Substituted pyrrolopyrimidine JAK inhibitors and methods of making and using same

Abstract

To provide new pyrrolopyridine compounds for the treatment of disease, and pharmaceutical compositions comprising the same.SOLUTION: The present invention provides a composition comprising the structure of formulas (I) to (IV) or derivatives thereof as an active ingredient, where R groups, ring labels, and n values are defined in the specifications.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 581,428, filed November 3, 2017, and U.S. Provisional Application No. 62 / 670,448, filed May 11, 2018. The disclosures of both of these applications are incorporated herein by reference. The disclosure of this application is incorporated herein by reference. [Background technology]

[0002] Janus kinases (JAKs) are a subgroup of non-receptor tyrosine kinases that are essential for transducing signals emanating from type I and type II cytokine receptors and whose enzymatic activity is essential for the biological activity of cytokines. The JAK kinase family consists of four family members: JAK1, JAK2, JAK3 and Tyk2, and these kinases are central to the control of cytokine signaling in the immune system and more broadly in other tissues. The kinase activity of JAKs is directed towards the JAKs themselves, the intracellular portion of the cytokine receptor, and several other substrates, including members of the STAT family of transcription factors. STATs (STAT1 to STAT6) have specific and distinct effects on gene transcription in many cell types, including immune cells, and are important in processes such as cell proliferation and differentiation. The widespread role of these kinases in immunity and inflammation has led to the development of many small molecule drugs to intervene in diseases where the cause of the disease is JAK kinase signaling. Summary of the Invention [Problem to be solved by the invention]

[0003] The present invention relates to novel pyrrolopyridine compounds and compositions and their application as medicaments for the treatment of diseases. [Means for solving the problem]

[0004] Novel pyrrolopyridine compounds and compositions and their application as pharmaceuticals for the treatment of diseases are disclosed herein. Methods for inhibiting JAK1 and JAK3 kinase activity in a human or animal subject are also provided for the treatment of JAK1 and / or JAK3 mediated conditions. Embodiments herein are directed to having the structure of Formulas (I)-(IV) or derivatives thereof, where the R groups, ring labels, and n values ​​are defined herein: [ka]

[0005] Novel pyrrolopyridine compounds and compositions and their application as pharmaceuticals for the treatment of diseases are disclosed herein. Methods for inhibiting JAK1 and JAK3 kinase activity in a human or animal subject are also provided for the treatment of JAK1 and / or JAK3 mediated conditions.

[0006] Janus kinases (JAKs) are a subgroup of non-receptor tyrosine kinases that are essential for transducing signals emanating from type I and type II cytokine receptors and whose enzymatic activity is essential for the biological activity of cytokines. The JAK kinase family consists of four family members: JAK1, JAK2, JAK3 and Tyk2, and these kinases are central to the control of cytokine signaling in the immune system and, more broadly, in other tissues. The kinase activity of JAKs is directed against the JAKs themselves, the intracellular portion of the cytokine receptor, and several other substrates, including members of the STAT family of transcription factors. STATs (STAT1 to STAT6) have specific and distinct effects on gene transcription in many cell types, including immune cells, and are important in processes such as cell proliferation and differentiation. Given the widespread role of these kinases in immunity and inflammation, many small molecule drugs have been developed to intervene in diseases whose etiology is due to JAK kinase signaling. Initially, these drugs were developed for systemic administration to prevent organ transplant rejection. These drugs were subsequently developed as potential treatments for hematological malignancies, as well as autoimmune and inflammatory diseases, including rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, atopic dermatitis, alopecia disorders, and vitiligo vulgaris, to name a few. More recently, due to the hematological, immunosuppressive, and metabolic toxicities associated with systemic inhibition of JAK kinases, local delivery of these inhibitors as topical agents has been described. Among these, these include alopecia areata, atopic dermatitis, vitiligo vulgaris, psoriasis, inflammatory bowel disease, and dry eye. This literature describes compounds that are expected to have excellent oral and topical bioavailability and are useful against systemic autoimmune diseases, as well as compounds that are designed to have limited stability and therefore limited systemic exposure, and are therefore best suited for local (e.g., topical) drug delivery.

[0007] It has been shown that signal transduction of cytokine-activated cytokine receptors occurs via JAK kinases associated with the receptor cytoplasmic domain. Receptor stimulation leads to activation of JAK and subsequent phosphorylation of the cytoplasmic domain of the associated receptor chain. This creates an SH2-binding domain that serves to recruit latent cytoplasmic transcription factors known as STATs (signal transducers and activators of transcription). While bound to phosphorylated cytokine receptors, STATs themselves become phosphorylated on tyrosine residues. This leads to the formation of SH2-domain mediated homo- and hetero-dimers and translocation to the nucleus. These proteins then induce the transcription of genes associated with the activation of the original cytokine receptor. Both of these events (phosphorylation of STAT proteins in minutes and STAT-induced gene transcription in hours) are suitable for characterizing the cellular potency of compounds and also affect structure-activity relationships. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Before describing the compositions and methods of the present invention, it is to be understood that the present invention is not limited to the specific processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terms used in this description are intended to describe only the specific versions or embodiments, and are not intended to limit the scope of the embodiments herein, which will be limited only to the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the embodiments herein, the preferred methods, devices, and materials are described herein. All publications described herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the embodiments herein are not entitled to antedate such disclosure by prior invention.

[0009] definition It should also be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "JAK inhibitor" is a reference to one or more JAK inhibitors known to those of skill in the art and equivalents thereof, and so forth. The term "about," as used herein, is intended to qualify the numerical value it modifies and to present such value as variable within a margin of error. If no specific margin of error is recited, such as, for example, the standard deviation for the average value given in a chart or table of data, the term "about" should be considered to mean plus or minus 10% of the numerical value of the number with which it is used. Thus, about 50% means a range of 45% to 55%. In embodiments or claims where the term comprising is used as a transitional phrase, such embodiments may also contemplate replacing the term "comprising" with the term "consisting of" or "consisting essentially of."

[0010] As used herein, the terms "consists of" or "consisting of" mean that a composition, formulation, or method includes only those elements, steps, or ingredients specifically recited in a particular claimed embodiment or claim. As used herein, the terms "consisting essentially of" or "consists essentially of" mean that a composition, formulation, or method includes only those elements, steps, or ingredients specifically recited in a particular claimed embodiment or claim, and may include additional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient(s) in a formulation or method for treating a specified condition (e.g., nutrient depletion) is the therapeutic agent(s) specifically recited in a particular embodiment or claim. As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other. For example, an embodiment in which two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH. As used herein, the term "derivative thereof" refers to a salt thereof, a pharma- ceutically acceptable salt thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to a patient. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

[0011] When ranges of values ​​are disclosed and when the notation "from n1 to n2" or "between n1 and n2" (where n1 and n2 are numbers) is used, unless otherwise specified, the notation is intended to include the numbers themselves and the range therebetween. The range may be integer or continuous, between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbons exist in integers. In contrast, as an example, the range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and any number of significant figures therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0012] The term "acyl", as used herein, alone or in combination, refers to a carbonyl bound to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bound to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bound to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0013] The term "alkenyl", as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system bonded at two or more positions, e.g., ethenylene (-CH=CH-). Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include an "alkenylene" group.

[0014] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like. The term "alkyl," as used herein, alone or in combination, refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, said alkyl contains 1 to 10 carbon atoms. In further embodiments, said alkyl contains 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein.

[0015] Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl, and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon bonded at two or more positions, e.g., methylene (-CH2-). Unless otherwise specified, the term "alkyl" can include an "alkylene" group.

[0016] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be monodialkylated or dialkylated, for example, to form N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups. The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached. The term "alkylthio", as used herein, alone or in combination, refers to an alkylthioether (RS-) group, in which the term alkyl is as defined above and the sulfur may be oxidized once or twice. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0017] The term "alkynyl," as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkynyl contains 2 to 6 carbon atoms. In further embodiments, said alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, e.g., ethynylene (-C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0018] The terms "amido" and "carbamoyl", as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido", as used herein, alone or in combination, refers to a -C(O)N(RR') group with R and R' as defined herein or as defined by the specifically listed designated "R" group. The term "N-amido", as used herein, alone or in combination, refers to a RC(O)NH(R')- group with R and R' as defined herein or as defined by the specifically listed designated "R" group. The term "acylamino", as used herein, alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-). The term "amino," as used herein, alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be substituted. Additionally, R and R' may combine to form a heterocycloalkyl, any of which may be substituted.

[0019] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, such polycyclic ring systems being fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group. The terms "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group. The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0020] The terms "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkynyl group. The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refer to an acyl group derived from an aryl-substituted alkanecarboxylic acid, such as, for example, benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like. The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0021] The terms "benzo" and "benz" as used herein, alone or in combination, refer to the divalent group CH= derived from benzene. Examples include benzothiophene and benzimidazole. The term "carbamate," as used herein, alone or in combination, refers to a carbamic acid ester (-NHCOO-), which may be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and which may be substituted as defined herein. The term "O-carbamyl," as used herein, alone or in combination, refers to a -OC(O)NRR' group, with R and R' as defined herein. The term "N-carbamyl," as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.

[0022] The term "carbonyl" as used herein, alone includes formyl [-C(O)H] and in combination, a -C(O)- group. The terms "carboxyl" or "carboxy", as used herein, refer to -C(O)OH, or the corresponding "carboxylate" anion, as in carboxylate salts. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0023] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted. The term "compound" also includes the incorporation of all isotopes at any enrichment (e.g., tritium, deuterium) at any position within the structures depicted. The term "cyano" as used herein, alone or in combination, refers to -CN.

[0024] The term "cycloalkyl", or alternatively, "carbocycle", as used herein, alone or in combination, refers to a saturated or partially saturated, monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety of which contains 3 to 12 carbon atom ring members, and which may be a benzo-fused ring system, optionally substituted as defined herein. In certain embodiments, said cycloalkyl contains 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. "Bicyclic" and "tricyclic", as used herein, are intended to include both fused ring systems, e.g., decahydronaphthalene, octahydronaphthalene, as well as polycyclic (multicentric) saturated or partially unsaturated species. The latter type of isomer is commonly exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0025] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties which are linked at a carbon atom. The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties which are linked at a carbon atom.

[0026] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine. The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "haloalkyl", as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above, in which one or more hydrogens are replaced by halogen. Specifically, monohaloalkyl, dihaloalkyl and polyhaloalkyl groups are included. Monohaloalkyl groups, as one example, can have iodo, bromo, chloro or fluoro atoms in the group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group that is attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0027] The term "halocycloalkyl", as used herein, alone or in combination, refers to a cycloalkyl group having the meaning as defined above, in which one or more hydrogens are replaced by halogen. Specifically included are monohalocycloalkyl, dihalocycloalkyl and polyhalochaloalkyl groups. As an example, monohaloalkyl groups can have iodo, bromo, chloro or fluoro atoms in the group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, chlorocyclobutyl and chlorocyclopentyl.

[0028] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable linear or branched chain, or combination thereof, that is fully saturated or contains 1 to 3 degrees of unsaturation and consists of the stated number of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, where the N and S atoms may be optionally oxidized and the N heteroatom may be optionally quaternized. The heteroatom(s) may be located at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.

[0029] The term "heteroaryl", as used herein, alone or in combination, refers to a 5-15 membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl contains 1-4 heteroatoms as ring members. In further embodiments, the heteroaryl contains 1-2 heteroatoms as ring members. In certain embodiments, the heteroaryl contains 5-7 atoms. The term also encompasses fused polycyclic groups in which a heterocycle is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0030] The terms "heterocycloalkyl" and, interchangeably, "heterocycle", as used herein, alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group, respectively, containing at least one heteroatom as a ring member, each of which may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl contains 1-4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl contains 1-2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl contains 3-8 ring members in each ring. In further embodiments, the heterocycloalkyl contains 3-7 ring members in each ring. In still further embodiments, the heterocycloalkyl contains 5-6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, as well as carbocyclic fused and benzofused ring systems. Additionally, both terms also include systems in which a heterocycle is fused to an aryl group, as defined herein, or to an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydro-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocyclic groups may be optionally substituted unless specifically prohibited.

[0031] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups linked by a single bond, ie, --NN--. The term "hydroxy," as used herein, alone or in combination, refers to --OH. The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. The term "imino," as used herein, alone or in combination, refers to =N-. The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =NO-.

[0032] The phrase "in the backbone" refers to the longest contiguous or adjacent chain of carbon atoms starting from the point of attachment of the group to any one of the compounds of the formulae disclosed herein. The term "isocyanato" refers to a --NCO group. The term "isothiocyanato" refers to the group -NCS.

[0033] The phrase "straight chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur. The term "lower", as used herein, alone or in combination, unless specifically defined, means containing 1 to 6 (inclusive) carbon atoms (i.e., C1-C6 alkyl). The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as specified. The term "lower heteroaryl," as used herein, alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, where between 1 and 4 of said members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl, where each of the fused rings contains 5 or 6 ring members and contains between 1 and 4 heteroatoms selected from N, O, and S. The term "lower cycloalkyl", as used herein, alone or in combination, refers to a monocyclic cycloalkyl having between 3 and 6 ring members (i.e., C3-C6 cycloalkyl). Lower cycloalkyl may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] The term "lower heterocycloalkyl," as used herein, alone or in combination, refers to a monocyclic heterocycloalkyl having between 3 and 6 ring members, of which between 1 and 4 are heteroatoms selected from N, O, and S (i.e., C3-C6 heterocycloalkyl). Examples of lower heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl may be unsaturated. The term "lower amino," as used herein, alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen and lower alkyl, any of which may be substituted. The term "mercaptyl", as used herein, alone or in combination, refers to an RS-group, where R is as defined herein. The term "nitro," as used herein, alone or in combination, refers to --NO.

[0035] The term "N-oxide" is formed from tertiary basic amines or imines present in the molecule using a convenient oxidizing agent. The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--. The term "oxo," as used herein, alone or in combination, refers to =O. The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced with halogen atoms. The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced with halogen atoms.

[0036] The term "substantially free," as used herein, refers to a compound that is free from all other compounds within the limits of detection, as measured by any means, including nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GC / MS), or liquid chromatography / mass spectrometry (LC / MS), either alone or in combination.

[0037] The terms "sulfonate," "sulfonic acid," and "sulfonic" as used herein, alone or in combination, refer to the -SO3H group and its anion, where sulfonic acid is used in salt formation. The term "sulfanyl," as used herein, alone or in combination, refers to --S--. The term "sulfinyl," as used herein, alone or in combination, refers to --S(O)--. The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-. The term "N-sulfonamido" refers to a RS(=O)2NR'- group, with R and R' as defined herein. The term "S-sulfonamido" refers to a -S(=O)2NRR' group, with R and R' as defined herein.

[0038] The terms "thia" and "thio," as used herein, alone or in combination, refer to an --S- group or an ether, where the oxygen is replaced by a sulfur. The oxidized derivatives of the thio group, namely, sulfinyl and sulfonyl, are included in the definition of thia and thio. The term "thiol," as used herein, alone or in combination, refers to a --SH group.

[0039] The term "thiocarbonyl" as used herein, alone, includes thioformyl-C(S)H, and in combination is a -C(S)- group. The term "N-thiocarbamyl" refers to a ROC(S)NR'- group, with R and R' as defined herein. The term "O-thiocarbamyl" refers to a -OC(S)NRR' group, with R and R' as defined herein. The term "thiocyanato" refers to the group -CNS.

[0040] The term "trihalomethanesulfonamide" refers to a X3CS(O)2NR- group, where X is a halogen and R is as defined herein. The term "trihalomethanesulfonyl" refers to a X3CS(O)2- group where X is a halogen. The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.

[0041] The term "trisubstituted silyl", as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with a group listed herein under the definition of amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like. Any definition herein can be used in combination with any other definition to describe a composite structural group.By convention, any such definition's appendant is attached to the parent moiety.For example, the composite group alkylamide represents an alkyl group that is attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group that is attached to the parent molecule via an alkyl group.

[0042] When a group is defined as "void", what is meant is that said group is not present. The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or specific specified series of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower Haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxy ester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. When structurally possible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms, e.g., methylenedioxy or ethylenedioxy. Optionally substituted groups may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level of substitution between fully and monosubstituted (e.g., -CH2CF3). When substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent qualifies as "substituted," the substituted form is specifically intended. Additionally, a different set of optional substituents for a particular moiety may be defined as appropriate, and in these cases, the optional substitution is often as defined immediately following the phrase "optionally substituted with."

[0043] The term R or R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be substituted. Such R and R' groups are to be understood as being optionally substituted as defined herein. Regardless of whether an R group has a number designation, all R groups, including R, R' and Rn (where n = (1, 2, 3, ... n)), all substituents, and all terms are to be understood as being independent of each other with respect to selection from a group. If any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than once in a formula or generic structure, its definition at each occurrence is independent of its definition at all other occurrences. Those skilled in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position from either end in a chain of elements as described. For example, an unsymmetrical group, such as -C(O)N(R)-, may be attached to the parent moiety at either the carbon or the nitrogen.

[0044] Stereocenters exist in some of the compounds disclosed herein. These centers are designated by the symbols "R" or "S" depending on the configuration of the substituents around the stereocenter. It should be understood that the present invention encompasses all stereochemical isomeric forms, including diastereomers, enantiomers, atropisomers, racemic and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing fixed stereocenters, or by preparation of racemic mixtures of products followed by separation of the enantiomers, such as conversion to a diastereomeric mixture, followed by separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of a particular stereochemical configuration are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and the appropriate mixtures thereof. Additionally, the present compounds may exist as tautomers. All tautomeric isomers are provided by the present invention. Additionally, the compounds disclosed herein may exist in unsolvated as well as solvated forms with pharma-ceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0045] The term "bond" refers to a covalent bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. The bond may be a single, double, or triple bond unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0046] The term "disease", all as used herein, is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder", "syndrome", and "condition" (such as in medical conditions) in the sense that it reflects an abnormal condition of the human or animal body or an abnormal condition of a part of the human or animal body that impairs normal functioning, is typically manifested by characteristic signs and symptoms, and results in a reduction in the life span or quality of life in a human or animal. The term "combination therapy" refers to administering two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure.Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single topical composition with a fixed ratio of active ingredients, or in multiple, separate topical compositions for each active ingredient.In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner.In either case, the treatment regimen provides the beneficial effect of drug combination in treating the conditions or disorders described herein.

[0047] A "JAK1 and / or JAK3 inhibitor" refers to an inhibitor of JAK1 and / or JAK3 activity that has an IC of about 100 μM or less, as measured in the JAK1 and JAK3 enzyme assays generally described herein. 50 , more typically IC of about 50 μM or less 50 In some embodiments, the compounds have an IC of about 1 μM to about 50 μM with respect to JAK1 and / or JAK3. 50 Indicates IC 50 is the concentration of an inhibitor that reduces enzyme activity (e.g., JAK1 and / or JAK3) to half-maximal levels. Certain compounds disclosed herein have been found to exhibit inhibition against JAK1 and / or JAK3. In some embodiments, the compounds have an IC of about 300 nM or less with respect to JAK1 and / or JAK3. 50 In some embodiments, the compounds exhibit an IC of about 1 nM or less with respect to JAK1 and / or JAK3.50 In certain embodiments, the compounds exhibit an IC of about 50 μM or less with respect to JAK1 and / or JAK3 as measured in the JAK1 and / or JAK3 assays described herein. 50 in further embodiments, the compounds exhibit an IC 50 in yet further embodiments, the compounds exhibit an IC 50 in yet further embodiments, the compounds exhibit an IC 50 Shows.

[0048] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or disorder or effect a clinical endpoint. As used herein, the term "therapeutic agent" refers to an agent utilized to treat, combat, ameliorate, prevent, or ameliorate an undesirable condition or disease in a patient. In part, embodiments of the present invention are directed to the treatment of JAK1 and / or JAK3 mediated diseases. The term "therapeutically acceptable" refers to compounds, or derivatives thereof, that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, and that are effective for their intended use, consistent with a reasonable benefit / risk ratio.

[0049] As used herein, reference to "treatment" of a patient is intended to include prevention. Treatment may also be preventative in nature, i.e., treatment may also include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of prevention of infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease may not mean completely suppressing any disease-related effects at any level, but may instead mean preventing disease symptoms to a clinically significant or detectable level. Prevention of disease may also mean preventing disease progression to a later stage of disease.

[0050] "Administering", when used in conjunction with a therapeutic agent, means administering the therapeutic agent directly into or onto a target tissue, or administering the therapeutic agent to a patient, whereby the therapeutic agent positively affects the targeted tissue. Thus, as used herein, the term "administering", when used in conjunction with the compounds of the embodiments herein, can include, but is not limited to, providing the compound into or onto a target tissue; providing the compound to a patient systemically, for example, by intravenous injection, whereby the therapeutic agent reaches the target tissue; providing the compound to the target tissue in a form that encodes its sequence (e.g., by so-called gene therapy techniques). "Administering" a composition can be accomplished by injection, topical, oral, or any of these methods in combination with other known techniques.

[0051] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock, such as cows, goats, sheep, pigs, and rabbits, and companion animals, such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0052] The term "prodrug" refers to a compound that has enhanced activity in vivo. Certain compounds disclosed herein can also exist as prodrugs as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that undergo easy chemical changes under physiological conditions to provide the compounds. In addition, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds using appropriate enzymes or chemical reagents when placed in a transdermal patch reservoir. Prodrugs are often useful because in some situations, they are easier to administer than the compounds, or parent drugs. Prodrugs can be bioavailable, for example, by oral administration, whereas the parent drugs are not bioavailable. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drugs. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.

[0053] The term "therapeutically acceptable salts" as used herein refers to water- or oil-soluble or dispersible salts or zwitterionic forms of the compounds disclosed herein that are therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds, or separately by reacting the appropriate compounds in their free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate. , mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, the basic groups of the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, methyl, ethyl, propyl, and butyl bromides, and methyl, ethyl, propyl, and butyl iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, decyl, lauryl, myristyl, and stearyl bromides, and decyl, lauryl, myristyl, and stearyl iodides; and benzyl and phenethyl bromides.Examples of acids that can be utilized to form therapeutically acceptable addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids, such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth ion. Thus, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein. Novel compounds and pharmaceutical compositions, certain of which have been found to inhibit JAK1 and / or JAK3 kinases, have been discovered along with methods of synthesizing and using the compounds, including, but not limited to, methods for treating JAK1 and / or JAK3 mediated diseases in patients by locally administering the compounds.

[0054] The compounds of the present invention may be selective in various ways among the JAK1 and / or JAK3 isoforms. For example, the compounds described herein may be selective for JAK1 and / or JAK3 over other isoforms, such as JAK2 and Tyk-2, may be pan-inhibitors of all isoforms, or may be selective for only one isoform. In certain embodiments, the compounds of the present invention are selective for JAK1 and / or JAK3 over other isoforms. In some embodiments, the compounds disclosed herein are selective for JAK1 and / or JAK3 over JAK2 and Tyk-2. Selectivity can be determined using enzyme assays, cellular assays, or both. In some embodiments, the compounds disclosed herein are at least about 10x selective for JAK1 and / or JAK3 receptors over JAK2 receptors. In some embodiments, the compounds disclosed herein are at least about 10x selective for JAK1 and / or JAK3 receptors over Tyk-2 receptors.

[0055] compound Embodiments herein are directed to the compounds and pharmaceutical compositions, certain of which have been found to inhibit JAK1 and / or JAK3 kinases, along with methods of synthesizing and using the compounds. Some embodiments include methods for treating disease in a patient by locally administering a compound of an embodiment herein. Certain compounds disclosed herein can possess useful JAK1 and / or JAK3 inhibitory activity and can be used to treat or prevent diseases or conditions in which JAK1 and / or JAK3 play an active role. Thus, embodiments are also directed to pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharma- ceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments are directed to methods for inhibiting JAK1 and / or JAK3. Other embodiments are directed to methods for treating JAK1 and / or JAK3-mediated disorders in patients in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the invention. Use of certain compounds disclosed herein in the manufacture of a medicament for the treatment of a disease or condition ameliorated by inhibition of JAK1 and / or JAK3 is also provided.

[0056] Also provided are embodiments in which any embodiment herein can be combined with any one or more of the other embodiments, unless otherwise stated, and in which combinations are not mutually exclusive. Also provided is a compound selected from the examples disclosed herein.The compound of the embodiments of the present specification can also refer to its salt, its ester, its free acid form, its free base form, its solvate, its deuterated derivative, its hydrate, its N-oxide, its clathrate, its prodrug, its polymorph, its stereoisomer, its enantiomer, its diastereomer, its racemate, its mixture of stereoisomers, its tautomer, its mixture of tautomers, or combination of the above-mentioned compounds of the embodiments of the present specification.

[0057] The compounds described herein may contain stereocenters, may be chiral, and may therefore exist as enantiomers. When compounds according to embodiments herein possess two or more stereocenters, they may further exist as diastereomers. The embodiments herein include all possible stereoisomers as substantially pure resolved enantiomers, their racemic mixtures, as well as mixtures of diastereomers. In some embodiments, formulas are shown without a definite stereochemistry at certain positions. The embodiments herein include all stereoisomers of such formulas and pharma-ceutically acceptable salts thereof. Diastereoisomeric pairs of stereoisomers can be separated, for example, by fractional crystallization from a suitable solvent, and the enantiomeric pairs thus obtained can be separated into individual stereoisomers by conventional means, for example, using an optically active acid or base as a resolving agent, or by a chiral HPLC column. Additionally, any enantiomer or diastereomer of a compound of the general formula can be obtained by stereospecific or stereoselective synthesis using optically pure or enantiomerically enriched starting materials or reagents of known configuration. The scope of the embodiments herein as described and claimed encompasses the racemates of the compounds as well as individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.

[0058] Conventional techniques for the preparation / isolation of individual enantiomers include stereoselective synthesis from suitable enantiomerically enriched or optically pure precursors, or racemate resolution using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound contains an acidic or basic moiety, an acid or base, for example, tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. The chiral compounds of the embodiments herein (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% isopropanol, typically 2-20%, and 0-5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate produces the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).

[0059] Atropisomers are stereoisomers that result from restricted rotation around a single bond when the steric torsional barrier to rotation is high enough to allow for the isolation of the conformers. Oki (Oki, M; Topics in Stereochemistry 1983, 1) defined atropisomers as conformers that interconvert with half-lives of more than 1000 seconds at a given temperature. The scope of the embodiments described and claimed herein includes racemates of the compounds as well as individual atropisomers (atropisomers that are "substantially free" of their corresponding atropisomers) and stereoisomer-enriched mixtures, i.e., mixtures of atropisomers. Separation of the atropisomers is likely accomplished by chiral resolution methods, such as selective crystallization. In an atropenantioselective or atropselective synthesis, one atropisomer is formed at the expense of the other. Atropselective synthesis can be achieved by the use of chiral auxiliaries, such as the Corey-Bakshi-Shibata (CBS) catalyst (an asymmetric catalyst derived from proline) in the total synthesis of kniphorone, or by approaches based on thermodynamic equilibration, where an isomerization reaction favors one atropisomer over the other.

[0060] Suitable pharma- ceutically acceptable acid addition salts of the compounds of the embodiments herein can be prepared from inorganic or organic acids. All of these salts can be prepared in a conventional manner from the corresponding compounds of the embodiments herein, for example, by treating the compound with the appropriate acid or base.

[0061] Pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, and diphosphoric acid; and organic acids, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylamino acid, and the like. Sulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, malonic acid, galactic acid, galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucoic acid, ascorbic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), napadisilic acid (1,5-naphthalenedisulfonic acid), etc.

[0062] Salts derived from pharma-ceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including alkylamines, arylalkylamines, heterocyclylamines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0063] Other preferred salts according to embodiments herein include an equivalent amount of an anion (X - ) is attached to the positive charge of the N atom. X - X may be anions of various mineral acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate, etc., or anions of organic acids, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. - is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X - is chloride, bromide, trifluoroacetate or methanesulfonate. As used herein, N-oxides are formed from tertiary basic amines or imines present in the molecule, using a convenient oxidizing agent.

[0064] The compounds of the embodiments herein may exist in both non-solvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the embodiments herein and an amount of one or more pharma-ceutically acceptable solvent molecules. When the solvent is water, the term hydrate is utilized. Examples of solvate forms include, but are not limited to, the compounds of the embodiments herein combined with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. In the embodiments herein, it is specifically envisioned that one solvent molecule may be combined with one molecule of the compounds of the embodiments herein, e.g., hydrate. Furthermore, in the embodiments of the present specification, more than one solvent molecule may be bound to one molecule of the compound of the embodiments of the present specification, for example, dihydrate is specifically envisaged.In addition, in the embodiments of the present specification, less than one solvent molecule may be bound to one molecule of the compound of the embodiments of the present specification, for example, hemihydrate is specifically envisaged.Furthermore, the solvate of the embodiments of the present specification is envisaged as the solvate of the compound of the embodiments of the present specification that retains the biological effectiveness of the non-solvated form of the compound.

[0065] Embodiments herein also include isotopically labeled compounds of embodiments herein in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from that normally found in nature. Examples of isotopes suitable for inclusion in compounds of embodiments herein include hydrogen isotopes, e.g., 2 H and 3 Carbon isotopes such as H, e.g. 11 C. 13 C and 14 Chlorine isotopes such as C, e.g.31 Fluorine isotopes such as Cl, e.g. 18 Iodine isotopes such as F, e.g. 123 I and 125 Nitrogen isotopes such as I, e.g. 13 N and 15 Oxygen isotopes such as N, e.g. 15 O. 17 O and 18 Phosphorus isotopes such as O, e.g. 32 P, etc., and sulfur isotopes, e.g. 35 Certain isotopically labeled compounds of the embodiments herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection. Substitution with heavier isotopes, e.g., deuterium, 2H, etc., can confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some circumstances. Positron emitting isotopes, e.g., 11 C. 18 F, 15 O and 13 Substitutions such as with N may be useful in positron emission tomography (PET) experiments to examine substrate receptor occupancy.

[0066] Isotopically labeled compounds of embodiments herein can generally be prepared by conventional techniques known to those of skill in the art, or by analogous processes described herein using appropriate isotopically labeled reagents in place of non-labeled reagents otherwise utilized. Preferred isotopically labeled compounds include deuterated derivatives of the compounds of the embodiments herein. As used herein, the term deuterated derivatives encompasses the compounds of the embodiments herein in which at least one hydrogen atom at a particular position has been replaced with deuterium. Deuterium (D or 2H) is a stable hydrogen isotope that exists at a natural abundance of 0.015 mole %.

[0067] Hydrogen-deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced with a deuterium atom. The exchange (incorporation) reaction can be total or partial. Typically, deuterated derivatives of the compounds of the embodiments herein have an isotopic enrichment factor (the ratio of the abundance of an isotope to the natural abundance of that isotope, i.e., the percentage of incorporation of deuterium in place of hydrogen at a given position in a molecule) of at least 3500 (52.5% deuterium incorporation) for each deuterium present at a site designated as a potential site of deuteration on the compound. In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuteration sites.

[0068] The isotopic enrichment factor can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0069] Prodrugs of the compounds described herein are also within the scope of the embodiments herein. Thus, certain derivatives of the compounds of the embodiments herein (which may themselves have little or no pharmacological activity) can be converted into the compounds of the embodiments herein with desired activity when administered into or on the body, for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Prodrugs according to embodiments herein can be generated, for example, by replacing appropriate functional groups present within the compounds of embodiments herein with certain moieties known to those of skill in the art as "promoieties," for example, as described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[0070] For compounds of the embodiments herein that are solid, it will be understood by those of skill in the art that the compounds and salts of the invention may exist in different crystalline or polymorphic forms, or amorphous forms, all of which are intended to be within the scope of the embodiments herein. The compounds disclosed herein can exist and therefore include all stereoisomers, conformations and mixtures thereof in all proportions, as well as isotopic forms such as deuterated compounds.

[0071] The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable. However, salts that are non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compounds of interest. Basic addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). Basic addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate ions of metal cations or ammonia or organic primary, secondary, or tertiary amines.Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. In certain embodiments, the compound has structural formula (I):

[0072] [ka] wherein R1 is selected from -CO2R5, -C1-C5 alkyl-CO2R5, -C3-C6-cycloalkyl-CO2R5, -NHCO2R5, -N(C1-C5 alkyl)-CO2R5, -O-CO2R5, or -C1-C5 alkyl-O-CO2R5; R2 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring A is substituted at one or more carbons with one, two, or three R3 substituents, each R3 group being independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; two R groups on the same or different carbon atoms of ring A may be linked to form a spirocyclic or bicyclic ring with ring A; R4 is selected from -C(O)-R6, -CH2R6, -C(O)-CH=CH2, -C(O)-C(CHOCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR7R8, -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R5 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, where the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R6 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR7R8, -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R7 and R8 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, where the alkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -CN; R7 and R8 may be linked to form a ring, forming a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom, forming a ring such as morpholine. In certain embodiments, the compound has structural formula (Ia):

[0073] [ka] wherein R 21 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring B may contain one, two, or three R 31 Each R 31groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring B 31 The groups may be linked to form a spirocyclic or bicyclic ring together with ring B; R 41 is -C(O)-R 61 , -CH2R 61 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 71 R 81 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 51 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 61 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 71 R 81 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 71 and R 81is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 71 and R 81 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (Ib):

[0074] [ka] wherein R 22 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring C may contain one, two, or three R 32 Each R 32 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring C 32 the groups may be linked to form a spirocyclic or bicyclic ring together with Ring C; R 42 is -C(O)-R 62 , -CH2R 62 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR72 R 82 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 52 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 62 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 73 R 83 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 72 and R 82 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 72 and R 82 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (Ic):

[0075] [ka] wherein R 23is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring D may contain one, two, or three R 33 Each R 33 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring D 33 the groups may be linked to form a spirocyclic or bicyclic ring together with Ring D; R 43 is -C(O)-R 63 , -CH2R 63 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 73 R 83 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 53 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 63 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 73 R 83, -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 73 and R 83 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 73 and R 83 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (Id):

[0076] [ka] wherein R 24 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring E may contain one, two, or three R 34 Each R 34 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring E 34 the groups may be linked to form a spirocyclic or bicyclic ring together with ring E; R 44 is -C(O)-R 64 , -CH2R 64 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 74 R 84 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 54 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 64 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 74 R 84 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 74 and R 84 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 74 and R 84may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (Ie):

[0077] [ka] wherein R 25 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring F may contain one, two, or three R 35 Each R 35 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring F 35 the groups may be linked to form a spirocyclic or bicyclic ring together with ring F; R 45 is -C(O)-R 65 , -CH2R 65 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 75 R 85 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 55 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 65 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 75 R 85 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 75 and R 85 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 75 and R 85 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has the structural formula (If):

[0078] [ka] wherein R 26 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring G may contain one, two, or three R 36 Each R 36 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring G 36 the groups may be linked to form a spirocyclic or bicyclic ring together with ring G; R 46 is -C(O)-R 66 , -CH2R 66 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 76 R 86 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 56 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 66 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 76 R 86 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 76and R 86 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 76 and R 86 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (Ig):

[0079] [ka] wherein R 27 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring H may have one, two, or three R on one or more carbons. 37 Each R 37 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring H 37 the groups may be linked to form a spirocyclic or bicyclic ring together with ring H; R 47 is -C(O)-R 67 , -CH2R 67, -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR 77 R 87 , -C(O)-C1-C5 alkyl, or -C(O)-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 57 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 67 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 77 R 87 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 77 and R 87 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 77 and R 87 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (II):

[0080] [ka] wherein R 10 -CO2R 50 , -C1-C5-alkyl-COR 50 , -C3-C6-cycloalkyl-COR 50 , -NHCO2R 50 , -N(C1-C5 alkyl)-CO2R 50 , -O-CO2R 50 , or -C1-C5 alkyl-O-COR 50 is selected from R 20 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring I may have one, two, or three R 30 Each R 30 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 70 C(O)-CH=CH2, -NR 70 C(O)-C(CH2OCH3)=CH2, -NR 70 C(O)-CH=CHCH3, or -NR 70 C(O)-CH=CHCH2NR 80 R 90 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring I 30 Two or three R on different carbon atoms of a group or ring I 30 the groups may be linked together with Ring I to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 40 is H, -OH, -C(O)-R 60, -OR 60 , -OC(O)-R 60 , -NR 70 -C(O)-R 60 , -C1-C4 alkyl-C(O)-R 60 , -SO2-R 601 , -SO2-NR 80 R 90 , -C1-C4 alkyl-SO2-R 60 , or -C1-C4 alkyl-SO2NR 80 R 90 is selected from R 50 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 60 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 70 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 80 and R 90 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C6 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 80 and R 90 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IIa):

[0081] [ka] wherein R 201 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring J may contain one, two, or three R 301 Each R 301 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 701 C(O)-CH=CH2, -NR 701 C(O)-C(CH2OCH3)=CH2, -NR 701 C(O)-CH=CHCH3, or -NR 701 C(O)-CH=CHCH2NR 801 R 901 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring J 301 Two or three R on different carbon atoms of the group or ring J 301 the groups may be linked together with ring J to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 401 is H, -OH, -C(O)-R 601 , -OR 601 , -OC(O)-R 601 , -NR 701 -C(O)-R 601 , -C1-C4 alkyl-C(O)-R 601 , -SO2-R 601 , -SO2-NR 801 R 901 , -C1-C4 alkyl-SO2-R 601 , or -C1-C4 alkyl-SO2NR 801 R901 is selected from R 501 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 601 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 701 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 801 and R 901 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 801 and R 901 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IIb):

[0082] [ka] wherein R 202 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring K may contain one, two, or three R 302 Each R 302 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 702 C(O)-CH=CH2, -NR 702 C(O)-C(CH2OCH3)=CH2, -NR 702 C(O)-CH=CHCH3, or -NR 702 C(O)-CH=CHCH2NR 802 R 902 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring K 302 Two or three R on different carbon atoms of a group or ring K 302 the groups may be linked together with ring K to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 402 is H, -OH, -C(O)-R 602 , -OR 602 , -OC(O)-R 602 , -NR 702 -C(O)-R 602 , -C1-C4 alkyl-C(O)-R 602 , -SO2-R 602 , -SO2-NR 802 R 902 , -C1-C4 alkyl-SO2-R 602 , or -C1-C4 alkyl-SO2NR 802 R 902 is selected from R 502 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 602is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 702 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 802 and R 902 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 802 and R 902 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IIc):

[0083] [ka] wherein R 203 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring L may contain one, two, or three R 303 Each R 303 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 703 C(O)-CH=CH2, -NR 703 C(O)-C(CH2OCH3)=CH2, -NR703 C(O)-CH=CHCH3, or -NR 703 C(O)-CH=CHCH2NR 803 R 903 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring L 303 Two or three R on different carbon atoms of the group or ring L 303 the groups may be linked together with ring L to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 403 is H, -OH, -C(O)-R 603 , -OR 603 , -OC(O)-R 603 , -NR 703 -C(O)-R 603 , -C1-C4 alkyl-C(O)-R 603 , -SO2-R 603 , -SO2-NR 803 R 903 , -C1-C4 alkyl-SO2-R 603 , or -C1-C4 alkyl-SO2NR 803 R 903 is selected from R 503 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 603 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 703 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 803and R 903 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 803 and R 903 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IId):

[0084] [ka] wherein R 204 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring M may have one, two, or three R 304 Each R 304 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 704 C(O)-CH=CH2, -NR 704 C(O)-C(CH2OCH3)=CH2, -NR 704 C(O)-CH=CHCH3, or -NR 704 C(O)-CH=CHCH2NR 804 R 904 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring M 304Two or three R on different carbon atoms of the group or ring M 304 the groups may be linked to form, together with ring M, a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 404 is H, -OH, -C(O)-R 604 , -OR 604 , -OC(O)-R 604 , -NR 704 -C(O)-R 604 , -C1-C4 alkyl-C(O)-R 604 , -SO2-R 604 , -SO2-NR 804 R 904 , -C1-C4 alkyl-SO2-R 604 , or -C1-C4 alkyl-SO2NR 804 R 904 is selected from R 504 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 604 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 704 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 804 and R 904 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 804 and R 904may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IIe):

[0085] [ka] wherein R 205 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring N may have one, two, or three R 305 Each R 305 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 705 C(O)-CH=CH2, -NR 705 C(O)-C(CH2OCH3)=CH2, -NR 705 C(O)-CH=CHCH3, or -NR 705 C(O)-CH=CHCH2NR 805 R 905 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring N 305 Two or three R on different carbon atoms of a group or ring N 305 the groups may be linked together with ring N to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 405 is H, -OH, -C(O)-R 605 , -OR 605 , -OC(O)-R605 , -NR 705 -C(O)-R 605 , -C1-C4 alkyl-C(O)-R 605 , -SO2-R 605 , -SO2-NR 805 R 905 , -C1-C4 alkyl-SO2-R 605 , or -C1-C4 alkyl-SO2NR 805 R 905 is selected from R 505 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 605 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 705 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 805 and R 905 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 805 and R 905 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has the structural formula (IIf):

[0086] [ka] wherein R 206 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring O may have one, two, or three R on one or more carbons. 306 Each R 306 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 706 C(O)-CH=CH2, -NR 706 C(O)-C(CH2OCH3)=CH2, -NR 706 C(O)-CH=CHCH3, or -NR 706 C(O)-CH=CHCH2NR 806 R 906 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring O 306 Two or three R on different carbon atoms of the group or ring O 306 the groups may be linked together to form a spirocyclic, bicyclic, or tricyclic ring system together with ring O, such as adamantyl; R 406 is H, -OH, -C(O)-R 606 , -OR 60 , -OC(O)-R 606 , -NR 706 -C(O)-R 606 , -C1-C4 alkyl-C(O)-R 606 , -SO2-R 606 , -SO2-NR 806 R 906 , -C1-C4 alkyl-SO2-R 606 , or -C1-C4 alkyl-SO2NR 806 R 906 is selected from R 506 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 606 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 706 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 806 and R 906 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 806 and R 906 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IIg):

[0087] [ka] wherein R 207 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring P may contain one, two, or three R 307Each R 307 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 707 C(O)-CH=CH2, -NR 707 C(O)-C(CH2OCH3)=CH2, -NR 707 C(O)-CH=CHCH3, or -NR 707 C(O)-CH=CHCH2NR 807 R 907 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring P 307 Two or three R on different carbon atoms of the group or ring P 307 the groups may be linked together with ring P to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl; R 407 is H, -OH, -C(O)-R 607 , -OR 607 , -OC(O)-R 607 , -NR 707 -C(O)-R 607 , -C1-C4 alkyl-C(O)-R 607 , -SO2-R 607 , -SO2-NR 807 R 907 , -C1-C4 alkyl-SO2-R 607 , or -C1-C4 alkyl-SO2NR 807 R 907 is selected from R 507 is selected from -C1-C5 alkyl, or -C3-C5 cycloalkyl, the alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; R 607is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C5 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 707 is selected from H, -C1-C5 alkyl, or -C3-C5 cycloalkyl; R 807 and R 907 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, the alkyl groups being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 807 and R 907 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (III):

[0088] [ka] wherein R 1000 -CO2R 5000 , -C1-C5 alkyl-CO2R 5000 , -C3-C6-cycloalkyl-COR 5000 , -NHCO2R 5000 , -N(C1-C5 alkyl)-CO2R 5000 , -O-CO2R 5000 , or -C1-C5 alkyl-O-COR 5000 is selected from R 2000 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0, 1 or 2; Ring Q is substituted at one or more carbons with one, two, or three R3 substituents, each R 3000 groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, each alkyl or cycloalkyl group being optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same or different carbon atoms of ring Q 3000 the groups may be linked to form a spirocyclic or bicyclic ring together with ring Q; R 4000 is -C(O)-R 6000 , -CH2R 6000 , -C(O)-CH=CH2, -C(O)-C(CHOCH)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCHNR, -C(O)-C-C alkyl, or -C(O)-C-C cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN; R 5000 is selected from H, -C1-C5 alkyl, and -C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C3-C6 cycloalkyl, or -O-C1-C5 alkyl; R 6000 is -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 7000 R 8000 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, trifluoromethyl, -O-C1-C5 alkyl, or -O-C3-C6 cycloalkyl; R 7000 and R 8000 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 7000 and R 8000 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, the compound has structural formula (IV):

[0089] [ka] wherein R 10000 -CO2R 50000 , -C1-C5-alkyl-COR 50000 , -C3-C6-cycloalkyl-COR 50000 , -NHCO2R 50000 , -N(C1-C5 alkyl)-CO2R 50000 , -O-CO2R 50000 , or -C1-C5 alkyl-O-COR 50000 is selected from R 20000 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, or -O-C1-C5 alkyl; n is 0 or 1, Ring S may contain one, two, or three R on one or more carbons. 30 Each R 30000 The groups are independently H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 70000 C(O)-CH=CH2, -NR 70000C(O)-C(CH2OCH3)=CH2, -NR 70000 C(O)-CH=CHCH3, or -NR 70000 C(O)-CH=CHCH2NR 80000 R 90000 wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; Two R on the same carbon atom of ring S 30000 Two or three R on different carbon atoms of the group or ring S 30 the groups may be linked together to form a spirocyclic, bicyclic, or tricyclic ring system, such as adamantyl, with ring S; R 40000 is H, -OH, -C(O)-R 60000 , -OR 60000 , -OC(O)-R 60000 , -NR 70000 -C(O)-R 60000 , -C1-C4 alkyl-C(O)-R 60000 , -SO2-R 60000 , -SO2-NR 80000 R 90000 , -C1-C4 alkyl-SO2-R 60000 , or -C1-C4 alkyl-SO2NR 80000 R 90000 is selected from R 50000 is selected from H, -C1-C5 alkyl, and -C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C3-C6 cycloalkyl, or -O-C1-C5 alkyl; R 60000 is selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, or -C1-C5 alkyl-C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -CN, alkyne, -OH, or -O-C1-C5 alkyl; R 70000is selected from H, -C1-C5 alkyl, or -C3-C6 cycloalkyl; R 80000 and R 90000 is independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C6 cycloalkyl, the alkyl group being optionally substituted with one or more groups selected from halogen, -OH, or -CN; R 80000 and R 90000 may be linked to form a ring to form a heterocycle such as piperidine, pyrrolidine, or together with another heteroatom to form a ring such as morpholine. In certain embodiments, a compound of structural formula (II), formula (IIa), or formula (IV) is not:

[0090] [ka] JPEG0007607732000021.jpg233149The present invention is further illustrated by the following examples of compounds of formula (I).

[0091] TIFF0007607732000022.tif223148 TIFF0007607732000023.tif208143 TIFF0007607732000024.tif187146 TIFF0007607732000025.tif223147 TIFF0007607732000026.tif218144 TIFF0007607732000027.tif203143 TIFF0007607732000028.tif208144 TIFF0007607732000029.tif203143 TIFF0007607732000030.tif203143 TIFF0007607732000031.tif192143 TIFF0007607732000032.tif187147 TIFF0007607732000033.tif229150 TIFF0007607732000034.tif213145 TIFF0007607732000035.tif208143 TIFF0007607732000036.tif125141 The present invention is further illustrated by the following examples of compounds of formula (II).

[0092] TIFF0007607732000037.tif73143 TIFF0007607732000038.tif187142 TIFF0007607732000039.tif213144 TIFF0007607732000040.tif197145 TIFF0007607732000041.tif223149 TIFF0007607732000042.tif208143 TIFF0007607732000043.tif213146 TIFF0007607732000044.tif218146 TIFF0007607732000045.tif208144 TIFF0007607732000046.tif192147 TIFF0007607732000047.tif73135 The present invention is further illustrated by the following examples of compounds of formula (III).

[0093] TIFF0007607732000048.tif125152 TIFF0007607732000049.tif62140 The present invention is further illustrated by the following examples of compounds of formula (IV).

[0094] JPEG0007607732000050.jpg224169 JPEG0007607732000051.jpg228167 JPEG0007607732000052.jpg218169

[0095] Pharmaceutical Compositions Some embodiments herein are directed to pharmaceutical compositions comprising a compound of an embodiment herein and a pharma- ceutically acceptable carrier or diluent. Also provided are pharmaceutical compositions comprising a compound as disclosed herein together with a pharma- ceutically acceptable carrier.

[0096] While it may be possible for the compounds described herein to be administered as drug substances, they may also be presented as pharmaceutical formulations. Thus, provided herein are pharmaceutical formulations that include one or more of the specific compounds disclosed herein, or derivatives thereof, together with one or more pharma- ceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Proper formulation depends on the chosen route of administration. Any of the well-known techniques, carriers, and excipients may be used as suitable and understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example by means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes. In some embodiments, pharmaceutical compositions for use in accordance with the embodiments herein may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.

[0097] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, oral buccal, sublingual, and intraocular), intravitreal, or intravaginal administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may include those suitable for administration by depot injection or implant. The formulations may include those suitable for administration by inhalation, such as, for example, a gas, vapor, or powder. The formulations may include those suitable for administration as an aerosol, such as, for example, via a nebulizer, humidifier, inhaler, and vaporizer. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, these methods include the step of combining a compound disclosed herein or a derivative thereof ("active ingredient") with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0098] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0099] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, and optionally mixing with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored, and can also be formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain active ingredients mixed with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0100] The compound can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The preparations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives. The compositions can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents, for example, suspending, stabilizing and / or dispersing agents. The preparations can be presented in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0101] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing the preparation of highly concentrated solutions.

[0102] In addition to the formulations described above, the compound can also be formulated as a depot preparation.This long-acting formulation can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound can be formulated into suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils, etc.) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0103] For intraoral buccal or sublingual administration, the compositions can take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner.Such compositions can contain the active ingredient in a flavored base, for example, sucrose and acacia or tragacanth. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. Certain compounds disclosed herein can be administered by local administration, which is non-systemic administration.This includes applying the compounds disclosed herein externally to the epidermis or oral cavity, and dropping such compounds into the ear, eye and nose.In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. In some embodiments, the compounds disclosed herein can be administered ophthalmologically. In some embodiments, the compounds disclosed herein can be administered as an ophthalmic composition. The compounds of the embodiments herein can be administered as a liquid preparation for topical administration, including, for example, eye washes, sprays, or eye drops. In some embodiments, the compounds disclosed herein can be administered as a semi-solid preparation, such as a cream, lotion, gel, ointment, or paste, for example, applied to the eyelid. In some embodiments, the compounds disclosed herein can be administered as a solid dosage form, for example, as a powder, for example, applied to the ocular surface to provide modified release. In some embodiments, the compounds of the embodiments herein are administered via a device for surgical implantation, parenteral products (e.g., intracorneal or intravitreal products), irrigation liquids, and the like. In some embodiments, the compositions comprising the compounds disclosed herein are sterile and free of particulate matter. In some embodiments, the compounds disclosed herein can be administered by intraocular injection, intraorbital injection, or intravitreal injection. In some embodiments, the intraocular injection can be to the anterior chamber of the eye, the posterior chamber of the eye, or a combination thereof. For example, the compounds disclosed herein can be administered to the retro-orbital region of the eye.

[0104] In some embodiments, formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels, jellies, foams, paints, lotions, and drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (by body weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, the active ingredient may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, the active ingredient may comprise 0.1% to 1% w / w of the formulation.

[0105] Gels for topical or transdermal administration may generally include a mixture of volatile solvent, non-volatile solvent, and water. In certain embodiments, the volatile solvent component of the buffer solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is believed to act as a percutaneous absorption enhancer while also providing a cooling effect to the skin as it evaporates. The non-volatile solvent portion of the buffer solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The non-volatile solvent slows down the evaporation of the volatile solvent and reduces the vapor pressure of the buffer solvent system. The amount of this non-volatile solvent component, as well as the volatile solvent, is determined by the pharmaceutical compound or drug used. If there is too little non-volatile solvent in the system, the pharmaceutical compound may crystallize due to evaporation of the volatile solvent, and an excess amount may result in a lack of bioavailability due to weak drug release from the solvent mixture. The buffer component of the buffer solvent system can be selected from any buffer solution commonly used in the art, and in certain embodiments, water is used. The common ratio of components is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. There are several optional components that can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents can include, but are not limited to, semi-synthetic cellulose derivatives (e.g., hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

[0106] Lotions include those suitable for application to the skin or eyes. Eye washes can include sterile aqueous solutions that may contain bactericides, and can be prepared in a manner similar to that for preparation of drops. Lotions or liniments for application to the skin can also include agents for quick drying and cooling the skin, such as alcohol or acetone, and / or moisturizing agents, such as glycerol or oils, such as castor oil or peanut oil.

[0107] Creams, ointments or pastes are semi-solid preparations of active ingredients for external application.They can be made by mixing the active ingredients in finely divided or powder form, alone or in solution or suspension in aqueous or non-aqueous fluid, with a greasy or non-greasy base with the aid of a suitable mechanism.The base can include hydrocarbons, such as hard, soft or liquid paraffin, glycerol, beeswax, metal soaps; mucilage; oils of natural origin, such as almond oil, corn oil, peanut oil, castor oil or olive oil; wool fat or its derivatives or fatty acids, such as stearic acid or oleic acid, together with alcohol, such as propylene glycol or macrogel.The preparation can incorporate any suitable surfactant, such as anionic, cationic or non-ionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives.Suspending agents, such as natural gums, cellulose derivatives, or inorganic materials, such as siliceous silica, and other ingredients such as lanolin, can also be included.

[0108] The drops may comprise a sterile aqueous or oily solution or suspension, which may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericide and / or antibacterial agent and / or any other suitable preservative, and in certain embodiments, a surfactant. The resulting solution may then be clarified by filtration, transferred to a suitable container, which may then be sealed and sterilized by autoclaving or by maintaining at 98-100°C for 30 minutes. Alternatively, the solution may be sterilized with a suitable antibacterial agent for inclusion in the drops, which are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, diluted alcohol and propylene glycol. Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.

[0109] For administration by inhalation, the compound can be conveniently delivered by insufflator, nebulizer pressurized pack or other convenient means of delivering aerosol spray.Pressurized pack can contain suitable propellants, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol, dosage unit can be determined by providing a valve that delivers a metered amount.Alternatively, for administration by inhalation or insufflation, the compound according to the present invention can also take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, for example, lactose or starch.The powder composition can also be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder can be administered with the aid of an inhaler or insufflator. Preferred unit dosage formulations contain an effective dose, as herein below recited, or an appropriate fraction thereof, of an active ingredient. It will be understood that in addition to the ingredients specifically mentioned above, the formulations described above can include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration can include flavoring agents.

[0110] The compound can be administered at a dose of 0.1-500mg / kg per day. The dose range for adult humans is generally 5mg-2g / day. Tablets or other presentation forms provided in separate units may conveniently contain one or more compounds in an amount effective at such doses, or multiples thereof, such as units containing 5mg-500mg, usually about 10mg-200mg.

[0111] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0112] When used as a pharmaceutical, the compound can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. The administration of the disclosed compounds or compositions can be oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal or intranasal), intraperitoneal, transmucosal, transdermal, rectal, topical (including cutaneous, oral buccal, sublingual, and intraocular), or intravaginal. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracerebral, for example, intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions for topical administration can include foams, transdermal patches, ointments, lotions, creams, gels, solutions, fluid emulsions, fluid suspensions, semisolids, pastes, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. In some embodiments, the compound can be included in such formulations with pharma- ceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. Those skilled in the art can refer to various pharmacological references for guidance. See, for example, Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13th Edition, McGraw Hill, New York (2018).

[0113] In some embodiments, the method of treating a JAK1 and / or JAK3 mediated disease comprises administering a pharmaceutical composition of the embodiments disclosed herein. In some embodiments, the compound is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount disclosed herein. Some embodiments disclosed herein also include pharmaceutical compositions containing one or more compounds disclosed herein as an active ingredient in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the method of making pharmaceutical compositions includes mixing active ingredients with excipients, diluting active ingredients with excipients, or encasing active ingredients in carriers, for example, in the form of capsules, sachets, paper, or other containers.When excipients function as diluents, they can be solid, semi-solid, or liquid materials, and act as vehicles, carriers, or media for active ingredients.Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, injectable sterile solutions, and sterile packaged powders, for example, containing up to 10% by weight of active compound.

[0114] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and eutectic solvent, eutectic-based ionic liquid, or methylcellulose containing ionic liquid.In addition, the formulation can include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl- and propyl hydroxybenzoate; sweeteners; and flavoring agents.The composition can be formulated to produce rapid, sustained, or delayed release of active ingredient after administration to a patient by utilizing procedures known in the art.

[0115] The composition can be formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as single unit dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients.

[0116] The active compounds may be effective over a wide dosage range and may generally be administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0117] In some embodiments, the pharmaceutical composition may comprise from about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the one or more compounds may comprise from about 0.01% to about 50%, from about 0.01% to about 45%, from about 0.01% to about 40%, from about 0.01% to about 30%, from about 0.01% to about 20%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.05% to about 50%, from about 0.05% to about 45%, from about 0.05% to about 40%, from about 0.05% to about 5 ... % to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 45%, about 5% to about 40%, about 5% to The amount is within about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, or a value within one of these ranges. Specific examples include about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two of these values. All of the above represent percentages by weight of the composition. In some embodiments, the composition is suitable for topical administration. In some embodiments, the composition is suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, oral buccal, sublingual, and intraocular), intravitreal, or vaginal administration.

[0118] In some embodiments, the compound is within a therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about 400 mg, about 50 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about 500 mg, about 500 mg to about 10 ... It may be about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg to about 120 mg, or a range between any two of these values. Specific examples include, for example, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400 mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, or any value between the ranges disclosed above.

[0119] In some embodiments, the therapeutically effective amount may vary according to, for example, the particular use for which the treatment is made, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound in a pharmaceutical composition may vary depending on several factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compound may be provided in an aqueous physiological buffer for parenteral administration containing about 0.1 to about 10% w / v of the compound. Some typical dose ranges for the compound are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological potency of the selected compound, the formulation of excipients, and its route of administration. The effective dose may be extrapolated from dose-response curves derived from in vitro or animal model test systems. The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, e.g., prophylactic or therapeutic, the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0120] To prepare solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogenous, the active ingredient is usually evenly dispersed throughout the composition so that the composition can be easily subdivided into equally therapeutically effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, for example, containing about 0.1 to about 1000 mg of the active ingredient. The tablet or pill of the present invention may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, the tablet or pill may comprise an inner and an outer component, the latter being in the form of an envelope over the former.The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release.Various materials may be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0121] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral administration or administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0122] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable, aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions can contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, compositions are administered by oral or nasal respiratory routes for local or systemic action. Compositions can be nebulized by using inert gases. Nebulized solutions can be inhaled directly from the nebulizer, or the nebulizer can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner. In some embodiments, the compositions administered to a patient may be in the form of pharmaceutical compositions described above. In some embodiments, these compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for ready use or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the compound preparation is about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5, or about 5.5 to about 7.5. It is understood that the use of certain of the aforementioned excipients, carriers, or stabilizers results in the formation of pharmaceutical salts.

[0123] How to use The present invention relates to a method for modulating JAK1 and / or JAK3 mediated function in a subject comprising administration of a therapeutically effective amount of a compound disclosed herein. The present invention also relates to a method of inhibiting at least one JAK1 and / or JAK3 function, comprising contacting JAK1 and / or JAK3 with a compound as described herein. One can monitor JAK1 and / or JAK3 cellular phenotype, cell proliferation, activity, changes in biochemical output generated by active JAK1 and / or JAK3, expression of JAK1 and / or JAK3, or binding of JAK1 and / or JAK3 to natural binding partners. Such methods can be modes of treatment of disease, biological assays, cellular assays, biochemical assays, etc.

[0124] Also provided herein is a method for treating JAK1 and / or JAK3 mediated disease, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as disclosed herein, its derivative, or a combination thereof.In certain embodiments, the therapeutically effective amount of a compound as disclosed herein, its derivative, or a combination thereof may be in the form of a pharmaceutical composition.In embodiments, the pharmaceutical composition may include a pharmaceutically acceptable excipient. In embodiments, the JAK1 and / or JAK3 kinase-related disease or disorder treated by the compounds of the present invention includes autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, or cardiovascular or cerebrovascular disorders.Thus, in some embodiments, the present invention provides a method for treating a JAK1 and / or JAK3-mediated disease or disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a provided compound, or a composition thereof.Such JAK1 and / or JAK3-mediated disease or disorder includes, but is not limited to, those described herein.

[0125] In some embodiments, the JAK1 and / or JAK3 mediated disease or disorder is selected from a skin disorder, pruritus, a hair loss disorder, cancer, a neoplasm, Alzheimer's disease, an inflammatory condition, a connective tissue disease, and an autoimmune condition. In certain embodiments, the JAK1 and / or JAK3 mediated disease or disorder is a neoplasm, malignancy, myeloproliferative disorder, hematopoietic neoplasm, myeloid neoplasm, myelofibrosis, lymphoid neoplasm including primary myelofibrosis, polycythemia vera, essential thrombocythemia, acute and chronic leukemia, lymphoma, cutaneous lymphoma including mycosis fungoides, other myeloid malignancies, and myelodysplastic syndromes.

[0126] In certain embodiments, the JAK1 and / or JAK3 mediated disease is an autoimmune disorder or response, widespread activation of an immune response, bacterial infection, viral infection, inflammation, chronic and / or acute inflammatory disorders or conditions, and / or autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, or cardiovascular or cerebrovascular disorders, skin disorders, pruritus, hair loss disorders, cancer or malignancies, autoimmune connective tissue diseases and autoimmune conditions; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (e.g., , relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-associated arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathy (ankylosing spondylitis), gout, scleroderma (systemic scleroderma, juvenile scleroderma), Reiter's syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus Systemic lupus erythematosus (SLE), lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / disciform lupus, chilblain lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy; carditis, myocarditis, angiogenic disorders, myelodysplastic syndromes, atherosclerosis, restenosis (restenosis of atherosclerotic coronary arteries), acute coronary syndromes, myocardial infarction, cardiac allograft vasculopathy, transplant arteriopathy; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa) inflammation, vasculitis syndromes (including Takayasu's arteritis, Wegener's granulomatosis, Behçet's disease), STING-associated vasculitis in infancy (SAVI); gastrointestinal diseases, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, enterocolitis syndrome / spastic colon, celiac disease; acute and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis, e.g. due to primary biliary cirrhosis or fatty liver disease (e.g. alcoholic and non-alcoholic steatosis);

[0127] Esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; nephropathy: immune-mediated glomerular nephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, diabetic kidney disease / diabetic nephropathy, renal fibrosis, renal ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, immune-mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, associated ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, chronic kidney disease (e.g. diabetic nephropathy), hypertension-induced nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute pulmonary injury, drug-induced lung injury; Meniere's disease; eye disorders, including (for example) eye inflammation, uveitis, dry eye / keratoconjunctivitis sicca, scleritis, episcleritis, keratitis / keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathies (including diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelodysplastic syndromes, idiopathic thrombocytopenic purpura; bone resorption disorders; neurodegenerative disorders, nervous system / neuromuscular disorders, ( For example, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury; nervous system injury, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke / neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders; pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia) paresthesia, nerve irritation, peripheral neuropathy;Pruritus / itch (atopic pruritus, dry pruritus, psoriasis-associated pruritus / psoriatic itch / psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, bile duct itch, hepatobiliary-associated itch, renal-associated itch / renal itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichen simplex chronicus-associated pruritus, lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch / atopic pruritus, bullous itch, brachioradial pruritus) neurogenic itch, neuropathic itch, paresthesia paresthesia, pruritic papular rash of HIV, psychogenic itch, swimmer's itch, pruritic or uremic itch, urticarial itch;

[0128] Skin disorders, such as: cutaneous drug reactions / drug eruptions, xerosis / dry skin, skin rash, skin sensitization, skin irritation, sunburn, razor rash, body lice, head lice / pediculosis, hairy lice, cutaneous larva migrans, scabies, parasitic infections, insect infestation, urticarial / rash, papular urticaria, insect bites, insect stings, dandruff, foreign bodies or devices on the skin, fungal infections, herpes, chickenpox / varicella, eosinophilic folliculitis, skin disease of pregnancy / pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory skin disease, neutrophilic skin disease, histiocytic neutrophilic skin disease, intestinal bypass syndrome Skin diseases, Psoriasis / Psoriasis Vulgaris, Lichen Planus, Lichen Sclerosus, Acne (Acne Vulgaris, Acne Comedonal, Inflammatory Acne, Nodular and Cystic Acne, Cicatricial Acne, Keloid Acne Neck), Atopy (Allergic Contact Sensitization, Allergic Dermatitis) Dermatitis (Atopic Dermatitis / Eczema, Contact Dermatitis, Photodermatitis, Seborrheic Dermatitis, Stasis Dermatitis, Acute Febrile Neutrophilic Dermatopathy (Sweet's Syndrome), Chronic Atypical Neutrophilic Dermatopathy with Lipodystrophy and High Temperature Syndrome (Candle Syndrome), Hidradenitis Suppurativa, Rash, Pyoderma Gangrenosum, Alopecia (Eyebrow Alopecia, Internasal Hair Alopecia, Cicatricial Alopecia (Parietal Efferent) Cicatricial alopecia), Non-cicatricial alopecia (Alopecia areata (AA) (Patchy AA, Alopecia totalis (AT), Alopecia universalis (AU), Serpiginous pattern alopecia areata, Sisaihpo pattern alopecia areata)), Androgenic / Androgenic alopecia (AGA) / Male and female pattern AGA), Telogen effluvium, Tinea capitis, Hypotrichosis (Hereditary hypotrichosis simplex), Lichen planopilaris (Frontal fibrosing alopecia), Punctate palmoplantar keratoderma, Erythema elevatum elevata (EED), Neutrophilic exudative hidradenitis, Cylindrical cell neutrophilic granulomatous dermatitis, Neutrophilic urticarial dermatosis, Segmental vitiligo vitiligo including (monosegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo), nonsegmental vitiligo (digitofacial, facial, or extremity vitiligo, central facial vitiligo, mucosal vitiligo, confetti vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo, Koebner phenomenon, vitiligo, generalized vitiligo, generalized vitiligo), mixed vitiligo / segmental associated nonsegmental vitiligo, focal vitiligo, isolated mucosal vitiligo or vitiligo with or without leukoderma (including body hair);Bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), gestational pemphigoid, xeroderma pigmentosum; fibrotic and scarring disorders: fibroids, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, mild scarring, e.g., scleroderma, increased fibrosis, keloids, post-surgical scarring; wound healing, surgical scarring, radiation-induced fibrosis (e.g., of the head and neck, digestive system or lungs), CNS scarring , gastrointestinal or digestive fibrosis, renal fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, scarring enhancement, trauma or scabies healing, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis;

[0129] Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cryopyrin-associated periodic syndrome (Muckle-Wells syndrome, familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue injury, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Casselman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, glucose intolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immunosenescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjögren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, drug-induced autoimmune disease, HIV-associated autoimmune syndrome, metal-induced autoimmune disease, autoimmune hearing loss, autoimmune thyroid disorders; allergies and allergic reactions, including hypersensitivity reactions, e.g., type I hypersensitivity reactions (e.g., including anaphylaxis), type II hypersensitivity reactions (e.g., Goodpasture's disease, autoimmune hemolytic anemia), type III hypersensitivity reaction disorders (e.g., Arthus reaction, serum sickness), and type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, septic syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome);

[0130] Acute and chronic infections, Sepsis syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome); Rejection: Graft-versus-host reaction / Graft-versus-host disease, Allograft rejection (e.g. acute allograft rejection or chronic allograft rejection), Early transplant rejection; Malignancies, cancer, lymphoma, leukemia, multiple myeloma, solid tumors, teratomas, metastatic and bone disorders, internal cancer, bone , cancer of the mouth / pharynx, esophagus, larynx, stomach, intestine, colon, rectum, lung (e.g., non-small cell lung cancer or small cell lung cancer), liver (hepatic), pancreas, nerve, brain (e.g., glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, and schwannoma), head and neck, throat, ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gallbladder, cervix, thyroid, prostate, eye (ocular malignancies), and skin (melanoma, keratoacanthoma); as well as fibrous carcinoma, fibroma, fibroadenoma, fibrosarcoma, myeloproliferative Disorders, neoplasms (hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms (myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemias (acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphomas ( Selected from the group consisting of Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased exogenous or synthetic opioid accumulation, paresthesia femoral pain, obsessive-compulsive disorder, obsessive-compulsive disorder-related nostalgia, and combinations thereof.

[0131] In some embodiments, additional exemplary disorders include, but are not limited to, complications resulting from organ transplantation (including xenotransplantation), such as graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplantation, diabetes, myeloproliferative disorders, rejection (e.g., acute allograft rejection); bone resorption disorders, asthma (e.g., bronchial asthma), atopy, autoimmune thyroid disorders, lipodystrophy and chronic atypical neutrophilic dermatosis with hyperthermia syndrome (candlelight syndrome), SAVI (STING-associated vasculopathy with stimulator of interferon genes in infancy), ulcerative colitis, inflammatory bowel disease, Crohn's disease, celiac disease, ulcerative colitis, basilar arthritis, bronchitis, and bronchitis. Chet's disease, myasthenia gravis, nephropathy, and myocarditis, secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, drug-induced autoimmune disease, HIV-associated autoimmune syndrome; acute and chronic infections, septic syndromes (e.g., sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome; hyperoxia-induced inflammation, reperfusion injury, post-operative trauma, tissue injury, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia).

[0132] In one embodiment, the vitiligo is segmental vitiligo, i.e. including monosegmental, bisegmental or multisegmental vitiligo, non-segmental vitiligo, i.e. including limbal, facial or limbofacial vitiligo, central facial vitiligo, mucosal vitiligo, confetti vitiligo, vitiligo tricolor, marginal inflammatory vitiligo, vitiligo tetracolor, blue vitiligo, Koebner phenomenon, vitiligo, generalized vitiligo, generalized vitiligo, mixed vitiligo (segmental associated non-segmental vitiligo), localized vitiligo, isolated mucosal vitiligo, or vitiligo with or without leukoderma (including body hair), or any type of vitiligo as set forth in Table 1 below:

[0133] JPEG0007607732000053.jpg122170

[0134] In one embodiment, the skin disorder is atopic dermatitis, psoriasis, plaque psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, allergic dermatitis, inflammatory skin disease, or neutrophilic skin disease.

[0135] "Pruritis" as used herein is interchangeable with "itch." In some embodiments, pruritus includes chronic idiopathic pruritus, as well as the pruritic components of other pruritic disorders. In some embodiments, pruritus may be a symptom of a disease or condition selected from the group consisting of allergic reactions, arthropod bites, athlete's foot, atopic dermatitis (AD), atopic itch, atopic dermatitis-associated itch, autoimmune responses, autoimmune connective tissue diseases, bacterial infections, bile duct itch, widespread activation of immune responses, body lice, bullous diseases, brachioradial pruritus, brain tumors, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T Cellular lymphoma, nervous system damage, dandruff, delusional parasitosis, dermatomyositis, skin diseases of pregnancy, diabetes mellitus, drug eruptions, dysregulation of neuronal processes and sensory perception, eczema, eosinophilic folliculitis, foreign bodies or devices on the skin, fungal infections, gestational pemphigoid, head lice, herpes, hidradenitis suppurativa, rash, Hodgkin's disease, hyperparathyroidism, idiopathic chronic itching, inflammation, insect infestations, insect bites, insect stings, intrahepatic cholestasis of pregnancy, iron deficiency anemia, exogenous opioids or synthetic Increased adult opioid accumulation, internal cancer, jaundice, lichen planus, lichen sclerosus, lupus erythematosus, lymphoma, lymphoma-associated itch, leukemia-associated itch, malignant tumors, mastocytosis, menopause, multiple sclerosis, neoplasms, nerve irritation, neurogenic itch, neuropathic itch, paresthesia, paresthesia obsessive-compulsive disorder, paresthesia, parasitic infections, papular urticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, psychiatric disorders, psychogenic itch, pruritus of HIV Papular rash, pruritic urticarial papules and plaques of pregnancy (PUPPP), psoriasis, psoriasis-associated itch, psoriatic itch, hair lice, punctate palmoplantar keratoderma, kidney itch, rheumatoid arthritis, scabies, scarring, razor rash, seborrheic dermatitis, stasis dermatitis, sunburn, swimmer's prurigo, systemic immunosenescence, tactile hallucinations, Th17-related inflammation, thyroid disease, uremia, pruritus or uremic itch, urticaria, urticarial itch, chickenpox, viral infections, trauma or scabies healing, and xerosis.

[0136] In one embodiment, the hair loss disorder is selected from alopecia, alopecia areata, patchy alopecia areata, alopecia totalis, alopecia universalis, serpiginous pattern alopecia areata, sisaihpo pattern alopecia areata, androgenic alopecia (male and female pattern hair loss), telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, cicatricial alopecia, lichen planopilaris, parietal centrifugal cicatricial alopecia, or frontal fibrosing alopecia. In one embodiment, the connective tissue disease is selected from SLE (systemic lupus erythematosus), cutaneous lupus (e.g., SCLE, discoid lupus), chilblain lupus erythematosus, myositis, polymyositis, dermatomyositis, scleroderma, Sjogren's syndrome, polychondritis (relapsing polychondritis), vasculitis, or large vessel vasculitis. In one embodiment, the nephropathy is selected from immune-mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, associated ischemia / reperfusion injury, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease or diabetic kidney disease.

[0137] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, or pancreatic cancer. In one embodiment, the cancer is lymphoma, leukemia, or multiple myeloma.

[0138] In one embodiment, said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD). In one embodiment, said myeloproliferative disorder is myelofibrosis. In one embodiment, said myeloproliferative disorder is primary myelofibrosis (PMF). In one embodiment, the bone resorption disorder is osteoporosis, osteoarthritis, hormone imbalance-associated bone resorption, hormone therapy-associated bone resorption, autoimmune disease-associated bone resorption, or cancer-associated bone resorption.

[0139] In some embodiments, the JAK1 and / or JAK3 mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scars, spinal cord injury, CNS scars, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, gastrointestinal or digestive fibrosis, renal fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). , cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic and nonalcoholic steatosis), radiation-induced fibrosis (e.g., of the head and neck, digestive system, or lungs), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic cicatricial, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0140] In some embodiments, the JAK1 and / or JAK3 mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome. In some embodiments, the JAK1 and / or JAK3 mediated disease or disorder is a neoplasm. Exemplary neoplasms include cancer. In some embodiments, exemplary neoplasms include angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and Schwartz's disease. melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Kaposi's sarcoma, melanoma, teratomas, rhabdomyosarcoma, metastatic and bone disorders, as well as cancer of the bone, mouth / pharynx, esophagus, larynx, stomach, intestine, colon, rectum, lung (e.g., non-small cell lung cancer or small cell lung cancer), liver, pancreas, nerve, brain (e.g., glioma or glioblastoma multiforme), head and neck, throat, ovary, uterus, prostate, testis, bladder, kidney, breast, gallbladder, cervix, thyroid, prostate, and skin.

[0141] In some embodiments, JAK1 and / or JAK3 mediated disorder is cardiovascular or cerebrovascular disorder.Exemplary cardiovascular disorder includes atherosclerosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vascular disorder and stroke.Exemplary cerebrovascular disease includes central nervous system disorder with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia and peripheral neuropathy. Also provided herein are compounds as disclosed herein for use as pharmaceuticals. Also provided herein are compounds as disclosed herein for use as a medicament for the treatment of a JAK1 and / or JAK3 mediated disease. There is also provided the use of compounds as disclosed herein as pharmaceuticals. There is also provided the use of a compound as disclosed herein as a pharmaceutical for the treatment of a JAK1 and / or JAK3 mediated disease. Also provided is a compound as disclosed herein for use in the manufacture of a medicament for the treatment of a JAK1 and / or JAK3 mediated disease. There is also provided the use of compounds as disclosed herein for the treatment of a JAK1 and / or JAK3 mediated disease. Also provided herein are methods of inhibiting JAK1 and / or JAK3, comprising administering a compound as disclosed herein, or a derivative thereof.

[0142] Also provided herein is a method for achieving an effect in a patient, comprising administering to the patient a therapeutically effective amount of a compound as disclosed herein, or a salt thereof, wherein the effect is selected from cognitive enhancement. In certain embodiments, the JAK1 and / or JAK3 mediated disease is selected from pruritus, alopecia, alopecia areata, vitiligo, male pattern baldness, female pattern baldness, atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis. The compounds can be administered in various modes, for example, orally, parenterally (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneally, intrathecally, intrathecally, transmucosally, transdermally, rectally, intranasally, topically (including, for example, dermal, intrabuccal, sublingual, and intraocular), intravitreally, or intravaginally. The specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations, the exact disorder being treated, and the severity of the symptom or condition being treated. Also, the route of administration can vary depending on the condition and its severity.

[0143] Thus, in another aspect, certain embodiments provide a method for treating a JAK1 and / or JAK3 mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound disclosed herein in combination with at least one additional agent known in the art for the treatment of said disorder effective to reduce or prevent said disorder in the subject. In a related aspect, certain embodiments provide a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of a JAK1 and / or JAK3 mediated disorder.

[0144] In certain embodiments, the topically or orally administered JAK1 and / or JAK3 inhibitors / antagonists described herein can be used for the treatment of alopecia areata (e.g., patchy alopecia areata, alopecia totalis, alopecia universalis) alone or in combination with topical or intralesional corticosteroids, topical minoxidil, oral finasteride, oral dutasteride, contact sensitization therapy, e.g., with squaric acid dibutyl ester, dinitrochlorobenzene, diphencyprone, topical or oral methoxalen and ultraviolet light (PUVA), topical anthralin, hair transplant surgery, or other therapies known to have beneficial effects on the condition. In certain embodiments, the JAK1 and / or JAK3 inhibitors / antagonists disclosed herein, administered topically or orally, can be used for the treatment of male or female pattern baldness (androgenic alopecia), alone or in combination with topical minoxidil, oral finasteride (for men), oral dutasteride (for men), topical antiandrogens, hair transplant surgery, or other therapies known to have beneficial effects on the condition.

[0145] In certain embodiments, the compounds are used alone or in combination with topical corticosteroids, topical tacrolimus, topical vitiligo ... It may be used in combination with pimecrolimus, phototherapy, e.g., ultraviolet phototherapy using UVB, narrow band UVB, oral or topical psoralens and ultraviolet A (PUVA), calcipotriene or other topical vitamin D analogues, excimer laser phototherapy, systemic immunosuppressants, surgical treatments, e.g., skin minigrafts, autologous epidermal suspension transplants, camouflage, e.g., using make-up or dihydroxyacetone, or other treatments known to have a beneficial effect on the condition.

[0146] Particular JAK1 and / or JAK3 mediated diseases to be treated with the compounds, compositions, and methods disclosed herein include skin disorders, pruritus, cancer, Alzheimer's disease, inflammatory conditions, and autoimmune conditions. In one embodiment, the skin disorder is pruritus, atopic dermatitis, psoriasis, acne vulgaris, comedonal acne, inflammatory acne, nodular cystic acne, cicatricial acne, hidradenitis suppurativa, pyoderma gangrenosum, skin sensitization, skin irritation, skin rash, contact dermatitis, or allergic contact sensitization. In one embodiment, the bone resorption disorder is osteoporosis, osteoarthritis, hormone imbalance-associated bone resorption, hormone therapy-associated bone resorption, autoimmune disease-associated bone resorption, or cancer-associated bone resorption. In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0147] Combination therapy The compounds and pharmaceutical compositions of the disclosure can be used to prevent or treat JAK-mediated disorders by sequential or co-administration with another pharmaceutical agent.

[0148] In certain cases, it may be appropriate to administer at least one of the compounds described herein or a derivative thereof in combination with another pharmaceutical agent. By way of example only, if hypertension is one of the side effects experienced by a patient when a compound described herein is administered, it may be appropriate to administer an antihypertensive agent in combination with the first pharmaceutical agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another pharmaceutical agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another pharmaceutical agent (including a therapeutic regimen) that also has a therapeutic benefit. By way of example only, an increase in therapeutic benefit in the treatment of diabetes involving administering one of the compounds described herein may also occur by providing the patient with another pharmaceutical agent for diabetes. In any event, the overall benefit experienced by the patient, regardless of the disease, disorder, or condition being treated, may be simply an additive benefit of the two pharmaceutical agents, or the patient may experience a synergistic benefit.

[0149] Specific non-limiting examples of possible combination therapies include the use of compounds of embodiments herein with the following: chemotherapeutic or anti-proliferative agents, anti-inflammatory agents, immunomodulatory or immunosuppressive agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, or agents for treating immune deficiency disorders. Specific non-limiting examples of possible combination therapies for inflammation include the use of certain compounds of the present disclosure with: (1) corticosteroids, including but not limited to cortisone, dexamethasone, and methylprednisolone; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON™), flurbiprofen (ANSAID™), ketoprofen, oxaprozin (DAYPRO™), ), diclofenac sodium (VOLTAREN™), diclofenac potassium (CATAFLAM™), etodolac (LODINE™), indomethacin (INDOCIN™), ketorolac (TORADOL™), sulindac (CLINORIL™), tolmetin (TOLECTIN™), meclofenamate (MECLOMEN™), mefenamic acid (PONSTEL™), nabumetone (RELAFEN™), and piroxicam (FELDENE™); (3) immunosuppressants, including, but not limited to, methotrexate (RHEUMATREX™), leflunomide (ARAVA™), azathioprine (IMURAN™), cyclosporine (NEORAL™, SANDIMMUNE™), tacrolimus and cyclophosphamide (CYTOXAN™); (4) CD20 blocking agents, including, but not limited to, rituximab (RITUXAN™); (5) tumor necrosis factor (TNF) blocking agents, including, but not limited to, etanercept (ENB™). REL™), infliximab (REMICADE™), and adalimumab (HUMIRA™); (6) interleukin-1 receptor antagonists, including, but not limited to, anakinra (KINERET™); (7) interleukin-6 inhibitors, including, but not limited to, tocilizumab (ACTEMRA™); (8) interleukin-17 inhibitors, including, but not limited to, AIN457; (9) Janus kinase inhibitors, including, but not limited to, tasocitinib;and (10) syk inhibitors, including but not limited to fostamatinib.

[0150] Specific non-limiting examples of possible combination therapies for the treatment of cancer include the use of certain compounds of the present disclosure with: (1) alkylating agents, including but not limited to, cisplatin (PLATIN™), carboplatin (PARAPLATIN™), oxaliplatin (ELOXATIN™), streptozocin (ZANOSAR™), busulfan (MYLERAN™), and cyclophosphamide (ENDOXAN™); (2) aryl esters. (2) analgesic agents, including, but not limited to, mercaptopurine (PURINETHOL™), thioguanine, pentostatin (NIPENT™), cytosine arabinoside (ARA-C™), gemcitabine (GEMZAR™), fluorouracil (CARAC™), leucovorin (FUSILEV™), and methotrexate (RHEUMATREX™); (3) plant alkaloids and terpenoids, including, but not limited to, vincristine, benzodiazepine, benzoquinone, benzoic acid ... (4) topoisomerase inhibitors, including, but not limited to, irinotecan (CAMPTOSAR™), topotecan (HYCAMTIN™), and etoposide (EPOSIN™); (5) cytotoxic antibiotics, including, but not limited to, actinomycin D (COSMEGEN™), doxorubicin (ADRIAMYCIN™), bleomycin (Ventilator®), cyclosporine ... (6) angiogenesis inhibitors, including, but not limited to, sunitinib (SUTENT™) and bevacizumab (AVASTIN™); (7) tyrosine kinase inhibitors, including, but not limited to, imatinib (GLEEVEC™), erlotinib (TARCEVA™), lapatinib (TYKERB™), and axitinib (INLYTA™);and (8) immune checkpoint inhibitors, including, but not limited to, atezolizumab (TECENTRIQ™), avelumab (BAVENCIO™), durvalumab (IMFINZI™), ipilimumab (YERVOY™), pembrolizumab (KEYTRUDA™), nivolumab (OPDIVO™), and tremelimumab;

[0151] In some embodiments, the compounds disclosed in the embodiments herein can also be co-administered (concurrently or sequentially) with various other pharmaceutical agents or treatments, such as pharmaceutical agents or treatments administered systemically, orally or parenterally. Examples of such systemic treatments include topical or systemic corticosteroids (e.g., prednisone, etc.), antibiotics (e.g., erythromycin, tetracycline, and dicloxacillin), antifungal agents (e.g., ketoconazole and fluconazole, available under the trade name Diflucan™), antiviral agents (e.g., valacyclovir, available under the trade name Valtrex™, acyclovir, and famciclovir, available under the trade name Famvir™), corticosteroids, immunosuppressants (e.g., cyclophosphamide, , commercially available under the trademark Cytoxan™, azathioprine, methotrexate, mycophenolate), biologics (e.g., rituximab, commercially available under the trademark Rituxan™, etanercept, commercially available under the trademark Enbrel™, adalimumab, commercially available under the trademark Humira™, infliximab, commercially available under the trademark Remicade™, ustekinumab, commercially available under the trademark Stelara™, and alefacept, commercially available under the trademark Amevive™), and / or thyroid hormone substitutes.

[0152] In some embodiments, other therapeutic agents that can be used in combination with the compounds disclosed herein include, for example, mercaptopurine, topical or systemic corticosteroids, such as prednisone, methylprednisolone and prednisolone, alkylating agents, such as cyclophosphamide, calcineurin inhibitors, such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH), such as mycophenolate, mycophenolate mofetil, azathioprine, various antibodies, such as antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3), and irradiation. These various agents can be used according to their standard or general dosage as specified in the prescription information that accompanies the commercially available form of the drug (see also the 2006 Edition of The Physician's Desk Reference for prescription information). In some embodiments, the standard dosage of these agents can be reduced when used in combination with the compounds of the embodiments herein. Without limiting the scope of the disclosure, it is believed that such combinations can provide synergistic results with better efficacy, lower toxicity, longer duration of action, or more rapid response to therapy. In some embodiments, the combination therapy in the embodiments herein can be administered in subtherapeutic amounts of either the compound in the embodiments herein or the additional pharmaceutical agent, or both.Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan™; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol™; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune™; tacrolimus is currently available from Fujisawa under the trade name Prograf™; cyclosporine is currently available from Novartis under the trade name Sandimmune™ and is currently available from Abbott under the trade name Gengraf™; IMPDH inhibitors, such as mycophenolate mofetil and mycophenolic acid, are currently available from Roche under the trade name Cellcept™ and from Novartis under the trade name Myfortic™; azathioprine is currently available from Glaxo Smith It is currently available from Kline under the trade name Imuran™; as well as antibodies are currently available from Ortho Biotech under the trade name Orthoclone™, from Novartis under the trade name Simulect™ (basiliximab), and from Roche under the trade name Zenapax™ (daclizumab).

[0153] In some embodiments, the compounds of the embodiments herein are administered simultaneously or adjunctively with the above-mentioned pharmaceutical agents or therapies and / or pharmaceutical agents or therapies for another disease.For example, the compounds of the embodiments herein can be combined with thyroid hormone replacement therapy or anti-inflammatory or immunomodulatory therapy. In some embodiments, the combination therapy in the embodiments herein may involve administration of sub-therapeutic amounts of either the compound in the embodiments herein or the additional pharmaceutical agent, or both.

[0154] In any case, the multiple pharmaceutical agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. When administered simultaneously, the multiple pharmaceutical agents can be provided in a single, integrated form, or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the pharmaceutical agents can be given in multiple doses, or both can be given in multiple doses. If not simultaneously, the timing between the multiple doses can be any period ranging from a few minutes to 8 weeks, or any interval suitable to maintain the desired therapeutic effect. In some embodiments, the timing between the multiple doses can be 1 minute, 1 hour, 6 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0155] One or more additional pharmaceutical agents, such as anti-inflammatory agents, steroids, immunosuppressants, and one or more other ITK kinase inhibitors and / or other kinase inhibitors, such as JAK3 kinase, JAK1 kinase, JAK1 / 2 kinase, or JAK2 kinase inhibitors, such as those described in WO99 / 65909, WO00 / 00202, and / or WO / 2004 / 099205, or other agents, can be used in combination with the compounds of the invention for the treatment of diseases, disorders, or conditions associated with JAK1 and / or JAK3. In certain embodiments, the additional pharmaceutical agent is selected from taxanes, inhibitors of bcr-abl, inhibitors of EGFR, DNA damaging agents, antimetabolites, paclitaxel, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin, anthracyclines, AraC, 5-FU, camptothecin, doxorubicin, idarubicin, paclitaxel, docetaxel, vincristine, MEK inhibitors, U0126, KSP inhibitors, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab, tremelimumab, and durvalumab.

[0156] In some embodiments, the composition further comprises an additional pharmaceutical agent selected from a chemotherapeutic or anti-proliferative agent, an antiviral agent, an antibiotic, an antihistamine, an emollient, systemic phototherapy, psoralen photochemotherapy, laser therapy, hormone replacement therapy, an anti-inflammatory agent, an immunomodulatory or immunosuppressant agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating an immune deficiency disorder. In some embodiments, one or more compounds of the embodiments herein can be used in combination with one or more other therapeutic agents used in the treatment of JAK-mediated disorders, and can improve the therapeutic response without exacerbating the toxic effects of the other therapeutic agents alone. In some embodiments, the compounds of the embodiments herein can be used in combination with one or more other ITK inhibitors, and / or JAK1 and / or JAK3 inhibitors and / or JAK2 inhibitors and / or TYK2 inhibitors for the treatment of JAK-mediated disorders. Additive or synergistic effects are the desired outcome of such combinations. The additional agent can be combined with the compound of the present invention in a single dosage form or in a continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, one or more additional agents can be administered to a patient in combination with at least one JAK1 and / or JAK3 inhibitor / antagonist described herein, where the additional agent is administered in an intermittent administration as opposed to a continuous administration.

[0157] General synthetic methods for preparing compounds The compounds of the present invention can be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using routine methods known in the art. Representative procedures for the preparation of the compounds of the present invention are outlined in Schemes 1-5 below. Additional schemes used for analogs are provided in the Examples. Solvents and reagents whose synthetic preparations are not described below can be purchased from Sigma-Aldrich or Fisher Scientific. Additional schemes for the synthesis of specific analogs are also provided in the Examples section.

[0158] Scheme 1 depicts a general synthesis of compounds of formula (I), where R1, R2, R3, and R4 are defined as above, n is 0, 1, or 2, and X is a halogen. PG1 is an indole protecting group, such as benzenesulfonyl, toluenesulfonyl, mesitylenesulfonyl, t-butyl carbamate (Boc), allyl, benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), or p-methoxybenzyl. PG2 is a secondary amine protecting group, such as t-butyl carbamate (Boc), benzyl carbamate (Cbz), benzyl (Bn), p-methoxybenzyl (PMB), or N-acetyl (Ac). Compound CI is formed by coupling DI to EI. Compound BI is generated by removing the amine protecting group PG2. BI is coupled to a compound of formula HOR4 or halo-R4 to generate compound AI. Finally, removal of the indole protecting group PG1 generates a compound of formula (I). Alternatively, both CI protecting groups can be removed and the intermediate can be coupled to a compound of formula HOR4 to generate compound I. Scheme 1. General synthesis of pyrrolopyridine analogues of formula (I)

[0159] [ka] Scheme 2 illustrates a general synthesis for compounds of formula I where R1 is a -CO2R5 group. Commercially available ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (CAS#885500-55-0) can be protected under standard reaction conditions using SEM-Cl, a base such as sodium hydride in a solvent such as DMF or THF, followed by addition of SEM-Cl. The synthesis of diamine 3 (CAS#1251908-18-5) has been previously described (Shirakami et al., WO2010119875) and can be converted to intermediate 3a by reduction of the Boc protecting group with lithium aluminum hydride in a solvent such as THF. Alternatively, diamine 3 (CAS#1251908-18-5) can be deprotected using TFA in methylene chloride to give 3b. Secondary or primary amines 3a or 3b can be used to displace the chloride of 2 via nucleophilic aromatic substitution with heating in a solvent such as NMP. The resulting benzyl-protected amines 4a or 4b can be deprotected with palladium on carbon in a solvent such as methanol. Once deprotected, amines 5a or 5b can be coupled with a variety of carboxylic acids under standard amide coupling procedures; reaction with acid 6 using triethylamine, tripropylphosphonic anhydride in dichloromethane is shown as an example. Final deprotection using tetra-butylammonium fluoride in THF can produce the final compounds 8a, ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate or 8b, ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. In addition to 3a and 3b, other amines can also be utilized. For example, (R)-1-benzylpiperidin-3-amine can be used and the corresponding analogs lacking the methyl group on the piperidine can be synthesized. Scheme 2. Synthesis of 5-ester pyrrolopyridines

[0160] [ka]

[0161] Analogs bearing a linker between the carbonyl group of the ester and the pyrrolopyridine core can be obtained by the method described in Scheme 3. Commercially available 4-chloro-1-[tris(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (9) can be selectively lithiated at the 5-position using s-BuLi (Heinrich et al., J. Med. Chem. 2013) and reacted with I2 to generate 4-chloro-5-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10). Alternatively, the lithiated intermediate can be reacted directly with an electrophile such as ethyl 2-bromoacetate to generate intermediate 12. Other electrophiles such as allyl bromide can be used in subsequent steps with the ester formed by known methods. Compound 10 can be transformed by palladium-catalyzed cross-coupling in a variety of ways to generate the desired analogs. Exemplified here is reaction with ethyl acrylate (Heck reaction) followed by reduction of the double bond to produce intermediate 11. Intermediates 11 and 12 can be converted to JAK inhibitors using protected diamines such as (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine or (3R,4R)-1-benzyl-4-methylpiperidin-3-amine by methods described in Scheme 2.

[0162] Scheme 3. Preparation of 5-alkyl-ester pyrrolopyridines

[0163] [ka] Scheme 4 depicts a general synthesis of compounds of formula (II). 10 , R 20 , R 30, and R 40 is defined as above, n is 0 or 1, and X is a halogen. 10 is an indole protecting group, such as benzenesulfonyl, toluenesulfonyl, mesitylenesulfonyl, t-butylcarbamate (Boc), allyl, benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), or p-methoxybenzyl. Compound FII has the formula NH 20 Compound DII is formed by coupling FII with a compound of formula EII. Compound CII is formed by removing the ketal group from a compound of formula DII. Compound BII is formed by reducing the ketone from a compound of formula CII using sodium borohydride. Compound AII is formed by coupling a compound of formula BII with a compound of formula HOR under standard acylation or alkylation conditions. 40 Finally, the indole protecting group PG 10 Removal of BII produces a compound of formula (II). Optionally, BII may be deprotected to produce a compound of formula (II) by removal of R 40 We obtain II, where is OH. Scheme 4. General synthesis of formula (II)

[0164] [ka]

[0165] Compounds of formula II can be produced by the method described in Scheme 5, which illustrates the synthesis of methyl 4-((4-(2-cyanoacetoxy)-2-methylcyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. Commercially available 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (13) can be converted to N,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (15) by reductive amination using sodium cyanoborohydride. Nucleophilic aromatic displacement of, for example, an aromatic chloride of 16 with 15 under thermal conditions in water or NMP gives the ketal-protected intermediate 17. Deprotection followed by reduction can produce the alcohol 19. Ester formation and deprotection gives the final analog 22. Scheme 5. Synthesis of 5-ester pyrrolopyridines

[0166] [ka]

[0167] While the present invention has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention. All printed patents and publications referenced in this application are hereby incorporated by reference in their entirety.

[0168] Exemplary synthetic methods for certain compounds detailed in the Examples section are further exemplified by the following: Synthesis of Example 1: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0169] [ka] Scheme 6. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0170] [ka] Preparation of (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine

[0171] [ka] To a solution of tert-butyl ((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate (1 g, 3.28 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (4.9 mL, 4.9 mmol, 1 M in THF) and the mixture was heated to 60° C. for 5 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.6 g, crude): MS (ES) m / z 219 (M+H). Step 1: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0172] [ka] To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.17 g, 0.75 mmol) in diphenyl ether (0.1 mL) was added (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.18 g, 0.83 mmol). The mixture was subjected to microwave irradiation at 190° C. for 0.5 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a viscous liquid (0.035 g, 12% yield): MS (ES) m / z 407.2 (M+H). Step 2: Preparation of ethyl 4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0173] [ka] To a solution of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.09 g, 0.2 mmol) in tetrahydrofuran (1 mL) was added palladium on carbon (0.25 g, 50% wet weight w / w) and the mixture was stirred under hydrogen atmosphere at room temperature for 30 h. The reaction was partitioned between 50% methanol / ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure to give 4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (crude 0.07 g, 100% yield): MS (ES) m / z 317.2 (M+H). Step 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0174] [ka] To a solution of ethyl 4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.07 g, 0.22 mmol) in dichloromethane (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl (0.068 g, 0.4 mmol), 1-hydroxybenzotriazole (0.05 g, 0.44 mmol), N,N-diisopropylethylamine (0.05 g, 0.4 mmol) and cyanoacetic acid (0.028 g, 0.33 mmol) and the mixture was stirred at ambient temperature for 12 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (6% methanol / dichloromethane) to give ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.013 g, 5% yield): 1 H NMR (400 MHz, DMSO-d6, at 90℃) δ 11.58 (s, 1H), 8.32 (s, 1H), 7.33 (s, 1H), 6.54 (br s, 1H) 4.28-4.29 (m, 2H) 3.81-3.94 (m, 4H), 3.37-3.49 (m, 3H), 2.94 (s, 3H), 2.16 (m, 1H), 1.61 (m, 2H), 1.30-1.33 (t, J = 12 Hz, 3H), 0.94-0.96 (m, 3H); MS (ES) m / z 384.2 (M+H).

[0175] Synthesis of Example 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [ka] Scheme 7. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0176] [ka] Preparation of (3R,4R)-1-benzyl-4-methylpiperidin-3-amine

[0177] [ka] A solution of tert-butyl (3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate (2 g, 6.57 mmol) in HCl was stirred in dioxane (10 mL, 4M) at ambient temperature for 4 h. The reaction mixture was concentrated under reduced pressure and neutralized with triethylamine (7 mL). The residue was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (1.3 g, crude): MS (ES) m / z 205.1 (M+H). Step 1: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0178] [ka] To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (9 g, 40.17 mmol) in N-methyl-2-pyrrolidone (100 mL) was added (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (9.8 g, 48.2 mmol) and triethylamine (4.5 mL) in a sealed tube and the mixture was heated to 170° C. for 16 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a semi-solid (10 g, 64% yield): MS (ES) m / z 393.4 (M+H). Step 2: Preparation of ethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0179] [ka] To a solution of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 25.5 mmol) in tetrahydrofuran (120 mL) was added palladium on carbon (30 g, 50% wet weight w / w) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 30 h using a Parr-shaker (70 psi). The reaction mixture was partitioned between 50% methanol / ethyl acetate and filtered through Celite. The filtrate was concentrated to give ethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (4.7 g, 95% yield): MS (ES) m / z 303.1 (M+H). Step 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0180] [ka] To a solution of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (4.7 g, 15.8 mmol) in dichloromethane (50 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl (4.9 g, 31.6 mmol), 1-hydroxylbenzotriazole (4.2 g, 31.7 mmol), N,N-diisopropylethylamine (12.2 mL, 31.6 mmol) and cyanoacetic acid (2.7 g, 31.7 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (6% methanol / dichloromethane) to give ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.8 g, 66% yield): 1 H NMR (400 MHz, DMSO-d6, at 90℃) δ 11.49 (s, 1H), 8.79-8.81 (m, 1H), 8.56 (s, 1H), 7.16 (s, 1H) 6.64 (s, 1H) 4.27-4.36 (m, 4H), 3.91 (m, 1H), 3.70 (m, 1H), 3.42 (m, 1H), 3.15 (m, 1H), 2.88 (m, 1H), 2.14 (br s, 2H), 1.64 (m, 1H), 1.30-1.33 (t, J = 8.75 Hz, 3H), 0.95 (bs, 3H); MS (ES) m / z 370.3 (M+H). Synthesis of Example 21: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0181] [ka] Scheme 8. Preparation of 2-Methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0182] [ka] Step 1: Preparation of 2-methoxyethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0183] [ka] To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (4.0 g, 17.80 mmol) in methoxyethanol (40 mL) was added cesium carbonate (29.0 g, 89.0 mmol) and the mixture was stirred at ambient temperature for 16 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (40% ethyl acetate / hexanes) to give 2-methoxyethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a white solid (2.6 g, 57% yield): MS (ES) m / z 255 (M+H). Step 2: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0184] [ka] A solution of 2-methoxyethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.6 g, 2.35 mmol), (3R,4R)-1-benzyl-4-methylpiperidin-3-amine (0.48 g, 2.35 mmol) and triethylamine (0.1 mL) in N-methyl-2-pyrrolidone (10 mL) in a sealed tube was heated to 140° C. for 12 hours. The reaction mixture was cooled to ambient temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (45% ethyl acetate / hexanes) to give 2-methoxyethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.35 g, 35% yield): MS (ES) m / z 423 (M+H). Step 3: Preparation of 2-methoxyethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0185] [ka] To a solution of 2-methoxyethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.35 g, 0.82 mmol) in tetrahydrofuran (10 mL) was added palladium on carbon (0.3 g, 50% wet weight w / w) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 48 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give 2-methoxyethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (crude product 0.16 g 58% yield): MS (ES) m / z 333 (M+H). Step 4: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0186] [ka] A solution of 2-methoxyethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.16 g, 0.48 mmol) in N,N-dimethylformamide (10 mL) was added to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. . HCl (0.14 g, 0.96 mmol), 1-hydroxybenzotriazole (0.13 g, 0.96 mmol), N,N-disopropylethylamine (0.25 mL, 1.44 mmol) and cyanoacetic acid (0.08 g, 0.96 mmol) were added and the mixture was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) to give 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.03 g, 16% yield): 1H NMR (400 MHz, DMSO-d6, at 80℃) δ 11.52 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 7.16 (s, 1H) 6.65 (s, 1H) 4.34-4.36 (m, 3H ), 4.24 (m, MS (ES) m / z 400 (M+H). Synthesis of Example 24: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0187] [ka] Scheme 9. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0188] [ka] A solution of ethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 0.311 mmol), acrylonitrile (0.035 g, 0.66 mmol) and triethylamine (0.13 mL, 0.99 mmol) in ethanol (10 mL) was heated at 70° C. for 2 h. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure and the crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.07 g, 63% yield): 1H NMR (400 MHz, DMSO-d6) δ 11.61 (br s, 1H), 9.08 (d, J = 9.2 Hz, 1H), 8.52 (s, 1H), 7.13 (s, 1H), 6.62 (s, 1H), 4.37 (br s, 1H), 4.24-4.25 (m, 2H), 2.79 (d, J = 8.8 Hz, 2H), 2.43-2.60 (m, 4H), 2.02 (br s,1H), 1.87 (br s, 1H), 1.70-1.55 (br s, 2H), 1.22-1.31 (m, 4H), 0.85 (d, J = 6.0 Hz, 3H); MS (ES) m / z 356.2 (M+H). Synthesis of Example 34: Preparation of ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0189] [ka] Scheme 10. Preparation of ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0190] [ka] Step-1: Preparation of ethyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0191] [ka] A solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.5 g, 2.23 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.53 g, 2.67 mmol) and triethylamine (0.3 mL) in N-methyl-2-pyrrolidone (10 mL) was subjected to microwave irradiation at 180° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. The crude material was purified by flash chromatography (50% ethyl acetate / hexanes) to give ethyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.6 g, 35% yield): MS (ES) m / z: 389.2 (M+H). Step 2: Preparation of ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate hydrochloride

[0192] [ka] To a solution of ethyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.6 g, 1.17 mmol) in dichloromethane (15 mL) was added HCl in dioxane (2.0 mL, 4 M) at 0° C. and the mixture was stirred at ambient temperature for 6 h. The solution was concentrated under reduced pressure to give ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl as an off-white solid (0.3 g, crude): MS (ES) m / z: 289.2 (M+H). Step 3: Preparation of ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0193] [ka] To a solution of ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate HCl salt (0.13 g, 0.45 mmol) in tetrahydrofuran:water (1:1, 2 mL:2 mL) was added N,N-diisopropylethylamine (0.2 mL, 0.92 mmol) followed by acryloyl chloride (0.01 mL, 0.092 mmol) at 0° C. The mixture was stirred for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (ethyl acetate / hexanes) to give ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.035 g, 22% yield): 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.85 (br s, 1H), 8.53 (s, 1H), 7.19 (s, 1H), 6.75- 6.82 (m, 1H), 6.50- 6.59 (m, 1H), 6.01-6.21 (m, 1H), 5.32 - 5.66 (m, 1H), 4.24 (q, J = 7.2 Hz, 2 H), 4.11 (m, 1 H), 3.72-3.84 (m, 1H) 3.57 (m, 1H), 2.06 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.31 (t, J = 6.8 Hz, 3 H), 1.22 - 1.25 (m, 1H ), 0.82-1.09 (m, 1H); MS (ES) m / z: 343.2 (M+H). Synthesis of Examples 68A and 68B: Preparation of the Enantiomers of (trans)-Ethyl 4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 68A and 68B

[0194] [ka] Scheme 11. Preparation of the enantiomers of (trans)-ethyl 4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0195] [ka]

[0196] Chiral separation of (trans)-(rac)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate The enantiomers of (trans)-(rac)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate were separated by chiral chromatography.

[0197] Conditions for analysis: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm) Mobile phase: n-hexane:ethanol with 0.1% DEA (50:50) Flow rate: 1.0mL / min Enantiomer 1: Retention time 4.161 min Enantiomer 2: Retention time 5.296 min Step 1: Preparation of (trans)-tert-butyl-(3-hydroxycyclopentyl)carbamate

[0198] [ka] To a solution of one of the enantiomers of (trans)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate (1.2 g, 3.42 mmol) in methanol (30 mL) was added potassium carbonate (0.71 g, 5.14 mmol) and the mixture was stirred at ambient temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (30% ethyl acetate / hexanes) to give tert-butyl-(3-hydroxycyclopentyl)carbamate as an off-white solid (0.42 g, 60.95% yield): 1 H NMR (400 MHz, DMSO-d6) δ 6.72 (br s, 1H), 4.37 (d, J = 3.6 Hz, 1H), 4.09-4.10 (m, 1H), 3.89-3.91 (m, 1H), 1.75-1.91 (m, 2H), 1.66-1.70 (m, 1H), 1.44-1.51 (m, 1H), 1.35 (s, 9H), 1.19-1.31(m, 2H). Step 2: Preparation of (trans)-3-(methylamino)cyclopentan-1-ol

[0199] [ka] To a solution of one of the enantiomers of (trans)-tert-butyl-(3-hydroxycyclopentyl)carbamate (0.15 g, 0.74 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (2.23 mL, 2.23 mmol (1.0 M solution in tetrahydrofuran) dropwise at 0° C. and the mixture was heated at 70° C. for 4 h. After cooling, the reaction mixture was quenched with aqueous sodium hydroxide and ethyl acetate and the suspension was filtered through Celite. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 3-(methylamino)cyclopentan-1-ol as a yellow oil (0.1 g, 80% yield): MS (ES) m / z 116 (M+H). Step 3: Preparation of (trans)-ethyl 4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0200] [ka] A solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.15 g, 0.66 mmol) and one of the enantiomers of 3-(methylamino)cyclopentan-1-ol (0.092 g, 0.8 mmol) in dimethylsulfoxide (3 mL) was heated under microwave irradiation for 2 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (9% methanol / dichloromethane) to give ethyl 4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (0.015 g, 7.42% yield). (Example 68A) (trans)-Ethyl 4-((-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Enantiomer 1

[0201] [ka] 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.20 (m, 1H), 7.24-7.26 (m, 1H), 6.57-6.58 (m, 1H), 4.66-4.80 (m, 1H), 4.57 (m, 1H), 4.06-4.27 (m, 3H), 2.82 (s, 3H), 1.78-1.96 (m, 3H), 1.60-1.76 (m, 2H), 1.48-1.50 (m, 1H), 1.30 (t, J = 8.8Hz, 3H); MS (ES) m / z 304 (M+H). (Example 68B) (trans)-Ethyl 4-((-3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, enantiomer 2

[0202] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (br s, 1H), 8.20 (m, 1H), 7.24-7.26 (m, 1H), 6.57-6.58 (m, 1H), 4.66-4.74 (m, 1H), 4.54-4.55 (m, 1H), 4.20-4.27 (m, 3H), 2.78 (s, 3H), 1.80-1.94 (m, 3H), 1.71-1.78 (m, 2H), 1.48-1.51 (m, 1H), 1.31 (t, J = 8.8 Hz, 3H). Synthesis of Example 69: Isolation of Trans Enantiomer-2, (trans)-Ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0203] [ka] 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.24 (s, 1H), 7.26-7.28 (m, 1H), 6.55-6.56 (m, 1H), 5.21-5.22 (m, 1H), 4.57-4.61 (m, 1H), 4.26 (q, J = 6.8 Hz 2H), 3.94 (s, 2H), 2.84 (s, 3H), 2.11-2.20 (m, 2H), 1.92-2.0 (m, 3H),1.83-1.86 (m, 1H), 1.29 (t, J = 7.6 Hz, 3H).Retention time: 21.666 minutes Synthesis of Example 70: Isolation of Trans Enantiomer-1, (trans)-Ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0204] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.24 (s, 1H), 7.26-7.28 (m, 1H), 6.55-6.56 (m, 1H), 5.21-5.22 (m, 1H), 4.57-4.61(m, 1H), 4.25 (q, J = 6.8 Hz, 2H), 3.94 (s, 2H), 2.82 (s, 3H), 2.10-2.11 (m, 2H), 1.85-1.96 (m, 3H), 1.68-1.70 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H); Retention time: 19.434 minutes

[0205] Synthesis of Examples 72-75: Preparation of the enantiomers of (trans)-ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate: 72 and 75 and (trans)-ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate: 73 and 74

[0206] [ka] Scheme 13. Preparation of the enantiomers of (trans)-ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate and (trans)-ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0207] [ka] Step-1: Preparation of (trans)-(rac)-3-aminocyclopentan-1-ol hydrochloride

[0208] [ka] To a solution of (trans)-(rac)-tert-butyl-(3-hydroxycyclopentyl)carbamate (0.27 g, 1.34 mmol) in dichloromethane (5 mL) was added HCl in dioxane (4 M, 5 mL) at 0° C., the solution was warmed to ambient temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether to give 3-aminocyclopentan-1-ol hydrochloride as a yellow oil (0.18 g, 96% yield): MS (ES) m / z 102 (M+H). Step-2: Preparation of (trans)-ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0209] [ka] A solution of (trans)-(rac)-ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.05 g, 0.22 mmol), 3-aminocyclopentan-1-ol HCl (0.036 g, 0.26 mmol) and triethylamine (0.15 mL, 1.11 mmol) in dimethylsulfoxide (3 mL) was heated at 150° C. for 1 h under microwave irradiation. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (9% methanol / dichloromethane) to give ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.01 g, 17% yield): MS (ES) m / z 290 (M+H). Step 3: Preparation of (trans)-(rac)-ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0210] [ka] To a solution of (trans)-(rac)-ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.14 g, 0.48 mmol) in dichloromethane (10 mL) was added 2-cyanoacetic acid (0.062 g, 0.72 mmol), 4-dimethylaminopyridine (0.06 g, 0.48 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (0.14 g, 0.72 mmol) and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (5% methanol / dichloromethane) to give ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.035 g, 20% yield): MS (ES) m / z 357 (M+H). Synthesis of Example 72: Isolation of Trans Enantiomer-2, (trans)-Ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0211] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (br s, 1H), 8.82 (d, J = 7.6 Hz, 1H), 8.52 (s, 1H), 7.17-7.18 (m, 1H), 6.67 (s, 1H), 4.61-4.63 (m, 2H), 4.21-4.26 (m, 3H), 1.98-2.37 (m, 3H), 1.68-1.69 (m, 1H), 1.53 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).Retention time: 7.625 minutes Analysis conditions: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm) Fluid methanol and 0.1% DEA (50:50) Flow rate: 0.5mL / min Synthesis of Example 73: Isolation of Trans Enantiomer-1, (trans)-Ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0212] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.81 (d, J = 3.8 Hz, 1H), 8.53 (s, 1H), 7.17 (s, 1H), 6.65 (s, 1H), 5.30 (br, 1H), 4.63-4.66 (m, 1H), 4.25 (q, J = 6.8 Hz, 2H), 3.99 (s, 2H), 2.05-2.31 (m, 3H), 1.93-2.0 (m, 1H), 1.79-1.81 (m, 1H), 1.60-1.67 (m, 1H), 1.30 (t, J = 6.8 Hz, 3H). Retention time: 9.484 minutes Analysis conditions: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm) Fluid methanol and 0.1% DEA (50:50) Flow rate: 0.5mL / min Synthesis of Example 74: Isolation of Trans Enantiomer-2, (trans)-Ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0213] [ka] 1H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 5.25 (br s, 1H), 4.63-4.67 (m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.99 (s, 2H), 2.14-2.31 (m, 3H), 1.93-2.00 (m, 1H), 1.80 (m, 1H), 1.63-1.65 (m, 1H),1.33 (t, J = 7.2 Hz, 3H). Retention time 4.846 minutes Analysis conditions: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm) Fluid methanol and 0.1% DEA (50:50) Flow rate: 0.5mL / min Synthesis of Example 75: Isolation of Trans Enantiomer-1, (trans)-Ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0214] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.80 (d, J = 7.6 Hz 1H), 8.51 (s, 1H), 7.17 (s, 1H), 6.66 (s, 1H), 4.59-4.66 (m, 2H), 4.21-4.26 (m, 3H), 2.23-2.31 (m, 1H), 2.05-2.10 (m, 1H), 1.93-2.04 (m, 1H), 1.64-1.69 (m, 1H), 1.46-1.58 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).Holding time: 7.540 minutes Analysis conditions: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm) Fluid methanol and 0.1% DEA (50:50) Flow rate: 0.5mL / min Synthesis of Example 92: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0215] [ka] Scheme 14. Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0216] [ka] Preparation of ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride

[0217] [ka] To a stirred solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1 g, 17.47 mmol) in dioxane (5 mL) was added 1,4-dioxane . Hydrochloride (10 mL) was added at 0° C. and the solution was stirred for 2 h. The reaction was concentrated under reduced pressure to give crude (1r,4r)-4-aminocyclohexyl)methanol hydrochloride as a semi-solid (0.6 g crude product). Step 1: Preparation of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0218] [ka] To a stirred solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 13.39 mmol) in N-methylpyrrolidine (10 mL) was added triethylamine (0.3 mL) and ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride (2.59 g, 19.9 mmol). The solution was heated in a sealed tube at 160° C. for 2 h. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (55% ethyl acetate / hexanes) to give ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (3 g, 71% yield): MS (ES) m / z 318.1 (M+H). Step 2: Preparation of ethyl 1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0219] [ka] To a solution of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.5 g, 4.73 mmol) in dichloromethane (20 mL) was added triethylamine (1.2 mL, 12.08 mmol), 4-dimethylaminopyridine (0.28 g, 2.36 mmol) and 4-toluenesulfonyl chloride (2.7 g, 14.19 mmol) at 0° C. The mixture was stirred at room temperature for 12 h, at which point the reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by using flash chromatography (55% ethyl acetate / hexanes) to give ethyl 1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (1.6 g, 55% yield): MS (ES) m / z 626.1 (M+H). Step-3: Preparation of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0220] [ka] To a solution of ethyl 1-tosyl-4-(((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.6 g, 2.56 mmol) in dimethylsulfoxide (5 mL) was added potassium ethanethiolate (0.33 g, 2.89 mmol) and the mixture was stirred at 50° C. for 3 h. The reaction mixture was cooled to ambient temperature and quenched with ice water. The resulting solid was filtered, washed with water and dried to give ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a white solid (1.6 g, 74%): MS (ES) m / z 530.1 (M+H).

[0221] Step 4: Preparation of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid

[0222] [ka] A solution of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.3 g, 0.56 mmol) in hydrogen peroxide (0.15 mL) was treated with formic acid (0.8 mL) at 0° C. and the solution was stirred at room temperature for 2.5 h. The reaction mixture was quenched with ice water and the resulting solid was filtered, washed with water and dried to give ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid as a white solid (0.21 g, 66% yield): MS (ES) m / z 535.1 (M+H). Step 5: Preparation of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0223] [ka] To a stirred solution of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.21 g, 0.39 mmol) in N,N-dimethylformamide (0.1 mL) was added thionyl chloride (2.0 mL) at 0° C. and the solution was stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure to give ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a pale yellow solid (0.35 g crude). Step 6: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0224] [ka] To a solution of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.21 g, 0.37 mmol) in tetrahydrofuran (10 mL) was added methylamine (15 mL, 2.0 M in tetrahydrofuran) and the solution was stirred at room temperature in a sealed tube for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate, which was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40% ethyl acetate / hexanes) to give ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (0.07 g, 70% yield): MS (ES) m / z 548.1 (M+H).

[0225] Step 7: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0226] [ka] To a solution of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.14 g, 0.25 mmol) in tetrahydrofuran (1 mL) was added potassium tert-butoxide (0.07 g, 0.63 mmol) and the solution was stirred at room temperature for 2.5 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40% ethyl acetate / hexanes) to give ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.07 g, 37% yield): 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.71-8.73 (m, 1H), 8.51 (s, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 6.51 (s, 1H), 4.22-4.24 MS (ES) m / z 382.1 (M+H). Synthesis of Example 94: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0227] [ka]

[0228] Scheme 15: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0229] [ka] Preparation of ((1r,4r)-4-(methylamino)cyclohexyl)methanol

[0230] [ka] To a stirred solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (4 g, 17.47 mmol) in tetrahydrofuran (75 mL) was slowly added lithium aluminum hydride (26 mL, 26.2 mmol, 1 M solution in tetrahydrofuran) at 0° C. and the mixture was slowly heated at 60° C. for 12 h. The reaction mixture was cooled to room temperature, quenched with ethyl acetate, and filtered through Celite. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ((1r,4r)-4-(methylamino)cyclohexyl)methanol as a yellow solid (3 g crude): MS (ES) m / z 144.1 (M+H). Step 1: Preparation of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0231] [ka] To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 13.39 mmol) in diphenyl ether (10 mL) was added ((1r,4r)-4-(methylamino)cyclohexyl)methanol (3.4 g, 24.10 mmol) and the solution was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (55% ethyl acetate / hexanes) to give ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (1 g, 27% yield): MS (ES) m / z 332.2 (M+H).

[0232] Step 2: Preparation of ethyl 4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0233] [ka] To a stirred solution of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.0 g, 3.02 mmol) in dichloromethane (20 mL) was added triethylamine (1.2 mL, 12.08 mmol) at 0° C., followed by 4-dimethylaminopyridine (0.18 g, 1.51 mmol) and 4-toluenesulfonyl chloride (1.7 g, 9.06 mmol). The mixture was stirred at room temperature under N2 atmosphere for 12 h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (20% ethyl acetate / hexanes) to give ethyl 4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (1.4 g, 73% yield): MS (ES) m / z 640.2 (M+H).

[0234] Step 3: Preparation of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0235] [ka] To a stirred solution of ethyl 4-(methyl((1r,4r)-4-((tosyloxy)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.4 g, 2.18 mmol) in dimethylsulfoxide (30 mL) was added potassium ethanethioate (0.28 g, 2.47 mmol) and the mixture was stirred at 50° C. for 3 h. The reaction mixture was quenched with ice water and the resulting solid was filtered, washed with water and dried to give ethyl 4-(((1r,4r)-4-((acetylthio)-methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (1.0 g, 84% yield): MS (ES) m / z 544.2 (M+H).

[0236] Step 4: Preparation of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonic acid

[0237] [ka] A stirred solution of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.1 g, 2.02 mmol) in hydrogen peroxide (1 mL) was treated with formic acid (9 mL) at 0° C. and the solution was stirred at room temperature for 2.5 h. The reaction mixture was quenched with ice water and the resulting solid was filtered, washed with water and dried to give ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonate as an off-white solid (0.55 g, 50% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.9 (d, J = 7.6 Hz, 2H), 7.7 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 8 Hz, 2 H), 6.67 (d, J = 3.2 Hz, 1H), 4.25-4.18 (q, 2H), 3.64-3.60 (m, 2H), 2.75 (s, 3H), 2.37-02.32 (m, 5H), 2.06-2.03 (m, 2H), 1.75-1.70 (m, 5H), 1.29 (t, J = 6.8 Hz, 3H), 1.06 - 0.96 (m, 2H).

[0238] Step 5: Preparation of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0239] [ka] To a solution of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)-methanesulfonic acid (0.5 g, 0.9 mmol) in N,N-dimethylformamide (0.5 mL) was added thionyl chloride (5 mL) at 0° C. and the solution was stirred for 2.5 h. The reaction mixture was concentrated under reduced pressure to give ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a colorless liquid (0.35 g crude): MS (ES) m / z 568.2 (M+H).

[0240] Step 6: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0241] [ka] To a stirred solution of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.35 g, 0.61 mmol) in tetrahydrofuran (10 mL) was added methylamine (15 mL, 2.0 M in tetrahydrofuran) and the solution was stirred at room temperature for 12 h. The reaction mixture was quenched with water, extracted with ethyl acetate, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by using flash chromatography (40% ethyl acetate / hexanes) to give ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a yellow solid (0.300 g, 87%): MS (ES) m / z 563.2 (M+H).

[0242] Step 7: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0243] [ka] To a stirred solution of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.3 g, 0.53 mmol) in tetrahydrofuran (8 mL) was added potassium tert-butoxide (0.15 g, 1.33 mmol) and the solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified using flash chromatography (45% ethyl acetate / hexanes) to give ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.08 g, 37% yield): 1 H NMR (400 MHz, DMSO-d6): δ 11.64 (s, 1H), 8.18 (s, 1H), 7.25 (s, 1H), 6.85 (d, J = 4.8 Hz, 1H), 6.40 (s, 1H), 4.25-4.20 (q, 2H), 3.81 (bs, 1H), 2.90 (d, J = 5.6 Hz, 2H), 2.80 (s, 3H), 2.55 (d, J = 4.8 Hz, 3H), 2.05-2.02 (m, 2H), 1.81-1.76 (m, 5H), 1.29 (t, J = 6.8 Hz, 3H), 1.21-1.19 (m, 2H); MS (ES) m / z 409.0 [M+H]. Synthesis of Example 113: Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0244] [ka] Scheme 16. Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0245] [ka] Step 1: Preparation of 3-aminocyclopentan-1-ol trifluoroacetate

[0246] [ka] To a solution of tert-butyl (3-hydroxycyclopentyl)carbamate (1.0 g, 5.47 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at ambient temperature for 5 hours and then concentrated under reduced pressure to dryness to give 3-aminocyclopentan-1-ol trifluoroacetate (1.17 g, crude product). Step 2: Preparation of ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0247] [ka] A stirred solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.27 g, 5.44 mmol), 3-aminocyclopentan-1-ol trifluoroacetate (1.17 g, 5.44 mmol), triethylamine (2.27 g, 16.3 mmol) in N-methyl-2-pyrrolidone (10 mL) was heated at 160° C. in a sealed tube for 12 h. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified using flash chromatography (10% methanol / dichloromethane) to give ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a colorless gum (0.82 g, 50% yield): MS (ES) m / z 290.1 ​​(M+H). Step 3: Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0248] [ka] To a suspension of potassium carbonate (0.86 g, 6.25 mmol) in ethanol (10 mL) was added ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.74 g, 2.56 mmol) and the mixture was stirred at ambient temperature for 0.5 h. Acrylonitrile (1.35 g, 25.6 mmol) was then added and the mixture was stirred for 15 h. The solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC (0.1% ammonia in water:acetonitrile) to give ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.05 g, 6% yield): 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (br s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.50 (s, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 4.59-4.5 (m, 1H ), 4.25 (q, J = 7.2 Hz, 2H), 4.02-4.10 (m, 1H), 3.56-.351 (m, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.26-2.19 (m, 1H), 2.15-2.07 (m, 1H), 1.90-1.82 (m, 2H), 1.73-1.69 (m, 2H), 1.29 (t, J = 6.2 Hz, 3H); MS (ES) m / z 343.1 (M+H). Prep HPLC analysis conditions Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 μm) Mobile phase (A): 0.1% ammonia in water Mobile phase (B): ACN Flow rate: 1.0mL / min Retention time: 12.61 minutes Synthesis of Example 117: Preparation of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0249] [ka] Scheme 17. Preparation of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0250] [ka] Step 1: Preparation of ethyl (R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0251] [ka] To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5 g, 22.3 mmol) in N-methyl-2-pyrrolidone (35 mL) was added (R)-1-benzylpiperidin-3-amine (8.48 g, 44.6 mmol) and triethylamine (1 mL) in a sealed tube. The mixture was heated to 170° C. for 16 h. After cooling to room temperature, the reaction mixture was quenched with water to precipitate a solid, which was filtered, washed with water, dried and concentrated under reduced pressure to give ethyl (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as a brown solid (8 g, 95% yield): MS (ES) m / z 379.1 (M+H). Step 2: Preparation of ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0252] [ka] To a solution of ethyl (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.25 g, 0.66 mmol) in methanol (5 mL) was added 10% palladium on carbon (0.3 g, 50% wet weight, w / w) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 12 hours. The reaction mixture was partitioned between 50% methanol / ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure to give ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.1 g, 90% yield): MS (ES) m / z 289.3 (M+H).

[0253] Step 3: Preparation of ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0254] [ka] To a solution of ethyl (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (9 g, 31.3 mmol) in dichloromethane (50 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl (9.7 g, 62.5 mmol), 1-hydroxybenzotriazole (8.43 g, 62.5 mmol), N,N-diisopropylethylamine (11.3 mL, 62.5 mmol) and cyanoacetic acid (0.76 g, 9.0 mmol) and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (5% methanol / dichloromethane) to give ethyl (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (7.5 g, 68% yield): 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.86-8.79 (m, 1H), 8.54 (s, 1H), 7.20 (s, 1H), 6.67 (s, 1H), 4.17-4.44 (m, 3H), MS (ES) m / z 356.1 (M+H). Synthesis of Example 118: Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0255] [ka] Scheme 18. Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0256] [ka] Step 1: Preparation of 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[0257] [ka] To a solution of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 0.25 mmol) in methanol (10 mL) was added lithium hydroxide (0.017 g, 0.75 mmol) and the mixture was heated to 60° C. for 10 h. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in water, acidified with 2N hydrochloric acid and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.085 g, 91% yield): MS (ES) m / z 365.2 (M+H). Step 2: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0258] [ka] To a solution of 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.08 g, 0.22 mmol) in methanol (10 mL) was added sulfuric acid (1.0 mL) and the solution was heated to 80° C. for 48 h. After cooling to ambient temperature, the reaction was quenched with saturated bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, crude): MS (ES) m / z 379.1 (M+H).

[0259] Step 3: Preparation of methyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [ka] To a solution of methyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 0.34 mmol) in tetrahydrofuran (5 mL) was added palladium on carbon (0.5 g, 50% wet weight w / w) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 12 h. The resulting solution was partitioned between 50% methanol / ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure to give methyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.09 g, 93% yield): MS (ES) m / z 289.2 (M+H).

[0260] Step 4: Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

Claims

1. Formula or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a combination thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1, a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a combination thereof.

3. The pharmaceutical composition of claim 2, for topical administration.

4. 3. The pharmaceutical composition according to claim 2 for treating a JAK1 and / or JAK3 mediated disease.

5. The JAK1 and / or JAK3 mediated disease is an autoimmune disorder or response, widespread activation of the immune response, chronic and / or acute inflammatory disorder or condition, and / or an autoinflammatory disorder, a fibrotic disorder, a skin disorder, pruritus, a hair loss disorder, a cancer or malignancy, an autoimmune connective tissue disease, an autoimmune condition, Th17-associated inflammation, myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis, psoriatic arthritis, scleroderma (systemic sclerosis, juvenile scleroderma), cutaneous lupus (subacute cutaneous lupus, chronic cutaneous / discoid lupus, chilblain lupus erythematosus), pruritus / itch (atopic pruritus, dry pruritus, psoriasis-associated pruritus / psoriatic itch / psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, bile duct itch, hepatobiliary itch, renal itch / renal itch, uremic itch, chronic lichen simplex itch, lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch / atopic pruritus, bullous itch, brachioradial itch), neurogenic itch, neuropathic itch, paresthesia paresthesias, HIV pruritic papular rash , psychogenic itch, swimmer's itch, pruritic or uremic itch, urticarial itch, skin disorders, cutaneous drug reactions / drug eruptions, xerosis / dry skin, skin rash, skin sensitization, skin irritation, sunburn, razor rash, body lice, head lice / pediculosis, hair lice, cutaneous larva migrans, scabies, parasitic infections, insect infestation, urticarial / rash, papular urticaria, insect bites, insect stings, dandruff, foreign body or device on skin, fungal infection, herpes, chickenpox / varicella, eosinophilic folliculitis, skin diseases of pregnancy / pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory skin diseases , Neutrophilic Dermatosis, Histiocytic Neutrophilic Dermatosis, Intestinal Bypass Syndrome Dermatosis, Psoriasis / Psoriasis Vulgaris, Lichen Planus, Lichen Sclerosus, Acne (Acne Vulgaris, Acne Comedonal, Inflammatory Acne, Nodular Cystic Acne, Cicatricial Acne, Keloid Acne Neck), Atopic (Allergic Contact Sensitization, Allergic Dermatitis) Dermatitis (Atopic Dermatitis / Eczema, Contact Dermatitis, Photodermatitis, Seborrheic Dermatitis, Stasis Dermatitis, Acne with Acne ...Internasal hair alopecia, cicatricial alopecia (parietal centrifugal cicatricial alopecia), non-cicatricial alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), serpiginous pattern alopecia areata, sisaihpo pattern alopecia areata)), androgenic / androgenic alopecia (AGA) / male and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex), lichen planopilaris (frontal fibroplastic alopecia), punctate palmoplantar keratoderma, erythema edullivanis (EED), neutrophils Vitiligo vulgaris, including hidradenitis vulgaris, columnar cell neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, segmental vitiligo (unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo vulgaris), nonsegmental vitiligo (digital, facial, or extremofacial vitiligo) vitiligo, central facial vitiligo, mucosal vitiligo, confetti-type vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetrachromatic vitiligo, blue vitiligo vulgaris, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo vulgaris, generalized vitiligo vulgaris), mixed vitiligo vulgaris Non-segmental vitiligo associated with macular / segmental type, Localized vitiligo, Isolated mucosal vitiligo or vitiligo with or without leukoderma (including body hair), Bullous diseases, Immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), Pemphigoid of Gestation, Xeroderma pigmentosum, fibrotic and scarring disorders, Scar, Scleroderma, Increasing fibrosis, Keloid, Post-surgical scar, Wound healing, Surgical scar, Radiation-induced fibrosis (e.g. of the head and neck, digestive system or lungs), Eye scar, Fibrosclerosis, Increasing scar 5. The pharmaceutical composition of claim 4, which is selected from the group consisting of wound or scabies healing, keloids, Sjogren's syndrome, sarcoidosis, allergies and allergic reactions including hypersensitivity reactions, such as type I hypersensitivity reactions (including, for example, anaphylaxis), type II hypersensitivity reactions (including, for example, Goodpasture's disease, autoimmune hemolytic anemia), type III hypersensitivity reaction disorders (including, for example, Arthus reaction, serum sickness), and type IV hypersensitivity reactions (including, for example, contact dermatitis, allograft rejection), and combinations thereof.

6. The pharmaceutical composition of claim 4 , which is administered in combination with another therapeutic agent.

7. 7. The pharmaceutical composition of claim 6, wherein the additional therapeutic agent is selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressant, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating an immunodeficiency disorder, and combinations thereof.

8. The pharmaceutical composition of claim 4, formulated for topical administration.

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