or ketal (R ₂ C(OR) ₂ ), respectively, in which the carbonyl group (R ₂ C=0) is converted to a diether (R ₂ C(OR) ₂ ), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

[0150] 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 (-NH-Troc), as an aliyloxy amide (-NH- Alloc), as a 2(-phenylsulphonyi)eihyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a niiroxide radical (>N-0«).

[0151] 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.

[0152] 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 )

Prodrugs and Other Modifications

[0153] In addition to salt forms, 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.

[0154] A compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties. Such 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.

Synthesis

[0155] Methods of synthesizing the herein described compounds will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds are known in the art and include, for example, those such as described in R Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser’s 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.

Methods of Use and Activity

[0158] 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. Specifically, in one embodiment, 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. In one embodiment, the kinase inhibited is a rho kinase (e.g , ROCK1 or ROCK2). In another embodiment, the kinase inhibited is a JAK (e.g., JAK2) kinase.

[0157] JAK inhibitors are useful in treating various JAK-associated diseases or disorders.

Examples of JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease).

Further examples of 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. In some embodiments, the autoimmune disease is arthritis.

[0158] Further examples of JAK-assodated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atropic eczema), and rhinitis. Further examples of 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).

[0159] Further examples of 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. Example CTCLs include Sezary syndrome and mycosis fungoides. Other examples of JAK-associated diseases or conditions include pulmonary arterial hypertension.

[0160] Other examples of JAK-associated diseases or conditions include inflammation-associated cancers. In some embodiments, the cancer is associated with inflammatory bowel disease. In some embodiments, the inflammatory bowel disease Is ulcerative colitis. In some embodiments, the inflammatory bowel disease Is Crohn's disease. In some embodiments, the inflammation-associated cancer is colitis-associated cancer. In some embodiments, the inflammation-associated cancer is colon cancer or colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stroma! tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.

[0161] 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. In one embodiment, the compounds are administered in a pharmaceutically acceptable composition, such as In or with a pharmaceutically acceptable carrier.

[0162] In another embodiment, 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. In one embodiment, the compounds of the present disclosure are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.

[0163] 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. Examples of these types of diseases indude neurodegeneraiive diseases, such as 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.

[0164] In some embodiments, the compounds of the present disclosure will be administered in conjunction with one or more additional therapeutic agents. Suitable classes of 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.

[0165] Beta blockers. These compounds are thought to lower intraocular pressure (iOR) by reducing the production of aqueous humor. Examples include levobunolol (BETAGAN™), timolol (BET!MOL™, T!MOPT!C™), betaxo!o! (BETOPT!C™) and metipranoiol (OPTIPRANOLOL™) [0166] Alpha-agonists These compounds are thought to lower IOP by reducing the production of aqueous humor and increasing drainage. Examples include apraclonidine (!GPIDINE™) and brimonidine (AIPHAGAN™)

[0167] Carbonic anhydrase inhibitors. These compounds are thought to lower IOP by also reducing the production of aqueous humor. Examples include dorzo!amide (TRUSOPT™) and brinzGiamide (AZOPT™).

[0168] Prostaglandin-like compounds. These compounds are thought to lower IOP by increasing the outflow of aqueous humor by the uveoscleral pathway. Examples include AR-102, latanoprost (XALATAN™), bi atoprost (LUMIGAN™), tafluprost (ZiGPTAN™), and travoprost (TRAVATAN™)

[0169] Miotic or cholinergic agents. These agents are thought to function by causing the pupil to constrict, which opens drainage channels in the eye. Examples include pilocarpine (iSGPTQ CARPINE™, PILGPINE™) and carbachol (ISOPTO CARBACHOL™)

[0170] Epinephrine compounds. These compounds, such as dipivefrin (PROPINE™), are thought to function by both decreasing the outflow of aqueous humor, as well as increasing fluid drainage.

[0171] Neuroprotective or anti-inflammatory compounds. These compounds, such as Af!ibercept (EYLEA™) 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. [0172] Thus, provided herein are 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.

[0173] 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.

[0174] In one aspect, provided herein are methods of 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.

[0175] In some embodiments, the ocular disorder is glaucoma.

[0176] In another aspect, provided herein are methods of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, provided herein.

[0177] In some embodiments of these aspects, the compound is administered topically to an eye of the subject.

[0178] In some embodiments, 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.

[0179] In some embodiments, 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.

[0180] In some embodiments, 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.

[0181] In some embodiments, provided herein are methods of 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.

[0182] In some embodiments of these methods, the method further comprises administering one or more additional therapeutic agents. In some embodiments, 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. In some embodiments, the one or more additional therapeutic agents is a prostaglandin or a prostaglandin-like compound. In some embodiment, the prostaglandin-like compound is AR-102, latanoprost, bimatoprost, tafluprost, or travoprosi

[0183] Also provided herein are methods of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound, a composition, or a pharmaceutical composition provided herein.

[0184] In some embodiments, 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.

[0185] In some embodiments, 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.

[0186] In some embodiments, 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.

Compositions and Administration

[0187] 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.

[0188] In some embodiments, the administration of 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.

[0189] Also provided herein are compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the compositions provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier.

[0190] Pharmaceutical 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. Thus, 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).

[0191] The route by which the compounds of the present disclosure (component A) will be administered and the form of the composition will dictate the type of carrier (component B) to be used. The 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).

[0192] 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.

[0193] 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%.

[0194] 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%.

[0195] 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%.

[0196] 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%.

[0197] Ingredient e) for solid dosage forms is a colorant such as an FD&C dye. When used, the amount of ingredient e) in the systemic or topical composition is typically about 0.005 to about 0.1 %.

[0198] 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%.

[0199] 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%. [0200] Ingredient h) is an antioxidant such as butyiated hydroxyanisole (“BHA”), butyiated hydroxyto!uene (“BHT”), and vitamin E. The amount of ingredient h) in the systemic or topical composition is typically about 0.1 to about 5%.

[0201] 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%.

[0202] 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%.

[0203] 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%.

[0204] 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%.

[0205] 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%.

[0208] Although the amounts of components A and B in the systemic compositions will vary depending on the type of systemic composition prepared, the specific derivative selected for component A and the ingredients of component B, in general, system compositions comprise 0 01 % to 50% of component A and 50 to 99.99% of component B.

[0207] 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. In one embodiment, component a) comprises propylene glycol and m) comprises ethanol or ethyl oleate.

[0208] Compositions for oral administration can have various dosage forms. For example, 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%.

[0209] 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.

[0210] Capsules (including implants, time release and sustained release formulations) 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.

[0211] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. One skilled in the art would know how to select appropriate ingredients without undue experimentation.

[0212] 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.

[0213] Compositions for ora! administration can also have liquid forms. For example, 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

[0214] Other 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.

[0215] In one embodiment of the disclosure, the compounds of the present disclosure are topically administered. 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.

[0216] 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.

[0217] 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. For example, 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.

[0218] 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. Thus, these compounds are useful in the treatment of glaucoma. The preferred route of administration for treating glaucoma is topically.

[0219] The exact amounts of each component in the topical composition depend 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. One skilled in the art understands how to calculate and understand an IC ₅₀ - The remainder of the composition, up to 100%, is component B.

[0220] 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).

[0221] Component B may comprise a single ingredient or a combination of two or more ingredients. In the topical compositions, 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.

[0222] 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.

[0223] 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. Specific emollients for skin include stearyi alcohol and polydimeihyisiloxane.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] Ingredient u) is a thickener. The amount of ingredient u) in the topical composition is typically about 0 to about 95%.

[0228] 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. For ocular applications, specific powders include ftefa-cyciodextrin, hydroxypropyl cyclodextrin, and sodium polyacry!ate. For gel dosing ocular formulations, sodium polyacrylaie may be used.

[0229] 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.

[0230] 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.

[0231] The 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

(Cl 45,380), D&C Orange No. 4 (Cl 15,510), D&C Orange No. 5 (Cl 45,370), D&C Red No. 27

(Cl 45,410), D&C Red No. 13 (Cl 15,830), D&C Red No. 7 (Cl 15,850), D&C Red No. 6 (Cl

15,850), D&C Yellow No. 5 (Cl 19,140), D&C Red No. 36 (Cl 12,085), D&C Orange No 10 (Cl 45,425), D&C Yellow No. 6 (Cl 15,985), D&C Red No. 30 (Cl 73,360), D&C Red No. 3 (Cl 45,430), the dye or lakes based on Cochineal Carmine (Cl 75,570) and mixtures thereof.

[0232] 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

[0233] In a particularly preferred embodiment of the disclosure, 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.

[0234] 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.

[0235] 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.

[0238] Examples of cc) 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.

[0237] 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).

[0238] The disclosure will be further explained by the following illustrative Examples that are to be considered to be non-limiting. Examples

Example 1 : ROCK and JAK assays.

ROCK Kinase inhibition Assays.

[0239] All compounds were initially prepared as 10 mM stocks in anhydrous dimethy!su!foxide (DMSO). A 20 pL aliquot of the 10 mM solutions was transferred to individual wells in column 1 of a 98-weil polypropylene microtiter plate (Corning #3363) and diluted with DMSO to give a final compound concentration of 4 mM. Test compounds were then serially diluted 1 :5 in DMSO for an 1 1-point concentration response and further diluted in the assay buffer bringing all compound concentrations to a final range of 100 mM to 10 pM in 2.5% DMSO. 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 mί 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. Protein kinase activity was quantitated using Promega’s K!NASE-GLO™ luminescent Kinase Assay Kit according to the manufacturer’s directions 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). 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). Percent of Control (POC) values were determined for each concentration of compound tested according to the equation: POC = ((Test well value - BKG)/ (CTRL - BKG))*1 QQ

[0240] IGso values were calculated using the following 4-parameter logistic curve-fitting algorithm: f(x) = {A+((B~A)/(1+((x/C) ^A D))))

[0241] ICso values were converted to K, values using the Cheng-Prusoff Equation: K, = IC50 / (1 + ([ATPj/Km ATP])).

JAK Kinase Assays,

[0242] Compounds were prepared in the exact same manner as described in the ROCK Kinase

Assay with the exception to the substrate and enzyme. The JAK 2X substrate/enzyme solution consisted of acceptor substrate (800nM Abi peptide EAiYAAPFAKKK (SEQ ID NO:2)), JAK2 or

JAK3 enzyme (1 QnM) and DTT (2uM) All other steps and solutions remain identical to the

ROCK Kinase Assay above. Results are shown below in Table 2 and Table 3. .

Example 2, PT -HT assay

[0243] Porcine Trabecular Meshwork cells (PTM) 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.

JAK1 JAK2 JAK3 TyK !KKb PTM STATS STATS NfkB

ROCK1 ROCK2

Compound Ki Ki Ki Ki Ki iC5Q XC50 XC50 XC50

Ki nM Ki nM

nM nM nM nM nM nM nM nM nM

Example 3, Formulations.

[0244] in some embodiments, topical pharmaceutical compositions for lowering intraocular pressure comprising the compounds provided herein are prepared by conventional methods and formulated as shown in Table 4.

Table 4.

[0245] A compound according to this disclosure is used as the ihieny!cyclopropy! amino acid isoqulnoiyi amide. When the composition is topically administered to the eyes once daily, the above composition decreases intraocular pressure in a subject suffering from glaucoma.

Example 4. Pharmacological Activity for Glaucoma Assay.

[0246] 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 U Hacksell, “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.

Example 5. Storage.

[0247] A compound or composition provided herein is prepared and placed in a container for storage at ambient or elevated temperature. When the compound or composition is stored in 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. Without wishing to be bound by theory, 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)). 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. Compounds and compositions benefiting from reduced discoloration, decomposition, or both during storage, include 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.

[0248] Other suitable containers and packaging are described, for example, in International publication numbers WO 2018/159700, WO 2018/159701 , and WO 2018/159702, and JP 6236167 B2, the contents of which are incorporated herein by reference.

[0249] 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. In some cases, the vehicle is an aqueous vehicle. In other cases, the vehicle is a non-aqueous vehicle.

[0250] The preceding disclosures are illustrative embodiments. It should be appreciated by those of skill in the art that the devices, techniques and methods disclosed herein elucidate representative embodiments that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0251] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in ail instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0252] The terms "a" and "an" and "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or dearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. Ail methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0253] The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or."

[0254] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or In any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0255] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects those of ordinary skill in the art to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context

[0256] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of excludes any element, step, or ingredient not specified in the claims. The transition term“consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characterisiic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0257] Further, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.