Substituted (7H-Pyrrolo[2,3-D]Pyrimidin-4-yl) Amino Compounds Useful as JAK1 Inhibitors

Abstract

The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof. The variables R, R 1 -R 3 and ring A are described herein. A can be a cyclohexyl ring. The compounds are inhibitors of JAK1 kinase and are useful in methods for treating allergic, inflammatory, or autoimmune diseases in patients, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a salt thereof. The present disclosure also provides formulations comprising the compound of formula I. TIFF2022545836000021.tif45150

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 891,706, filed August 26, 2019, the entire contents of which are incorporated herein by reference. Technical Field The present disclosure provides substituted (7H-pyrrolo-[2,3-D]pyrimidin-4-yl)amino compounds and pharma- ceutically acceptable salts thereof that are useful as JAK1 inhibitors. The present disclosure also provides pharmaceutical compositions and dosage forms that include such compounds. The present disclosure further provides methods of treating certain allergic, inflammatory, and autoimmune diseases using the (7H-pyrrolo-[2,3-D]pyrimidin-4-yl)amino compounds of the present disclosure. [Background technology]

[0002] Protein kinases are enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine kinases and serine / threonine kinases. Inappropriate kinase activity resulting from mutation, overexpression, or improper regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines, is implicated in many diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, and neurological and neurodegenerative disorders.

[0003] The JAK (Janus-associated kinase) family includes four non-receptor tyrosine kinases, JAK1, JAK2, JAK3 and Tyk2, which play important roles in cytokine signaling and growth factor-mediated signaling. Upon binding to their receptors, cytokines activate JAKs, which in turn phosphorylate cytokine receptors, thereby creating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family, ultimately resulting in gene expression. A number of cytokines are known to activate the JAK family.

[0004] JAK1 kinase interacts with, among others, type I interferon receptors (e.g., IFN alpha), type II interferon receptors (e.g., IFN gamma), common gamma chain γc (e.g., IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), and the interleukin-6 family (IL-10, IL-13 and IL-22). After binding of these cytokines to their receptors, receptor oligomerization occurs, bringing the cytoplasmic tails of the associated JAK kinases into close proximity and promoting phosphorylation and activation of tyrosine residues of the JAK kinases. The phosphorylated JAK kinases bind to and activate various STAT proteins. These STAT proteins then dimerize and translocate to the nucleus, where they function as both signaling molecules and transcription factors, ultimately binding to specific DNA sequences present in the promoters of cytokine-responsive genes. A variety of immunodeficiency and autoimmune diseases, such as allergy, asthma, alopecia areata, transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematological cancers, result from disruption of JAK / STAT pathway signaling.

[0005] A key element of JAK1 is its ability to pair with other JAK kinases at the intracellular domains of different subunits of the receptor. For example, JAK3 binds to the common γ chain (γc) of various cytokine receptors. JAK1 is dominant over JAK3, and inhibition of JAK1 has been shown to be sufficient to inactivate signaling through the common γ chain despite the activity of JAK3. Thus, selective inhibition of JAK1 may be sufficient to treat many inflammatory and autoimmune diseases associated with cytokine signaling through the JAK1 / JAK3-STAT pathway. Summary of the Invention [Problem to be solved by the invention]

[0006] To date, there are few selective JAK1 inhibitors with little or no off-target activity against other JAK kinases. Compounds identified as JAK1 selective inhibitors show only slight JAK1 selectivity. Therefore, there is a need to develop highly potent and selective JAK1 inhibitors for treating JAK1-associated disorders, including allergic, inflammatory, and autoimmune diseases. [Means for solving the problem]

[0007] overview The present disclosure relates to a compound represented by formula (I): [ka] Formula (I) and pharma- ceutically acceptable salts thereof.

[0008] In formula (I), the variables R, R 1 -R 3 and ring A have the following definitions: R is C optionally substituted with halogen, cyano, or amino. 1 -C 6 It is an alkyl. R 1 and R2 is hydrogen, C 1 -C 6 Alkyl, (C 3 -C 6 Cycloalkyl)C 0 -C 2 Alkyl, (phenyl)C 0 -C 2 Alkyl, and (4-6 membered heterocycle)C 0 -C 2 alkyl. R 3 is C 1 -C 4 The 4- to 6-membered heterocycle is saturated, partially unsaturated, or unsaturated and contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. One or more of the heteroatoms of the 4- to 6-membered heterocycle is O or S. Ring A: [ka] C having one or two heteroatoms independently selected from N, O, and S 3 -C 7 It is a cycloalkyl or a 4-6 membered heterocycloalkyl ring. For example, ring A can be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

[0009] [ka] Formula (IA) or a pharma- ceutically acceptable salt thereof.

[0010] In formula (I), the variables R, R 1 , and R 2 has the following definition: R is C optionally substituted with halogen, cyano, or amino. 1 -C 6 It is an alkyl. R1 and R 2 is hydrogen, C 1 -C 6 Alkyl, or (C 3 -C 6 Cycloalkyl)C 0 -C 2 alkyl.

[0011] The present disclosure also includes a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, in association with a pharma- ceutically acceptable excipient.

[0012] The present disclosure includes a method of treating an allergic, inflammatory, or autoimmune disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a salt thereof. The compound of formula (I) may be in the form of a formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description Terminology The compounds currently disclosed are described using standard nomenclature.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Unless clearly prohibited by context, each compound name includes the free acid or free base form of the compound, as all pharma-ceutically acceptable salts of the compound.

[0014] The phrase "compounds of formula (I)" includes all compounds satisfying formula (I), including any enantiomers, racemates and stereoisomers, and all pharma- ceutically acceptable salts of such compounds, and also includes all subgroups of formula (I), unless expressly contraindicated by the context in which the phrase is used. Formula (I) includes formula (IA) and formula (IB).

[0015] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The terms "comprise," "have," "include," and "contain" should be construed as open-ended terms (i.e., meaning "including, but not limited to"). The recitation of ranges of values ​​is intended to serve as a shorthand method of individually referring to each separate value falling within the range, unless otherwise stated herein, and each separate value is incorporated herein as if each were individually set forth herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to better illustrate and does not impose limitations on the scope of the disclosure unless otherwise asserted. No language in the specification should be construed as indicating any element not claimed as essential to the practice used herein. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] "Active agent" means a compound (including the compounds disclosed herein), element, or mixture that, when administered to a patient alone or in combination with other compounds, elements, or mixtures, imparts a direct or indirect physiological effect to the patient. An indirect physiological effect may occur via metabolism or other indirect mechanisms.

[0017] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CH 2 CF 3 is methylene (CH 2 ) group.

[0018] "Alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms, typically from 1 to about 8 carbon atoms. 1 -C 6 The term alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having 1-8 carbon atoms, 1-4 carbon atoms, or 1 or 2 carbon atoms, e.g., C 1 -C 8 Alkyl, C 1 -C 8 Alkyl, and C 1 -C 2 Contains an alkyl group having an alkyl group.

[0019] "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group having the indicated number of carbon atoms, typically from about 3 to about 8 carbon atoms. Monocyclic cycloalkyl groups usually have from 3 to about 6 ring atoms. 3 -C 6 Cycloalkyl refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Cycloalkyl groups include cycloalkyl groups that have no substituents. Cycloalkyl groups include cycloalkyl groups that have 1-4 alkyl substituents, e.g., 1, 2, 3, or 4 substituents. In some embodiments, cycloalkyl groups include cycloalkyl groups that have 3-6 carbon ring atoms and 0-2 alkyl substituents, e.g., (C 3 -C 6 Cycloalkyl)C 0 -C 2 Contains alkyl.

[0020] "Halo" or "halogen" means any of fluoro, chloro, bromo, and iodo.

[0021] The term "heterocycloalkyl" refers to a saturated ring group having 3 to 7 ring atoms, typically having 1 or 2 ring atoms independently selected from N, O, and S. Examples of heterocycloalkyl groups include azepine, azetidinyl, morpholinyl, pyranyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl, and tetrahydrofuran.

[0022] The term "heterocyclic group" refers to a cyclic group containing at least one ring heteroatom selected from N, O, and S. A heterocyclic group can be fully saturated, i.e., a heterocycloalkyl group, a partially unsaturated group, e.g., a heterocycloalkenyl group, or an aromatic group, e.g., a heteroaryl group. A heterocyclic group can contain one ring having 4-7 ring members and one, two, three, or four heteroatoms independently selected from N, O, and S. It is preferred that no more than two heteroatoms are O or S, and that the O and S atoms are not adjacent. A heterocyclic group can also contain two fused rings or two rings in a spiro orientation; only one ring of a two-ring heterocyclic group is required to contain a heteroatom.

[0023] The term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a selection from the specified group, provided that the normal valence of the specified atom is not exceeded. When the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. When an oxo group replaces an aromatic moiety, a corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted with oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure means a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent. Unless otherwise specified, the substituents are named on the core structure. For example, if an aminoalkyl is listed as a possible substituent, it should be understood that the point of attachment of this substituent to the core structure is on the alkyl moiety.

[0024] A "pharmaceutical composition" is a composition that contains at least one active agent, such as a compound or salt of formula (I), and at least one other substance, such as an excipient. A pharmaceutical composition meets the US FDA Good Manufacturing Practice (GMP) standards for human or non-human drugs.

[0025] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds, where the parent compound is modified by making its inorganic and organic, non-toxic, acid or base addition salts. The salts of the compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent, or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where feasible. The salts of the compounds further include solvates of the compounds and compound salts.

[0026] Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and, for example, quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 )n-COOH (where n is 0-4), and the like.

[0027] "Excipients" are generally inert ingredients that are safe, non-toxic, and not biologically or otherwise undesirable and are useful in preparing pharmaceutical compositions, and include excipients that are acceptable for veterinary and human pharmaceutical use.

[0028] The term "carrier" as applied to pharmaceutical compositions of the present disclosure refers to a diluent, excipient, or vehicle with which an active compound is provided. Excipients are generally inert ingredients that are safe, non-toxic, and not biologically or otherwise undesirable and are useful in preparing pharmaceutical compositions, and include excipients that are acceptable for veterinary and human pharmaceutical use.

[0029] A "patient" refers to a human or non-human animal in need of treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments, the patient is a human patient. In certain embodiments, the patient is a companion animal, such as a cat or dog, or a livestock animal, such as a horse, cow, or pig.

[0030] "Administering a compound of formula (I) with at least one additional active agent" means that the compound of formula (I) and the additional active agent are provided simultaneously in a single dosage form, provided simultaneously in separate dosage forms, or provided in separate dosage forms for administration separated by a time during which both the compound of formula (I) and the at least one additional active agent are in the patient's bloodstream. The compound of formula (I) and the additional active agent do not need to be prescribed to the patient by the same medical practitioner. The additional active agent(s) do not require a prescription. Administration of the compound of formula (I) or the at least one additional active agent can be via any suitable route, for example, oral tablet, oral capsule, oral liquid, inhalation, injection, suppository, or topical contact.

[0031] As used herein, "treatment" includes providing a compound of formula (I) as the sole active agent or together with at least one additional active agent sufficient to accomplish the following: (a) inhibiting the disease, i.e., arresting its onset; and (b) alleviating the disease, i.e., causing regression of the disease. "Treating" and "treatment" also mean providing a therapeutically effective amount of a compound of formula (I), as the sole active agent or together with at least one additional agent, to a patient having a bacterial infection.

[0032] The "therapeutically effective amount" of the compound or composition of formula (I) of the present disclosure means an amount effective to produce a therapeutic effect, such as an improvement in symptoms, when administered to a patient, for example, an amount effective to reduce symptoms of an inflammatory disorder. For example, a patient with an inflammatory condition may exhibit elevated levels of certain liver enzymes or elevated white blood cell counts. Thus, a therapeutically effective amount is an amount sufficient to provide a significant reduction in elevated liver enzyme levels or white blood cell counts, or an amount sufficient to return liver enzyme levels or white blood cell counts to normal ranges.

[0033] Chemical description Formula (I) includes all its subformulas. In certain circumstances, compounds of formula (I) may contain one or more asymmetric elements, such as a stereocenter, a stereocenter line, for example, an asymmetric carbon atom, so that the compounds can exist in different stereoisomeric forms. These compounds may be, for example, racemic or optically active forms. In the case of compounds with two or more asymmetric elements, these compounds may further be mixtures of diastereomers. It is understood that for compounds with asymmetric centers, all optical isomers and mixtures thereof are included. Furthermore, compounds with carbon-carbon double bonds may occur in Z and E forms, and all isomers of the compounds are included in the present disclosure. In these circumstances, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Separation of the racemates can also be accomplished by conventional methods, such as, for example, crystallization in the presence of a resolving agent or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column.

[0034] If a compound exists in various tautomeric forms, the present disclosure is not limited to any one particular tautomer, but rather includes all tautomers.

[0035] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C. 13 C, and 14 Contains C.

[0036] Certain compounds may be modified by the incorporation of variables such as R, R 1 , R 2 , and R 3The compounds are described herein using general formulas including: Unless otherwise specified, each variable within such formula is defined independently of other variables. Thus, if a group is said to be substituted with, for example, 0-2 R*, then that group may be substituted with up to 2 R* groups, with R* at each occurrence being selected independently of the definition of R*. Additionally, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0037] In addition to the compounds of formula (I) and (IA) described above, the present disclosure also includes compounds of formula (I) and (IA) in which one or more of the following conditions are met for the variables of formula (I) and (IA): Embodiments of the present disclosure include any combination of the conditions described below so long as a stable compound results. [ka] Formula (I) [ka] Formula (IA)

[0038] Compounds having any combination of the following variable definitions that result in a stable compound are included in the disclosure.

[0039] In formula (I) or (IA), R is a C optionally substituted with halogen, cyano, or amino. 1 -C 6 It is an alkyl.

[0040] In formula (I) or (IA), R 1 and R 2 , Hydrogen, C 1 -C 6 Alkyl, or (C 3 -C 6 Cycloalkyl)C 0 -C 2 alkyl.

[0041] The present disclosure also includes compounds having the stereochemistry of formula (Ia). [ka] Formula (IB)

[0042] In formula (IB), R is a C optionally substituted with halogen, cyano, or amino. 1 -C 6 It is an alkyl.

[0043] In formula (IB), R 1 and R 2 is hydrogen, C 1 -C 6 Alkyl, or (C 3 -C 6 Cycloalkyl)C 0 -C 2 alkyl.

[0044] Variable group R The present disclosure includes compounds and salts of any of the above formulas where R has any of the following definitions: (a) R is C optionally substituted with halogen, cyano, or amino. 1 -C 6 It is an alkyl. (b) R is C substituted with fluoro, chloro, bromo, or iodo. 1 -C 6 It is an alkyl. (c) R is a C substituted with cyano or amino. 1 -C 6 It is an alkyl. (d) R is methyl, propyl, isopropyl, butyl, pentyl, or hexyl. (e) R is methyl, propyl, isopropyl, butyl, pentyl, or hexyl substituted with fluoro, chloro, bromo, or iodo. (f) R is methyl, propyl, isopropyl, butyl, pentyl, or hexyl substituted with cyano or amino. (g) R is -CH 2CN or -CH 2 CF 3 It is.

[0045] Variable group R 1 This disclosure is based on 1 includes compounds and salts of any of the above formulae having any of the following definitions: (a)R 1 is hydrogen. (b)R 1 is C optionally substituted with halogen, cyano, or amino 1 -C 6 It is an alkyl. (c)R 1 is C substituted with fluoro, chloro, bromo, or iodo 1 -C 6 It is an alkyl. (d)R 1 is a C substituted with cyano or amino 1 -C 6 It is an alkyl. (e)R 1 is methyl, propyl, isopropyl, butyl, pentyl, or hexyl. (f)R 1 is methyl, propyl, isopropyl, butyl, pentyl, or hexyl substituted with fluoro, chloro, bromo, or iodo. (g)R 1 is methyl, propyl, isopropyl butyl, pentyl, or hexyl substituted with cyano or amino. (h)R 1 -CH 2 CN or -CH 2 CF 3 It is. (i)R 1 is optionally substituted with halogen, cyano, or amino (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (j)R 1is substituted with fluoro, chloro, bromo, or iodo (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (k)R 1 is substituted with cyano or amino (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (l)R 1 is C 3 -C 6 It is cycloalkyl. (m)R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (n)R 1 is hydrogen, C 1 -C 6 Alkyl, (C 3 -C 6 Cycloalkyl)C 0 -C 2 Alkyl, (phenyl)C 0 -C 2 Alkyl, (Tetrahydrofuranyl)C 0 -C 2 Alkyl, (Furanyl)C 0 -C 2 Alkyl, (pyrrolidinyl)C 0 -C 2 Alkyl, (pyrrolyl)C 0 -C 2 Alkyl, (thienyl)C 0 -C 2 Alkyl, (imidazolyl)C 0 -C 2 Alkyl, (oxazolyl)C 0 -C 2 Alkyl, (pyridinyl)C 0 -C 2 Alkyl, or (pyrazinylalkyl)C 0 -C 2 It is an alkyl. (o)R 1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with fluoro, chloro, bromo, or iodo. (p)R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with cyano or amino. (q)R 1 is (C 3 -C 6 Cycloalkyl)C 1 It is an alkyl. (r)R 1 is (C 3 -C 6 Cycloalkyl)C 2 It is an alkyl.

[0046] Variable group R 2 This disclosure is based on 2 includes compounds and salts of any of the above formulae having any of the following definitions: (a)R 2 is hydrogen. (b)R 2 is C optionally substituted with halogen, cyano, or amino 1 -C 6 It is an alkyl. (c)R 2 is C substituted with fluoro, chloro, bromo, or iodo 1 -C 6 It is an alkyl. (d)R 2 is a C substituted with cyano or amino 1 -C 6 It is an alkyl. (e)R 2 is methyl, propyl, isopropyl, butyl, pentyl, or hexyl. (f)R 2 is methyl, propyl, isopropyl, butyl, pentyl, or hexyl substituted with fluoro, chloro, bromo, or iodo. (g)R 2is methyl, propyl, isopropyl, butyl, pentyl, or hexyl substituted with cyano or amino. (h)R 2 -CH 2 CN or -CH 2 CF 3 It is. (i)R 2 is optionally substituted with halogen, cyano, or amino (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (j)R 2 is substituted with fluoro, chloro, bromo, or iodo (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (k)R 2 is substituted with cyano or amino (C 3 -C 6 Cycloalkyl)C 0 -C 2 It is an alkyl. (l)R 2 is C 3 -C 6 It is cycloalkyl. (m)R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (n)R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with fluoro, chloro, bromo, or iodo. (o)R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with cyano or amino. (p)R 2 is (C 3 -C 6 Cycloalkyl)C 1 It is an alkyl. (q)R 2 is (C 3 -C 6Cycloalkyl)C 2 It is an alkyl.

[0047] Pharmaceutical Compositions The compounds disclosed herein can be administered as neat chemicals, but are preferably administered as pharmaceutical compositions.Therefore, pharmaceutical compositions are provided herein that comprise the compound of formula (I) or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.The pharmaceutical composition can comprise the compound of formula (I) or a salt as the only active agent, or can comprise one or more additional active agents.

[0048] The compounds disclosed herein can be administered orally, topically, intravenously, intramuscularly, parenterally, by inhalation or spray, sublingually, transdermally, buccal administration, rectally, as eye drops, or by other means in dosage unit formulations containing conventional pharma- ceutically acceptable carriers. Pharmaceutical compositions can be formulated in any pharma- ceutically useful form, for example, as aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or eye drops. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of suitable size containing an appropriate amount of active ingredient, for example, an effective amount to achieve a desired purpose.

[0049] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated.Carriers can be inert or can have their own pharmaceutical benefits.The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0050] Types of carriers include, but are not limited to, binders, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.Some carriers may be listed in more than one category, for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations.Exemplary pharma-ceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oils.Any active agent may be included in the pharmaceutical composition, but does not substantially interfere with the activity of the compounds described herein.

[0051] The pharmaceutical compositions can be formulated for oral administration. These compositions contain 0.1-99% by weight (wt.%) of the compound of formula (I) of the present disclosure, typically at least about 5% by weight of the compound of formula (I) of the present disclosure. Some embodiments contain about 25% to about 50% by weight or about 5% to about 75% by weight of the compound of formula (I) of the present disclosure.

[0052] The disclosed compound can also be formulated for intravenous administration.The intravenous formulation of the compound of formula (I) can include one or more of the following: surface stabilizer (such as povidone or dextran), surfactant, preservative, pH adjuster, saline, or sucrose.The injectable or intravenous formulation of the disclosed compound of formula (I) can include 0.25mg / mL, 0.5mg / mL, 1mg / mL, 2mg / mL, 5mg / mL, 10mg / mL, or 15mg / mL.

[0053] Treatment method A method for treating an allergic, inflammatory, or autoimmune disease in a patient includes administering a therapeutically effective amount of a compound of the present invention. The compounds described herein may be provided as the sole active agent or may be provided together with one or more additional active agents.

[0054] In some embodiments, the method of treating pruritus, allergic dermatitis, eczema, or psoriasis in a patient comprises administering a therapeutically effective amount of a compound of the present disclosure.

[0055] The compounds of formula (I) or pharma-ceutically acceptable salts and pharmaceutical compositions thereof can be used to treat a variety of conditions, such as: allergic reactions such as mammalian allergic dermatitis, including equine allergic diseases such as bite hypersensitivity, summer eczema, and equine skin pruritus; Arthritis, such as rheumatoid arthritis, juvenile arthritis and psoriatic arthritis;

[0056] Asthma and other obstructive airways diseases, such as chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstructive pulmonary disease;

[0057] For example, those designated as single-organ or single-cell type autoimmune diseases such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, pernicious anemia autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic progressive hepatitis, ulcerative colitis and membranous nephropathy; for example, systemic lupus erythematosus, rheumatoid arthritis, Sjoegren's disease, and other autoimmune disorders. Autoimmune diseases or disorders such as Renn's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, as well as those designated as involving a systemic autoimmune disease such as Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile diabetes mellitus, and additional autoimmune diseases that may be O-cell (humoral) or T-cell system, such as thyroiditis;

[0058] cancers or tumors such as gastrointestinal / gastrointestinal cancer, colon cancer, liver cancer, skin cancer including mast cell tumors and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemias such as acute myeloid leukemia and chronic myeloid leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myeloma including multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, and angiogenesis-related disorders including solid tumors; diabetes, including type I diabetes and diabetic complications;

[0059] Ocular diseases, disorders or conditions such as autoimmune diseases of the eye, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukemia, ocular pemphigoid, Mooren's ulcer, scleritis, Graves' disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenosis, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, and ocular neovascularization;

[0060] enteritis, allergies or conditions such as Crohn's disease and / or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, and mastocytosis;

[0061] Neurodegenerative diseases such as motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative diseases caused by trauma, stroke, glutamate neurotoxicity or hypoxia; ischemic / reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and platelet aggregation;

[0062] Skin diseases, conditions or disorders, such as atopic dermatitis, allergic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; and

[0063] islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease; organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and graft rejection such as xenografts.

[0064] The compounds of the invention are JAK inhibitors with selective potency against JAK1. In some embodiments, greater than 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% of JAK1 activity is inhibited in a human or non-human patient.

[0065] In certain embodiments, compounds of the present disclosure preferentially inhibit the activity of JAK1 over the activity of JAK2. For example, preferential inhibition can be greater than or equal to the IC 50 IC of JAK1 inhibition against 50 The JAKl / JAK2 potency ratio can be measured by the JAKl / JAK2 potency ratio, which is defined as the inverse ratio of the IC of JAKl and / or JAK2 inhibition. In certain embodiments, the JAKl / JAK2 potency ratio is at least 30, 35, 40, 45, 50, 55, 60, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 85 or more. In other embodiments, the JAKl / JAK2 potency ratio is about 30 to about 85, about 40 to about 85, about 50 to about 85, about 60 to about 85, or about 70 to about 85. In some embodiments, the IC of JAKl and / or JAK2 inhibition is 50 is measured by enzyme assay. In certain embodiments, the IC 50 is measured, for example, by inhibition of IL6-stimulated STAT3 phosphorylation ex vivo using a sample (e.g., a blood sample) from a subject administered a compound of formula (I). In certain embodiments, the IC 50 is measured, for example, by inhibition of EPO-stimulated STAT5 phosphorylation ex vivo using a sample (eg, a blood sample) from a subject administered a compound of formula (I).

[0066] In certain embodiments, the compounds of the present disclosure preferentially inhibit the activity of JAK1 over the activity of JAK3. For example, preferential inhibition can be greater than or equal to the IC 50 IC of JAK1 inhibition against 50 The JAKl / JAK3 potency ratio can be measured by the JAKl / JAK3 potency ratio, which is defined as the inverse ratio of the IC of JAKl and / or JAK3 inhibition. In certain embodiments, the JAKl / JAK3 potency ratio is at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 56, 57, 58, 59, 60, 65, 70 or more. In other embodiments, the JAKl / JAK3 potency ratio is about 3 to about 70, about 10 to about 70, about 20 to about 70, about 30 to about 70, about 40 to about 70, about 50 to about 70, or about 60 to about 70. In some embodiments, the IC of JAKl and / or JAK3 inhibition is 50 is measured by enzyme assay. In certain embodiments, the IC 50 is measured, for example, by inhibition of IL6-stimulated STAT3 phosphorylation ex vivo using a sample (e.g., a blood sample) from a subject administered a compound of formula (I). In certain embodiments, a patient (e.g., a human) is in need of treatment for a condition treatable by inhibition of JAK1 activity. In certain embodiments, the condition is treatable by inhibition of JAK1 activity in a patient (e.g., a human). Such conditions may include inflammatory diseases / disorders, or autoimmune diseases / disorders.

[0067] The pharmaceutical compositions disclosed herein are useful for treating human and non-human patients, including, for example, livestock and companion animals.

[0068] An effective amount of the pharmaceutical composition provided by the present disclosure may be an amount sufficient to accomplish the following: (a) cause regression of the disorder; or (b) cause healing of the disorder; (c) reduce the severity of at least one symptom of the disorder; or (d) significantly reduce the likelihood of an asymptomatic patient at risk of the disorder from developing symptoms of the disorder, or significantly reduce the severity of the symptoms of the disorder if the disorder occurs. The amount of the pharmaceutical composition required to inhibit progression or cause regression of the disorder includes an amount effective to stop the worsening of the symptoms or reduce the symptoms experienced by the affected patient. Alternatively, the halt in progression or regression of inflammatory or allergic symptoms may be indicated by any of several markers of the disease.

[0069] The method of treatment includes providing a patient with a particular dosage of a compound of formula (I). Dosage levels of about 0.1 mg to about 140 mg per kg of body weight per day of each active agent are useful in treating the above conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration. In certain embodiments, 25 mg to 500 mg, or 25 mg to 200 mg of a compound of formula (I) is administered to a patient daily. The frequency of administration can also vary depending on the compound used and the particular disease being treated. However, for the treatment of most allergic, inflammatory, or autoimmune diseases, a dosing regimen of four times per day or less is preferred, with a dosing regimen of once or twice per day being particularly preferred.

[0070] However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the particular disease in the patient being treated. EXAMPLES

[0071] Abbreviation ACN Acetonitrile DCM Dichloromethane DIPEA N,N-Diisopropylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) IS internal standard

[0072] General method Reagents and solvents are of standard commercial grade. They are used without further purification unless purification is specifically mentioned in the examples. The following reaction schemes show the general synthetic procedures for the compounds of the present disclosure. All starting materials are prepared by the procedures described in these schemes or by procedures known to those skilled in the art.

[0073] 1H NMR (400 MHz) spectra were recorded on a Bruker spectrometer at room temperature using TMS or residual solvent peaks as internal standards. Line positions or multiples are indicated (δ) and coupling constants (J) are given as absolute values ​​in Hertz (Hz). Multiplicities in 1H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).

[0074] LC-MS was performed on a Shimadzu LCMS-2020 equipped with an LC-20AD or 30AD pump, an SPD-M20A PDA and an Alltech 3300 ELSD; mobile phase: A: water (0.1% formic acid), B: ACN; 5 min run; column: Sepax BR-C 1 8 4.6 × 50 mm, 3 μm; flow rate: 1.0 ml / min; oven temperature: 40 °C; gradient: 20% B for 0.2 min, increasing to 70% B within 1.8 min, 70% B for 2.8 min, returning to 20% B within 0.2 min, 20% B for 2 min.

[0075] Example 1: Synthesis of Compounds Compounds 1 to 4 were synthesized according to Scheme I.

[0076] Scheme I [ka]

[0077] Synthesis of Compound B To a stirred solution of compound A (2.25 g, 9.89 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (2.55 g, 19.78 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.19 g, 10.38 mmol). The mixture was stirred at 80° C. overnight. TLC showed the reaction was complete. Water was added to the reaction mixture and it was extracted with ethyl acetate (50 ml). The organic layer was washed with brine (3×40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with a 5% solution of ethyl acetate in hexane (50%) and dichloromethane (50%)) to give compound B (2.7 g, 56% yield) as a white solid. 1H NMR (400 MHz, CDCl3):δ 1.27-1.38(m, 4H), 1.45(s, 9H), 1.76-1.79(m, 2H), 2.06-2.12(m, 2H), 2.38(s, 3H), 3.13(s, 3H), 3.40-3.45(m, 1H), 4.40-4.42(m, 1H), 4.66-4.72(m, 1H), 6.60(d, J=4.4 Hz, 1H), 7.26(s, 1H), 7.29(s, 1H), 7.44(d, J=4.0 Hz, 1H), 8.05(d, J=8.4 Hz, 2H), 8.37(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value: C 25 H 33 N 5 O4S: 499.23. Actual value: 500.5.

[0078] Synthesis of compound C To a stirred solution of compound B (2.7 g, 5.41 mmol) in methanol (50 ml) was added lithium hydroxide monohydrate (2.27 g, 54.1 mmol). The mixture was stirred at 50° C. overnight. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. Water was added (10 ml) and the mixture was adjusted to pH=6.0 with 2M hydrochloric acid, filtered and the solid collected. The solid was washed with diethyl ether (20 ml) and dried to give compound B (1.53 g, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6):δ 1.29-1.36(m, 2H), 1.39(s, 9H), 1.63-1.75(m, 4H), 1.86-1.89(m, 2H), 3.1 5(s, 3H), 3.27-3.30(m, 1H), 4.66-4.68(m, 1H), 6.52(s, 1H), 6.73(d, J=8.0 Hz, 1H), 7.10-7.12(m, 1H), 8.08(s, 1H), 11.58(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 18 H 27 N 5 O 2 :345.22. Actual value:346.3.

[0079] Synthesis of Compound D To a solution of compound C (1.53 g, 4.43 mmol) in 4 M hydrochloric acid in methanol (60 ml). The resulting mixture was stirred at 50° C. overnight. TLC showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The solid was washed with diethyl ether (20 ml) and dried to give compound D (960 mg, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6):δ 1.65-1.72(m, 2H), 1.84-1.89(m, 4H), 2.08-2.10(m, 2H), 3.08-3.09(m, 1H), 3.34(s, 3H), 4.4 6-4.54(m, 1H), 6.89(s, 1H), 7.47(s, 1H), 8.28-8.35(m, 3H), 12.88(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 13 H 19 N 5 :345.16. Actual value:245.9.

[0080] Synthesis of 1 To a stirred solution of compound D (150 mg, 0.61 mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml) was added N,N-diisopropylethylamine (393.4 mg, 3.05 mmol) and methylcarbamic acid chloride (70.7 mg, 0.73 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC indicated completion of the reaction. The resulting mixture was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluting with 8% dichloromethane in methanol) to give 1 (83.3 mg, 45% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.31(m, 2H), 1.64-1.72(m, 4H), 1.89-1.92(m, 2H), 2.54(d, J=4.4 Hz, 3H), 3.16(s, 3H), 3.38-3.42(m, 1H), 4.68(s, 1H), 5.59-5.63(m, 1H), 5.73(d, J=8.0 Hz, 1H), 6.52-6.53(m, 1H), 7.10-7.12(m, 1H), 8.08(s, 1H),11.58(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 15 H 22 N 6 O: 302.19. Measured value: 302.9.

[0081] Synthesis of 2 To a stirred solution of compound D (145 mg, 0.59 mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml) was added N,N-diisopropylethylamine (380.6 mg, 2.95 mmol) and isocyanatoethane (62 mg, 0.88 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. Water (15 ml) was added to the resulting mixture and filtered to collect the solid. The solid was washed with diethyl ether (20 ml) and dried to give 2 (105.5 mg, 56% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ0.98(t, J=7.2 Hz, 3H), 1.23-1.33(m, 2H), 1.64-1.78(m, 4H), 1.89-1.93(m, 2H), 2.97-3.03(m, 2H), 3.16( s, 3H), 3.36-3.43(m, 1H), 4.68(s, 1H), 5.64-5.70(m, 2H), 6.52-6.53(m, 1H), 7.11(t, J=2.8 Hz, 1H), 8.08(s, 1H),11.58(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 16 H 24 N 6 O: 316.2. Actual value: 317.0.

[0082] Synthesis of 3 To a stirred solution of compound D (150 mg, 0.61 mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml) was added N,N-diisopropylethylamine (393.4 mg, 3.05 mmol) and 1-isocyanatopropane (78 mg, 0.92 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. Water (15 ml) was added to the resulting mixture, which was filtered to collect the solid. The solid was washed with diethyl ether (20 ml) and purified by silica gel chromatography (eluted with 7% dichloromethane in methanol) to give 3 (105.3 mg, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.83(t, J=7.2 Hz, 3H), 1.24-1.30(m, 2H), 1.34-1.41(m, 2H), 1.64-1.75(m, 4H), 1.90-1.93(m, 2H), 2.91-2.96(m, 2H), 3.16(s, 3H), 3.36-3.42(m, 1H), 4.68-4.70(m, 1H), 5.65(d, J=8.0 Hz, 1H), 5.72-5.76(m, 1H), 6.52-6.54(m, 1H), 7.10-7.12(m, 1H), 8.08(s, 1H),11.58(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 17 H 26 N 6 O: 330.22. Measured value: 331.3.

[0083] Synthesis of 4 To a stirred solution of compound D (130 mg, 0.53 mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml) was added N,N-diisopropylethylamine (341.8 mg, 2.65 mmol) and 2-isocyanatopropane (54 mg, 0.64 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. Water (15 ml) was added to the resulting mixture, which was filtered to collect the solid. The solid was washed with diethyl ether (20 ml) and purified by silica gel chromatography (eluting with 7% dichloromethane in methanol) to give 4 (103.5 mg, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.02 (d, J=6.4 Hz, 6H), 1.21-1.32(m, 2H), 1.64-1.74(m, 4H), 1.90-1.93(m, 2H), 3.16(s, 3H), 3.37-3.41(m, 1H), 3.63-3.68(m, 1H) , 4.68(s, 1H), 5.54-5.57(m, 2H), 6.52-6.53(m, 1H), 7.10-7.12(m, 1H), 8.08(s, 1H),11.57(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 17 H 26 N 6 O: 330.22. Measured value: 331.3.

[0084] Compound 5 was synthesized according to Scheme II.

[0085] Scheme II [ka]

[0086] Synthesis of compound E To a stirred solution of 2-aminoacetonitrile hydrochloride (1 g, 10.87 mmol) in N,N-dimethylformamide (20 ml) was added a solution of pyridine (1.03 g, 13.04 mmol) and 4-nitrophenyl carbonochloridate (2.6 g, 13.04 mmol) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at 0° C. for 15 min and continued to stir at room temperature overnight. TLC showed the reaction was complete. Water was added to the reaction mixture and extracted with ethyl acetate (80 ml). The organic layer was washed with brine (3×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 10%-30% ethyl acetate in hexanes) to give compound E (500 mg, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.26 (d, J=6.0 Hz, 2H), 7.46-7.48 (m, 2H), 8.28-8.30 (m, 2H), 8.81-8.24 (m, 1H).

[0087] Synthesis of 5 To a stirred solution of compound D (250 mg, 1.02 mmol) in N,N-dimethylformamide (5 ml) was added N,N-diisopropylethylamine (658 mg, 5.10 mmol) and 4-nitrophenyl(cyanomethyl)carbamate (88% purity by 1H NMR) (306 mg, 1.22 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 7% dichloromethane in methanol) to give 5 (118.9 mg, 35% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ1.26-1.38(m, 2H), 1.65-1.76(m, 4H), 1.91-1.94(m, 2H), 3.16(s, 3H), 3.42-3.46(m, 1H), 4.03(d, J=6.0 Hz, 2H), 4.69(s, 1H), 6.26(d, J=7.6Hz, 1H), 6.35(d, J=6.0Hz, 1H), 6.53-6. 54(m, 1H), 7.11-7.12(m, 1H), 8.09(s, 1H), 11.59(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 16 H 21 N 7 O: 327.18. Measured value: 328.3.

[0088] Compound 6 was synthesized according to Scheme III. Scheme III [ka]

[0089] Synthesis of compound F To a stirred solution of 2,2,2-trifluoroethanamine (1 g, 10.10 mmol) in ethyl acetate (50 ml) was added a solution of trimethylamine (255 mg, 2.52 mmol) and triphosgene (1.49 g, 5.05 mmol) in ethyl acetate (10 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, continued stirring at room temperature for 1 h, and refluxed for 5 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude compound F (1 g, crude material) as a yellow oil.

[0090] Synthesis of 6 To a stirred solution of compound D (250 mg, 1.02 mmol) in N,N-dimethylformamide (20 ml) was added N,N-diisopropylethylamine (526 mg, 4.08 mmol) and 1,1,1-trifluoro-2-isocyanatoethane (191 mg, 1.53 mmol). The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluted with 7% dichloromethane in methanol) to give 6 (107.2 mg, 28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6):δ 1.26-1.36(m, 2H), 1.66-1.77(m, 4H), 1.92-1.94(m, 2H), 3.16(s, 3H), 3.43-3.45(m, 1H), 3.77-3.86(m, 2H), 4.68(s, 1H), 6.07(d, J=8.0 Hz, 1H), 6.35-6.39(m, 1H), 6.55(s, 1H), 7.13-7.14(m, 1H), 8.10(s, 1H), 11.63(s, 1H);LC-MS:(ES+):m / z [M+H] + Calculated value:C 16 H 21 F 3 N 6 O: 370.17. Measured value: 371.3.

[0091] The following compounds of formula (I) (in Table 1) were prepared by the methods shown in Schemes I-III. [Table 1] [Table 2]

[0092] Example 2: Potency against JAK family kinases A. JAK1, JAK2, and JAK3 enzyme assays IC of JAK1 versus JAK2 50 The JAK1 / JAK2 potency ratio, defined as the inverse ratio of the IC of JAK1 to JAK3, is at least about 30, and in some cases is 50-85 or more. 50 The JAKl / JAK3 potency ratio, defined as the inverse ratio of JAK1 to JAK3, is at least about 3, and in some cases is 40-70 or more.

[0093] Assay results show IC 50 The values ​​shown are very low, demonstrating the selectivity of compounds of formula (I) for JAK1 over JAK2 and JAK3, and providing a basis for determining whether a more selective biochemical profile by sparing JAK2 or JAK-dependent cellular pathways translates into an improved clinical profile.

[0094] The JAK enzyme assay used the following reagents: JAK1 (BPS Bioscience, San Diego, CA Catalog No. 40449) JAK2 (Carna Bio, USA, Inc. Natick, MA, Catalog No. 08-045) JAK3 (Carna Bio, USA, Inc. Natick, MA, Catalog No. 08-046) TYK2 (Carna Bio, USA, Inc. Natick, MA, Catalog No. 08-147) Peptide FAM-P22 (GL Biochem, Catalog No. 112393) Peptide FAM-Pep D (GL Biochem, Cat. No. 358783) Peptide FAM-P30 (GL Biochem, Cat. No. 263631) ATP (Millipore Sigma, Catalog No. A7699-1G, CAS No. 987-65-5) DMSO (Millipore Sigma, Cat. No. D2650) EDTA (Millipore Sigma, Cat. No. E5134, CAS No. 60-00-4) Brij-35 [Sigma, Catalog No. B4184] 96-well plates (Corning, Corning, NY, Cat. No. 3365) 384-well plate (Corning, Corning, NY, Cat. No. 3573) Oclacitinib [HUIFEIChem(WuXi)PharmaTech Co. Ltd., Batch No.: D0228-W-0814-1] Tofacitinib (Med Chem Express, Monmouth Junction, NJ, catalog number HY-40354) Filgotinib [MCE, Catalog No. HY-18300]

[0095] 1. Preparation of Assay Plates Each sample or reference compound was diluted in DMSO to 50x the highest desired inhibitor concentration. Each sample or reference compound was serially diluted using a 96-well source plate to give 10 concentrations for testing. 10 μL from each well of the source plate was transferred to a 96-well intermediate plate. To each well of the intermediate plate, 90 μL of 1x kinase buffer (50 mM HEPES, pH 7.5, 0.0015% Brij-35) was added and the intermediate plate was shaken on a shaker for 10 minutes. 5 μL from each well of the 96-well intermediate plate was transferred to a 384-well plate.

[0096] Kinase reaction 10 μL of 2.5x enzyme solution (enzyme in 1x kinase base buffer) was added to each well of the assay plate. The assay plate was incubated at room temperature for 10 minutes. 10 μL of 2.5x peptide solution (FAM-labeled peptide and ATP in 1x kinase base buffer) was added to each well of the assay plate. The kinase reaction proceeded for 60 minutes at 28°C, followed by the addition of 25 μL of stop buffer. Data was collected using the CALIPER program. The converted data from the CALIPER program were converted to inhibition values ​​as follows: % Inhibition = (Maximum Conversion) / (Maximum - Minimum) x 100. The term "Maximum" refers to the DMSO control and "Minimum" refers to the low control. Curve fitting of the data was performed using Xlfit excel add-in version 5.4.0.8 to obtain IC 50 The values ​​were obtained. The formula used was Y=Bottom+(Top-Bottom) / (1+(LogIC50 / X)^HillSlope. The peptide substrates, peptide concentrations, enzyme concentrations, and ATP concentrations used for each kinase are shown in Table 2. [Table 3]

[0097] The results are shown in Table 3. [Table 4]

[0098] Oclacitinib, tofacitinib, and filgotinib were used as reference compounds. [ka]

[0099] As shown in Table 3, oclacitinib showed similar activity against JAK1 and JAK2, tofacitinib inhibited JAK1, JAK2, and JAK3 similarly, and filgotinib showed selectivity for JAK1 and JAK2 over JAK3. Among the reference compounds, with regard to JAK1 / JAK2 selectivity, only oclacitinib showed selectivity for JAK1 / JAK2 (i.e., 45%). Tofacitinib and filgotinib were not selective for JAK1 / JAK2. Advantageously, compounds 1-6 showed superior selectivity for JAK1 over JAK2 (i.e., 87%, 2.9-fold, 3.7-fold, 3.35-fold, 2.4-fold, and 6-fold, respectively). With regard to the JAK1 / JAK3 selectivity of the reference compounds, oclacitinib and filgotinib showed selectivity for JAK1 over JAK3 (i.e., 10.6-fold and 21-fold, respectively), while tofacitinib showed selectivity for JAK3 over JAK1. The selectivity of compounds 1-6 for JAK1 over JAK3 was significantly improved over the reference compounds (i.e., 3.96-fold, 10.4-fold, 10.9-fold, 15.4-fold, 3.5-fold, and 18.3-fold, respectively). Of the reference compounds, only oclacitinib was selective for JAK1 over both JAK2 and JAK3 (i.e., 45% and 10.6-fold, respectively). Surprisingly and unexpectedly, compounds 1-6 were selective for JAK1 over JAK2 and JAK1 over JAK3, showing superior values ​​compared to the reference compounds.

[0100] Example 3: Metabolic Stability Assay Stock solutions of sample and reference compounds were prepared in DMSO (10 mM). Spike solutions (500 μM) for each sample and reference compound were prepared by diluting 10 μL of the stock solution with ACN (190 μL). Microsome spike solutions with a microsome concentration of 0.75 mg / mL were prepared for each sample: 1.5 μL of the respective 500 μM spike solution was mixed with 18.75 μL of microsome solution (pooled liver microsomes, 20 mg / mL in 250 mM sucrose, Corning, Cat. No. 452601, Lot No. 8176003) and 479.75 μL of buffer (0.1 M potassium phosphate buffer, 1.0 mM EDTA, pH 7.4). The microsome spike solutions were cooled on ice. An assay plate with wells designated for the different time points (0, 5, 15, 30 and 45 min) was cooled on ice. Thirty microliters of each microsomal spike solution was added to the designated wells for different time points (0, 5, 15, 30, and 45 min). 135 uL of ACN containing IS was placed in the wells of the plate labeled as 0 min, followed by 15 uL of NaDPH stock solution (6 mM NaDPH, 1.0 mM EDTA, pH 7.4 in 0.1 M potassium phosphate buffer). The rates for 5, 15, 30, and 45 min were incubated at 37°C for 5 min. At 5, 10, 30, and 45 min, 135 uL of ACN containing IS was added to the corresponding wells of the plate to quench the reaction. The plate was shaken for 10 min [IKA vibrator, MTS 2 / 4] and centrifuged at 5594G for 15 min (Thermo Multifuge x 3R). 50 uL of the supernatant from each well was transferred to a 96-well sample plate containing 50 uL of ultrapure water (Millipore, ZMQS50F01) for LC-MS analysis.

[0101] [Table 5]

[0102] In the metabolic stability assay, oclacitinib and ketanserin were used as reference compounds. The microsomal assay primarily evaluates metabolism by the cytochrome P450 system (phase I enzymes). As shown in Table 4, compounds 3, 5, and 6 had dramatically improved half-lives compared to the reference compounds. Thus, compounds 3, 5, and 6 are less vulnerable to first-pass metabolism by the liver compared to the reference compounds.

Claims

1. Formula (I): 【Chemistry 1】 Formula (I) [In the formula, R is C optionally substituted with halogen, cyano, or amino. 1 -C 6 is alkyl; R 1 and R 2 is hydrogen, C 1 -C 6 Alkyl, (C 3 -C 6 Cycloalkyl)C 0 -C 2 Alkyl, (phenyl)C 0 -C 2 Alkyl, and (4- to 6-membered heterocycle)C 0 -C 2 independently selected from alkyl; R 3 is C 1 -C 4 is alkyl; and Ring A: 【Chemistry 2】 is a C 3 -C 7 cycloalkyl or a 4-6 membered heterocycloalkyl ring having 1 or 2 heteroatoms independently selected from N, O, and S. or a pharma- ceutically acceptable salt thereof.

2. 2. The compound or salt of claim 1, wherein Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

3. Formula (IA): 【Chemistry 3】 Formula (IA) [In the formula, R is C optionally substituted with halogen, cyano, or amino. 1 -C 6 is alkyl; and R 1 and R 2 is hydrogen, C 1 -C 6 Alkyl, or (C 3 -C 6 Cycloalkyl)C 0 -C 2 alkyl, independently selected from 2. The compound according to claim 1, wherein:

4. R is methyl, ethyl, propyl, isopropyl, -CH 2 CN, or -CH 2 CF 3 4. The compound or salt of claim 3,

5. R 1 and R 2 The compound or salt according to any one of claims 1 to 4, wherein both of are hydrogen.

6. The compound of formula (I) may be represented by formula (IB): 【Chemistry 4】 Formula (IB) The compound or salt according to any one of claims 1 to 4, which is a compound having the stereochemistry:

7. R 1 and R 2 The compound or salt according to any one of claims 1 to 4 or claim 6, wherein at least one of is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

8. R 1 and R 2 At least one of 3 -C 6 8. The compound or salt according to any one of claims 1 to 4 or claims 6 to 7, which is cycloalkyl.

9. R 1 and R 2 At least one of (C 3 -C 6 Cycloalkyl)C 1 8. The compound or salt according to any one of claims 1 to 4 or claims 6 to 7, which is alkyl.

10. R 1 and R 2 At least one of (C 3 -C 6 Cycloalkyl)C 2 8. The compound or salt according to any one of claims 1 to 4 or claims 6 to 7, which is alkyl.

11. The compound or salt of claim 6, wherein R 1 and R 2 are both hydrogen.

12. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 11, together with a pharma- ceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is an aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or eye drops.

14. The pharmaceutical composition according to claim 12 or 13, wherein the pharmaceutical composition comprises from about 0.1 to about 99% by weight (wt.%) of the compound or salt.

15. A pharmaceutical composition for treating an allergic, inflammatory, or autoimmune disease in a patient, comprising a therapeutically effective amount of a compound or salt according to any one of claims 1 to 11.

16. 16. The pharmaceutical composition of claim 15, wherein the allergic, inflammatory, or autoimmune disease is pruritus, allergic dermatitis, eczema, or psoriasis.

17. 16. The pharmaceutical composition of claim 15, wherein the allergic, inflammatory, or autoimmune disease is an allergic reaction, arthritis, asthma, obstructive airways disease, cancer, diabetes, eye disease, enteritis, neurodegenerative disease, skin disease, or transplant reaction.

18. 18. The pharmaceutical composition according to any one of claims 15 to 17, wherein the pharmaceutical composition is administered orally, topically, intravenously, intramuscularly, parenterally, by inhalation or spray, sublingually, transdermally, buccally, rectally, or as eye drops.

19. 18. The pharmaceutical composition of any one of claims 15 to 17, wherein the compound or salt has a JAKl / JAK2 potency ratio of at least 30.

20. The pharmaceutical composition of any one of claims 15 to 18, wherein the compound or salt has a JAKl / JAK3 potency ratio of at least 3.

21. The pharmaceutical composition according to any one of claims 15 to 20, wherein the patient is a human.

22. The pharmaceutical composition according to any one of claims 15 to 20, wherein the patient is a companion animal or a livestock animal.

23. 21. A method of treating an allergic, inflammatory, or autoimmune disease in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 12 to 20, wherein the patient is a companion animal or a livestock animal.

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