Pyrrolopyrimidine ITK inhibitors

Abstract

To provide methods or compositions for treating ITK (Interleukin-2 inducible T-cell kinase)-mediated disorders.SOLUTION: There are provided compounds and compositions useful in the treatment of ITK mediated diseases, such as inflammation, having the structures of Formulas (I)-(IV), wherein: X is N or CR3; n is 0, 1 or 2; m is 0, 1, or 2; R1 is selected from COOR6, C1 to C5 alkyl-COOR6, bicycloalkyl, C1 to C5-alkyl-heterocyclyl, or the like; and R2 to R6 are each selected from H, CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, or the like.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 717,400, filed August 10, 2018, which is incorporated by reference herein in its entirety for all purposes. The present disclosure relates to novel pyrrolopyrimidine compounds and compositions and their use as pharmaceuticals for the treatment of disease. [Background technology]

[0002] The present disclosure relates to novel pyrrolopyrimidine compounds and compositions and their use as pharmaceuticals for the treatment of disease. Summary of the Invention [Problem to be solved by the invention]

[0003] The present disclosure relates to novel pyrrolopyrimidine compounds and compositions, and their use as pharmaceuticals for the treatment of diseases. Disclosed herein are compounds, pharmaceutical compositions of such compounds, methods of making and using such compounds. Methods for inhibiting ITK activity in a human or animal subject are also provided for the treatment of diseases, such as those caused by inflammation. [Means for solving the problem]

[0004] Embodiments are directed to the compounds disclosed herein, pharmaceutical compositions of such compounds, methods of making and methods of using such compounds, as described herein. Some embodiments disclosed herein are directed to compounds of formula (I) and derivatives thereof:

[0005] [ka] (I) (In the formula, X is N or CR3; n is 0, 1 or 2; m is 0, 1 or 2; R1 is selected from COOR6, C1-C5 alkyl-COOR6, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR6 or C1-C5-alkyl-COOR6; R2 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, CN, OH, C1-C5 alkoxy and halogen, and two R2 groups on the same carbon may be linked with or without a heteroatom to form a spirocyclic ring system; R3 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R4 is selected from H, C1-C6 alkyl; R5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl; R6 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH-C1-C5 alkyl, and C1-C5 alkyl-N-(C1-C5 alkyl)(C1-C5 alkyl);

[0006] Some embodiments disclosed herein are directed to compounds of formula (II) and derivatives thereof: [ka] (In the formula, X is N or CR 23 and n is 0, 1 or 2; m is 0, 1 or 2; R 21 COOR 26 , C1-C5 alkyl-COOR 26 , bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 26 , or C1-C5-alkyl-COOR 26 and optionally substituted with one or more groups selected from R 22 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, CN, OH, C1-C5 alkoxy, halogen, and two R2 groups on the same carbon may be linked with or without a heteroatom to form a spirocyclic ring system; R 23 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 24 is selected from H, C1-C6 alkyl; R 25is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl; R 26 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0007] Some embodiments disclosed herein are directed to compounds of formula (III) and derivatives thereof: [ka] (In the formula, X is CR 33 or N, n is 1 or 2, When n is 1, m is 0, 1, or 2; when n is 2, m is 1; R 31 COOR 36 , C1-C5 alkyl-COOR 36 , bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 36 , or C1-C5-alkyl-COOR 36 and optionally substituted with one or more groups selected from R 32is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, R 33 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 34 is selected from H, C1-C6 alkyl; R 35 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-NH, C-C alkylNH(C-C alkyl), C-C alkyl-N(C-C alkyl)(C-C alkyl), C-C alkyl-C-C alkoxy; R 36 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0008] Some embodiments disclosed herein are directed to compounds of formula (IV) and derivatives thereof: [ka] (In the formula, X is CR 43 or N, n is 1 or 2, When n is 1, m is 0, 1, or 2; when n is 2, m is 1; R 41 COOR 46 , C1-C5 alkyl-COOR 46, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 46 , or C1-C5-alkyl-COOR 46 and optionally substituted with one or more groups selected from R 42 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, R 43 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 44 is selected from H, C1-C6 alkyl; R 45 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy; R 46 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0009] In some embodiments, the compounds disclosed herein may possess useful ITK inhibitory activity. Some embodiments herein are directed to using the compounds disclosed herein to treat or prevent diseases or conditions in which ITK plays an active role. In some embodiments, a method for treating an ITK-mediated disease or disorder in a subject comprises administering to the subject a compound of an embodiment herein. Some embodiments provide a method for treating an ITK-mediated disorder in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound or composition according to the present disclosure. Also provided is the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by inhibition of ITK. DETAILED DESCRIPTION OF THE INVENTION

[0010] definition Before describing the compositions and methods of the present invention, it should be understood that the invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It should also be understood that the terminology used in this description is for the purpose of describing particular versions or embodiments only, and is not intended to limit the scope of the embodiments herein, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill 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 mentioned 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 virtue of prior invention.

[0011] 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 an "ITK inhibitor" is a reference to one or more ITK inhibitors and equivalents thereof known to those skilled in the art, and so forth. The term "about," as used herein, is intended to qualify the numerical value it modifies and to express such value as variable within a margin of error. Unless a specific margin of error, such as the standard deviation for a given mean value in a chart or table of data, is recited, 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."

[0012] As used herein, the terms "consists of" or "consisting of" mean that the pharmaceutical composition, composition or method includes only those elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim. As used herein, the terms "consisting essentially of" or "consists essentially of" mean that a pharmaceutical composition 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 composition or method for treating a specified condition (e.g., nutrient deficiency) are the therapeutic agent(s) specifically recited in a particular embodiment or claim.

[0013] 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 from 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 from an embodiment in which the same group is NH. The term "inhibit" means to limit, prevent, or block the action or function of a target enzyme and / or to prevent, alleviate, or eliminate the onset of one or more symptoms associated with a disease, condition, or disorder, or to prevent, alleviate, or eliminate a disease, condition, or disorder. Unless otherwise indicated, the term "skin" means the outer covering or membrane of the body, consisting of the dermis and epidermis, and lying above the subcutaneous tissue.

[0014] 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, this notation is intended to include the numbers themselves and the range therebetween. The range may be integer or continuous, between and including the endpoints. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbons occur 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.).

[0015] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety (wherein the atom bonded to the carbonyl is carbon). An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded 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. 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, the alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, e.g., ethenylene [(-CH=CH-),(-C::C-)]. 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.

[0016] 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.

[0017] Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, 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 (-CH-). Unless otherwise specified, the term "alkyl" can include an "alkylene" group. 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 can be monodialkylated or dialkylated, forming, for example, 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.

[0018] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (RS-) group, wherein the term alkyl is as defined above and sulfur may be oxidized once or twice. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. 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-, -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, etc. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0019] 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 by the specifically enumerated designated "R" groups. 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 by the specifically enumerated designated "R" groups. 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 (CHC(O)NH-).

[0020] 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. 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.

[0021] 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. 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.

[0022] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy. 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 an --OC(O)NRR' group, with R and R' as defined herein. The term "N-carbamyl," as used herein, alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0023] The term "carbonyl," as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group. The terms "carboxyl" or "carboxy," as used herein, refer to -C(O)OH, or the corresponding "carboxylic acid" anion, as in carboxylate salts. An "O-carboxy" group refers to the group RC(O)O-, where R is as defined herein. A "C-carboxy" group refers to the group -C(O)OR, where R is as defined herein. The term "compound," as used herein, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes (e.g., tritium, deuterium) within the structures depicted.

[0024] The term "cyano," as used herein, alone or in combination, refers to --CN. The terms "cycloalkyl," or alternatively, "carbocycle," as used herein, alone or in combination, refer to saturated or partially saturated, monocyclic, bicyclic, or tricyclic alkyl groups, each cyclic moiety containing 3 to 12 carbon atom ring members, which may be benzo-fused ring systems, optionally substituted as defined herein. In certain embodiments, the 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 (multi-center) 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 joined at a carbon atom. The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties which are joined at a carbon atom. 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.

[0026] 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 hydrogen atoms have been replaced with halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups are included. Monohaloalkyl groups, for example, can have an iodo, bromo, chloro, or fluoro atom within 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 above-defined meaning in which one or more hydrogen atoms have been replaced with halogen. Monohalocycloalkyl, dihalocycloalkyl, and polyhalochaloalkyl groups are specifically included. As an example, a monohaloalkyl group may have an iodo, bromo, chloro, or fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may 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 are optionally oxidized and the N heteroatom is optionally quaternized. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH-NH-OCH.

[0029] The term "heteroaryl," as used herein, alone or in combination, refers to a 5- to 15-membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, wherein 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 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl contains 5 to 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, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl contains 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl contains 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl contains 3 to 7 ring members in each ring. In yet further embodiments, the heterocycloalkyl contains 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and 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, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[0031] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined 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 the -NCO group. The term "isothiocyanato" refers to the group --NCS. 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 alkyl," as used herein, alone or in combination, unless specifically defined otherwise, means containing from 1 to 6, inclusive, carbon atoms (i.e., C1-C6 alkyl).

[0033] 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, wherein between 1 and 4 of said members may be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl, wherein 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., C-C cycloalkyl). A 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, means a monocyclic heterocycloalkyl having between 4 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 oxetane, azetidiene, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls 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.

[0035] 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 -NO2. The term "N-oxide" is formed from the tertiary base 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.

[0036] 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. 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. The terms "sulfonate," "sulfonic acid," and "sulfonic acid," 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--.

[0037] 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 an RS(=O)2NR'- group, with R and R' as defined herein. The term "S-sulfonamido" refers to a -S(=O)2NRR' group, where R and R' are as defined herein. The terms "thia" and "thio," as used herein, alone or in combination, refer to an -S- group or ethers in which the oxygen is replaced by a sulfur. The oxidized derivatives of the thio group, i.e., 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.

[0038] The term "thiocarbonyl," as used herein, alone includes a thioformyl-C(S)H, and in combination is a -C(S)- group. The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein. The term "O-thiocarbamyl" refers to an --OC(S)NRR' group, where R and R' are as defined herein. The term "thiocyanato" refers to the group -CNS.

[0039] 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. 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.

[0040] 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 attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group. When a group is defined as "void", it means that the group is not present.

[0041] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group can 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 carboxyester, 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 can 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 listed without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, a different set of optional substituents for a particular moiety may be defined as desired; in these cases, the optional substitution is often as defined immediately preceding the phrase "optionally substituted with."

[0042] 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 optionally substituted. Such R and R' groups are understood to be 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 understood to be 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 of skill in the art will further recognize that a particular group may be attached to a parent molecule or may occupy a position from either end of a chain of elements as described. For example, an unsymmetrical group such as -C(O)N(R)- can be attached to the parent moiety at either the carbon or the nitrogen.

[0043] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the asymmetric center. It is understood that the present invention encompasses all stereoisomeric forms, including diastereomeric, enantiomeric, 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 the defined stereochemical configuration, or by conversion to a diastereomeric mixture followed by separation of a mixture of stereoisomeric products by separation or recrystallization, chromatographic techniques, direct separation of stereoisomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of specific configurations are commercially available or can be made and resolved by techniques known in the art. Furthermore, the compounds disclosed herein can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, endo, exoentgegen (E), and zusammen (Z) isomers, and appropriate mixtures thereof. Furthermore, compounds may exist as tautomers. All tautomeric isomers are provided by the present invention. Furthermore, the compounds disclosed herein may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, solvated forms are considered equivalent to unsolvated forms.

[0044] The compounds described herein may contain one or more asymmetric centers and thus may exist as stereoisomers. Embodiments herein include all such possible stereoisomers as substantially pure resolved stereoisomers, their racemic mixtures, and mixtures of diastereomers. In some embodiments, the formula is shown without a definitive stereochemistry at a particular position. In other embodiments, the compound is isolated as a single stereoisomer, but the absolute configuration of the asymmetric center is unknown or only the relative stereochemical configuration (i.e., cis or trans isomerism) is known. In such embodiments, the formula is shown with absolute assignments tentatively designated to represent these as single stereoisomers, and the relative stereochemical configuration is also described. Embodiments herein include all possible stereoisomers as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. Diastereoisomeric pairs of enantiomers 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 optically active acids or bases as resolving agents, or by chiral HPLC columns. Furthermore, any stereoisomer 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 racemates of the compounds as well as individual enantiomers, diastereomers, stereoisomers, and stereoisomer-enriched mixtures.

[0045] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate enantiomerically enriched or optically pure precursors, or racemate resolution using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an appropriate optically active compound, such as an alcohol, or, if the compound contains an acidic or basic moiety, an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. The chiral compounds (and their chiral precursors) of embodiments herein can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of 0-50% isopropanol, typically 2-20%, and a hydrocarbon, typically heptane or hexane, containing 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).

[0046] Atropisomers are stereoisomers that result from hindrance of rotation about a single bond when the steric rotational hindrance 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 greater than 1000 seconds at a given temperature. The scope of the described and claimed embodiments herein encompasses racemic forms of the compounds as well as individual atropisomers (atropisomers that are "substantially free" of their corresponding enantiomers) and stereoisomer-enriched mixtures, i.e., mixtures of atropisomers. Separation of atropisomers can be achieved by chiral resolution methods, such as selective crystallization. In 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 thermodynamic equilibration-based approaches when an isomerization reaction favors one atropisomer over the other.

[0047] As used herein, the term "derivative thereof" refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal 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. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to patients, such as mammals. The term "pharmaceutically acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

[0048] Suitable pharmaceutically 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 by conventional means from the corresponding compound of the embodiments herein by, for example, treating the compound with the appropriate acid or base. 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. Examples of suitable sucrose-based fatty acids include sulfonic acid, stearic acid, alginic acid, beta-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), and napadisilic acid (1,5-naphthalenedisulfonic acid).

[0049] Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically 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.

[0050] Other preferred salts according to embodiments herein include an equivalent amount of an anion (X - ) is a quaternary ammonium compound in which the positive charge of the N atom is attached. 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. X 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.

[0051] In some embodiments, the salt is a hydrochloride salt. In some embodiments, the salt is a besylate salt. In some embodiments, the salt is a trifluoroacetate salt. The compounds of the embodiments herein can exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the embodiments herein and a certain amount of one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the term hydrate is used. Examples of solvate forms include, but are not limited to, compounds of the embodiments herein combined with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (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 compound of the embodiments herein, for example, a hydrate.

[0052] Furthermore, in the embodiments herein, more than one solvent molecule may be bound to one molecule of the compound of the embodiments herein, for example, a dihydrate is specifically envisaged.In addition, in the embodiments herein, less than one solvent molecule may be bound to one molecule of the compound of the embodiments herein, for example, a hemihydrate is specifically envisaged.In addition, the solvate of the embodiments herein is envisaged as a solvate of the compound of the embodiments herein that retains the biological effectiveness of the non-solvated form of the compound.

[0053] 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 14Chlorine 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 present embodiments, 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 due to their ease of incorporation and rapid means of detection. Heavier isotopes, such as deuterium, 2 Substitution with positron-emitting isotopes, such as H, can confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some circumstances. 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.

[0054] 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 the 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 has been replaced with deuterium at a specific position. Deuterium (D or 2 H) is a stable hydrogen isotope present at a natural abundance of 0.015 mole %. 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.

[0055] Typically, deuterated derivatives of the compounds of 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. Isotopic enrichment factors can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0056] The term "prodrug" refers to a compound that is made to be more active in vivo. 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, for example, by hydrolytic cleavage, into the compounds of the embodiments herein having the desired activity when administered to or on the body. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in Prodrugs 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) or Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).

[0057] Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Furthermore, 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 may be bioavailable, for example, by oral administration, whereas the parent drugs are not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drugs. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug is, without limitation, a compound that is administered as an ester (the "prodrug"), but is then metabolically hydrolyzed to the active carboxylic acid. Additional examples include peptidyl derivatives of the compounds. Prodrugs according to embodiments herein can be generated, for example, by replacing appropriate functional groups present within compounds according to embodiments herein with certain moieties known to those skilled in the art as "promoieties," for example, as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0058] The terms "excipient" and "pharmaceutically acceptable excipient" as used herein are generally intended to be synonymous and are used interchangeably with the terms "carrier," "pharmaceutically acceptable carrier," "diluent," and "pharmaceutically acceptable diluent." 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. 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.

[0059] The term "disease," as used herein, is intended to be generally synonymous with, and is used interchangeably with, "disorder," "syndrome," and "condition" (such as a medical condition), all in the sense of reflecting an abnormal condition of the human or animal body, or of a portion 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 lifespan or quality of life of a human or animal. The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule with a fixed ratio of active ingredients, or in multiple, separate capsules 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 effects of the drug combination in treating the conditions or disorders described herein.

[0060] The term "ITK inhibitor" refers to an inhibitor of ITK activity that has an IC50 of about 100 μM or less, more typically about 50 μM or less, as measured in the ITK enzyme assay generally described herein. 50 IC 50is the concentration of an inhibitor that reduces an enzyme activity (e.g., ITK) to half-maximal levels. Certain compounds disclosed herein have been found to exhibit inhibition of ITK. In certain embodiments, a compound has an IC of about 10 μM or less with respect to ITK, as measured in the ITK binding assay described herein. 50 In a further embodiment, the compound exhibits an IC of about 5 μM or less with respect to ITK. 50 In still further embodiments, the compound has an IC of about 1 μM or less with respect to ITK. 50 In still further embodiments, the compound has an IC of about 200 nM or less with respect to ITK. 50 Shows. The term "immune checkpoint inhibitor" refers to a compound or pharmaceutical composition that inhibits an immune checkpoint molecule.

[0061] "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, thereby positively affecting 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 the target tissue; providing the compound to a patient systemically, for example, by intravenous injection, thereby allowing the therapeutic agent to reach the target tissue; or 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 administration, oral administration, or any of these methods in combination with other known techniques.

[0062] 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. The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or disorder or achieve a clinical endpoint. As used herein, the terms "therapeutic" or "therapeutic agent" or "pharmaceutically active agent" refer to an agent utilized to treat, combat, ameliorate, prevent, or improve an undesirable condition or disease in a patient. In part, embodiments of the present invention are directed to the treatment of ITK-mediated diseases.

[0063] A "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve a desired effect, e.g., inhibiting, blocking, or reversing cell activation, migration, or proliferation. Activities contemplated by the methods of the present invention include medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a compound administered in accordance with the present invention to achieve a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide dosage range; for example, daily doses typically fall within the range of 0.001 to 10 mg / kg, more typically 0.01 to 1 mg / kg. However, it should be understood that the above dosage ranges are in no way intended to limit the scope of the present invention, since the effective amount to be administered will be determined by a physician taking into account relevant circumstances, including the condition being treated, the choice of compound to be administered, and the selected route of administration. A therapeutically effective amount of a compound of the present invention is typically an amount sufficient to achieve an effective systemic or local concentration in tissue when the compound is administered in a physiologically acceptable excipient composition.

[0064] 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, or allergic response, and that are effective for their intended use, consistent with a reasonable benefit-to-risk ratio. The terms "treat," "treated," "treating," or "treatment," as used herein, refer to both therapeutic treatment and prophylactic or preventative measures, the purpose being to prevent or delay (alleviate) an undesired physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilization of the condition, disorder, or disease state (i.e., not worsening); delaying the onset or slowing the progression of a condition, disorder, or disease; amelioration of a condition, disorder, or pathology; and remission of a condition, disorder, or disease (whether partial or total, and whether the condition, disorder, or disease is induced or maintained), or enhancement or improvement (whether detectable or undetectable) of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to that expected if not receiving treatment. Treatment can also be preventative in nature, i.e., treatment can include disease prevention. Disease prevention can include complete protection from disease, such as in the case of preventing infection by a pathogen, or can include prevention of disease progression. For example, disease prevention may not mean completely suppressing any disease-related effects at any level, but instead can mean preventing disease symptoms to a clinically significant or detectable level. Disease prevention can also mean preventing disease progression to a later stage, as well as prolonging disease-free survival compared to the disease-free survival period in the absence of treatment, and prolonging disease-free survival compared to the disease-free survival period in the absence of treatment.

[0065] Also provided are compounds selected from the examples disclosed herein.The compounds of the embodiments herein can also refer to their salts, esters, free acid forms, free base forms, solvates, cocrystals, deuterated derivatives, hydrates, N-oxides, clathrates, prodrugs, polymorphs, stereoisomers, geometric isomers, tautomers, tautomer mixtures, enantiomers, diastereomers, racemates, stereoisomer mixtures, isotopes (e.g., tritium, deuterium), or combinations of the aforementioned compounds of the embodiments herein. The present disclosure relates to novel pyrrolopyrimidine compounds and compositions, and their use as pharmaceuticals for the treatment of diseases. Methods for inhibiting ITK activity in a human or animal subject are also provided for the treatment of diseases, such as those caused by inflammation.

[0066] The Tec (hepatocellular carcinoma-expressed tyrosine kinase) family of tyrosine kinases (TFTK) consists of five family members: Tec, BTK (Bruton's tyrosine kinase), BMX (myeloid kinase on X chromosome, also known as ETK), RLK (resting lymphocyte kinase, also known as TXK), and ITK (interleukin-2-inducible T cell kinase, also known as EMT and TSK). These kinases are central to hematopoietic cell biology, more specifically, regulating the development and activity of lymphoid and myeloid cells. While TFTKs share structural similarities with other nonreceptor tyrosine kinases, they also display family-specific motifs, resulting in diverse domain architectures associated with complex localization, scaffolding, and activation mechanisms. Generally, TFTKs contain an amino-terminal pleckstrin homology domain (PH domain), involved in lipid interaction and membrane targeting, followed by a Zn-terminal pleckstrin homology domain (PH domain), which is involved in lipid interaction and membrane targeting. 2+TFTKs contain a BTK homology domain (BH) that binds to ATP, and an SH3 domain generally involved in proline-rich domain binding. A phosphotyrosine-binding SH2 domain and a carboxy-terminal ATP-binding kinase domain complete the TFTK structure. Expression of TFTK is generally restricted to hematopoietic cells, with the exception of ETK and TEC, which are expressed in hepatocytes and endothelial cells, respectively. BMX is expressed in monocytes, granulocytes, and cardiac endothelium, whereas BTK is expressed in B cells and mast cells but not in plasma cells or T cells. TEC, RLK, and ITK are all expressed in T cells. To date, the TFTK with the most clear biological role in T cells is ITK.

[0067] Antigen / MHC-dependent activation of the T cell receptor (TCR) has been shown to transduce its signal through ITK. TCR stimulation leads to activation of the kinase LCK, followed by phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on CD3, which triggers the binding and activation of the kinase ZAP70. ZAP70 then phosphorylates the adaptor proteins LAT and SLP-76, forming a heteromultimeric signaling complex with LCK and other proteins. This heteromultimeric signaling complex activates PI3K, generating PIP3 at the plasma membrane. ITK binds to this signaling complex through its SH2 and SH3 domains and binds PIP3 through its PH domain, leading to LCK-dependent phosphorylation of ITK Y511 and subsequent autophosphorylation of ITK Y180. Activated ITK phosphorylates PLCγ1, which, once activated, hydrolyzes PIP2 to the second messengers IP3 and DAG. The cellular consequences of this series of events include calcium mobilization and flux, activation of the PKC and MEK / ERK pathways, and transcriptional activation via AP1, NFκactivNFAT. As a key enzyme in the TCR activation pathway, ITK influences T cell function in several ways, including positive and negative selection, cell differentiation, and cytokine production and release.

[0068] The role of ITK in T cell function has been elucidated by genetic knockdown / kinase inactivation of the ITK gene in rodents and by characterization of human ITK mutant individuals. Mice with null mutations in the itk gene exhibited reduced numbers of mature T cells, blocked thymocyte development, and reduced TCR-driven T cell proliferative responses. Interestingly, IL2 and CD28 signaling and PMA / ionomycin-driven responses remained unchanged, suggesting that ITK responses are membrane-proximal and stimulus-specific. ITK appears to be involved in amplifying TCR signaling as an "on / off" switch. This is because dual knockdown of TFTK-, ITK-, and RLK-expressing T cells in mice produced a more complete TCR-inactivated phenotype compared with ITK gene deletion alone. In contrast to the modulatory role ITK appears to have on naive T cell activation, ITK plays a more important role in T helper cell differentiation. Some experiments in ITK-deficient mice demonstrated a reduced Th2 protective response to parasitic infection. This reduction in Th2 responses was associated with reduced concentrations of the Th2 cytokines IL4, IL5, IL13, and IL10, as well as decreased RLK expression. In contrast to the requirement for ITK to initiate Th2-driven responses, the effect of ITK on Th1 responses is less pronounced. For example, IFNγ production in ITK knockout cells is partially inhibited, while double ITK / RLK knockouts have a more severe phenotype. Evaluation of Th17 T helper cells in ITK knockout in vivo and in vitro experiments revealed reduced IL17A mRNA and protein, but little effect on IL17F. The role of ITK in cytotoxic CD8+ T cells was investigated using ITK knockout mice. Stimulation of ITK-deficient CD8+ T cells resulted in reduced activation of PLCg1, ERK, and p38 MAPK, as well as increased Ca2+ expression. 2+This results in a loss of response, leading to a reduction in proliferative responses and effector cytokine production (IL2, IL4, and IFNγ), but the cytotoxic capacity of these cells is unaffected. In addition to the defects observed in CD4+ and CD8+ T cells, natural killer T cell development and TCR-stimulated responses are reduced in ITK knockout cells and animals.

[0069] Gene knockout experiments in rodents reflect the effects of enzyme expression on biological responses, but not necessarily catalytic activity. In the case of ITK, in addition to its catalytic role, it also plays a scaffolding role via its multidomain structure. It is important to clarify the cell biology implications of blocking each of these functions. Kinase-independent ITK activities include recruitment of the guanine nucleotide exchange factor VAV to the plasma membrane (PH and SH2 domain-dependent) associated with actin polymerization, antigen receptor stimulation, and receptor activation of SRF. However, ITK knockout mice expressing a transgene lacking the ITK kinase domain demonstrated that the kinase domain is essential for the induction of normal Th2 responses.

[0070] Recently, a relationship between ITK expression and activity and human disease has been reported in individuals exhibiting mutations in the gene encoding this protein and / or in experiments characterizing the correlation between expression and disease. The ITK gene was found to be elevated in peripheral blood T cells from patients with moderate to severe atopic dermatitis, a Th2-driven chronic inflammatory skin disease. Investigation of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis identified ITK as an important risk factor. Human primary immunodeficiency was discovered in two brothers who died from immune dysregulation resulting in lymphocyte proliferation after Epstein-Barr virus (EBV) infection. This disorder is associated with a missense (R335W) mutation in the SH2 domain of ITK, resulting in structural instability and reduced steady-state levels of the enzyme. This finding was confirmed and expanded in experiments identifying three patients with a C1764G nonsense mutation in ITK, resulting in a premature stop codon and reduced protein expression and / or activity. These patients were presented with EBV-positive Hodgkin's lymphoma. These two reports suggest that mutational disruption of the ITK gene in humans results in an autosomal recessive lymphoproliferative disorder and identify this kinase as a key modulator of T cell biology.

[0071] In addition to the human genetic data summarized above, animal models support ITK as a therapeutic target for autoimmune and inflammatory diseases. ITK knockout mice demonstrate reduced airway hyperresponsiveness and inflammation in models of allergic asthma. In mouse models of atopic dermatitis, ITK-deficient mice do not develop inflammation, and ITK inhibition reduces responses in wild-type mice. TCR-dependent Ca2+ upregulation has also been shown to be involved in the regulation of TCR-dependent Ca2+ upregulation. 2+ ITK-dependent regulation of recruitment and transcription factor induction makes ITK a key factor in defense against influenza A and HIV infection and viral replication. ITK inhibitors have been shown to alter HIV replication at multiple stages and have potential as effective HIV therapeutics.

[0072] From an oncological perspective, experiments have demonstrated that ITK inhibitors selectively target the killing of acute lymphoblastic T-cell leukemia and cutaneous T-cell lymphoma while minimally affecting normal T cells. ITK is highly expressed in transformed T-cell lines compared with normal T cells and other cancer cell lines. The effect of ITK inhibition on T-cell tumors was confirmed in mouse xenograft models. Cancer evasion of the immune system as a result of induction of tumor antigen tolerance to priming is important for tumor survival. Tumors that create a microenvironment that induces T-cell unresponsiveness demonstrate altered T-cell gene expression suggestive of a bias toward a Th2 phenotype. ITK inhibition favors Th1 differentiation and can be used to enhance cancer immunotherapy.

[0073] The utility of simultaneously inhibiting signals downstream of both T cell receptors and cytokine receptors is best exemplified in the field of organ transplantation (Halloran). In the immediate post-transplant setting, standard treatment is to prevent immunological graft rejection by administering a cocktail of inhibitors that act at different points on lymphocyte activation. The most common drugs used both in the early post-transplant period, as well as at the time of discharge, are calcineurin inhibitors, such as Prograf or Neoral, which block TCR signaling, and antimetabolites, such as mycophenolate mofetil or rapamycin, which block proliferation induced downstream of cytokines such as IL-2 or IL-15. These drugs cannot be used as monotherapy because high doses would be required, resulting in drug-specific toxicity. By using these drugs simultaneously at suboptimal doses, synergistic immunosuppression can be achieved with less toxicity. ITK is downstream of the TCR, and JAK3 is downstream of the common g-chain of cytokine receptors. By covalently modifying cysteines within the catalytic domains of both kinases, it is possible to inhibit both enzymes with a single drug, thereby synergistically inhibiting T cell activation.

[0074] The detailed description set forth herein is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not intended to be limited in scope by the specific embodiments disclosed herein, as these embodiments are intended to be illustrative of some aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. Indeed, various modifications of the present disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description without departing from the spirit or scope of the inventive findings. Such modifications are also intended to fall within the scope of the appended claims. All references cited herein are incorporated herein by reference. The discussion of references herein is intended merely to summarize the assertions made by their authors and does not constitute an admission that any reference constitutes common art relevant to patentability. Applicant reserves the right to challenge the accuracy and pertinence of the cited references.

[0075] compound In some embodiments, the compounds have structural formula (I) and derivatives thereof: [ka] (In the formula, X is N or CR3; n is 0, 1 or 2; m is 0, 1 or 2; R1 is selected from COOR6, C1-C5 alkyl-COOR6, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR6 or C1-C5-alkyl-COOR6; R2 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, CN, OH, C1-C5 alkoxy and halogen, and two R2 groups on the same carbon may be linked with or without a heteroatom to form a spirocyclic ring system; R3 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R4 is selected from H, C1-C6 alkyl; R5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl; R6 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH-C1-C5 alkyl, and C1-C5 alkyl-N-(C1-C5 alkyl)(C1-C5 alkyl);

[0076] In one embodiment of the compounds of structural formula (I), the compounds of the disclosure are administered with a pharmaceutically acceptable carrier, adjuvant, or vehicle. Embodiments of the present disclosure are directed to compounds of structural formula (II) and derivatives thereof:

[0077] [ka] (In the formula, X is N or CR 23 and n is 0, 1 or 2; m is 0, 1 or 2; R 21 COOR 26 , C1-C5 alkyl-COOR 26, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 26 , or C1-C5-alkyl-COOR 26 and optionally substituted with one or more groups selected from R 22 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, CN, OH, C1-C5 alkoxy, halogen, and two R2 groups on the same carbon may be linked with or without a heteroatom to form a spirocyclic ring system; R 23 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 24 is selected from H, C1-C6 alkyl; R 25 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl; R 26 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0078] In one embodiment of the compounds of structural formula (II), the compounds of the present disclosure are administered with a pharmaceutically acceptable carrier, adjuvant, or vehicle. Embodiments of the present disclosure are directed to compounds of structural formula (III) and derivatives thereof:

[0079] [ka] (In the formula, X is CR 33 or N, n is 1 or 2, When n is 1, m is 0, 1, or 2; when n is 2, m is 1; R 31 COOR 36 , C1-C5 alkyl-COOR 36 , bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 36 , or C1-C5-alkyl-COOR 36 and optionally substituted with one or more groups selected from R 32 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, R 33 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 34 is selected from H, C1-C6 alkyl; R 35is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-NH, C-C alkylNH(C-C alkyl), C-C alkyl-N(C-C alkyl)(C-C alkyl), C-C alkyl-C-C alkoxy; R 36 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0080] In one embodiment of the compounds of structural formula (III), the compounds of the present disclosure are administered with a pharmaceutically acceptable carrier, adjuvant, or vehicle. Embodiments of the present disclosure are directed to compounds of structural formula (IV) and derivatives thereof:

[0081] [ka] (In the formula, X is CR 43 or N, n is 1 or 2, When n is 1, m is 0, 1, or 2; when n is 2, m is 1; R 41 COOR 46 , C1-C5 alkyl-COOR 46 , bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cycloalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR 46, or C1-C5-alkyl-COOR 46 and optionally substituted with one or more groups selected from R 42 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cycloalkyl, R 43 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl; R 44 is selected from H, C1-C6 alkyl; R 45 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkylNH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy; R 46 is selected from H, C-C alkyl, C-C cycloalkyl, C-C-alkyl-C-C-cycloalkyl, C-C alkyl-C-C alkoxy, C-C alkyl-OH, C-C alkyl-NH, C-C alkyl-NH-C-C alkyl, and C-C alkyl-N—(C-C alkyl)(C-C alkyl);

[0082] In one embodiment of the compounds of structural formula (IV), the compounds of the present disclosure are administered with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the compound of formula (I), or a derivative thereof, can be selected from the following:

[0083] TIFF2025037892000009.tif236157 TIFF2025037892000010.tif225157 TIFF2025037892000011.tif227158 TIFF2025037892000012.tif219158 TIFF2025037892000013.tif223158 TIFF2025037892000014.tif229158 TIFF2025037892000015.tif225158 TIFF2025037892000016.tif222159 TIFF2025037892000017.tif224158 TIFF2025037892000018.tif234158 TIFF2025037892000019.tif213158 TIFF2025037892000020.tif218158 TIFF2025037892000021.tif205157 TIFF2025037892000022.tif175158

[0084] In some embodiments, the compound of formula (III), or a derivative thereof, can be selected from the following: TIFF2025037892000023.tif220161 TIFF2025037892000024.tif66161

[0085] Pharmaceutical Composition Also provided are pharmaceutical compositions comprising the compounds disclosed herein in association with a pharmaceutically acceptable excipient.

[0086] In certain embodiments, the pharmaceutical compositions can include from about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the one or more compounds can be 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%, or from about 0.05% to about 50%. % 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 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 which represent a percentage by weight of the pharmaceutical composition.

[0087] In some embodiments, the compound is in 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 mg to 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.

[0088] Although the compounds described herein can be administered as drug substances, they can also be present as pharmaceutical compositions. Accordingly, provided herein are pharmaceutical compositions comprising one or more of the specific compounds disclosed herein, or derivatives thereof, together with one or more pharmaceutically acceptable excipients thereof, and optionally one or more other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Proper formulation of a pharmaceutical composition depends on the chosen route of administration. Any well-known techniques and excipients may be used as appropriate and understood in the art. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0089] In some embodiments, pharmaceutical compositions for use in accordance with embodiments herein may be formulated in a conventional manner using one or more physiologically acceptable excipients.

[0090] 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 arts 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, intrathecal, intradural, 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 administration 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, etc. may be necessary or desirable. Coated condoms, gloves, etc. may also be useful. In some embodiments, the compound may be contained in such pharmaceutical compositions together with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives, etc. Those skilled in the art can refer to various pharmacological references for guidance. For example, see 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).

[0091] In some embodiments, the method for treating an ITK-mediated disease comprises administering a compound or 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, as the active ingredient, one or more compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the method for preparing a pharmaceutical composition includes mixing an active ingredient with an excipient, diluting the active ingredient with an excipient, or encapsulating the active ingredient in a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material, and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition 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, sterile injectable solutions, and sterile-packaged powders, for example, containing up to 10% by weight of the active compound.

[0092] 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, pharmaceutical compositions can include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl- and hydroxypropyl benzoates; sweeteners; and flavoring agents.Pharmaceutical compositions can be formulated to produce rapid, sustained, or delayed release of active ingredients after administration to patients by utilizing procedures known in the art.

[0093] Pharmaceutical compositions can be formulated into unit dosage forms. 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 substance calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intrathecal, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, oral buccal, sublingual, and intraocular), intravitreal, or intravaginal administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient. Compositions can include those suitable for administration by depot injection or implant. Compositions can include those suitable for administration by inhalation, such as gases, vapors, or powders. Compositions can include those suitable for administration as aerosols, for example, via nebulizers, humidifiers, inhalers, and vaporizers. Compositions can be conveniently presented in unit dosage form and can be prepared by any method well known in the field of pharmacy.Typically, these methods comprise the step of combining the compound disclosed herein or its derivative (" active ingredient ") with a carrier that constitutes one or more accessory ingredients.Generally, compositions are prepared by uniformly and intimately combining active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired composition.

[0094] Compositions 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.

[0095] Orally usable pharmaceutical preparations 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 compounds 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 compositions for oral administration should be in a dosage appropriate for such administration. Push-fit capsules can contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Dragee cores can be 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.

[0096] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical 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, containing, for example, about 0.1 to about 1000 mg of the active ingredient.

[0097] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablets or pills may contain an inner and outer component, the latter in the form of an outer coating 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. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral or injectable administration 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.

[0098] The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable compositions can be presented in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. Pharmaceutical compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, such as suspending, stabilizing, and / or dispersing agents. The compositions 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) form, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type previously described.

[0099] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the composition 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 for the preparation of highly concentrated solutions. In addition to the pharmaceutical compositions described above, the compound can also be formulated as a depot preparation.Such long-acting compositions can be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection.Thus, for example, the compound can be formulated into suitable polymeric or hydrophobic materials (for example, emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0100] For oral buccal or sublingual administration, the pharmaceutical 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, such as sucrose and acacia or tragacanth. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. Certain compounds disclosed herein can be administered by local administration, i.e., non-systemic administration.This includes applying the compounds disclosed herein to the epidermis or oral cavity externally, so that the compound does not enter the bloodstream significantly, and dropping the compound into the ear, eye and nose.In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. In some embodiments, the pharmaceutical composition is suitable for topical administration. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the composition is suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intrathecal, transmucosal, transdermal, rectal, intranasal, topical (including, for example, cutaneous, oral buccal, sublingual, and intraocular), intravitreal, or intravaginal administration.

[0101] 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, eyewash, spray, 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, applied to the eyelid. In some embodiments, the compounds disclosed herein can be administered as a solid dosage form, for example, as a powder, 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, etc. In some embodiments, pharmaceutical 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 into 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.

[0102] In some embodiments, pharmaceutical compositions 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, fluids, emulsions, fluid suspensions, semi-solids, gels, paints, lotions, creams, ointments, pastes, jellies, foams, and drops suitable for ophthalmic, otic, or nasal administration. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (weight percent) of the composition. 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 composition.

[0103] Gels for topical or transdermal administration generally contain a mixture of a volatile solvent, a non-volatile solvent, and water. In certain embodiments, the volatile solvent component of the buffer solvent system may contain a lower (C1-C6) alkyl alcohol, a lower alkyl glycol, and a lower glycol polymer. In a further embodiment, the volatile solvent is ethanol. The volatile solvent component is believed to act as a percutaneous absorption enhancer while also providing a cooling effect on 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 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 upon evaporation of the volatile solvent, while an excess amount may result in poor drug release from the solvent mixture, resulting in a lack of bioavailability. 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 the components is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. There are several optional ingredients that can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents include, but are not limited to, semi-synthetic cellulose derivatives (e.g., hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

[0104] 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 preparing drops. Lotions or liniments for application to the skin can also include agents for accelerating 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.

[0105] Creams, ointments, or pastes are semi-solid pharmaceutical compositions of active ingredients for external application.They can be prepared by mixing the active ingredients in finely divided or powder form with a greasy or non-greasy base using a suitable mechanism, either alone or in solution or suspension in an aqueous or non-aqueous fluid.The base can include hydrocarbons such as hard, soft, or liquid paraffin, glycerol, beeswax, metal soaps; mucilage; natural oils 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 alcohols such as propylene glycol or macrogels.The pharmaceutical composition can incorporate any suitable surfactant, such as anionic, cationic, or nonionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives.Suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as silica, and other ingredients such as lanolin can also be included.

[0106] Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution containing 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 maintaining at 98-100°C for 30 minutes. Alternatively, the solution may be sterilized by filtration and transferred to a container using a sterile technique. Examples of bactericides and antibacterial agents suitable for inclusion in drops include phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol, and propylene glycol. Pharmaceutical compositions 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.

[0107] For administration by inhalation, the compound can be conveniently delivered using an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray.Pressurized packs can contain a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.In the case of a pressurized aerosol, the 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 be in 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 using an inhaler or insufflator. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, pharmaceutical compositions are administered orally or via nasal respiratory routes for local or systemic effect. The compositions can be nebulized by using an inert gas. 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 via nasal routes from devices that deliver the composition in an appropriate manner.

[0108] In some embodiments, the pharmaceutical composition administered to a patient may be in the form of a pharmaceutical composition 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, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the compound preparation is from about 3 to about 11, from about 5 to about 9, from about 5.5 to about 6.5, or from about 5.5 to about 7.5. It is understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts. Preferred pharmaceutical compositions in unit dosage form contain an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. It will be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions described above may include other agents conventional in the art having regard to the type of pharmaceutical composition in question; for example, pharmaceutical compositions suitable for oral administration may include flavoring agents.

[0109] In some embodiments, a therapeutically effective amount may vary depending, for example, on the particular use for which the treatment is given, 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 dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compound may be provided in an aqueous physiological buffer solution 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 will likely depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological potency of the selected compound, the composition of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0110] 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., prophylaxis or therapy, 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. The active compounds can be effective over a wide dosage range and can generally be administered in a therapeutically effective amount, however, it will be understood that the amount of compound actually administered will normally be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc. The compounds can be administered orally or via injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adult humans is generally 5 mg to 2 g per day. Tablets or other presentation forms provided in individual units may conveniently contain an amount of one or more compounds effective at such dosages, or a multiple thereof, e.g., units containing 5 mg to 500 mg, usually about 10 mg to 200 mg. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0111] Compounds can be administered in various ways, for example, orally, topically or by injection.The exact amount of compound administered to patients is the responsibility of the attending physician.The specific dosage level for any specific patient will depend on various factors, including the activity of the specific compound used, age, body weight, general health condition, sex, dietary habits, time of administration, administration route, excretion rate, drug combinations, the exact disorder being treated, and the severity of the symptom or condition being treated.In addition, administration route can vary depending on the condition and its severity. The composition can further comprise one or more additional pharmaceutical agents, for example, a chemotherapeutic agent, a steroid, an anti-inflammatory compound, or an immunosuppressant.

[0112] Treatment method Some embodiments herein relate to a method of modulating ITK-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method of inhibiting ITK in a subject comprises administering to the subject a compound of an embodiment herein. The present invention also relates to methods for inhibiting at least one ITK function, comprising contacting ITK with a compound as described herein. The method can monitor cellular phenotype, cell proliferation, activity, changes in biochemical output produced by active ITK, expression of ITK, or binding of ITK to a natural binding partner. Such methods can be modes of disease treatment, biological assays, cellular assays, biochemical assays, etc.

[0113] The compounds of the present invention may be useful as JAK3 kinase inhibitors as well as ITK inhibitors. This dual use of a single compound, inhibiting either the ITK or JAK3 pathway individually or both pathways simultaneously, can provide beneficial effects. As a result, the compounds of the present invention may find utility in treating a wide range of diseases or conditions mediated by ITK activity, JAK3 activity, or both. Accordingly, some embodiments herein are directed to using the compounds disclosed herein to treat or prevent diseases or conditions in which JAK, particularly JAK3, plays an active role. In some embodiments, a method of treating a JAK3-mediated disease or disorder in a subject comprises administering to the subject a compound of an embodiment herein. Some embodiments provide a method for treating a JAK3-mediated disorder in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound or composition according to the present disclosure. Also provided is the use of the compounds disclosed herein for use in the manufacture of a medicament for treating a disease or condition ameliorated by inhibition of JAK3, ITK, or a combination thereof. The embodiments discussed herein directed to methods of treatment for ITK-mediated conditions or diseases can also be applied to methods of treatment for JAK3-mediated conditions or diseases.

[0114] Also provided herein is a method for treating ITK-mediated or JAK3-mediated diseases, comprising administering to a patient in need thereof 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. Also provided herein are methods for inhibiting ITK or JAK3 activity in a population of cells, comprising administering to the population of cells one or more compounds disclosed herein, derivatives thereof, or combinations thereof, in an amount effective to inhibit ITK or JAK3 activity in the population of cells. In some embodiments, the population of cells is a population of human cells. In some embodiments, the present invention provides a method for treating an ITK-mediated or JAK3-mediated disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of an embodiment herein, or a composition thereof, such as, but not limited to, those described herein.

[0115] In some embodiments, diseases or disorders associated with ITK kinase or JAK3 kinase treated by the compounds of the invention include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, cardiovascular or cerebrovascular disorders, respiratory diseases, allergies and allergic diseases and allergic hypersensitivity disorders, immunological disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain, and other diseases and disorders associated with ITK. In some embodiments, the ITK-mediated 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, an autoimmune condition, asthma, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, contact hypersensitivity, and inflammatory bowel disease. In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be administered in a therapeutically effective amount to prevent or treat HIV.

[0116] In certain embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a neoplasm, malignant tumor, myeloproliferative disorder, hematopoietic neoplasm, myeloid neoplasm, lymphoid neoplasm including myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia, leukemia, childhood leukemia, acute leukemia, acute lymphoblastic T-cell leukemia, acute and chronic leukemia, systemic lymphoma, lymphoma including T-cell lymphoma, B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous lymphoma, other myeloid malignancies including but not limited to cutaneous T-cell lymphoma (CTCL), mycosis fungoides, and cutaneous B-cell lymphoma, and myelodysplastic syndrome. In certain embodiments, the ITK-mediated or JAK3-mediated disease or disorder is resistant to previous therapy (e.g., resistant to or failed cancer chemotherapy).

[0117] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease, seronegative spondyloarthritis, osteoarthritis, enthesitis, enthesopathy, infectious arthritis, Lyme disease, inflammatory arthritis, inflammatory bowel disease-associated arthritis, myositis, autoimmune myositis, carditis, myocarditis, dermatomyositis, juvenile dermatomyositis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis, and the like. inflammation, gout, scleroderma, juvenile scleroderma, Reiter's syndrome, spondylitis, spondyloarthritis, spondyloarthropathy, lupus, systemic lupus erythematosus (SLE), childhood systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus, discoid lupus erythematosus, psoriatic arthritis, reactive arthritis, Sjogren's syndrome, polymyositis, polymyalgia rheumatica, mixed connective tissue disease, vasculitis, large vessel vasculitis, small vessel vasculitis, vasculitis syndromes, including Takayasu's arteritis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, Rucoidosis, familial Mediterranean fever, cryopyrin-associated periodic syndrome (for example), Muckle-Wells syndrome, familial cold-associated autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome; gastrointestinal diseases (for example, inflammatory bowel disease, irritable bowel syndrome, spastic colon, Crohn's disease, ulcerative colitis, acute and chronic pancreatitis, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, periodontitis, gingivitis, esophagitis, gastritis, eosinophilic gastritis, gastric and duodenal ulcers, peritonitis, periodontitis, enteritis, colitis); pulmonary respiratory disorders , (e.g.) pulmonary inflammation, sinusitis, rhinitis, pneumonia, bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, bronchial asthma, allergic asthma, eosinophilic asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease; endocrine disorders (e.g.) diabetes mellitus, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease; autoimmune hemolytic anemia, pernicious anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia;Nervous system / neuromuscular disorders (e.g., neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), familial ALS, Alzheimer's disease, myasthenia gravis (Lambert-Eaton myasthenic syndrome (LEMS)), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury); nephropathies (e.g., immune-mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, including diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-related, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease); ocular disorders (e.g., dry eye, uveitis, keratoconjunctivitis sicca, scleritis, episcleritis, keratoconjunctiv ... including uveal ulcers, keratopathy, chorditis, retinal vasculitis, optic neuritis, retinopathy, diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration, and ocular malignancies; allergies and allergic reactions, including hypersensitivity reactions, such as type I hypersensitivity reactions (including, for example, 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); fibrotic and scarring disorders, such as liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, mild scarring, e.g., scleroderma, increased fibrosis, keloids, and post-surgical scarring;Skin disorders, such as psoriasis, atopy, atopic dermatitis, acne, acne vulgaris, comedonal acne, inflammatory acne, nodular and cystic acne, cicatricial acne, keloid acne nuchal, hidradenitis suppurativa, neutrophilic dermatosis, pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), erythema elevatum diutinum (EED), neutrophilic exudative hidradenitis, histiocytic neutrophilic dermatosis, intestinal bypass syndrome dermatosis, Behçet's disease, and cytoplasmic hidradenitis. Neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, alopecia, non-cicatricial alopecia, alopecia areata (AA), including patchy AA, alopecia totalis (AT), alopecia universalis (AU), androgenetic alopecia (AGA), male and female pattern AGA, serpiginous pattern alopecia areata, sisaihpo pattern alopecia areata, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, cicatricial alopecia, flat Lichen pilaris, parietal centrifugal cicillario alopecia, frontal fibrosing alopecia, brow alopecia, internasal hair alopecia; vitiligo, e.g., segmental vitiligo, monosegmental, bisegmental, or multisegmental vitiligo, nonsegmental vitiligo (digital, facial, or extremity-related vitiligo, central facial vitiligo, mucosal vitiligo, confetti vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, vitiligo, blue vitiligo, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo, generalized vitiligo), mixed vitiligo (including segmental-associated non-segmental vitiligo), localized vitiligo, isolated mucosal vitiligo or vitiligo vulgaris with or without leukoderma (including body hair); immune bullous diseases such as (for example), bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease;Skin drug reactions, and pruritus (itch), including (for example) atopic pruritus, dry pruritus, psoriasis-associated pruritus ("psoriatic itch"), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic pruritus, hepatobiliary-associated pruritus, renal-associated pruritus, lichen simplex chronicus-associated prurigo nodularis, type II diabetes, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmune diseases, autoimmune hearing loss ( including Meniere's disease), interstitial cystitis, enterocolitis, eye inflammation, non-small cell lung cancer, small cell lung cancer, skin cancer, organ transplant rejection, bone marrow graft rejection, 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 marrow transplant rejection (e.g., acute allograft rejection); Absorption disorders, asthma (e.g., bronchial asthma), atopy, autoimmune thyroid disorders, chronic atypical neutrophilic dermatosis with lipodystrophy and hypertension (CANDLE syndrome), SAVI (STI associated vasculopathy with interferon gene stimulator in infancy (STING)-associated vasculopathy), nephropathy, myocarditis, secondary hematologic manifestations of autoimmune diseases (e.g., anemia), autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-associated autoimmune diseases, drug-induced autoimmune diseases, HIV-associated autoimmune syndrome; acute and chronic infections; sepsis 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-surgical trauma, tissue injury, pain such as (for example) acute pain, chronic pain, neuropathic pain, or fibromyalgia, autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, or cardiovascular or cerebrovascular disorders, skin disorders, pruritus, hair loss disorders, cancer, neoplasms, inflammatory conditions, connective tissue diseases and autoimmune conditions, neoplasms, malignancies, myeloproliferative disorders, hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms, such as myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocytosis acute and chronic leukemias, including psoriasis, lymphomas, cutaneous lymphomas, other myeloid malignancies, including mycosis fungoides, and myelodysplastic syndromes, atopic dermatitis, psoriasis, plaque psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, allergic dermatitis, inflammatory skin diseases, neutrophilic dermatoses, pruritus, atopic itch, atopic dermatitis-associated itch, autoimmune response, autoimmune connective tissue disease, bacterial infection, bile duct itch, widespread activation of immune response, body lice, bullous diseases, brachioradial pruritus, brain tumors, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T-cell 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, pemphigoid of pregnancy, head lice, herpes, hidradenitis suppurativa, pyoderma gangrenosum, rash, Hodgkin's disease, hyperparathyroidism, idiopathic chronic itch, inflammation, insect infestation, 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-related itch, leukemia-related itch, malignancy, mastocytosis, menopause, multiple sclerosis, neoplasms, nerve irritation, neurogenic itch, neuropathic itch, paresthesia, paresthesia obsessive-compulsive disorder, paresthesia, parasitic infection, papular urticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, psychiatric disorders, psychogenic itch, pruritic papular rash of HIV, pruritic urticarial papules and plaques of pregnancy (PUPP); Psoriasis-related itch, psoriatic itch, hair lice, punctate palmoplantar keratoderma, kidney itch, rheumatoid arthritis, scabies, increased scarring, razor rash, seborrheic dermatitis, congestion dermatitis, sunburn, swimmer's prurigo, systemic immunosenescence, tactile hallucinations, Th17-related inflammation, thyroid disease, uremia, uremic itch, urticaria, urticarial itch, chickenpox, viral infection, trauma or scabies healing, xerosis, chilblains, lupus erythematosus, polychondritis, relapsing polychondritis, immune-mediated nephropathy, prostate cancer, kidney cancer, liver cancer, breast cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, lymphoma, leukemia, Multiple myeloma, 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), systemic mast cell disease (SMCD), systemic sclerosis / scleroderma, lupus nephritis, wound healing, surgical scars, spinal cord injury, CNS scars, acute lung injury, cystic fibrosis, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension Pressure-induced nephropathy, gastrointestinal or digestive tract fibrosis, liver or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), liver 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, gastrointestinal system, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, mediastinal fibrosis fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, obesity, steroid resistance, impaired glucose tolerance, metabolic syndrome, 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 lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, and cancers of the bone, mouth / pharynx, esophagus, larynx, stomach, intestines, colon, rectum, liver, nerves, brain (e.g., glioma or glioblastoma multiforme), head and neck, throat, ovary, uterus, testes, bladder, kidney, gallbladder, cervix, atherosclerosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, stroke, spinal cord injury, neuronal ischemia, and peripheral neuropathy;

[0118] 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 diseases, asthma (e.g., bronchial asthma), atopy, autoimmune thyroid disorders, chronic atypical neutrophilic dermatosis with lipodystrophy and hypertension syndrome (CANDLE syndrome), SAVI (STING-associated vasculopathy with onset of interferon genes in infancy), ulcerative colitis, inflammatory bowel disease, Crohn's disease, celiac disease, ulcerative colitis , Behcet'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, sepsis 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-surgical trauma, tissue injury, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is asthma. In one embodiment, the asthma is allergic asthma, non-allergic asthma, allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma, asthma with fixed airflow obstruction, exercise-induced asthma, cough-variant asthma, occupational asthma, nocturnal (nocturnal) asthma, asthma associated with obesity, eosinophilic asthma, steroid-resistant asthma / severe asthma, extrinsic asthma, or intrinsic / unknown cause asthma.

[0119] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is vitiligo vulgaris. In one embodiment, the vitiligo vulgaris is segmental vitiligo, including monosegmental, bisegmental, or multisegmental vitiligo, non-segmental vitiligo, 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), focal vitiligo, isolated mucosal vitiligo, or vitiligo with or without leukoderma (including body hair), or any type of vitiligo vulgaris listed in Table 1 below:

[0120] TIFF2025037892000025.tif140156

[0121] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a skin disorder, hi 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. In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is pruritus. "Pruritus," 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 can 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, biliary itch, widespread activation of the immune response, body lice, bullous diseases, brachioradial pruritus, brain tumors, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T Cell 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, pemphigoid of pregnancy, 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-related itch, leukemia-related itch, malignancy, mastocytosis, menopause, multiple sclerosis, neoplasms, nerve irritation, neurogenic itch, neuropathic itch, paresthesia, paresthesia obsessive-compulsive disorder, paresthesia, parasitic infection, papular urticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, psychiatric disorders, psychogenic itch, HIV pruritus Papular rash, pruritic urticarial papules and plaques of pregnancy (PUPPP), psoriasis, psoriasis-related itch, psoriatic itch, hair lice, punctate palmoplantar keratoderma, kidney itch, rheumatoid arthritis, scabies, increased 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 infection, trauma or scabies healing, and xerosis.

[0122] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is hair loss disorder.In one embodiment, hair loss disorder is selected from: alopecia, alopecia areata, patchy alopecia areata, alopecia totalis, alopecia universalis, serpentine pattern alopecia areata, sisaihpo pattern alopecia, androgenetic alopecia (male and female pattern hair loss), telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, cicatricial alopecia, lichen planopilaris, parietal centrifugal cicatricial alopecia, frontal fibrosing alopecia, eyebrow alopecia, folliculitis barbae or internasal hair loss.

[0123] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a connective tissue disease. 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 some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is nephropathy. 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. In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is cancer. In one embodiment, the cancer is a solid tumor.

[0124] In one embodiment, the cancer is prostate cancer, genitourinary cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, skin cancer, bone cancer, ovarian cancer, liver cancer, non-small cell lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid gland, adrenal gland, nervous tissue, head and neck, colon, stomach, bronchus, kidney cancer, basal cell carcinoma, squamous cell carcinoma, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, myeloma, giant cell tumor, giant cell carcinoma, thyroid cancer ... These tumors include: cell lung tumors, islet cell tumors, primary brain tumors, lymphoid and granulocytic tumors, hairy cell tumors, adenomas, hyperplasias, medullary carcinomas, pheochromocytomas, mucosal neuromas, intestinal ganglioneuromas, ovarian tumors, cervical dysplasias, neuroblastomas, retinoblastomas, soft tissue sarcomas, malignant carcinoids, localized skin lesions, rhabdomyosarcomas, Kaposi's sarcoma, osteogenic sarcomas, malignant hypercalcemia, adenocarcinomas, glioblastoma multiforme, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas.

[0125] In one embodiment, the cancer is lymphoma, leukemia, or multiple myeloma. In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a myeloproliferative disorder (MPD). In one embodiment, the 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, the myeloproliferative disorder is myelofibrosis. In one embodiment, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a bone resorption disease, hi one embodiment, the bone resorption disease is osteoporosis, osteoarthritis, hormone imbalance-related bone resorption, hormone therapy-related bone resorption, autoimmune disease-related bone resorption, or cancer-related bone resorption. In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue diseases, 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, kidney fibrosis, liver or bile duct fibrosis, and 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 non-alcoholic 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 fibrosis, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0126] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, impaired glucose tolerance, and metabolic syndrome. In some embodiments, the ITK-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 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, teratoma, rhabdomyosarcoma, metastatic and bone disorders, and 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, testicle, bladder, kidney, breast, gallbladder, cervix, thyroid, prostate, and skin. In some embodiments, ITK-mediated 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 disease 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.

[0127] Also provided herein are compounds as disclosed herein for use as pharmaceuticals.Also provided herein are compounds as disclosed herein for use as pharmaceuticals for the treatment of ITK-mediated or JAK3-mediated diseases.Also provided are the use of compounds as disclosed herein as pharmaceuticals. Also provided is the use of a compound as disclosed herein as a medicament for treating an ITK-mediated or JAK3-mediated disease. Also provided is the compound disclosed herein for use in the manufacture of a medicament for treating an ITK-mediated or JAK3-mediated disease. Also provided is the use of a compound disclosed herein for treating an ITK-mediated or JAK3-mediated disease. Also provided is a method of inhibiting ITK, comprising contacting ITK with a compound disclosed herein. Also provided is a method of inhibiting JAK3, comprising contacting JAK3 with a compound disclosed herein.

[0128] 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, wherein the effect is selected from cognitive enhancement. In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from pruritus, alopecia, alopecia areata, vitiligo, male pattern androgenetic alopecia, female pattern androgenetic alopecia, atopic dermatitis, and psoriasis. In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from arthritis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, adult-onset Still's disease, and seronegative spondyloarthritis.

[0129] In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, enteritis, colitis, gastritis, and eosinophilic gastritis. In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from asthma, allergic asthma, eosinophilic asthma, sinusitis, and rhinitis. In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, and leukemia. In certain embodiments, the ITK-mediated or JAK3-mediated disease is selected from organ or bone marrow transplant rejection, and graft-versus-host disease (GVHD). Some embodiments are directed to a method of inhibiting ITK or JAK3 activity in a biological sample, comprising contacting the biological sample with a compound or pharmaceutical composition described herein.

[0130] In addition to being useful for human treatment, the compounds and compositions 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. Combination therapy The compounds of the present invention can be used alone or in combination with other pharmaceutically active compounds to treat conditions such as those previously described above. The compound(s) of the present invention and the other pharmaceutically active compound(s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. Thus, in one embodiment, the present invention includes a method for treating a condition by administering to a subject a therapeutically effective amount of one or more compounds of the present invention and one or more additional pharmaceutically active compounds.

[0131] In one embodiment, the composition further comprises an additional pharmaceutical agent selected from the group consisting of chemotherapeutic or antiproliferative agents, antiviral agents, antibiotics, antihistamines, emollients, systemic phototherapy agents, psoralen photochemotherapeutic agents, laser therapy agents, hormone replacement therapy agents, anti-inflammatory agents, immunomodulatory or immunosuppressant agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, agents for treating immune deficiency disorders, and immune checkpoint inhibitors. The compounds and pharmaceutically acceptable compositions of the present disclosure can be utilized in combination therapy, i.e., the compounds and pharmaceutically acceptable compositions may be potentially useful in combination with other therapies for the treatment of immune, inflammatory, proliferative, and allergic disorders. Examples include, but are not limited to, co-administration with steroids, leukotriene antagonists, antihistamines, anticancer drugs, protein kinase inhibitors, cyclosporine, rapamycin, or immune checkpoint inhibitors.

[0132] Cancer cells often use immune checkpoint molecules to evade or suppress attacks by the immune system. Thus, the expression of immune checkpoint molecules on the surface of cancer cells prevents immune cells, such as T cells, from recognizing them as "foreign" or "abnormal." Consequently, immune checkpoint inhibitors are compounds that block inhibitory immune checkpoint molecules, leading to immune system activation via T cell recognition. Inhibitory checkpoint molecules are increasingly being considered as novel targets for cancer immunotherapy due to the efficacy of two checkpoint inhibitor drugs—ipilimumab (e.g., YERVOY™, a monoclonal antibody that acts to activate the immune system by targeting CTLA-4) and pembrolizumab (e.g., KEYTRUDA™, a humanized antibody that targets the programmed cell death 1 (PD-1) receptor)—first indicated for the treatment of advanced melanoma. Another checkpoint inhibitor, known as nivolumab (e.g., OPDIVO™), blocks the interaction between PD-1 and programmed cell death ligand 1 (PD-L1), preventing immune inhibition.

[0133] In the methods disclosed herein, any molecule capable of inhibiting one or more immune checkpoint molecules can be used as an additional pharmaceutical agent. Such immune checkpoint inhibitors include, without limitation, antibodies or functional fragments thereof, inhibitory polypeptides, small molecule chemical compounds, and / or inhibitory nucleic acids (such as, but not limited to, antisense oligonucleotides, small inhibitory RNAs (siRNAs), small hairpin RNAs (shRNAs), and / or catalytic nucleic acids, e.g., ribozymes). Immune checkpoint molecules suitable for targeting by checkpoint inhibitors for use in any of the methods disclosed herein include, without limitation, adenosine A 2AReceptor (A2AR), B7-H3 (also known as CD276; e.g., MGA271), cytotoxic T-lymphocyte-associated protein 4 (CTLA4; also known as CD152; e.g., ipilimumab; AGEN-1884 (Agenus), programmed cell death ligand 1 (PD-L1; also known as CD274; e.g., MDX-1105 (Bristol Myers Squibb), WBP-3155 (C-stone), LY3300054 (EliLilly)), programmed cell death protein 1 (PD-1; also known as CD279; e.g., pembrolizumab, SHR-1210 (Incyte), STI-A1110 (Sorrento), REGN2810 (Regeneron), CT-011 (pidilizumab; Curetech), PDR-001 (Novartis), BGB-A317 (BeiGene), TSR-042 (Tesaro), ENUMC-8 (Enumeral), MGD-013 (Macrogenics; bispecific antibody against PD1 and Lag3), B7-H4 (also known as VTCN1), T-cell immunoglobulin and mucin domain-containing-3 (TIM3; also known as HAVCR2), B- and T-lymphocyte attenuator (BTLA; also known as CD272), indoleamine-pyrrole 2,3-dioxygenase(ide), killer cell immunoglobulin-like receptor (KIR; e.g., lirilumab), lymphocyte activation gene 3 (LAG-3; e.g., BMS-986016), T-cell immunoreceptor with Ig and ITIM domains (TIGIT; also known as WUCAM and Vstm3), ILT-3, ILT-4, and / or V-domain Ig suppressor of T-cell activation (VISTA).

[0134] In some embodiments, the immune checkpoint inhibitor is an antagonistic antibody, such as, but not limited to, one or more of ipilimumab (Bristol-MyersSquibb), nivolumab (Bristol-MyersSquibb), pembrolizumab (Merck), durvalumab (Medimmune), atezolizumab (Genentech / Roche), tremelimumab (Medimmune), and / or avelumab (Pfizer). The compounds and pharmaceutical compositions of the present disclosure can be used to prevent or treat ITK-mediated disorders through sequential or co-administration with another pharmaceutical agent.

[0135] 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 administered one of the compounds described herein, it may be appropriate to administer an antihypertensive agent in combination with the first pharmaceutical agent. Alternatively, 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). Alternatively, by way of example only, the benefit experienced by a 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 increased therapeutic benefit in a treatment for diabetes that includes administering one of the compounds described herein may also occur by providing the patient with another pharmaceutical agent for diabetes. In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply the additive benefit of the two pharmaceutical agents, or the patient may experience a synergistic benefit.

[0136] Specific non-limiting examples of possible combination therapies include the use of compounds of embodiments herein with the following: chemotherapeutic or antiproliferative 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.

[0137] 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 (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.

[0138] 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) substituted ribonucleotides (RIs) with ribonucleotides (RIs); (2) analgesic antagonists, 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, thiamin mononitrate ... (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 (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;

[0139] 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, for example, 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, commercially available under the trade name Diflucan™), antiviral agents (e.g., valacyclovir, commercially available under the trade name Valtrex™, acyclovir, and famciclovir, commercially available under the trade name Famvir™), corticosteroids, immunosuppressants (e.g., cyclophosphamide, , sold under the trade name Cytoxan™, azathioprine, methotrexate, mycophenolate), biologics (e.g., rituximab, sold under the trade name Rituxan™, etanercept, sold under the trade name Enbrel™, adalimumab, sold under the trade name Humira™, infliximab, sold under the trade name Remicade™, ustekinumab, sold under the trade name Stelara™, and alefacept, sold under the trade name Amevive™), and / or thyroid hormone substitutes.

[0140] 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 drugs can be used according to their standard or general dosages, as specified in the prescription information accompanying the commercially available form of the drug (for prescription information, see also the 2006 Edition of The Physician's Desk Reference). In some embodiments, the standard dosages of these drugs 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 may 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 embodiments herein may involve administering either the compound of an embodiment herein or the additional pharmaceutical agent in subtherapeutic amounts, or both in subtherapeutic amounts.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 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 GlaxoSmithKline It is currently available from Kline under the trade name Imuran™; and 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). 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.

[0141] In any case, the multiple pharmaceutical agents (at least one of which is a compound disclosed herein) can be administered in any order or 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 may be administered in multiple doses, or both may be administered in multiple doses. If not administered simultaneously, the timing between multiple doses may be any period ranging from a few minutes to 8 weeks, or any interval appropriate to maintain the desired therapeutic effect. In some embodiments, the timing between multiple doses may 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.

[0142] Thus, in another aspect, certain embodiments provide a method for treating an ITK-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 treating the disorder effective to reduce or prevent the 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 treating an ITK-mediated disorder. In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of the present invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier.

[0143] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of anti-inflammatory agents, anti-atherosclerotic agents, immunosuppressant drugs, immunomodulatory drugs, cytostatic drugs, antiproliferative agents, angiogenesis inhibitors, kinase inhibitors, cytokine blockers, and inhibitors of cell adhesion molecules. In another embodiment, the pharmaceutical composition may further comprise one or more additional pharmaceutical agents, for example, a chemotherapeutic agent, a steroid agent, an anti-inflammatory compound, or an immunosuppressant.

[0144] The ITK inhibitor compositions described herein may also be used in combination with other therapeutic agents selected for their therapeutic value against the condition being treated. Generally, in the pharmaceutical compositions described herein and in embodiments utilizing combination therapy, the other agent need not be administered in the same pharmaceutical composition and may be administered by a different route due to different physical and chemical characteristics. Initial administration generally follows established protocols, with subsequent modifications to the dosage, mode, and time of administration based on the observed effects. In certain cases, it may be appropriate to administer the ITK inhibitor compositions described herein in combination with another therapeutic agent. By way of example only, if a rash is one of the side effects experienced by a patient upon administration of the ITK inhibitor compositions described herein, it may be appropriate to administer an antihistamine in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of the ITK inhibitor may be enhanced by the administration of another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefits. In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient will either be merely an additive benefit of the two therapeutic agents, or the patient will experience a synergistic benefit.

[0145] Therapeutically effective dosages vary when drugs are used in combination for treatment. Methods for experimentally determining the therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are reported methodologies. Combination treatments also include periodic treatments that start and stop at various time points to assist in the clinical management of patients. In any case, multiple therapeutic agents (one of which is the ITK inhibitor described herein) can be administered in any order or simultaneously. When administered simultaneously, multiple therapeutic agents can be provided in a single, integrated form, or in multiple forms (for example, as a single pill or as two separate pills). In some embodiments, one or both of the therapeutic agents may be given in multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than 12 weeks. In addition, the combination method and composition are not limited to the use of only two drugs, and the use of a combination of multiple treatments is also envisioned.It is understood that the dosage regimen for treating, preventing, or ameliorating the condition(s) to be remedied may be modified according to various factors.These factors include the disorder that the subject suffers from, as well as the subject's age, weight, sex, diet, and medical condition.Therefore, in some embodiments, the dosage regimen actually utilized will vary widely and therefore deviate from the dosage regimen described herein.

[0146] The pharmaceutical agents constituting the combination therapy disclosed herein may be in a combined dosage form intended for substantially simultaneous administration or in separate dosage forms. The pharmaceutical agents constituting the combination therapy may also be administered sequentially, with either agent being administered in a regimen requiring two-step administration. A two-step administration regimen may require continuous administration of the active agents or spaced-apart administration of the separate active agents. The period between multiple administration steps may range from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as the efficacy, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent. Circadian fluctuations in target molecule concentrations may be used to determine the optimal dosing interval.

[0147] In another embodiment, the ITK inhibitors may be used in a sequence that provides additional or synergistic benefit to the patient. The ITK inhibitor and additional therapy(ies) may be administered before, during, or after the onset of a disease or condition, and the timing of administering the pharmaceutical composition containing the ITK inhibitor may vary in some embodiments. Thus, for example, the ITK inhibitor may be used prophylactically and administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. The ITK inhibitor and composition may be administered to a subject during the onset of symptoms or as soon as possible after onset. While embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that in some embodiments of the present invention, various alternatives to the embodiments described herein may be utilized in the practice of the present invention.

[0148] ITK inhibitors can be used in combination with the following classes of drugs: NSAIDs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, antiproliferative agents, angiogenesis inhibitors, biological agents, steroids, vitamin D3 analogs, retinoids, other kinase inhibitors, cytokine blockers, corticosteroids, and inhibitors of cell adhesion molecules. If a subject has or is at risk of having atherosclerosis or an atherosclerosis-related condition, the ITK inhibitor compositions described herein may be used in any combination with one or more agents or methods for treating atherosclerosis or an atherosclerosis-related condition. Examples of therapeutic agents / treatments for treating atherosclerosis or atherosclerosis-related conditions include, but are not limited to, any of the following: torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), colesevelam, cholestyramine, colestipol, gemfibrozil, probucol, and clofibrate. When a subject is suffering from or at risk of suffering from an inflammatory condition, the ITK inhibitor compositions described herein may be used in any combination with one or more agents or methods for treating the inflammatory condition.

[0149] 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 an ITK-related disease, disorder, or condition. In certain embodiments, the additional pharmaceutical agent is selected from a taxane, an inhibitor of bcr-abl, an inhibitor of EGFR, a DNA damaging agent, an antimetabolite, paclitaxel, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin, an anthracycline, AraC, 5-FU, camptothecin, doxorubicin, idarubicin, paclitaxel, docetaxel, vincristine, a MEK inhibitor, U0126, a KSP inhibitor, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab, tremelimumab, and durvalumab.

[0150] In some embodiments, the composition further comprises an additional pharmaceutical agent selected from a chemotherapeutic or antiproliferative 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 immunodeficiency disorder.

[0151] In some embodiments, one or more compounds of the embodiments herein can be used in combination with one or more other therapeutic agents used to treat ITK-mediated disorders, resulting in an improved therapeutic response compared to the response to the other therapeutic agents alone, without exacerbating their toxic effects. In some embodiments, compounds of the embodiments herein can be used in combination with one or more other ITK inhibitors, and / or JAK1 and / or JAK2 and / or JAK3 inhibitors and / or TYK2 inhibitors for the treatment of ITK-mediated disorders. Additive or synergistic effects are desirable outcomes of such combinations. The additional agents can be combined with the compounds of the present invention in a single dosage form or in a continuous dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms. In some embodiments, one or more additional agents can be administered to a patient in combination with at least one ITK inhibitor described herein, where the additional agents are administered intermittently, as opposed to continuously.

[0152] For example, in certain embodiments, the topically or orally administered ITK 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 a beneficial effect on the condition. For example, in certain embodiments, the topically or orally administered ITK inhibitors / antagonists disclosed herein can be used for the treatment of male or female pattern baldness (androgenetic 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.

[0153] For example, in certain embodiments, the compound is used alone or in combination with a topical corticosteroid, topical tacrolimus, topical vitiligo ... The treatment may be used in combination with pimecrolimus, phototherapy such as ultraviolet phototherapy using UVB, narrow band UVB, oral or topical psoralen plus ultraviolet A (PUVA), calcipotriene or other topical vitamin D analogues, excimer laser phototherapy, systemic immunosuppressants, surgical treatments such as skin minigrafts, autologous epidermal suspension transplants, camouflage such as with makeup or dihydroxyacetone, or other treatments known to have a beneficial effect on the condition.

[0154] In certain embodiments, the compounds of the present disclosure can be used in combination with one or more agents that act by the same or different mechanisms to achieve treatment of gastrointestinal disorders. The different agents can be administered sequentially or simultaneously (in separate compositions or in the same composition). Classes of agents useful for combination therapy include, but are not limited to, aminosalicylates, steroids, systemic immunosuppressants, anti-TNFα antibodies, TNF alpha ligand inhibitors, TNF binders, anti-VLA-4 antibodies, anti-integrin Cv37 antibodies, antibacterial agents, glucocorticoid agonists, nuclear factor kappa B inhibitors, 5-lipoxygenase inhibitors, integrin alpha-4 / beta-7 antagonists, cyclooxygenase inhibitors, IL-23 antagonists, leukotriene BLT receptor antagonists, IL-6 antagonists, IL-8 antagonists, integrin antagonists, nicotinic acetylcholine receptor agonists, PPARγ agonists, sphingosine-1-phosphate receptor-1 modulators, B-phosphoryl agonists, and steroids. These include lymphocyte antigen CD20 inhibitors, calcineurin inhibitors, CD3 antagonists, cell adhesion molecule inhibitors, eosinophil peroxidase inhibitors, heparin agonists, ICAM1 gene inhibitors, IL-13 antagonists, IL-2 receptor alpha subunit inhibitors, insulin sensitizers, interferon beta ligands, interferon gamma receptor antagonists, interleukin-1 beta ligand modulators, MAdCAM inhibitors, PDE4 inhibitors, sphingosine-1-phosphate receptor-1 agonists, TLR-9 agonists, acetylcholinesterase inhibitors, ACTH receptor agonists, activin receptor antagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, and antidiarrheals.

[0155] Aminosalicylates that can be used in combination with the compounds disclosed herein include, but are not limited to, mesalamine, osalazine, and sulfasalazine. Examples of steroids include, but are not limited to, prednisone, prednisolone, hydrocortisone, budesonide, beclomethasone, and fluticasone. Systemic immunosuppressants useful for treating inflammatory disorders include, but are not limited to, cyclosporine, azathioprine, methotrexate, 6-mercaptopurine, and tacrolimus. In addition, anti-TNFα antibodies, including, but not limited to, infliximab, adalimumab, golimumab, and certolizumab, can be used in combination therapy. Useful compounds that act by other mechanisms include anti-VLA-4 antibodies, such as natalizumab, anti-integrin α4β7 antibodies, such as vedolizumab, antibacterial agents, such as rifaximin, and antidiarrheal drugs, such as loperamide. (Mozaffari et al. Expert Opin. Biol. Ther. 2014, 14, 583-600; Danese, Gut, 2012, 61, 918-932; Lam et al., Immunotherapy, 2014, 6, 963-971.)

[0156] Other compounds that can be used in combination with the disclosed compounds of the present invention include, but are not limited to, opaganib, abatacept, mongersen, filgotinib, LYC-30937, BI-655130, mirikizumab, adalimumab, tacrolimus, rituximab, GSK-2982772, andecaliximab, naltrexone, risankizumab, QBECO, alicaforsen, etrolizumab. , foralumab, ocrelizumab, vedolizumab, amiselimod, ozanimod, dolcanatide, catridecacog, budesonide, STNM-01, cannabidiol, telotristat etiprate, SHP-647, carotegrast methyl, peg-ilodecaquin, TOP-1288, iberogast N, PF-06480605, peficitinib, beclomethasone, recombinant interferon beta-1a, interferon-β-1a infliximab, golimumab, tralokinumab, ustekinumab, certolizumab pegol, thalidomide, upadacitinib, apremilast, natalizumab, interferon beta-1a, rifaximin, RBX-2660, etrasimod, zileuton, fingolimod, cobitolimod, ropivacaine, ABX-464, PF-06700841, prednisolone, GLPG-0974, valganciclovir Le, cyclosporine, VB-201, tulinercept, MDGN-002, PTG-100, dexamethasone, GED-0507-34-Levo, bertilimumab, brazikumab, KHK-4083, rosiglitazone, moclavimod, sotrastaurin, KAG-308, PUR-0110, E-6007, balsalazide, basiliximab, LP-02, ASP-3291, Trichuris suis ova (Trichuris suis ova), K(D)PT, midismase, DNVX-078, batelizumab, Alekel, low molecular weight heparin, methenkephalin, tridecactide, HMPL-004, SB-012, olsalazine, balsalazide, propionyl-L-carnitine, Clostridium butyricum, beclomethasone, and acemannan.

[0157] General synthetic methods for preparing compounds The compounds of the present invention can be prepared using the methods exemplified 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 conventional methods known in the art.The representative procedures for preparing the compounds of the present invention are outlined in Schemes 1 and 2 below.Solvents and reagents whose synthetic preparations are not described below can be purchased from Sigma-Aldrich or Fisher Scientific.

[0158] Scheme 1 covers the general synthesis of 3,4-disubstituted pyrrolopyrimidines and pyrrolopyridines. Protection of 1a as the 2-(trimethylsilyl)ethoxymethyl (SEM) amine is achieved using SEM chloride and a strong base such as sodium hydride in a solvent such as DMF or THF to give 1b. 1b can be converted to the desired R boronic ester using a transition metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water. 3 Suzuki or related transition metal mediated coupling with R or other coupling partners provides 1c. 3 The group may be further modified after the coupling reaction by methods known to those skilled in the art. 3Further examples of incorporating groups into the heterocyclic core are shown in Schemes 6-8. Addition of an amino heterocycle to 1c via nucleophilic aromatic substitution in dioxane / water in the presence of potassium hydroxide under thermal conditions can give 1d. Treatment of 1d with an acid such as trifluoroacetic acid (TFA) in methylene chloride to achieve deprotection of the carbamate and SEM ether can give 1e. Treatment of 1e with acrylic acid and a peptide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of a weak base such as diisopropylethylamine (DIEA) in DMF, or reaction with acryloyl chloride in the presence of a tertiary amine base such as triethylamine in a solvent such as tetrahydrofuran, gives acrylamide 1f.

[0159] Scheme 1. Preparation of 3,4-disubstituted pyrrolopyrimidines and pyrrolidines [ka]

[0160] Scheme 2 covers the general synthesis of 3,4-disubstituted pyrrolopyrimidines and pyrrolopyridines. Protection of 1a as the 2-(trimethylsilyl)ethoxymethyl (SEM) amine is achieved using SEM chloride and a strong base such as sodium hydride in a solvent such as DMF or THF to give 2a. 1b can be converted to the desired R 2 amine as a boronate ester using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water. 3 Suzuki or related coupling with the R group provides 2b. 3The group may be further modified after the coupling reaction by methods known to those skilled in the art. Addition of an amino heterocycle to 2b via nucleophilic aromatic substitution in dioxane / water in the presence of potassium hydroxide via thermal conditions gives 2c. Treatment of 2c with an acid such as trifluoroacetic acid (TFA) in methylene chloride achieves deprotection of the carbamate and SEM ether to give 2d. Treatment of 2d with acrylic acid and a peptide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of a weak base such as diisopropylethylamine (DIEA) in DMF, or reaction with acryloyl chloride in the presence of a tertiary amine base such as triethylamine in a solvent such as tetrahydrofuran gives acrylamide 2e.

[0161] Scheme 2. Preparation of 3,4-disubstituted pyrrolopyrimidines and pyrrolidines [ka]

[0162] Scheme 3 covers the general synthesis of 3-ester, 4-substituted pyrrolopyrimidines and pyrrolopyridines. Addition of an amino-heterocycle to 3a in dioxane / water in the presence of potassium carbonate using thermal conditions affords 3b. Treatment of 3b with an acid such as trifluoroacetic acid (TFA) in methylene chloride achieves carbamate deprotection to afford 3c. Treatment of 3c with acrylic acid and a peptide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of a weak base such as diisopropylethylamine (DIEA) in DMF affords acrylamide 3d. Alternatively, 3c can be acylated using acryloyl chloride in the presence of a weak base such as triethylamine in dichloromethane to afford 3d.

[0163] Scheme 3. Preparation of 3-ester 4-substituted pyrrolopyrimidines and pyrrolopyridines. [ka]

[0164] Scheme 4 covers the general synthesis of 3-ester, 4-substituted pyrrolopyrimidines and pyrrolopyridines. Addition of an amino heterocycle to 3a via nucleophilic aromatic substitution in dioxane / water in the presence of potassium carbonate under thermal conditions affords 4a. Treatment of 4a with an acid such as trifluoroacetic acid (TFA) in methylene chloride achieves carbamate deprotection to afford 4b. Treatment of 4b with acrylic acid and a peptide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of a weak base such as diisopropylethylamine (DIEA) in DMF affords acrylamide 4c. Alternatively, 4b can be acylated using acryloyl chloride in the presence of a weak base such as triethylamine in dichloromethane to afford 4c.

[0165] Scheme 4. Preparation of 3-ester 4-substituted pyrrolopyrimidines and pyrrolopyridines. [ka]

[0166] Scheme 5 covers the general synthesis of 3,5-disubstituted pyrrolopyrimidines and pyrrolopyrazines. Protected 5a was synthesized as in Scheme 1. 5a was converted to the desired R as a boronate ester using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water. 3 Suzuki or related coupling with R 3The group may be further modified after the coupling reaction using methods known to those skilled in the art. Using Buchwald or Hartwig conditions, an amino heterocycle is added to 5b in toluene in the presence of palladium acetate as a catalyst, a ligand such as Xantphos, and a base such as cesium carbonate to give 5c. Treatment of 5c with an acid such as trifluoroacetic acid (TFA) in methylene chloride, followed by treatment with sodium acetate in ethanol, achieves deprotection of the carbamate and SEM protecting groups to give 5d. Treatment of 5d with acrylic acid and a peptide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in DMF in the presence of a weak base such as diisopropylethylamine (DIEA) gives acrylamide 5e. 3 and R 5 The order of adding the substituents can be reversed. In this case, the amino heterocycle is added to 5f in toluene using Buchwald or Hartwig conditions in the presence of palladium acetate as a catalyst, a ligand such as xantphos, and a base such as cesium carbonate to give 5g. Halogenation of 5g with NBS in DMF gives bromo 5h. Using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water, 5h can be converted to the desired R as a boronate ester. 3 Suzuki or related coupling with the group gives 5c.

[0167] Scheme 5. Preparation of 3,5-disubstituted pyrrolopyrimidines and pyrrolopyrazines. [ka]

[0168] In Scheme 6, the selected R 3 The synthesis of alkyl groups attached to keto and heteroaromatic cores is addressed. This sequence involves metal-halogen exchange of iodo-substituted 5a (or Br) and conversion of the intermediate anion to the desired R3 Following this general procedure, 6a is treated with n-butyllithium in ether at −78° C., followed by treatment with the appropriate Weinreb amide, to give ketone 6b, keto-cycloalkyl 6f, or keto-heterocycle 6d. If desired, these ketone products can be further manipulated. For example, ketone 6f can be treated with methylmagnesium bromide in THF to give the intermediate alcohol, which can be further reduced using triethylsilane in a mixture of TFA / DCM to give alkyl 6g. Alternatively, the anion of 6a can be reacted with an aldehyde instead of the Weinreb amide to give the alcohol directly. In this case, the anion of 6a can be reacted with various aldehydes, such as 6i, to give alcohol 6j. This alcohol can be removed, if desired, using triethylsilane in a mixture of TFA / DCM to give 6k. In all cases, the protecting group for 6a, if desired, can be selected by one skilled in the art. In many cases, a (SEM) or besylate protecting group is preferred. The chemistry outlined in Scheme 6 is meant to be representative, with many more options available to those skilled in the art.

[0169] Scheme 6. R in the heteroaromatic core 3 Position generation. [ka]

[0170] In Scheme 7, R 3 In this study, we focused on the synthesis of 7a (X = Cl or OMe) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water to give the desired R boronic ester (7b), using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl). 3Suzuki or related coupling with the cyclopropyl group affords 7c. Cyclopropanation of 7c can be achieved via a variety of methods, including CH2I2 and Et2Zn, TMSCF3, using NaI, NMU, KOH, and Pd(OAc)2, to afford the desired substituted cyclopropyl 7d. Often, R or R 3-1 The substituents may be modified by conventional procedures known in the art.

[0171] Scheme 7. R for substituted cyclopropyl analogues 3 Position generation. [ka] (Simmons Smith: Simmons-Smith reagent)

[0172] In Scheme 8, R 3 where R is a substituted cycloalkyl group on a heteroaromatic core. 6a can be converted to the desired R as a boronate ester (8a) using a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) in the presence of a weak base such as potassium carbonate in a solvent mixture of dioxane / water. 3 Suzuki or related coupling with the aryl group affords 8b. Hydrogenation of 8b using hydrogen, Pd / C in a solvent such as ethanol affords 8c. Alternatively, 8b can be treated with CH2I2 and Et2Zn under Simmons-Smith conditions to form the bicyclic analog 8d.

[0173] Scheme 8. R for substituted cycloalkyl analogues 3 Location refinement. [ka] The present disclosure is further illustrated by the following examples.

[0174] Example 1 Preparation of ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka]

[0175] Step 1: Preparation of ethyl (R)-4-((1-(tert-butoxylcarbonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidinecarboxylate [ka] A mixture of ethyl 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.150 g, 0.665 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.146 g, 0.731 mmol), and N,N-diisopropylethylamine (0.346 mL, 1.99 mmol) in N-butanol (2 mL) was heated in a sealed vessel at 135° C. for 1 hour. At this time, the reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel, eluting with methanol and ethyl acetate. Pure fractions were pooled and concentrated to give ethyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidinecarboxylate as a clear oil (0.256 g, 99% yield): MS (ES) m / z 390.3 (M+H).

[0176] Step 2: Preparation of ethyl (R)-4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of ethyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidinecarboxylate (0.256 g, 0.657 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL, 13.1 mmol) at 0° C. The solution was stirred at ambient temperature for 1 hour. The reaction was concentrated under reduced pressure to give ethyl (R)-4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as an oil in quantitative yield. The material was used without further purification: (MS (ES) m / z 290.2 (M+H).

[0177] Step 3: Preparation of ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of ethyl (R)-4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.190 g, 0.657 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.340 mL, 1.96 mmol). Separately, a solution of prop-2-enoic acid (0.066 mg, 0.919 mmol) in dichloromethane (2 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.190 g, 0.985 mmol) and N,N-diisopropylethylamine (0.340 mL, 1.96 mmol). After 15 minutes at ambient temperature, a solution of the activated acid was added to the amine solution, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was then dissolved in ethyl acetate and washed with water and then brine. The ethyl acetate layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was chromatographed on silica gel, eluting with methanol and ethyl acetate. Pure fractions were pooled and concentrated to give ethyl (R)-4-((1-acryloylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (90 mg, 40% yield):1 H-NMR (400 MHz, DMSO-d6) δ 12.48 (br s, 1 H), 8.58 (br d, J = 7.04 Hz, 1 H), 8.21 (br d, J = 11.35 Hz, 1 H), 7.92 (s, 1 H), 6.49-6.89 (m, 1 H), 5.91-6.12 (m, 1 H), 5.42-5.72 (m, 1 H), 4.11-4.35 (m, 3 H), 3.83-4.08 (m, 1 H), 3.38-3.72 (m, 3 H), 1.87-2.10 (m, 1 H), 1.63-1.86 (m, 2 H), 1.47-1.62 (m, 1 H), 1.30 (t, J = 7.04 Hz, 3 H); MS (ES) m / z 344.3 (M+H).

[0178] Example 2 Preparation of ethyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka]

[0179] Step 1: Preparation of ethyl 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (4.00 g, 17.7 mmol) in DCM (40 mL) was added triethylamine (7.48 mL, 53.3 mmol) and N,N-dimethylaminopyridine (0.210 g, 1.77 mmol) at room temperature. Sulfonylbenzene chloride (4.00 g, 22.9 mmol) was then added dropwise over 10 minutes. The resulting reaction mixture was stirred at room temperature for another 30 minutes. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL) and washed with water. The organic layer was then washed with brine and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give the crude material, which was then purified on a Combi-flash purification apparatus using 20% ​​ethyl acetate in hexanes as the eluent to yield ethyl 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid: (5.3 g, 82% yield): MS (ES) m / z 366.3 (M+H). +1 .

[0180] Step 2: Preparation of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (5.30 g, 14.5 mmol) in n-butanol (50 mL) was added benzyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (4.53 g, 15.9 mmol) and N,N-diisopropylethylamine. The reaction mixture was heated to 130° C. in a sealed tube for 16 hours. After completion of the reaction, the reaction mixture was allowed to cool and concentrated under reduced pressure. The crude residue was then dissolved in ethyl acetate and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude material was purified on a Combi-flash purification apparatus using 50% ethyl acetate in hexane as the eluent to yield benzylethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a light brown solid. (6.5 g, 78% yield): MS (ES) m / z 578.1 (M+H). +1

[0181] Step-3: Preparation of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of benzylethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (6.50 g, 11.7 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (3.9 g, 35 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid (3.4 g, 69% yield): MS (ES) m / z 438.1 (M+H). +1 .

[0182] Step-4: Preparation of ethyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a nitrogen-purged solution of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3.4 g, 7.8 mmol) in tetrahydrofuran (100 mL) was added 10% Pd / C (3 g). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the crude desired compound. The crude product obtained was used in the next step without any purification (2.35 g, 100% yield): MS (ES) m / z 304.1 (M+H). +1 .

[0183] Step 5: Preparation of tert-butyl 4-((3-(1-cyclopropyl-2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of ethyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (2.4 g, 7.92 mmol) in THF / water (60 / 40 mL) was added triethylamine (3.3 mL, 23.7 mmol) at 0 °C. Then, acryloyl chloride (0.76 mL, 9.5 mmol) was added slowly at 0 °C. The resulting reaction mixture was stirred at the same temperature for 20 minutes. After completion of the reaction, the mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum to give the crude material, which was purified by silica gel chromatography (20% MeOH in DCM) to produce the pure title compound as a white solid (1.14 g, 40% yield): 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 7.9 (s, 1H), 6.81-6.74 (m, 1H), 6.1-6.05 (dd, J1= 2 Hz, J2= 16.8 Hz, 1H), 5.67-5.64 (m, 1H), 4.51 (bs, 2H), 4.29 (q, J1= 6.8 Hz, 2H), 3.93 (bs, 1H), 2.64 (bs, 1H), 1.92 (bs, 1H), 1.71-1.64 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.17 (d, J= 6.4 Hz, 3H); MS (ES) m / z 358.0 (M+H).

[0184] Example 3 Preparation of isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] The title compound was prepared as described in Scheme 9.

[0185] Scheme 9. Preparation of isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka]

[0186] Step 1: Preparation of propyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a suspension of potassium carbonate (0.153 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) were added benzylethyl-4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (prepared as described in Example 4, Step 5, 0.2 g, 0.37 mmol), n-propyl bromide (0.22 g, 1.85 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (30% ethyl acetate / hexanes) to give propyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a yellow solid (0.2 g, 93% yield): MS (ES) m / z 582.5 (M+H).

[0187] Step 2: Preparation of propyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of propyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.2 g, 0.34 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (5 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The reaction was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (70% ethyl acetate / hexanes) to give propyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.09 g, 58% yield): MS (ES) m / z 452.4 (M+H).

[0188] Step 3: Propyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.09 g, 0.2 mmol) in tetrahydrofuran (10 mL) was added palladium on carbon (0.05 g, 10% wet weight w / w) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give propyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.06 g, crude): MS (ES) m / z 318.1 (M+H).

[0189] Step 4: Preparation of propyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of propyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.06 g, 0.188 mmol) in tetrahydrofuran:water (3:2 mL) was added triethylamine (0.08 mL, 0.56 mmol), followed by a solution of acryloyl chloride (0.02 mL, 0.22 mmol) in tetrahydrofuran (0.5 mL) at 0° C. and stirred for 20 minutes. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% methanol / dichloromethane) to give propyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.02 g, 20% yield): 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 6.74-6.81 (m, 1H), 6.07 (d, J = 16.8 Hz, 1H), 5.65 (d, J = 10 Hz, 1H), 4.5 (br s, 3H), 4.2 (t, J = 6.4 Hz, 2H), 3.93 (bs, 1H), 1.91 (br s, 1H), 1.67-1.78 (m, 4H), 1.14-1.46 (m, J = 7.2 Hz, 5H), 0.95 (t, J = 7.2 Hz, 2H); MS (ES) m / z 371.1.0 (M+H).

[0190] Example 4 Preparation of isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] The title compound was prepared as described in Scheme 10.

[0191] Scheme 10. Preparation of isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka]

[0192] Step 1: Preparation of ethyl 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (4.0 g, 17.7 mmol) in dichloromethane (40 mL) was added triethylamine (7.48 mL, 53.28 mmol), N,N-dimethylaminopyridine (0.21 g, 1.77 mmol), followed by the dropwise addition of benzenesulfonyl chloride (4 g, 22.88 mmol) over a 10-minute period, and the mixture was stirred at ambient temperature for 0.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give ethyl 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid (5.3 g, 82% yield): MS (ES) m / z 366.3 (M+H).

[0193] Step 2: Preparation of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo-[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of ethyl 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (5.3 g, 14.5 mmol) in n-butanol (50 mL) was added benzyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (4.53 g, 15.9 mmol) and N,N-diisopropylethylamine (10.1 mL, 58 mmol), and the mixture was heated in a sealed tube at 130° C. for 16 hours. The mixture was cooled to ambient temperature, poured into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give benzylethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)6-methyl-piperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a light brown solid (6.5 g, 77.6% yield): MS (ES) m / z 578.1 (M+H).

[0194] Step 3: Preparation of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of benzylethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (6.5 g, 11.69 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (3.9 g, 35 mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid (3.4 g, 69% yield): MS (ES) m / z 438.1 (M+H).

[0195] Step 4: Preparation of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a suspension of sodium hydride (0.12 g, 3.29 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1.2 g, 2.74 mmol) at 0° C. The suspension was stirred for 15 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (0.55 g, 3.29 mmol) was added at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.9 g, 58% yield): MS (ES) m / z 568.2 (M+H).

[0196] Step 5: Preparation of 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid [ka] To a stirred solution of ethyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.85 g, 1.49 mmol) in tetrahydrofuran:methanol (10:10 mL) was added lithium hydroxide monohydrate (0.63 g, 14.9 mmol) and the mixture was stirred at ambient temperature for 16 hours. The volatiles were removed in vacuo and the residue was diluted with water and acidified with 1 N hydrochloric acid (pH = approx. 4). The aqueous layer was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid as a white solid (0.75 g, 93.7% yield): MS (ES) m / z 540.2 (M+H).

[0197] Step 6: Preparation of isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a suspension of potassium carbonate (0.19 g, 1.39 mmol) in N,N-dimethylformamide (10 mL) were added 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (0.25 g, 0.46 mmol) and isopropyl bromide (0.13 mL, 1.39 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (30% ethyl acetate / hexanes) to give isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxylate as a pale yellow solid (0.2 g, 74.3% yield): MS (ES) m / z 582.5 (M+H).

[0198] Step 7: Preparation of isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.2 g, 0.34 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (5 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (70% ethyl acetate / hexanes) to give isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.1 g, 64% yield): MS (ES) m / z 452.2 (M+H).

[0199] Step 8: Preparation of isopropyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of isopropyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.1 g, 0.22 mmol) in tetrahydrofuran (10 mL) was added palladium on carbon (0.05 g, 10 wet weight w / w) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give isopropyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.08 g, crude): MS (ES) m / z 318.3 (M+H).

[0200] Step 9: Preparation of isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a solution of isopropyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.08 g, 0.25 mmol) in tetrahydrofuran:water (3:2 mL) was added triethylamine (0.1 mL, 0.75 mmol), followed by a solution of acryloyl chloride (0.018 mL, 0.22 mmol) in tetrahydrofuran (0.5 mL) at 0° C. and stirred for 20 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% methanol / dichloromethane) to give isopropyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.02 g, 19% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 6.74-6.81 (dd, J1= 10.8 Hz, J2= 16.8 Hz, 1H), 6.05-6.09 (dd, J1= 2 Hz, J2= 16.8 Hz, 1H), 5.66 (d, J = 10.4 Hz, 1H), 5.10-5.16 (m, 1H), 4.5 (br s, 3H), 3.93 (br s, 1H), 1.92 (br s, 1H), 1.71-1.68 (m, 3H), 1.31 (d, J = 6 Hz, 6H), 1.16-1.21 (m, 3H); MS (ES) m / z 372.3(M+H).

[0201] Example 5 Preparation of (R)-1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 34. Scheme 34

[0202] [ka]

[0203] Step 1: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanol [ka] To a stirred solution of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared as described in Example 7, 2 g, 5.52 mmol) in diethyl ether (30 mL) was added n-butyllithium (5.17 mL, 8.28 mmol, 1 M in hexanes) at −78° C. and stirred for 0.5 h. Then, a solution of cyclopropanecarbaldehyde (0.64 mL, 8.28 mmol) in diethyl ether (3 mL) was added at −78° C. and the mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (40% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(cyclopropyl)methanol as a brown liquid (1.2 g, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 7.76 (s, 1H), 5.61 (s, 2H), 5.11 (s, 1H), 4.76 (s, 1H), 3.50 (t, J = 7.6 Hz, 2H), 1.31-1.32 (m, 1H), 0.82 (t, J = 8 Hz, 2H), 0.34-0.44 (m, 4H), 0.03 (s, 9H); MS (ES) m / z 354.0 (M+H).

[0204] Step 2: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)-methanol (1.2 g, 3.39 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (2.1 g, 5.09 mmol) at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and sodium thiosulfate and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone as a brown liquid (0.5 g, 45% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.02 (s, 1H), 5.62 (s, 2H), 3.52 (t, J = 8 Hz, 2H), 1.50-1.54 (m, 1H), 0.80 (t, J = 8 Hz, 2H), 0.48-0.59 (m, 4H), 0.08 (s, 9H); MS (ES) m / z 352.1 (M+H).

[0205] Step 3: Preparation of tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone (0.5 g, 1.42 mmol) in N-methyl-2-pyrrolidone (30 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.34 g, 1.70 mmol), and the mixture was heated in a sealed tube at 180° C. for 4 hours. The reaction mixture was cooled to ambient temperature, poured into water, and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (27% ethyl acetate / hexanes) to give tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.6 g, crude) as a brown liquid: MS (ES) m / z 516.2 (M+H).

[0206] Step 4: Preparation of tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.6 g, 1.16 mmol) in tetrahydrofuran (4 mL) was added tetrabutylammonium fluoride (10 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The reaction mixture was cooled to ambient temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (4% methanol / dichloromethane) to give tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a yellow liquid (0.17 g, 39% yield): MS (ES) m / z 386.2 (M+H).

[0207] Step 5: Preparation of (R)-cyclopropyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.17 g, 0.44 mmol) in dichloromethane (2 mL) was added hydrogen chloride (1.1 mL, 4.41 mmol, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 16 hours. The reaction was concentrated under reduced pressure, and the residue was washed with ether to give (R)-cyclopropyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride as an off-white solid (0.17 g, crude): MS (ES) m / z 286.1 (M+H).

[0208] Step 6: Preparation of (R)-1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of (R)-cyclopropyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride (0.17 g, 0.52 mmol) in tetrahydrofuran:water (10:6 mL) was added triethylamine (0.22 mL, 1.58 mmol), followed by acryloyl chloride (0.04 g, 0.42 mmol) at 0° C. and stirred for 15 minutes. The reaction mixture was quenched with sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (3% methanol / dichloromethane) to give (R)-1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as a white solid (0.03 g, 18% yield): 1H NMR (400 MHz, DMSO-d at 690℃): δ 12.2 (s, 1H), 9.07-9.09 (m, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 6.59 (br s, 1H), 5.93-5.97 (m, 1H), 5.50-5.53 (m, 1H), 4.15 (b, 1H), 3.91-3.95 (m, 1H), 3.60-3.64 (m, 1H), 3.37-3.47 (m, 2H), 2.75-2.76 (m, 1H), 1.98-2.01 (m, 1H), 1.78-1.79 (m, 1H), 1.66-1.68 (m, 1H), 1.51-1.57 (m, 1H), 1.01-1.02 (m, 2H), 0.92-0.95 (m, 2H); MS (ES) m / z 340.0 (M+H).

[0209] Example 6 Preparation of (R)-1-(3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 11.

[0210] Scheme 11. Preparation of (R)-1-(3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0211] Step 1: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopentyl)methanone [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopentyl)methanol (prepared as described in Example 13, 1.5 g, 3.93 mmol) in dichloromethane (20 mL) cooled to 0° C., pyridinium chlorochromate (1.48 g, 5.90 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate and saturated sodium thiosulfate and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (22% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopentyl)methanone as a brown liquid (1 g, 72% yield): MS (ES) m / z 380 (M+H).

[0212] Step 2: Preparation of tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopentyl)methanone (1 g, 2.63 mmol) in ethanol (30 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.789 g, 3.94 mmol) and the mixture was heated in a sealed tube at 180° C. for 4 hours. The reaction mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (25% ethyl acetate / hexanes) to give tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a brown liquid (0.5 g, 38.46% yield): MS (ES) m / z 530 (M+H).

[0213] Step 3: Preparation of tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.5 g, 0.94 mmol) in tetrahydrofuran (6 mL) was added tetrabutylammonium fluoride (8 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (4% methanol / dichloromethane) to give tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a yellow liquid (0.25 g, 63% yield): MS (ES) m / z 414 (M+H).

[0214] Step 4: Preparation of (R)-cyclopentyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.25 g, 0.60 mmol) in dichloromethane (2 mL) was added hydrogen chloride (2.5 mL, 6.05 mmol, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give (R)-cyclopentyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride as an off-white solid (0.15 g, crude): MS (ES) m / z 314 (M+H).

[0215] Step 5: Preparation of (R)-1-(3-((5-(cyclopentanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a solution of (R)-cyclopentyl(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone hydrochloride (0.15 g, 0.47 mmol) in tetrahydrofuran:water (10:6 mL) cooled to 0° C., a solution of triethylamine (0.1 mL, 0.96 mmol), acryloyl chloride (0.07 mL, 0.86 mmol) in tetrahydrofuran (0.5 mL) was added at 0° C. and stirred for 15 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) to give (R)-1-(3-((5-(cyclopentane-carbonyl)-7H-pyrrolo[2,3-2015]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as a white solid (0.04 g, 23% yield): 1 H NMR (400 MHz, DMSO-d at 690℃) δ 12.2 (s, 1H), 9.07 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 3.2 Hz, 2H), 6.62 (t, J = 15.2 Hz, 1H), 5.93 - 5.98 (m, 1H), 5.51 (d, J = 10 Hz, 1H), 4.16 (s, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.61-3.72 (m, 2H), 3.03-3.49 (m, 2H), 2.00-2.05 (m, 1H), 1.81-1.85 (m, 3H), 1.53-1.79 (m, 8H); MS (ES) m / z 368.4 (M+H).

[0216] Example 7 Preparation of 1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 12.

[0217] Scheme 12. Preparation of 1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka]

[0218] Step 1: Preparation of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [ka] To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.67 mmol) in dichloromethane (50 mL) was added N-bromosuccinimide (6.9 g, 39.21 mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction was concentrated under reduced pressure. The resulting solid was filtered, washed with water, and dried to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (7.7 g, crude): 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.60 (s, 1H), 7.92 (s, 1H); MS (ES) m / z 231.9 (M+2H).

[0219] Step 2: Preparation of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ka] To a suspension of sodium hydride (5 g, 21.55 mmol) in dimethylformamide (20 mL) was added 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 21.55 mmol) at 0° C. and stirred at ambient temperature for 30 minutes, followed by cooling to 0° C. and adding 2-(trimethylsilyl)ethoxymethyl chloride (4.58 mL, 25.86 mmol). The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (15% ethyl acetate / hexanes) to give 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (4.5 g, 58% yield): 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.14 (s, 1H), 5.60 (s, 2H), 3.51 (t, J = 7.6 Hz, 2H), 0.81 (t, J = 8 Hz, 2H), 0.08 (s, 9H); MS (ES) m / z 362.0 (M+H).

[0220] Step 3: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanol [ka] To a stirred solution of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.52 mmol) in diethyl ether (30 mL) was added n-butyllithium (5.17 mL, 8.28 mmol, 1.6 M in hexanes) at −78° C. and stirred for 10 minutes. A solution of cyclopropanecarbaldehyde (0.64 mL, 8.28 mmol) in diethyl ether (3 mL) was then added at −78° C., and the resulting mixture was stirred for 0.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (32% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanol as a brown liquid (1.2 g, 61% yield): 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.76 (s, 1H), 5.61 (s, 2H), 5.11 (s, 1H), 4.76 (s, 1H), 3.50 (t, J = 7.6 Hz, 2H), 1.31-1.32 (m, 1H), 0.82 (t, J = 8 Hz, 2H), 0.34-0.44 (m, 4H), 0.03 (s, 9H); MS (ES) m / z 354.1 (M+H).

[0221] Step 4: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanol (1.2 g, 3.39 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (2.1 g, 5.09 mmol) at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with sodium thiosulfate and dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone as a brown liquid (0.5 g, 45% yield): 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.02 (s, 1H), 5.62 (s, 2H), 3.52 (t, J = 8 Hz, 2H), 1.50-1.54 (m, 1H), 0.80 (t, J = 8 Hz, 2H), 0.48-0.59 (m, 4H), 0.08 (s, 9H); MS (ES) m / z 352.1 (M+H).

[0222] Step 5: Preparation of tert-butyl 3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone (0.45 g, 1.28 mmol) in N-methyl-2-pyrrolidone (30 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (0.33 g, 1.92 mmol), and the mixture was heated in a sealed tube at 120° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give tert-butyl 3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate as a brown liquid (0.4 g, 65% yield): 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.74 (s, 1H), 8.25 (s, 1H), 5.56 (s, 2H), 4.72-4.76 (m, 1H), 4.22-4.24 (m, 2H), 3.70-3.71 (m, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.78-2.82 (m, 1H), 1.44 (s, 9H), 1.14-1.17 (m, 2H), 1.01-1.09 (m, 2H), 0.83 (t, J = 7.6 Hz, 2H), 0.08 (s, 9H); MS (ES) m / z 488.2 (M+H)..

[0223] Step 6: Preparation of tert-butyl 3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-((5-(cyclopropanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate (0.4 g, 0.82 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (8 mL, 1 M solution in tetrahydrofuran) and the solution was heated to 80° C. for 16 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (4% methanol / dichloromethane) to give tert-butyl 3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate as an off-white solid (0.2 g, 69% yield): 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.47 (s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 4.70 (br s, 1H), 4.21-4.22 (m, 2H), 3.68-3.70 (m, 2H), 1.56-157 (m, 1H), 1.37 (s, 9H), 1.06-1.08 (m, 2H), 0.90-0.96 (m, 2H); MS (ES) m / z 358.1 (M+H).

[0224] Step 7: Preparation of (4-(azetidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone hydrochloride [ka] To a stirred solution of tert-butyl 3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidine-1-carboxylate (0.2 g, 0.56 mmol) in dichloromethane (2 mL) was added hydrogen chloride (1.4 mL, 56.02 mmol, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether to give (4-(azetidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone hydrochloride as an off-white solid (0.15 g, 94% yield): MS (ES) m / z 258.1 (M+H).

[0225] Step 8: Preparation of 1-(3-((5-(cyclopropanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of (4-(azetidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanone hydrochloride (0.15 g, 0.51 mmol) in tetrahydrofuran:water (10:6 mL) was added triethylamine (0.22 mL, 1.53 mmol), followed by acryloyl chloride (0.04 g, 0.40 mmol) at 0° C. and stirred for 15 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (3% methanol / dichloromethane) and further purified by using prep HPLC to give 1-(3-((5-(cyclo-propanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one as a white solid (0.04 g, 27%): 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.51 (d, J = 5.6 Hz, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 6.33-6.36 (m, 1H), 6.29-6.31 (m, 1H), 5.64-5.66 (m, 1H), 4.76-4.83 (m, 1H), 4.59 (t, J = 8.4 Hz, 1H) 4.31 (t, J = 10 Hz, 1H), 4.04-4.07 (m, 1H), 3.74-3.78 (m, 1H), 2.81-2.86 (m, 1H), 1.01-1.06 (m, 2H), 0.94-0.97 (m, 2H); MS (ES) m / z 312.1 (M+H).

[0226] Prep HPLC method: Column: ZORBAX XDBC-18 (150 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: 3.129 min.

[0227] Example 8 Preparation of (R)-1-(3-((3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 13.

[0228] Scheme 13. Preparation of (R)-1-(3-((3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0229] Step 1: Preparation of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloropropan-1-one [ka] To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 25.37 mmol) in dichloromethane (100 mL) was added aluminum chloride (10.12 g, 50.74 mmol) portionwise at 0 °C for 50 minutes at the same temperature. Chloropropanoyl chloride (4.8 mL, 76.11 mmol) was then added dropwise at 0 °C, and the mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The resulting solid was dissolved in methanol, triethylamine (30 mL) was added, and the solution was stirred at 65 °C for 16 hours. The reaction was concentrated under reduced pressure and the white solid was washed with saturated aqueous sodium bicarbonate, water and dried to give 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloropropan-1-one as a brown solid (4.5 g, 61.8%): MS (ES) m / z 286.9 (M+H).

[0230] Step 2: Preparation of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropan-1-one [ka] To a suspension of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloropropan-1-one (3.0 g, 10.43 mmol) in methanol (50 mL), potassium iodide (2.6 g, 15.64 mmol) was added and stirred at 70 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10% methanol in dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was washed with diethyl ether and n-pentane to give 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropan-1-one as a yellow solid (1.4 g, 47% yield): MS (ES) m / z 285.0 (M+H).

[0231] Step 3: Preparation of tert-butyl 4-bromo-3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka] To a suspension of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropan-1-one (1.4 g, 4.94 mmol) in tetrahydrofuran (30 mL), triethylamine (2.0 mL, 14.83 mmol), 4-dimethylaminopyridine (0.06 g, 0.49 mmol), and di-tert-butyl dicarbonate (1.7 mL, 7.41 mmol) were added at 0 °C, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give tert-butyl 4-bromo-3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a brown viscous oil (0.8 g, 42% yield): MS (ES) m / z 385.0 (M+H).

[0232] Step 4: Preparation of tert-butyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-bromo-3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.3 g, 0.78 mmol) in N,N-dimethyl sulfoxide (3 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.62 g, 3.14 mmol), and the mixture was heated in a sealed tube at 100° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) to give tert-butyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-3-(3-methoxy-propanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a light brown sticky mass (0.2 g, 50% yield): MS (ES) m / z 403.2 (M+H).

[0233] Step 5: Preparation of (R)-3-methoxy-1-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one hydrochloride [ka] To a stirred solution of tert-butyl (R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.4 g, 0.795 mmol) in dichloromethane (5 mL) was added hydrogen chloride (10 mL, 4 M in dioxane) at 0 ° C., and the mixture was warmed to ambient temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give (R)-3-methoxy-1-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one hydrochloride (0.35 g, crude): MS (ES) m / z 303.1 (M + H).

[0234] Step 6: Preparation of (R)-1-(3-((3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a solution of (R)-3-methoxy-1-(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)propan-1-one hydrochloride (0.12 g, 0.32 mmol) in tetrahydrofuran:water (7:3 mL) was added triethylamine (0.13 mL, 0.96 mmol), followed by a solution of acryloyl chloride (0.02 mL, 0.24 mmol) in tetrahydrofuran (0.4 mL) at 0° C. and stirred for 15 minutes. The reaction mixture was then quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) and further purified by using prep HPLC to give (R)-1-(3-((3-(3-methoxypropanoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as a white solid (0.06 g, 5.5% yield): 1H NMR (400 MHz, DMSO-d6, at 80℃) δ 12.0 (br s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J = 5.6Hz, 1H), 6.55-6.75 (m, 1H), 6.28 (d, J = 5.6 Hz, 1H), 5.99 (d, J = 16.4 Hz, 1H), 5.48-5.62 (m, 1H), 3.95-4.15 (m, 1H), 3.65-3.80 (m, 4H), 3.50-3.62 (m, 2H), 3.36-3.45 (m, 2H), 3.34 (s, MS (ES) m / z 357.4 (M+H).

[0235] Prep HPLC method: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic) Mobile phase (A): 0.1% ammonia in water Mobile phase (B): Methanol Flow rate: 1.0mL / min (45:55) Retention time: 3.186 minutes.

[0236] Example 9 Preparation of (R)-1-(3-((3-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0237] Step 1: Preparation of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.62 mmol) in 1.5 mL of dichloromethane was added aluminum chloride (2.43 g, 18.3 mmol). After stirring at ambient temperature for 1 hour, cyclopropanecarbonyl chloride (236 μL, 2.62 mmol) was added. The reaction was stirred overnight at ambient temperature. The reaction was quenched with a saturated solution of Rochelle's salt. The solution was stirred rapidly for 1 hour. The resulting yellow solid was collected by vacuum filtration to give 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine (580 mg, 2.62 mmol): MS (ES) m / z 221 (M+H).

[0238] Step 2: Preparation of tert-butyl (3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate [ka] To a solution of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine (95 mg, 0.430 mmol) obtained in Step 1 in N-methylpyrrolidine (2 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (258 mg, 1.29 mmol) and triethylamine (59.9 μL, 0.431 mmol). The solution was treated with microwave radiation at 130° C. for a total of 13 hours. After cooling, the solution was partitioned between ethyl acetate and water. The organic layer was concentrated, and the residue was purified using normal phase chromatography (ethyl acetate / heptane). The desired material was collected and concentrated to give tert-butyl (3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate (20.0 mg, 0.052 mmol) as a pale yellow oil: MS (ES) m / z 385 (M+H).

[0239] Step 3: Preparation of 1-[(3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidin-1-yl]prop-2-en-1-one [ka] To a solution of tert-butyl (3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate (20 mg, 0.0520 mmol) from Step 2 in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the solution was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL), and triethylamine (18.0 μL, 0.130 mmol) was added. To this solution was added a solution of N-[3-(dimethylamino)propyl]propanimidamide hydrochloride (12.0 mg, 0.0624 mmol), prop-2-enoic acid (3.55 μL, 0.0520 mmol), and triethylamine (18.0 μL, 0.130 mmol) in tetrahydrofuran (0.5 mL). The mixture was stirred at ambient temperature for 4 hours. The solution was partitioned between ethyl acetate and water. The organic layer was separated and concentrated. The crude material was purified using normal phase chromatography (dichloromethane / methanol) to give 1-[(3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidin-1-yl]prop-2-en-1-one (4.5 mg, 0.013 mmol): 1H NMR (400 MHz, DMSO-d6) δ 12.26 (br s, 1H), 8.85-9.02 (m, 1H), 8.43 - 8.52 (m, 1H), 7.84-7.93 (m, 1H), 6.48-6.89 (m, 1H), 5.86-6.16 (m, 1H), 5.40-5.72 (m, 1H), 4.38-4.64 (m, 1H), 4.08-4.34 (m, 1H), 3.52-3.91 (m, 2H), 3.38-3.51 (m, 1H), 2.96-3.12 (m, 1H), 1.91-2.10 (m, 1H), 1.36-1.91 (m, 3H), 0.86-1.05 (m, 4H); MS (ES) m / z 339 (M+H).

[0240] Example 10 Preparation of 1-(4-((3-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0241] Step 1: Preparation of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.62 mmol) in 1.5 mL of dichloromethane was added aluminum chloride (2.43 g, 18.3 mmol). After stirring at ambient temperature for 1 hour, cyclopropanecarbonyl chloride (236 μL, 2.62 mmol) was added. The reaction was stirred overnight at ambient temperature. The reaction was quenched with a saturated solution of Rochelle's salt. The solution was stirred rapidly for 1 hour. The resulting yellow solid was collected by vacuum filtration to give 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine (580 mg, 2.62 mmol): MS (ES) m / z 221 (M+H).

[0242] Step 2: Preparation of tert-butyl 4-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate [ka] To a solution of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.2265 mmol) obtained in Step 1 in N-methylpyrrolidine (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (136 mg, 0.680 mmol) and triethylamine (31.5 μL, 0.227 mmol). The solution was treated with microwave radiation at 130° C. for 19 hours. After cooling, the resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified using normal phase chromatography (dichloromethane / methanol). The desired material was collected and concentrated to give tert-butyl 4-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate (36.0 mg, 0.0936 mmol) as a pale yellow oil: MS (ES) m / z 385 (M+H).

[0243] Step 3: Preparation of 1-[4-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidin-1-yl]prop-2-en-1-one [ka] To a solution of tert-butyl 4-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidine-1-carboxylate (36 mg, 0.0936 mmol) from Step 2 in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the solution was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL), and triethylamine (32.5 μL, 0.234 mmol) was added. To this solution was added a solution of N-[3-(dimethylamino)propyl]propanimidamide hydrochloride (21.7 mg, 0.112 mmol), prop-2-enoic acid (6.41 μL, 0.0936 mmol), and triethylamine (32.5 μL, 0.234 mmol) in tetrahydrofuran (0.5 mL). The mixture was stirred at ambient temperature for 4 hours. The solution was partitioned between ethyl acetate and water. The organic layer was separated and concentrated. The crude material was purified using normal phase chromatography (dichloromethane / methanol) to give 1-[4-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)piperidin-1-yl]prop-2-en-1-one (7.50 mg, 0.0222 mmol): 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.16-12.33 (m, 1H), 8.88-8.99 (m, 1H), 8.48 (s, 1H), 8.24-8.32 (m, 1H), 7.82-7.90 (m, 1H), 6.78-6.89 (m, 1H), 6.04-6.17 (m, 1H), 5.59-5.73 (m, 1H), 4.40-4.64 (m, 1H), 4.07-4.22 (m, 1H), 3.64-4.01 (m, 2H), 3.35-3.42 (m, 1H), 2.93-3.16 (m, 1H), 2.70-2.88 (m, 1H), 1.91-2.07 (m, 1H), 1.23-1.49 (m, 2H), 0.78-1.05 (m, 4H); MS (ES) m / z 339 (M+H).

[0244] Examples 11 and 12 Preparation of 1-((R)-3-((5-((S)-tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared as described in Scheme 14.

[0245] Scheme 14. Preparation of 1-((R)-3-((5-((S)-tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0246] Preparation of N-methoxy-N-methyltetrahydrofuran-3-carboxamide [ka] To a stirred solution of tetrahydrofuran-3-carboxylic acid (1 g, 8.61 mmol) in dichloromethane (10 mL) was added N,O-dimethylhydroxylamine hydrochloride (2 g, 21.52 mmol) and triethylamine (3 mL, 30.14 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes, then propyl phosphonate anhydride solution (50% in ethyl acetate) (10 mL, 34.44 mmol) was added and stirred at ambient temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyltetrahydrofuran-3-carboxamide as a brown liquid (1.2 g, 92% yield): MS (ES) m / z 160 (M+H).

[0247] Step 1: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone [ka] To a stirred solution of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared as described in Example 7, 1.4 g, 3.86 mmol) in diethyl ether (20 mL) was added n-butyllithium (3.6 mL, 5.80 mmol, 1.6 M in hexanes) at −78° C. The mixture was stirred for 0.5 h, and then a solution of N-methoxy-N-methyl-tetrahydrofuran-3-carboxamide (0.84 mL, 5.80 mmol) in diethyl ether (2 mL) was added. The mixture was stirred at that temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (40% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone as a brown liquid (1.0 g, 68% yield): MS (ES) m / z 381.0 (M+H).

[0248] Step 2: Preparation of tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone (0.85 g, 2.23 mmol) in N-methyl-2-pyrrolidone (15 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.67 g, 3.34 mmol), and the mixture was heated in a sealed tube at 180° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (15% ethyl acetate / hexanes) to give tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a brown liquid (0.75 g, 62% yield): MS (ES) m / z 546 (M+H).

[0249] Step-3: Preparation of tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.75 g, 1.37 mmol) in tetrahydrofuran (6 mL) was added tetrabutylammonium fluoride (8 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The reaction was allowed to cool to ambient temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (4% methanol / dichloromethane) to give tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a yellow liquid (0.6 g, 79% yield): MS (ES) m / z 416 (M+H).

[0250] Step 4: Preparation of (4-(((R)-piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone hydrochloride [ka] To a stirred solution of tert-butyl (3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-piperidine-1-carboxylate (0.60 g, 1.44 mmol) in dichloromethane (2 mL) was added hydrogen chloride (2.5 mL, 6.05 mmol, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 16 hours. The reaction was concentrated under reduced pressure, and the residue was washed with diethyl ether to afford (4-(((R)-piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone hydrogen chloride as an off-white solid (1.0 g, crude): MS (ES) m / z 316 (M+H). The crude product was used in the next step.

[0251] Step 5: Preparation of 1-((3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of (4-(((R)-piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(tetrahydrofuran-3-yl)methanone hydrogen chloride (0.5 g, 1.58 mmol) in tetrahydrofuran:water (7.0:3.0 mL) was added triethylamine (0.48 mL, 0.4.75 mmol), followed by a solution of acryloyl chloride (0.25 mL, 2.85 mmol) in tetrahydrofuran (0.5 mL) at 0° C., and the mixture was stirred for 15 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) and further purified using prep HPLC to give 1-((3R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as an off-white solid (0.1 g, 23% yield). Prep HPLC method: Column: X-Bridge C18 (100 mm x 4.6 mm x 3.5 mic) Mobile phase (A): 0.1% ammonia in water Mobile phase (B): Methanol Flow rate: 1.0mL / min T / %B:0 / 20, 8 / 50, 12 / 80, 14 / 20, 15 / 20

[0252] Example 11 1-((R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The absolute configuration of the tetrahydrofuran asymmetric center is unknown, but is the opposite of Example 12.

[0253] The title compound was isolated as an off-white solid (0.02 g, 3.4%): 1 H NMR (400 MHz, DMSO-d6) δ 12.6 (br s, 1H), 9.02 (d, J = 6.8 Hz, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 6.78 (m, 2H), 5.94 (t, J = 14.8 Hz, 1H), 5.47-5.60 (m, 1H), 4.09-4.16 (m, 1H), 4.0-4.07 (m, 2H), 3.90-3.98 (m, 1H), 3.64-3.87 (m, 3H), 3.45-3.27 (br s, 2H), 2.14-1.99 (m, 3H), 1.78 (m, 1H), 1.52-1.54 (m, 1H), 1.21 (br s, 1H); MS (ES) m / z 370.0 (M+H). Retention time: 9.46 min.

[0254] Example 12 1-((R)-3-((5-(tetrahydrofuran-3-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The absolute configuration of the tetrahydrofuran asymmetric center is unknown, but is the opposite of Example 11. The title compound was isolated as an off-white solid (0.01 g, 2% yield): 1H NMR (400 MHz, DMSO-d at 690℃) δ 8.95 (d, J = 6.8 Hz, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 6.62 (m, 1H), 6.13 (s, 1H), 5.95 (d, J = 16.8 Hz, 1H), 5.51-5.52 (m, 1H), 4.16-4.18 (m, 1H), 3.93-4.04 (m, 3H), 3.63-3.80 (m, 4H), 3.05-3.48 (m, 2H), 2.10-2.14 (m, 2H), 2.02 (m, 1H), 1.56-1.81 (m, 3H); MS (ES) m / z 370.0 (M+H). Retention time: 9.905 min.

[0255] Example 13 Preparation of (R)-1-(3-((3-(cyclopentanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 15.

[0256] Scheme 15. Preparation of (R)-1-(3-((3-(cyclopentanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0257] Step 1: Preparation of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopentyl)methanone [ka] To a stirred solution of 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared as described in Example 7, 4 g, 8.28 mmol) in diethyl ether (50 mL) was added n-butyllithium (8.28 mL, 66.5 mmol, 1.6 M in hexane) at −78° C., followed by N-methoxy-N-methylcyclopentanecarboxamide (2.59 g, 16.56 mmol) in diethyl ether (4 mL) and stirring at the same temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (15% ethyl acetate / hexanes) to give (4-chloro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopentyl)methanone as a yellow liquid (2.3 g, 55% yield): MS (ES) m / z 379.1 (M+H).

[0258] Step 2: Preparation of tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a solution of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopentyl)methanone (1.5 g, 3.96 mmol) in N-methylpyrrolidone (10 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.95 g, 4.76 mmol), and the mixture was heated in a sealed tube at 150° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (10% ethyl acetate / hexanes) to give tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate as a pale yellow solid (1.2 g, crude): MS (ES) m / z 543.3 (M+H).

[0259] Step 3: Preparation of tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.7 g, 1.29 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (13 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate as a brown solid (0.28 g, crude yield): MS (ES) m / z 413.2 [M+H].

[0260] Step 4: Preparation of (R)-cyclopentyl(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone hydrochloride [ka] To a solution of tert-butyl (R)-3-((3-(cyclopentanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.28 g) in dichloromethane (4 mL) was added hydrogen chloride (4 mL, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give (R)-cyclopentyl(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone hydrochloride as a pale yellow solid (0.26 g, crude): MS (ES) m / z 313.1 [M+H].

[0261] Step 5: Preparation of (R)-(4-((1-(buta-1,3-dienyl)piperidin-3-yl)amino-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentyl)methanone [ka] To a stirred solution of (R)-cyclopentyl(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone hydrochloride (0.1 g, 0.28 mmol) in tetrahydrofuran:water (8:2 mL) was added triethylamine (0.08 mL, 0.57 mmol), followed by a solution of acryloyl chloride (0.01 g, 0.14 mmol) in tetrahydrofuran (0.2 mL) at 0° C. and stirred for 5 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) to give (R)-(4-((1-(buta-1,3-dienyl)piperidin-3-yl)amino-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentyl)methanone as a white solid (0.02 g, 17%): 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.92 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H,), 7.85 (d, J = 6.0 Hz, 1H), 6.72-6.82 (m, 1H), 6.48-6.60 (m, 1H), 6.24-6.29 (m, 1H), 5.90-6.09 (m, 2H), 5.63-5.66 (m, 1H), 5.49-5.50 (m, 1H), 4.21-4.32 (m, 1H), 3.68-3.79 (m, 2H), 3.46-3.60 (m, 2H), 2.86-2.99 (s, 1H), 1.96-2.09 (m, 1H), 1.59-1.83 (m, 8H); MS (ES) m / z 367.1 (M+H).

[0262] Example 14 Preparation of (R)-1-(3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 16.

[0263] Scheme 16. Preparation of (R)-1-(3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0264] Preparation of N-methoxy-N,1-dimethylcyclopropane-1-carboxamide [ka] A solution of 1-methylcyclopropane-1-carboxylic acid (2.0 g, 19.99 mmol) and carbonyldiimidazole (3.55 g, 21.92 mmol) in dichloromethane (70 mL) was stirred at ambient temperature for 1 hour, and then N,O-dimethylhydroxylamine (2.14 g, 21.99 mmol) was added and stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (21% ethyl acetate / hexanes) to give N-methoxy-N,1-dimethylcyclopropane-1-carboxamide as a colorless liquid (1.55 g, 52% yield): MS (ES) m / z 144.1 (M+H).

[0265] Step 1: Preparation of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(1-methylcyclopropyl)methanone [ka] To a solution of 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (prepared as described in Example 7, 1.5 g, 4.16 mmol) in diethyl ether (40 mL) was added n-butyllithium (3.87 mL, 6.24 mmol, 1.6 M in hexanes) at −78° C. and stirred for 0.5 h. Then, a solution of N-methoxy-N,O-dimethylcyclopropane-1-carboxamide (0.89 g, 6.24 mmol) in diethyl ether (40 mL) was added at −78° C. and stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (25% ethyl acetate / hexanes) to give (4-chloro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(1-methylcyclopropyl)methanone as a yellow sticky solid (1.0 g, 66% yield): MS (ES) m / z 365.1 (M+H).

[0266] Step 2: Preparation of tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo-[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(1-methylcyclopropyl)methanone (1.1 g, 3.02 mmol) in N-methyl-2-pyrrolidone (20 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.5 g, 7.55 mmol), N,N-diisopropylethylamine (1.57 mL, 9.06 mmol), and the mixture was heated in a sealed tube at 150° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate as a yellow sticky solid (0.52 g, 33% yield): MS (ES) m / z 529.3 (M+H).

[0267] Step 3: Preparation of tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.52 g, 0.98 mmol) in tetrahydrofuran (8 mL) was added tetrabutylammonium fluoride (8 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to give tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate as a yellow solid (0.26 g, 67% yield): MS (ES) m / z 399.2 (M+H).

[0268] Step 4: Preparation of (R)-(1-methylcyclopropyl)(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone [ka] To a solution of tert-butyl (R)-3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (0.26 g, 0.65 mmol) in dichloromethane (5 mL) was added hydrogen chloride (6.0 mL, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give (R)-(1-methylcyclopropyl)(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone hydrochloride as a light brown solid (0.22 g, crude). The crude product was used in the next step without further purification.

[0269] Step 5: (R)-1-(3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of (R)-(1-methylcyclopropyl)(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone hydrochloride (0.11 g, 0.29 mmol) in tetrahydrofuran:water (7.0:3.0 mL) was added triethylamine (0.11 mL, 0.87 mmol), followed by a solution of acryloyl chloride (0.02 mL, 0.22 mmol) in tetrahydrofuran (0.5 mL) at 0° C. and stirred for 15 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% methanol / dichloromethane) followed by prep HPLC to give (R)-1-(3-((3-(1-methylcyclopropane-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as a white solid (0.02 g, 6% yield): 1H NMR (400 MHz, DMSO-d at 680℃) δ 11.99 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.13 (s, 1H) 7.87 (d, J = 5.6 Hz, 1H), 6.61 (br s, 1H), 6.28 (d, J = 5.6 Hz, 1H), 5.98 (d, J = 15.2 Hz, 1H), 5.53 (br s, 1H), 3.7 (s, 1H), 3.55 (s, 1H), 3.38 (s, 1H), 2.04 (s, 1H), 1.81 (s, 1H), 1.65 (d, J = 9.2 Hz, 1H), 1.52-1.58 (m, 3H), 1.48 (s, 2H), 1.2 (s, 1H) 1.0 (s, 2H), 0.71 (s, 2H); MS (ES) m / z 353.1 (M+H). Prep HPLC method: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic) Mobile phase (A): 0.1% ammonia in water Mobile phase (B): ACN Flow rate: 1.0mL / min

[0270] Example 15 Preparation of (R)-1-(3-((3-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one [ka]

[0271] Step 1: Preparation of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.62 mmol) in 1.5 mL of dichloromethane was added aluminum chloride (2.43 g, 18.3 mmol). After stirring at ambient temperature for 1 hour, cyclopropanecarbonyl chloride (236 μL, 2.62 mmol) was added. The reaction was stirred at ambient temperature overnight. The reaction was quenched with a saturated solution of Rochelle's salt. The solution was stirred rapidly for 1 hour. The resulting yellow solid was collected by vacuum filtration to give 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine (580 mg, 2.62 mmol): MS (ES) m / z 221 (M+H).

[0272] Step 2: Preparation of 4-chloro-3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridine from step 1 (238 mg, 1.07 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (60% dispersion in mineral oil, 25.6 mg, 1.07 mmol). After 15 min, [2-(chloromethoxy)ethyl]trimethylsilane (207 μL, 1.17 mmol) was added. The reaction was complete within 2 h. The solution was quenched by the addition of water. The solution was extracted with ethyl acetate and concentrated. The crude material was purified using normal phase chromatography (ethyl acetate / heptane) to give 4-chloro-3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (195 mg, 0.556 mmol) as a yellow oil: MS (ES) m / z 351 (M+H).

[0273] Step 3: Preparation of tert-butyl (3R)-3-[(3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]pyrrolidine-1-carboxylate [ka] A mixture of 4-chloro-3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (45 mg, 0.13 mmol) obtained in Step 2, tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (23.8 mg, 0.128 mmol), cesium carbonate (125 mg, 0.385 mmol), bis(dibenzylideneacetone)palladium (3.68 mg, 0.00641 mmol), and Xantphos (7.41 mg, 0.0128 mmol) in 1,4-dioxane (1 mL) was treated with microwave irradiation at 120 °C for 4 h. After cooling, the solution was partitioned between ethyl acetate and water, and the organic layer was concentrated. The crude material was purified using normal phase chromatography (ethyl acetate / heptane) to give tert-butyl (3R)-3-[(3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]pyrrolidine-1-carboxylate (66.0 mg, 0.132 mmol): MS (ES) m / z 500 (M+H).

[0274] Step 4: Preparation of 1-[(3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)pyrrolidin-1-yl]prop-2-en-1-one [ka] To a solution of tert-butyl (3R)-3-[(3-cyclopropanecarbonyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]pyrrolidine-1-carboxylate (66 mg, 0.132 mmol) obtained in Step 3 in 2 mL of dichloromethane was added 1 mL of trifluoroacetic acid. The solution was stirred at ambient temperature for 3 hours. The solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (1 mL), and triethylamine (36.6 μL, 0.2636 mmol) was added. To this solution was added a solution of prop-2-enoic acid (9.49 mg, 0.1318 mmol), N-[3-(dimethylamino)propyl]propanimidamide hydrochloride (76.5 mg, 0.395 mmol), and triethylamine (36.6 μL, 0.264 mmol), and the mixture was stirred at ambient temperature for 2 hours. The solution was partitioned between ethyl acetate and water, and the organic layer was concentrated. The crude material was purified using normal phase chromatography (dichloromethane / methanol) to give 1-[(3R)-3-({3-cyclopropanecarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl}amino)pyrrolidin-1-yl]prop-2-en-1-one (6.00 mg, 0.0185 mmol) as a yellow oil: 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.23-12.36 (m, 1H), 8.97-9.13 (m, 1H), 8.47-8.52 (m, 1H), 8.25-8.34 (m, 1H), 7.83-7.98 (m, 1H), 6.45-6.69 (m, 1H), 6.03-6.17 (m, 1H), 5.52-5.74 (m, 1H), 4.36-4.68 (m, 1H), 3.91-4.33 (m, 2H), 3.60-3.83 (m, 1H), 3.42-3.60 (m, 1H), 2.77-3.09 (m, 1H), 2.18-2.40 (m, 1H), 1.78-2.07 (m, 1H), 0.75-1.06 (m, 4H); MS (ES) m / z 325 (M+H).

[0275] Example 16 Preparation of 1-(4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylbutan-1-one [ka] The title compound was prepared as described in Scheme 17.

[0276] Scheme 17. Preparation of 1-(4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylbutan-1-one [ka]

[0277] Step 1: Preparation of isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of potassium carbonate (0.15 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added benzylethyl-4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxylic acid (prepared as described in Example 4, 0.2 g, 0.37 mmol) and isobutyl bromide (0.25 g, 1.85 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (30% ethyl acetate / hexanes) to give isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a yellow solid (0.18 g, 82% yield): MS (ES) m / z 596.5 (M+H).

[0278] Step 2: Preparation of isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.18 g, 0.3 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (5 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 16 hours. After allowing the reaction mixture to cool to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (70% ethyl acetate / hexanes) to give isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.1 g, 71% yield): MS (ES) m / z 466.4 (M+H).

[0279] Step 3: Preparation of isobutyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of isobutyl 4-(((3R,6S)-1-((benzyloxy)carbonyl)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.1 g, 0.21 mmol) in tetrahydrofuran (10 mL) was added palladium on carbon (0.05 g, 10 wet weight w / w) under a nitrogen atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give isobutyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.06 g, crude): MS (ES) m / z 332.2 (M+H).

[0280] Step 4: Preparation of isobutyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate [ka] To a stirred solution of isobutyl 4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.06 g, 0.18 mmol) in tetrahydrofuran:water (3:2 mL) was added triethylamine (0.12 mL, 0.9 mmol), followed by a solution of acryloyl chloride (0.019 mL, 0.21 mmol) in tetrahydrofuran (0.5 mL) at 0° C. and stirred for 20 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% methanol / dichloromethane) to give isobutyl 4-(((3R,6S)-1-acryloyl-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid (0.013 g, 18.6% yield): 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 6.77 (dd, J1= 10.4, J2= 16.8 Hz, 1H), 6.07 (dd, J1= 1.6, J2= 16.8 Hz, 1H), 5.66 (dd, J1= 2.4 Hz, J2=10.8 Hz, 1H), 4.50 (br s, 2H), 4.03 (d, J = 6.4 Hz, 2H), 3.93 (br s, 1H), 2.03-1.91 (m, 2H), 1.73-1.63 (m, 3H), 1.31-1.12 (m, 4H), 0.95 (d, J = 6.8 Hz, 6H); MS (ES) m / z 386.2 (M+H).

[0281] Example 17 Preparation of 1-((2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 18.

[0282] Scheme 18. Preparation of 1-((2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one [ka]

[0283] Step 1: Preparation of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclobutyl)methanone [ka] To a stirred solution of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared as described in Example 7, 2 g, 5.52 mmol) in diethyl ether (30 mL) was added n-butyllithium (6.9 mL, 11.04 mmol, 1.6 M in hexane) at −78° C. and stirred for 10 minutes. This was followed by the addition of N-methoxy-N-methyl-cyclobutanecarboxamide (1.58 g, 11.04 mmol) in diethyl ether (5 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (15% ethyl acetate / hexanes) to give (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclobutyl)methanone as a brown liquid (1.2 g, 60% yield): MS (ES) m / z 366.1 (M+H).

[0284] Step 2: Preparation of benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate [ka] To a stirred solution of (4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclobutyl)methanone (0.8 g, 2.19 mmol) in n-butanol (50 mL) was added diisopropylethylamine (1.2 mL, 6.57 mmol), followed by benzyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate (0.65 g, 2.63 mmol), and the mixture was heated in a sealed tube at 130° C. for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (25% ethyl acetate / hexanes) to give benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate as a brown liquid (1.2 g, 95% yield): MS (ES) m / z 578.3 (M+H).

[0285] Step 3: Preparation of benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate [ka] To a stirred solution of benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (1.2 g, 2.07 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (21 mL, 1 M in tetrahydrofuran) and the mixture was heated to 80° C. for 48 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (4% methanol / dichloromethane) to give benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate as a yellow liquid (0.4 g, 43% yield): MS (ES) m / z 448.2 (M+H).

[0286] Step 4: Preparation of cyclobutyl(4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone [ka] To a stirred solution of benzyl (2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (0.35 g, 0.78 mmol) in tetrahydrofuran:methanol (10:5 mL) was added palladium on carbon (0.3 g, 10% wet weight w / w) under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. The reaction was filtered through Celite and the filtrate was concentrated under reduced pressure to give cyclobutyl(4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone as a pink liquid (0.18 g, 75% yield): MS (ES) m / z 314.2 (M+H).

[0287] Step 5: 1-((2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of cyclobutyl(4-(((3R,6S)-6-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (0.18 g, 0.57 mmol) in tetrahydrofuran:water (10:4 mL) cooled to 0° C., triethylamine (0.24 mL, 1.72 mmol) was added, followed by acryloyl chloride (0.05 g, 0.57 mmol) and stirred at 0° C. for 30 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (3% methanol / dichloromethane) to give 1-((2S,5R)-5-((5-(cyclobutanecarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one as a pink solid (0.07 g, 33% yield): 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.05 (d, J = 6.8 Hz, 1H), 8.13-8.17 (m, 2H), 6.75-6.81 (m, 1H), 6.05-6.09 (m, 1H), 5.64-5.67 (m, 1H), 4.51 (br s, 1H), 4.02-4.10 (m, 1H), 3.87-3.90 (m, 1H), 2.98-3.03 (m, 1H), 2.17-2.27 (m, 4H), 1.93-2.05 (m, 2H), 1.67-1.79 (m, 4H), 1.52-1.59 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H); MS (ES) m / z 368.3 (M+H).

[0288] Example 18 Preparation of (R)-1-(3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 19.

[0289] Scheme 19. Preparation of (R)-1-(3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0290] Step 1: Preparation of 4-chloro-5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ka] To a stirred solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(cyclopropyl)methanol (prepared as described in Example 7, 3.1 g, 8.80 mmol) in dichloromethane (30 mL) was added trifluroacetic acid (3.39 mL, 44.04 mmol) and triethylsilane (4.22 mL, 26.42 mmol) at 0° C. The mixture was stirred at ambient temperature for 0.5 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate 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 using flash chromatography (9% ethyl acetate / hexanes) to give 4-chloro-5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a pale yellow liquid (2.89 g, 88% yield): MS (ES) m / z 338.1 (M+H).

[0291] Step 2: Preparation of tert-butyl (R)-3-((5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of 4-chloro-5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.89 g, 8.57 mmol) in N-methyl-2-pyrrolidone (10 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (3.43 g, 1.71 mmol), and the mixture was heated in a sealed tube at 150° C. for 12 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (30% ethyl acetate / hexanes) to give tert-butyl (R)-3-((5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a pale yellow liquid (2.0 g, 62% yield): MS (ES) m / z 502.3 (M+H).

[0292] Step 3: Preparation of tert-butyl (R)-3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (2.0 g, 3.99 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (25 mL, 1 M in tetrahydrofuran) and the solution was heated to 80° C. for 12 hours. The reaction mixture was cooled to ambient temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (66% ethyl acetate / hexanes) to give tert-butyl (R)-3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a pale yellow liquid (1.02 g, 68% yield): MS (ES) m / z 372.2 (M+H).

[0293] Step 4: Preparation of (R)-5-(cyclopropylmethyl)-N-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (1 g, 2.69 mmol) in dichloromethane (10 mL) was added hydrogen chloride (5 mL, 4 M in dioxane) at 0° C., and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give (R)-5-(cyclopropylmethyl)-N-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride as a white solid (1 g, crude): MS (ES) m / z 272.4 (M+H).

[0294] Step 5: Preparation of (R)-1-(3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a solution of (R)-5-(cyclopropylmethyl)-N-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrogen chloride (0.35 g, 1.15 mmol) in tetrahydrofuran:water (7:3 mL) was added triethylamine (0.485 mL, 3.45 mmol), followed by acryloyl chloride (0.114 g, 1.26 mmol) at 0 °C, and the solution was stirred for 15 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (6% methanol / dichloromethane) to give the prep Further purification using HPLC gave (R)-1-(3-((5-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one as a colorless semi-solid (0.030 g, 8% yield): 1H NMR (400 MHz, DMSO-d6, at 80°C) δ 11.07 (br s, 1H), 8.07 (s, 1H), 6.87 (s, 1H), 6.60-6.80 (m, 1H), 6.38 (d, J = 16.3 Hz, 1H), 5.62 (d, J = 11.18 Hz, 1H), 5.45-5.55 (m, 1H), 4.17-4.32 (m, 1H), 3.40-3.94 (m, 1H), 3.15-3.82 (m, 1H), 3.40-3.47 (m, 1H), 3.28-3.38 (m, 1H), 2.71 (d, J = 5.99 Hz, 2H), 1.92-2.05 (m, 1H), 1.82-1.90 (m, 1H), 1.67-1.80 (m, 1H), 1.48-1.60 (m, 1H), 0.95-1.05 (m, 1H), 0.46 (d, J = 7.59 Hz, 2H), 0.13 (d, J = 3.99 Hz, 2H); MS (ES) m / z 326.1 (M+H). Prep HPLC method: Column: Inertsil ODS 3V (250 mm x 4.6 mm x 5 mic) Mobile phase (A): 0.1% ammonia in water Mobile phase (B): ACN Flow rate: 1.0mL / min

[0295] Example 19 Preparation of (R)-1-(3-((3-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] The title compound was prepared as described in Scheme 20.

[0296] Scheme 20. Preparation of (R)-1-(3-((3-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka]

[0297] Step 1: Preparation of 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine [ka] To a suspension of sodium hydride (0.22 g, 5.19 mmol) in N,N-dimethylformamide (15 mL) was added 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 4.32 mmol) at 0° C., and the suspension was stirred at ambient temperature for 0.5 hours. The mixture was cooled to 0° C., and (2-chloromethoxyethyl)trimethylsilane (0.92 mL, 5.19 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (5% ethyl acetate / hexanes) to give 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a viscous oil (1.5 g, 95% yield): MS (ES) m / z 362.0 (M+H).

[0298] Step 2: Preparation of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopropyl)methanol [ka] To a stirred solution of 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (prepared as described in Example 5, 1.6 g, 4.4 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (0.37 g, 5.2 mmol, 1.6 M in hexanes) at −78° C. and stirred for 30 minutes. A solution of cyclopropanecarbaldehyde (0.34 g, 5.3 mmol) in tetrahydrofuran (3 mL) was then added at −78° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (20% ethyl acetate / hexanes) to give (4-chloro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopropyl)-methanol as a colorless liquid (0.35 g, 23% yield). MS (ES) m / z 353.1 (M+H).

[0299] Step 3: Preparation of 4-chloro-3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine [ka] To a stirred solution of (4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopropyl)methanol (0.3 g, 0.85 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.6 mL, 5.6 mmol), followed by triethylsilane (0.4 mL, 3.4 mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using flash chromatography (30% ethyl acetate / hexanes) to give 4-chloro-3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a colorless liquid (0.21 g, 75% yield): MS (ES) m / z 337 (M+H).

[0300] Step 4: Preparation of tert-butyl (R)-3-((3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of 4-chloro-3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (0.2 g, 0.59 mmol) in toluene (5 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.178 g, 0.89 mmol), 2-dicyclohexylphospino-2',4',6'-triisopropylbiphenyl (0.028 g, 0.89 mmol), cesium carbonate (0.582 g, 1.78 mmol), and palladium(II) acetate (0.013 g, 0.057 mmol) under an argon atmosphere, and the resulting mixture was heated to 110°C for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified using flash chromatography (40% ethyl acetate / hexanes) to give tert-butyl (R)-3-((5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a colorless liquid (0.2 g, 90% yield): MS (ES) m / z 501.3 (M+H).

[0301] Step 5: Preparation of tert-butyl (R)-3-((3-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl (R)-3-((5-(cyclopropylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.2 g, 0.4 mmol) in tetrahydrofuran (5 mL) was added trifluoroacetic acid (0.3 mL) at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and basified with saturated sodium bicarbonate, at which point an oil separated and was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (40% ethyl acetate / hexanes) to give (R)-3-(cyclopropylmethyl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine as a colorless liquid (0.16 g, 68% yield): MS (ES) m / z 271.2 (M+H).

[0302] Step 6: Preparation of (R)-1-(3-((3-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] To a stirred solution of (R)-3-(cyclopropylmethyl)-N-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (0.1 g, 0.37 mmol) in tetrahydrofuran:water (8:2 mL) was added triethylamine (0.1 mL, 0.33 mmol), followed by a solution of acryloyl chloride (0.03 mL, 0.33 mmol) in tetrahydrofuran (0.2 mL) at 0° C. and stirred for 0.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. ...

Claims

1. Compounds of formula (I) and derivatives thereof: 【Chemistry 1】 (In the formula, X is N or CR 3 and n is 0, 1 or 2; m is 0, 1 or 2; R 1 is COOR 6 , C 1 -C 5 Alkyl-COOR 6 , bicycloalkyl, C 1 -C 5 -alkyl-heterocyclyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 3 -C 6 Cycloalkyl, C(O)C 1 -C 5 Alkyl, C(O)C 3 -C 6 Cycloalkyl, C(O)C 3 -C 6 heterocyclyl; Cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, CN, halogen, COOR 6 , or C 1 -C 5 -Alkyl-COOR 6 and optionally substituted with one or more groups selected from R 2 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, CN, OH, C 1 -C 5 alkoxy, and halogen; and two R 2 the groups may be linked, with or without heteroatoms, to form a spirocyclic ring system; R 3 H, CN, C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl; R 4 is H, C 1 -C 6 alkyl, R 5 is H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 -Alkyl-NH 2 , C 1 -C 6 AlkylNH(C 1 -C 6 Alkyl), C 1 -C 6 Alkyl-N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl), C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy or C 1 -C 6 alkyl-heterocyclyl; R 6 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-OH, C 1 -C 5 Alkyl-NH 2 , C 1 -C 5 Alkyl-NH-C 1 -C 5 Alkyl, and C 1 -C 5 Alkyl-N-(C 1 -C 5 Alkyl) (C 1 -C 5 alkyl).

2. Compounds of formula (II) and derivatives thereof: 【Chemistry 2】 (In the formula, X is N or CR 23 and n is 0, 1 or 2; m is 0, 1 or 2; R 21 is COOR 26 , C 1 -C 5 Alkyl-COOR 26 , bicycloalkyl, C 1 -C 5 -alkyl-heterocyclyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 3 -C 6 Cycloalkyl, C(O)C 1 -C 5 Alkyl, C(O)C 3 -C 6 Cycloalkyl, C(O)C 3 -C 6 heterocyclyl; Cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, CN, halogen, COOR 26 , or C 1 -C 5 -Alkyl-COOR 26 and optionally substituted with one or more groups selected from R 22 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, CN, OH, C 1 -C 5 alkoxy, halogen; and two R on the same carbon 2 the groups may be linked, with or without heteroatoms, to form a spirocyclic ring system; R 23 H, CN, C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl; R 24 is H, C 1 -C 6 alkyl, R 25 is H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 -Alkyl-NH 2 , C 1 -C 6 AlkylNH(C 1 -C 6 Alkyl), C 1 -C 6 Alkyl-N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl), C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy or C 1 -C 6 alkyl-heterocyclyl; R 26 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-OH, C 1 -C 5 Alkyl-NH 2 , C 1 -C 5 Alkyl-NH-C 1 -C 5 Alkyl, and C 1 -C 5 Alkyl-N-(C 1 -C 5 Alkyl) (C 1 -C 5 alkyl).

3. Compounds of formula (III) and derivatives thereof: 【Chemistry 3】 (In the formula, X is CR 33 or N, n is 1 or 2; when n is 1, m is 0, 1 or 2, when n is 2, m is 1; R 31 is COOR 36 , C 1 -C 5 Alkyl-COOR 36 , bicycloalkyl, C 1 -C 5 -alkyl-heterocyclyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 3 -C 6 Cycloalkyl, C(O)C 1 -C 5 Alkyl, C(O)C 3 -C 6 Cycloalkyl, C(O)C 3 -C 6 heterocyclyl, cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, CN, halogen, COOR 36 , or C 1 -C 5 -Alkyl-COOR 36 and optionally substituted with one or more groups selected from R 32 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -cycloalkyl, R 33 H, CN, C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl; R 34 is H, C 1 -C 6 alkyl, R 35 is H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 -Alkyl-NH 2 , C 1 -C 6 AlkylNH(C 1 -C 6 Alkyl), C 1 -C 6 Alkyl-N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl), C 1 -C 5 Alkyl-C 1 -C 5 alkoxy; R 36 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-OH, C 1 -C 5 Alkyl-NH 2 , C 1 -C 5 Alkyl-NH-C 1 -C 5 Alkyl, and C 1 -C 5 Alkyl-N-(C 1 -C 5 Alkyl) (C 1 -C 5 alkyl).

4. Compounds of formula (IV) and derivatives thereof: 【Chemistry 4】 (In the formula, X is CR 43 or N, n is 1 or 2; when n is 1, m is 0, 1 or 2, when n is 2, m is 1; R 41 is COOR 46 , C 1 -C 5 Alkyl-COOR 46 , bicycloalkyl, C 1 -C 5 -alkyl-heterocyclyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 3 -C 6 Cycloalkyl, C(O)C 1 -C 5 Alkyl, C(O)C 3 -C 6 Cycloalkyl, C(O)C 3 -C 6 heterocyclyl, cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are selected from C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, CN, halogen, COOR 46 , or C 1 -C 5 -Alkyl-COOR 46 and optionally substituted with one or more groups selected from R 42 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -cycloalkyl, R 43 H, CN, C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl; R 44 is H, C 1 -C 6 alkyl, R 45 is H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 -Alkyl-NH2,C 1 -C 6 AlkylNH(C 1 -C 6 Alkyl), C 1 -C 6 Alkyl-N(C 1 -C 6 Alkyl) (C 1 -C 6 Alkyl), C 1 -C 5 Alkyl-C 1 -C 5 alkoxy; R 46 is H, C 1 -C 5 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 5 -Alkyl-C 3 -C 6 -Cycloalkyl, C 1 -C 5 Alkyl-C 1 -C 5 Alkoxy, C 1 -C 5 Alkyl-OH, C 1 -C 5 Alkyl-NH 2 , C 1 -C 5 Alkyl-NH-C 1 -C 5 Alkyl, and C 1 -C 5 Alkyl-N-(C 1 -C 5 Alkyl) (C 1 -C 5 alkyl).

5. The compound, or a derivative thereof, 【Chemistry 5】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1 , selected from:

6. The compound, or a derivative thereof, 【Chemistry 6】 【change】 The compound of claim 3 selected from:

7. A pharmaceutical composition comprising one or more compounds selected from the compounds of formula (I), formula (II), formula (III), formula (IV) and derivatives thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

8. A method for inhibiting ITK or JAK3 activity in a cell population, comprising administering to the cell population one or more compounds selected from the compounds of formula (I), formula (II), formula (III), formula (IV) and derivatives thereof, in an amount effective to inhibit ITK or JAK3 activity in the cell population.

9. The method of claim 8 , wherein the cell population is a population of human cells.

10. The compound or compounds are 【Chemistry 7】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 9. The method of claim 8, wherein the compound of formula (I) is selected from the group consisting of:

11. The compound or compounds are 【Chemistry 8】 【change】 9. The method of claim 8, wherein the compound is a compound of formula (III) selected from:

12. A method for treating an ITK-mediated or JAK3-mediated disorder in a subject in need thereof, comprising administering to the subject one or more compounds selected from compounds of formula (I), formula (II), formula (III), formula (IV), and derivatives thereof, in an amount effective to treat the ITK-mediated or JAK3-mediated disorder.

13. The method of claim 12, wherein the subject is a human.

14. The ITK-mediated or JAK3-mediated disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, an autoinflammatory disorder, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis, Still's disease, adult-onset Still's disease, seronegative spondyloarthritis, osteoarthritis, enthesitis, enthesopathy, infectious arthritis, Lyme disease, inflammatory arthritis, inflammatory bowel disease-associated arthritis, myositis, autoimmune myositis, carditis, myocarditis, dermatomyositis, juvenile dermatomyositis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis, pain cold, scleroderma, juvenile scleroderma, Reiter's syndrome, spondylitis, spondyloarthritis, spondyloarthropathy, lupus, systemic lupus erythematosus (SLE), childhood systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus, discoid lupus erythematosus, psoriatic arthritis, reactive arthritis, Sjogren's syndrome, polymyositis, polymyalgia rheumatica, mixed connective tissue disease, vasculitis, large vessel vasculitis, small vessel vasculitis, vasculitis syndromes, including Takayasu's arteritis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, sarcoidosis, familial Mediterranean fever, cryopreservation, Phosphorus-associated periodic syndrome, Muckle-Wells syndrome, familial cold-induced autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, gastrointestinal disease, inflammatory bowel disease, irritable bowel syndrome, spastic colon, Crohn's disease, ulcerative colitis, acute and chronic pancreatitis, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, periodontitis, gingivitis, esophagitis, gastritis, eosinophilic gastritis, gastric and duodenal ulcers, peritonitis, periodontitis, enteritis, colitis, pulmonary respiratory disorders, pulmonary inflammation, sinusitis, rhinitis, pneumonia, bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, bronchial asthma, allergies Asthma, Eosinophilic Asthma, Churg-Strauss syndrome, Bronchiolitis, Bronchiolitis Obliterans, Chronic Obstructive Pulmonary Disease (COPD), Interstitial Lung Disease, Endocrine Disorders, Diabetes, Type I Diabetes, Hashimoto's Thyroiditis, Graves' Disease, Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Atrophic Gastritis of Pernicious Anemia, Autoimmune Encephalomyelitis, Autoimmune Orchitis, Goodpasture's Disease, Autoimmune Thrombocytopenia, Sympathetic Ophthalmia, Nervous System / Neuromuscular Disorders, Neurodegenerative Disorders, Multiple Sclerosis, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS), Familial ALS, Alzheimer's Disease,Myasthenia gravis (Lambert-Eaton myasthenic syndrome (LEMS)), Guillain-Barre syndrome, meningitis, encephalitis, traumatic brain injury, nephropathy, immune-mediated glomerular nephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, ischemic / reperfusion injury-related, HIV-associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, eye disorders, dry eye, uveitis, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, keratopathy, vocal cord inflammation, retinal vasculitis, optic neuritis, retinopathy, diabetes retinopathies, immune-mediated retinopathies, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration, ocular malignancies, allergies and allergic reactions, including hypersensitivity reactions, type I hypersensitivity reactions, anaphylaxis, type II hypersensitivity reactions, Goodpasture's disease, autoimmune hemolytic anemia, type III hypersensitivity reaction disease, Arthus reaction, serum sickness, type IV hypersensitivity reactions, contact dermatitis, allograft rejection, fibrosis and scarring disorders, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, mild scarring, scleroderma, increased fibrosis, keloids, post-surgical scarring, skin disorders, psoriasis, atopy, Pee dermatitis, acne, acne vulgaris, acne comedonal, inflammatory acne, nodular cystic acne, cicatricial acne, keloid acne nuchal, hidradenitis suppurativa, neutrophilic dermatosis, pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), erythema elevatum eudaimonia (EED), neutrophilic exostatic hidradenitis, histiocytic neutrophilic dermatosis, intestinal bypass syndrome dermatosis, Behçet's disease, cylindrical cell neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, alopecia, non-cicatricial alopecia, alopecia areata (AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU), androgenic alopecia (AGA), male and female pattern AGA, serpentine pattern alopecia areata, sisaihpo pattern alopecia areata, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, cicatricial alopecia, lichen planopilaris, parietal centrifugal cicatricial alopecia, frontal fibrosing alopecia, brow alopecia, internasal alopecia, vitiligo, segmental vitiligo, monosegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo, nonsegmental vitiligo, digital vitiligo, facial vitiligo, limbal vitiligo, central facial vitiligo, mucous membrane vitiligo, confetti vitiligo, vitiligo tricolor, marginal inflammatory vitiligo,vitiligo vulgaris, blue vitiligo, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo, generalized vitiligo, mixed vitiligo (segmental related non-segmental vitiligo), localized vitiligo, isolated mucosal vitiligo, vitiligo with leukoderma, vitiligo without leukoderma, immune bullous disease, bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease, cutaneous drug reactions, pruritus (itch), atopic pruritus, dry pruritus, psoriasis-associated pruritus (psoriatic itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, hepatobiliary-associated itch, kidney associated itch, lichen simplex chronicus-associated pruritus, prurigo nodularis, diabetes mellitus type II, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmune disease, autoimmune deafness, Meniere's disease, interstitial cystitis, enterocolitis, eye inflammation, non-small cell lung cancer, skin cancer, organ transplant rejection, bone marrow graft rejection, graft versus host reaction, graft versus host disease, allograft rejection, acute allograft rejection, chronic allograft rejection, early transplantation, diabetes mellitus, myeloproliferative disorders, rejection, bone resorption disorders, asthma, bronchial asthma, atopy, autoimmune thyroid disorders, lipodystrophy and hyperthermia syndrome. Chronic atypical neutrophilic dermatosis with pulmonary embolism (CANDLE syndrome), SAVI (STING-associated vasculopathy associated with stimulator of interferon genes in infancy), nephropathy, myocarditis, secondary hematologic manifestations of autoimmune disease, 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 syndrome, sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock. hyperoxia-induced inflammation, reperfusion injury, post-operative trauma, tissue injury, pain, acute pain, chronic pain, neuropathic pain, or fibromyalgia, autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, or cardiovascular or cerebrovascular disorders, skin disorders, pruritus, hair loss disorders, cancer, neoplasms, inflammatory conditions, connective tissue diseases and autoimmune conditions, neoplasms, malignant tumors, myeloproliferative disorders, hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms, e.g., myelofibrosis,Acute and chronic leukemias, including primary myelofibrosis, polycythemia vera, essential thrombocythemia, lymphomas, cutaneous lymphomas, other myeloid malignancies, including mycosis fungoides, and myelodysplastic syndromes, atopic dermatitis, psoriasis, plaque psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, allergic dermatitis, inflammatory skin diseases, neutrophilic skin diseases, pruritus, 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 Disease, brachioradial pruritus, brain tumor, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T-cell 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, pyoderma gangrenosum, rash, Hodgkin's disease, hyperparathyroidism, idiopathic chronic pruritus, inflammation, insect infestation, insect bites, insect stings, intrahepatic cholestasis of pregnancy, iron deficiency anemia, exogenous causes Increased accumulation of chronic or synthetic opioids, 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, paresthesia obsessive-compulsive disorder, paresthesia, parasitic infections, papular urticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, psychiatric disorders, psychogenic itch, pruritic papular rash of HIV, pruritic urticarial papules and plaques of pregnancy (PUPP) , psoriasis-associated itch, psoriatic itch, hair lice, punctate palmoplantar keratoderma, kidney itch, rheumatoid arthritis, scabies, increased scarring, razor rash, seborrheic dermatitis, stasis dermatitis, sunburn, swimmer's prurigo, generalized immune aging, tactile hallucinations, Th17-related inflammation, thyroid disease, uremia, uremic itch, urticaria, urticarial itch, chickenpox, viral infection, trauma or scabies healing, xerosis, chilblain lupus erythematosus, polychondritis, relapsing polychondritis, immune-mediated nephropathy, prostate cancer, kidney cancer, liver cancer, breast cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, pancreatic cancer, lymphoma, leukemia,Multiple myeloma, 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), Systemic mast cell disease (SMCD), Systemic sclerosis / scleroderma, Lupus nephritis, Wound healing, Surgical scar, Spinal cord injury, CNS scar, Acute lung injury, Cystic fibrosis, Adult respiratory distress syndrome, Acute lung injury, Drug-induced lung injury, Glomerulonephritis, Chronic kidney disease, Diabetic nephropathy, Hypertension-induced nephropathy , gastrointestinal or digestive tract fibrosis, liver or bile duct fibrosis, liver fibrosis, nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma, liver cirrhosis, primary biliary cirrhosis or cirrhosis due to fatty liver disease, alcoholic steatosis, nonalcoholic steatosis, radiation-induced fibrosis, head and neck fibrosis, gastrointestinal fibrosis, pulmonary fibrosis, primary sclerosing cholangitis, restenosis, cardiac fibrosis, endomyocardial fibrosis, atrial fibrosis, ophthalmic scarring, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, renal Myelogenic systemic fibrosis, obesity, steroid resistance, glucose intolerance, metabolic syndrome, angiogenic disorders, multiple myeloma, leukemia, acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, promyelocytic leukemia, lymphoma, B cell lymphoma, T cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease, non-Hodgkin's disease, myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannoma; melanoma, seminoma, teratocarcinoma, osteomyeloma 13. The method of claim 12, wherein the cancer is selected from cancers of the bone, mouth / pharynx, esophagus, larynx, stomach, intestine, colon, rectum, liver, nerve, brain, glioma, glioblastoma multiforme, head and neck, throat, ovary, uterus, testis, bladder, kidney, gallbladder, cervix, atherosclerosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, stroke, spinal cord injury, neuronal ischemia, peripheral neuropathy, and combinations thereof.

15. The compound or compounds are 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The method according to claim 12, wherein the compound is of formula (I) or a derivative thereof selected from:

16. The compound or compounds are 【Chemistry 10】 【change】 The method according to claim 12, wherein the compound is a compound of formula (III) or a derivative thereof selected from:

17. 13. The method of claim 12, further comprising sequential or co-administration of pharmaceutical agents.

18. 18. The method of claim 17, wherein the 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.

19. Use of a compound selected from the compounds of formula (I), (II), (III), (IV), and derivatives thereof, for the manufacture of a medicament for treating an ITK-mediated or JAK3-mediated disease.

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