Inhibitors of canine janus kinase and uses thereof

Abstract

Provided herein are compounds having inhibitory activity toward the Janus Kinase 1 (JAK-1) enzyme, and which are useful as therapeutic and / or prophylactic agents. The compounds may be useful in treating inflammatory disorders in non-human mammals, for example, in treating canine atopic dermatitis. Also provided herein are methods for preparation of such compounds.

Description

INHIBITORS OF CANINE JANUS KINASE AND USES THEREOFTECHNICAL FIELD

[0001] The present disclosure relates generally to canine Janus Kinase (JAK) inhibitors and methods for treating inflammatory disorders with such inhibitors.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and which is hereby incorporated by reference in its entirety. Said CRF copy, created on November 25, 2025, is named Al 12628_W12_SL.xml and is 4,542 bytes in size.BACKGROUND

[0003] Protein kinases are families of enzymes that catalyze the phosphorylation of specific amino acid residues present in certain proteins. Such protein kinases are broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity, which may arise from, e.g., arising mutation, overexpression, or inappropriate regulation, as well as over- or underexpression of growth factors or cytokines, has been implicated in many diseases. These diseases include but are not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, differentiation, survival, apoptosis, and mitogenesis, as well as cell cycle control and cell mobility, each of which have been implicated in the aforementioned diseases.

[0004] Accordingly, protein kinases have emerged as an important class of enzymes to target for therapeutic intervention. In particular, the Janus Kinases (JAKs) are a family of cellular protein tyrosine kinases that play a central role in cytokine signaling (Kisseleva et al., Gene 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253). The JAKs function as dimers in the signaling process of many cytokine receptors. The JAKs comprise four family members: JAK-1, JAK -2, JAK-3, and Tyrosine kinase 2 (TYK-2). Numerous cytokines are known to activate the JAK family. Upon binding to their receptors, cytokines activate the JAK, which then phosphorylates the cytokine receptor, creating docking sites for signaling molecules. These signaling molecules include members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression.

[0005] The JAKs play a critical role in both innate and adaptive immunity, making them attractive targets for the treatment of inflammatory diseases. Targeting the JAK signaling pathway for autoimmune diseases is supported by the involvement of various pro-inflammatory cytokines that signal via JAK pathways in the pathogenesis of these immune-related disorders. The activation of JAK signaling initiates expression ofsurvival factors, cytokines, chemokines, and other molecules that facilitate leukocyte cellular trafficking and cell proliferation, which contribute to inflammatory and autoimmune disorders. (O'Shea et al., N Engl J Med.2013, 368(2), 161-70).

[0006] In view of the potential for JAK inhibitors to target pathways implicated in a variety of diseases and disorders, including inflammatory disorders, it is desirable in the art to provide further JAK inhibitors and methods of utilizing such inhibitors in the treatment of diseases and disorders responsive to such inhibitors. In particular, there is a clear unmet need for new agents to control atopic dermatitis in animals that can address certain limitations of existing therapeutic agents.SUMMARY

[0007] The present disclosure relates to compounds which are inhibitors of Janus Kinases (JAKs), with efficacy against canine Janus Kinase- 1 (cJAK- 1) and selectivity over canine Janus Kinase-2 (cJAK-2), canine Janus Kinase-3 (cJAK-3), and canine Tyrosine Kinase 2 (cTYK-2). Accordingly, the disclosed compounds can be useful as therapeutic agents for indications where immunosuppression and / or immunomodulation would be desirable, including, but not limited, to canine atopic dermatitis.

[0008] Atopic Dermatitis (AD; also known as atopic eczema) is a genetically predisposed inflammatory, pruritic, chronic or chronically relapsing skin disease. It is most commonly associated with IgE antibodies to environmental allergens. Common clinical characteristics include erythema, edema, xerosis, erosions / excoriations, oozing and crusting. The disease typically affects dogs aged 6 months to 3 years and is characterized by pruritus and secondary skin lesions of a characteristic distribution around the face (mouth, eyes), concave aspect of the ear pinnae, ventral abdomen, flexor aspects of elbow, carpal, and tarsal joints, interdigital skin, and / or perineal area. Animals with atopic dermatitis are prone to secondary skin infections, ear infections and yeast infections. Atopic dermatitis cannot be cured. Therefore, the goal is to manage the disease to improve quality of life of canines and their owners.

[0009] The market for treating atopic dermatitis in animals has historically been dominated by corticosteroids and antihistamines, each suffering from various liabilities. For example, corticosteroids cause undesirable side effects in animals, specifically in companion animals such as dogs, while antihistamines suffer from poor efficacy. Particularly, the short- and long-term side effects of corticosteroids include polydipsia, polyphagia, polyuria, pancreatitis, gastrointestinal ulceration, lipidemias, diabetes, muscle wasting and iatrogenic Cushing’s syndrome. Further, the complicated dosing schedules can be challenging to dogs and their owners. A canine formulation of cyclosporine (ATOPIC A™) is marketed for atopic dermatitis, but is expensive, has a slow onset of efficacy, and exhibits gastrointestinal tolerability issues. In 2013, the United States FDA approved APOQUEL® (oclacitinib; N-methyl[trans-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) cyclohexyl]methanesulfonamide (2Z)-2 -butenedioate; Zoetis) for the treatment of pruritus associated withallergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age. APOQUEL® is a relatively selective JAK- 1 and JAK-3 inhibitor, blocking the effects of inflammatory cytokines released from activated lymphocytes (IL-2, -4, -6, -13) as well as IL-31, a cytokine directly involved in the sensation of itch. Despite its commercial success, APOQUEL® requires twice daily oral dosing during the initial induction phase, which lasts up to two weeks. In view of the challenges associated with orally medicating companion animals, it would be desirable to provide an alternative therapeutic agent with properties allowing once daily dosing.

[0010] Compounds of the present disclosure are JAK inhibitors with potency, efficacy, and selectivity for human JAK-1. In view of the very high homology between canine and human JAKs, such efficacy and selectivity obtained with respect to human subtypes is an appropriate surrogate for the canine subtypes, and it is expected that the canine in vitro pharmacological profile will mirror the human in vitro profile. The activity profile and selectivity for JAK-1 may allow for once-daily dosing while providing desirable efficacy and tolerability. These compounds therefore represent a valuable alternative to currently available therapeutic agents for the treatment of chronic pruritus and inflammation associated with atopic dermatitis. Accordingly, the present disclosure provides compounds of Formula I, their use as cJAK-1 inhibitors for the treatment of canine atopic dermatitis, pharmaceutical compositions containing these compounds, and methods for the preparation of these compounds.

[0011] In one aspect is provided a compound having a structure according to Formula (I):wherein:R1is H or CH3;R2is H, C1-C4alkyl, C3-C5cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3; orR1and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O;R3 is independently selected for each occurrence from the group consisting of F, Cl, -OCH3, CH3 and -CF3;R4is H, CH3, -CH2CH3, -CH2CF3, cyclopropyl, or -CH2OCH3;Z is N or CH; andx is 0, 1 or 2.

[0012] In some embodiments, Ri is H.

[0013] In some embodiments, Ri is CH3.

[0014] In some embodiments, R2 is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0015] In some embodiments, R2 is C1-C4 alkyl.

[0016] In some embodiments, Ri and R2 are each CH3.

[0017] In some embodiments, R2 is C3-C5 cycloalkyl.

[0018] In some embodiments, R2 is 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0019] In some embodiments, Ri and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O.

[0020] In some embodiments, R4 is H.

[0021] In some embodiments, R4 is CH3.

[0022] In some embodiments, R4 is CH2OCH3.

[0023] In some embodiments, R4 is CH2CF3.

[0024] In some embodiments, R4 is cyclopropyl.

[0025] In some embodiments, Z is CH.

[0026] In some embodiments, Z is N.

[0027] In some embodiments, the compound of Formula I is selected from the group consisting of:

[0028] In another aspect is provided a compound having a structure according to Formula (II):wherein:R5is H, CH3, -CH2CH3, -CH2CF3, or -CH2OCH3; andY is N or CH.

[0029] In some embodiments, Z is CH.

[0030] In some embodiments, Z is N.

[0031] In some embodiments, R5 is CH3.

[0032] In some embodiments, the compound of Formula II is selected from the group consisting of:

[0033] In still another aspect is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof.

[0034] In a further aspect is provided a method for treating allergic reactions, allergic dermatitis, atopic dermatitis, eczema, or pruritus in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof, or a composition of any thereof.

[0035] In some embodiments, the mammal is a companion animal. In some embodiments, the companion animal is a dog.

[0036] In some embodiments, the compound of Formula I or Formula II is administered orally, parenterally, or topically. In some embodiments, the compound of Formula I or Formula II is administered orally once daily.

[0037] These and other features, aspects, and advantages of the present disclosure will be apparent from a reading of the following detailed description. The present disclosure includes any combination of two, three, four or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined or otherwise recited in a specific example implementation described herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosure, in any of its aspects and example implementations, should be viewed as combinable, unless the context of the disclosure clearly dictates otherwise. It will therefore be appreciated that this Summary is provided merely for purposes of summarizing some example implementations so as to provide a basic understanding of some aspects of the disclosure. Accordingly, it will be appreciated that the above-described example implementations are merely examples and should not be construed to narrow the scope or spirit of the disclosure in any way. Other example implementations, aspects, and advantages will become apparent from the following detailed description.DETAILED DESCRIPTION

[0038] The present disclosure will now be described more fully hereinafter with reference to example embodiments thereof. Before describing several example embodiments of the technology, it is to be understoodthat the technology is not limited to the details of construction or process steps set forth in the following description. The technology is capable of other embodiments and of being practiced or being carried out in various ways.

[0039] The following description sets forth numerous exemplary configurations, methods, parameters, and the like in order to provide a thorough understanding of various embodiments of the disclosure. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0040] The present disclosure is generally directed to compounds of Formula I and Formula II:including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising said compounds, or stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. The disclosure particularly relates to such compounds, stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof with canine Janus Kinase- 1 (cJAK-1) inhibitory activity. Such compounds and pharmaceutical compositions of the disclosure may be useful for treating canine atopic dermatitis and the chronic pruritus and inflammation associated therewith. The compounds, compositions, and methods of treatment are further described herein below.Definitions

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. With respect to the terms used in this disclosure, the following definitions are provided. This application will use the following terms as defined below unless the context of the text in which the term appears requires a different meaning.

[0042] The articles "a" and "an" as used in this disclosure may refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" may mean one element or more than one element.

[0043] The term "and / or" as used in this disclosure may mean either "and" or "or" unless indicated otherwise.

[0044] The term "about" used throughout this specification is used to describe and account for small fluctuations. For example, the term "about" can refer to less than or equal to ±10%, less than or equal to ±5%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.2%, less than or equal to ±0.1% or less than or equal to ±0.05%. All numeric values herein are modified by the term "about," whether or not explicitly indicated. A value modified by the term "about" of course includes the specific value. For instance, "about 5.0" must include 5.0.

[0045] Unless the context requires otherwise, throughout the present specification and claims, as used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0046] " Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (w-propyl), 1-methylethyl (iso-propyl).1-butyl (w-butyl), 1-methylpropyl (sec-butyl). 2-methylpropyl (fro-butyl), 1,1 -dimethylethyl (tert-butyl), 1-pentyl (w-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0047] The term " Cx-y" when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term " Ci-ealkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -C1-6alkylene-may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0048] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula –o-alkyl, where alkyl is an alkyl chain as defined above.

[0049] " Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbonatoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (z.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0050] " Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0051] The terms " Cx-yalkenyl" and " Cx-yalkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, -C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0052] " Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, M-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (z.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (z.e., Ci-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (z.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (z.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (z.e., C5-C8 alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (z.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (z.e., C3-C5 alkylene).

[0053] " Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (z.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (z.e., C2-Cx alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (z.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (z.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (z.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (z.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (z.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (z.e., C3-C5 alkenylene).

[0054] " Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (z.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (z.e., C2-Cx alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (z.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (z. e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (z'.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (z'.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (z'.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (z'.e., C3-C5 alkynylene).

[0055] " Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, z'.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0056] " Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0057] " Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. " Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0058] " Carbocycle" refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0059] " Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like.

[0060] " Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0061] " Cycloalkylalkyl" refers to a radical of the formula -Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0062] " Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0063] " Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0064] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes ("haloalkanes") include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1 -chloro, 2-fluoroethane.

[0065] " Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0066] " Heterocycle" refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. " Heterocyclene" refers to a divalent heterocycle linking the rest of the molecule to a radical group

[0067] " Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0068] " Heterocycloalkylalkyl" refers to a radical of the formula -Rc-heterocycloalkyl where Rcis an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkylene chain at the nitrogen atom.

[0069] " Heteroaryl" or "aromatic heterocycle" refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, z.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl. phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (z.e. thienyl). An " X-membered heteroaryl" refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0070] " Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkylene chain at the nitrogen atom.

[0071] The term "amino" as used herein refers to -NH2.

[0072] The terms "hydroxy" and "hydroxyl" refer to -OH.

[0073] The term "oxo" as used herein refers to an "=O" group. It can also be abbreviated herein as C(O) or as C=O.

[0074] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0075] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino(=NNH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=NNH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa,-Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0076] As used herein, the term "unsubstituted" means that the specified group bears no substituents beyond the moiety recited (e.g, where valency is satisfied by hydrogen).

[0077] " Isomers" are different compounds that have the same molecular formula. " Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. " Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. " Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0078] In certain embodiments, the compounds of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The term "stereoisomers" may refer to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms but differ in three-dimensional structure. The term "stereoisomer" may refer to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.

[0079] When stereochemistry is not specified, certain molecules described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routineexperimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0080] In certain embodiments, the chiral centers of the present disclosure may have the S or R configuration as defined by the IUPAC 1974 Recommendations.

[0081] The term "radical of a compound" as used herein refers to a structure derived from a parent compound by removal of one or more atoms, e.g., hydrogen atoms. In one embodiment, a "radical of a compound" is a monovalent radical derived from the removal of one hydrogen atom from the parent compound.

[0082] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH₂CH(CH₃)CH₂-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene," "alkenylene," "arylene," and the like.

[0083] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.

[0084] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0085] " Stable compound" and "stable structure" may indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0086] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0087] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0088] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in tire sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository’ waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11)polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0089] The term "carrier," as used in this disclosure, may encompass carriers, excipients, and diluents and may mean a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent, such as one or more compounds, or pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers (e.g., stereoisomers), and tautomers thereof, of the disclosure, from one organ, or portion of the body, to another organ, or portion of the body of a subject. Carriers should be selected on the basis of compatibility and the release profile properties of the desired dosage form. Exemplary carrier materials may include, e.g., adjuvants, binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, e.g., Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975. Exemplary carrier materials may also include without limitation any adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0090] The terms "pharmaceutically acceptable" or "pharmacologically acceptable" may refer to a material which is not biologically, or otherwise, undesirable — the material may be administered to an individual without causing any substantially undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0091] A "pharmaceutical composition" may refer to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to a subject, e.g., mammals or humans. Such a medium may include all pharmaceutically acceptable carriers therefor.

[0092] The terms "subject," "individual," and "patient" may be used interchangeably and refer to non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).

[0093] As used herein, the phrase "a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0094] The terms "administer", "administered", "administers" and "administering" are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal,or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used.

[0095] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or salt described herein that is sufficient to affect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0096] As used herein, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. In some embodiments, a therapeutic benefit may include alleviating, abating or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0097] In some embodiments, the therapeutic benefit includes the eradication or amelioration of the underlying disorder being treated. In some embodiments, the therapeutic benefit includes the the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compounds or compositions are administered to a subject at risk of developing a particular disease, or to a subject exhibiting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0098] In certain embodiments, the term "prevent" or "preventing" as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0099] In certain embodiments, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.Compounds of the Disclosure

[0100] Generally, the present disclosure provides compounds having structures according to Formula I and Formula II:wherein each of Y, Z, R1-R5, and x are as defined herein.

[0101] In some embodiments, such compounds exhibit affinity, inhibitory activity, or both toward the canine JAK1 subtype, and may be useful for treating diseases and disorders mediated by the canine JAK1 subtype, such as canine atopic dermatitis. In some embodiments, a compound according to Formula I exhibits selectivity for the canine JAK1 subtype relative to other canine JAK subtypes, such as cJAK2, cJAK3, canine Tyrosine Kinase 2 (cTYK2), or combinations thereof. As described herein, such activity and selectivity may be desirable in providing a companion animal therapeutic agent with improved tolerability relative to known companion animal therapeutic agents for the treatment of e.g., canine atopic dermatitis, and may provide the potential for once daily dosing.

[0102] Accordingly, in one aspect is provide a compound having a structure according to Formula I,wherein:R1is H or CH3;R2is H, C1-C4alkyl, C3-C5cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3; orR1and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O;R3is independently selected for each occurrence from the group consisting of F, Cl, -OCH3, CH3and -CF3;R4is H, CH3, -CH2CH3, -CH2CF3, cyclopropyl, or -CH2OCH3;Z is N or CH; andx is 0, 1 or 2.

[0103] In some embodiments, R1is H.

[0104] In some embodiments, R1is CH3.

[0105] In some embodiments, R2is selected from the group consisting of C1-C4alkyl, C3-C5cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0106] In some embodiments, R2is C1-C4alkyl.

[0107] In some embodiments, R2is CH3.

[0108] In some embodiments, R1is H and R2is CH3

[0109] In some embodiments, R1and R2are each CH3.

[0110] In some embodiments, R2is C3-C5cycloalkyl. In some embodiments, R1is H and R2is C3-C5cycloalkyl.

[0111] In some embodiments, R2is phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0112] In some embodiments, R1is H and R2is 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl.

[0113] In some embodiments, R1and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O.

[0114] In some embodiments, x is 0.

[0115] In some embodiments, x is 1, and R3is F, Cl, -OCH3, CH3or -CF3. In some embodiments, x is 1, and R3is F. In some embodiments, x is 1, and R3is Cl.

[0116] In some embodiments, x is 2, and R3is independently selected for each occurrence from F, Cl, -OCH3, CH3and -CF3.

[0117] In some embodiments, x is 2, and one instance of R3is F, and the other instance of R3is Cl.

[0118] In some embodiments, x is 2, and both instances of R3are F.

[0119] In some embodiments, x is 2, and both instances of R3are Cl.

[0120] In some embodiments, R4is H.

[0121] In some embodiments, R4is CH3.

[0122] In some embodiments, R4is -CH2OCH3.

[0123] In some embodiments, R4is -CH2CF3.

[0124] In some embodiments, R4is cyclopropyl.

[0125] In some embodiments, Z is CH.

[0126] In some embodiments, Z is N.

[0127] In some embodiments, the compound of Formula I is selected from the group consisting of:

[0128] In some embodiments, the compound of Formula I is selected from the group consisting of:

[0129] In another aspect is provided a compound having a structure according to Formula (II):wherein:R5is H, CH3, -CH2CH3, -CH2CF3, or -CH2OCH3; andY is N or CH.

[0130] In some embodiments, Z is CH.

[0131] In some embodiments, Z is N.

[0132] In some embodiments, R5is CH3.

[0133] In some embodiments, Z is CH, and R5is H or CH3.

[0134] In some embodiments, Z is N, and R5is H or CH3.

[0135] In some embodiments, the compound of Formula II is selected from the group consisting of:

[0136] Exemplary, non-limiting, compounds of the disclosure according to Formula I and Formula II include those in Table 1. Accordingly, in some embodiments, a compound of Formula I or Formula II is selected from any of the compounds in Table 1.Table 1. Compounds of Formula I and Formula II Compound # Structure1 ^^ / Cl0 U |TX JUL F NHCl 0 H^FFUr N\ X LIHIN2o r Y^A XJ-AI^HH2M1 CAl 0AFH< ^FFUuANH V30i^iiX JUL F LJ i J'i / N. Cl 0H^FFH4JUCP KS; [j TT;S'N^NHCl 0 H^FFH 'nJIPharmacological profile of compounds of the disclosure

[0137] Compounds of Formula I and Formual II generally possess inhibitory activity toward one or more Janus Kinase (JAK) subtypes. The effect of compounds on the JAK enzyme and / or animal can be determined or measured. Methods for determining JAK activity include those described in the Examples of the present disclosure as well as those disclosed in WO1999 / 65908, WO1999 / 65909, WO2001 / 42246, W02002 / 00661, W02002 / 096909, W02004 / 046112 or W02007 / 012953, the content of each of which is incorporated herein by reference.

[0138] In some embodiments, a compound of Formula I or Formula II has a JAK1 activity, such as binding affinity, as measured by enzyme binding IC50, of less than about 1 micromole, such as less than about 500 nM, less than 250 nM, less than 100 nM, or less than 50 nM. In some embodiments, a compound of Formula I binds to JAK1 with an IC50between about 25 and about 100 nM, between about 100 and about 250 nM, between about 250 and about 500 nM, or between about 500 and about 1000 nM. In some embodiments, the compound of Formula I or Formula II has human JAK1 activity, canine JAK1 activity, or both.

[0139] In some embodiments, a compound of Formula I or Formula II exhibits binding selectivity toward JAK-1 relative to other enzymes, such as other JAK subtypes. In some embodiments, a compound of Formula I or Formula II has selectivity for JAK-1 over JAK-2 on the order of about 5-fold or greater, or about 10-fold or greater, such as from about 5 or about 10 to about 20, about 50, or about 100-fold. In some embodiments, the compound of Formula I or Formula II is selective for human JAK-1. In some embodiments, the compoundof Formula I or Formula II is selective for canine JAK-1. In some embodiments, the compound of Formula I is selective for both human and canine JAK-1.

[0140] In some embodiments, a compound of Formula I or Formula II is selective toward functional inhibition of JAK-1 (canine, human, or both). In some embodiments, a compound of Formula I or Formula II has selectivity for JAK-1 inhibition over JAK-2 inhibition on the order of about 5 -fold or greater, or about 10-fold or greater, such as from about 5 or about 10 to about 20, about 50, or about 100-fold.Preparation of Compounds of the Disclosure

[0141] Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the synthetic schemes in the following description, examples, and Figures in conjunction with the guidance provided herein. In the schemes described below and provided in the Figures, it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles or chemistry in accordance with the guidance provided herein. Protecting groups may be manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art based on the detailed teaching provided herein. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the present disclosure.

[0142] Generally, the methods of preparing compounds of the present disclosure comprise combinations of reactions and conditions. Schemes 1, 2, 3, and 4 illustrate representative, non-limiting alternative strategies for preparation of compounds of Formula I. Each aspect of the preparative methods according to Schemes 1-4 are discussed further herein below. The reactions in the schemes can be performed through chemical reactions using standard synthetic chemistry procedures and practices as known in the art or described herein. In each of Schemes 1-4, substituents R1, R2, R3, and R4 are each as described herein above with respect to Formula I.Scheme 114_ Boc5 6 7

[0143] The methods of preparing compounds of the present disclosure generally begin with preparation of an amino sulfonamide intermediate 4. Such compounds 4 may be prepared according to Scheme 1. With reference to exemplary Scheme 1, amino sulfonamide intermediates 4 may generally be prepared by allowing a commercially available nitrobenzenesulfonyl chloride 1 to react with an amine 2 in the presence of a suitable base, such as pyridine or a non-nucleophilic amine, to form a nitro sulfonamide 3. Such sulfonamides 3 may readily be reduced to amino sulfonamides 4 by, for example, hydrogenation over a suitable catalyst or reduction with iron, zinc, and the like under acidic conditions.

[0144] Alternatively, amino sulfonamides 4 may be prepared from a commercially available or readily prepared bromobenzenesulfonyl chloride 5. With continued reference to Scheme 1, a bromobenzenesulfonyl chloride 5 to react with an amine 2 in the presence of a suitable base, such as pyridine or a non-nucleophilic amine, to form a bromobenzenesulfonamide 6. Bromobenzenesulfonamide 6 is then amidated with e.g., BOC-protected ammonia in the presence of a palladium reagent to provide sulfonamide intermediate 7, which is then N-deprotected to form an amino sulfonamide 4. The amino sulfonamide intermediate 4 may then be incorporated into a compound of Formula I according to several alternative methods.

[0145] With reference to Schemes 1 and 2, in some embodiments, amine 2 is a primary amine. In some embodiments, amine 2 is a secondary amine. In some embodiments, amine 2 is a primary or secondary alkyl amine, benzylic amine, aryl amine, or heterocycloalkylamine. In some embodiments, Ri is H.

[0146] In some embodiments, Ri is CH3.

[0147] In some embodiments, R2 is H.

[0148] In some embodiments, R2 is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0149] In some embodiments, R2 is C1-C4 alkyl.

[0150] In some embodiments, R2 is CH3.

[0151] In some embodiments, Ri is H and R2 is CH3

[0152] In some embodiments, Ri and R2 are each CH3.

[0153] In some embodiments, R2 is C3-C5 cycloalkyl. In some embodiments, Ri is H and R2 is C3-C5 cycloalkyl.

[0154] In some embodiments, R2 is phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

[0155] In some embodiments, Ri is H and R2 is 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl.

[0156] In some embodiments, Ri and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O.

[0157] Amine components 2 may be commercially available or may be readily obtained by standard synthetic procedures.

[0158] In some embodiments, x is 0.

[0159] In some embodiments, x is 1, and R3 is F, Cl, -OCH3, CH3 or -CF3. In some embodiments, x is 1, and R3 is F. In some embodiments, x is 1, and R3 is Cl.

[0160] In some embodiments, x is 2, and R3 is independently selected for each occurrence from F, Cl, -OCH3, CH3 and -CF3.

[0161] In some embodiments, x is 2, and one instance of R3 is F, and the other instance of R3 is Cl.

[0162] In some embodiments, x is 2, and both instances of R3 are F.

[0163] In some embodiments, x is 2, and both instances of R3 are Cl.

[0164] In some embodiments, a compound of Formula I is prepared according to exemplary Scheme 2. With reference to Scheme 2, amino sulfonamide intermediate 4 is acylated with a suitable acid or acid chloride to form a bromoamide 8. The bromoamide 8 is then aminated with piperazine (optionally mon-N -protected) to form piperazine 9. The piperazine 9 is then alkylated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 to provide a compound of Formula I (11).Scheme 2

[0165] In some embodiments, a compound of Formula I is prepared according to exemplary Scheme 3. With reference to Scheme 3, amino sulfonamide intermediate 4 is acylated with acid 12 (wherein Z is N or CH) to form a piperidine or piperazine 13. The piperidine or piperazine 13, after N-deprotection, is then alkylated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 to provide a compound of Formula I (11).Scheme 3

[0166] In some embodiments, a compound of Formula I is prepared according to exemplary Scheme 4. With reference to Scheme 4, bromo sulfonamide intermediate 6 is amidated with amide 14 in the presence of a palladium catalyst to form a piperazine 15. The piperazine 15 is then alkylated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 to provide a compound of Formula I (11).Scheme 4

[0167] In some embodiments, a compound of Formula I is prepared according to exemplary Scheme 5. With reference to Scheme 5, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 is aminated with a protected piperazine, such as BOC-piperazine, to form protected piperazine 16. The preotected piperazine 16 is N-deprotected to form piperazine 17. Alkylation of 17 with an O-protected bromoacid (e.g., as a t-butyl ester) followed by O-deprotection then provides acid 18. Acid 18 is then amidated by coupling with amino sulfonamide intermediate4 to provide a compound of Formula I (11).Scheme 511

[0168] Schemes 6 and 7 illustrate representative, non-limiting alternative strategies for preparation of compounds of Formula II. Each aspect of the preparative methods according to Schemes 6 and 7 are discussed further herein below. The reactions in the schemes can be performed through chemical reactions using standard synthetic chemistry procedures and practices as known in the art or described herein. In Schemes 6 and 7, substituent R5 is as described herein above with respect to Formula II.

[0169] In some embodiments, a compound of Formula II is prepared according to exemplary Scheme 6. With reference to Scheme 6, a bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one isomer 19 is amidated with Boc-protected ammonia in the presence of a suitable catalyst (e.g., a palladium reagent) and subsequently N-deprotected in the presence of an acid to provide an amino-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one isomer 20. Acylation of 20 with a bromo acid chloride then provides an amide isomer 21, which is then aminated with a protected piperazine (e.g., Boc-piperazine) followed by N-deprotection to provide a piperazine isomer 22. The piperazine isomer 22 is then alkylated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 to provide a compound of Formula II (23).Scheme 6o

[0170] In other embodiments, a compound of Formula II (23) is prepared according to an alternative procedure as allustrated in Scheme 7. With reference to Scheme 7, the intermediate bromide 21 of Scheme 6 is aminated with tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate (24) followed by acid deprotection to provide a compound of Formula II (23).Scheme 7Boc

[0171] The isomeric bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-ones 19 of Scheme 6 may be prepared according to exemplary Scheme 8. With reference to Scheme 8, 4-bromophthalaldehyde 24 is subjected to a condensation reaction with 5-(trifluoromethyl)thiazol-2-amine 25 to form a mixture of two regioisomeric products 26. Treatment of 26 with acid at elevated temperature then hydrolyzes the imino groups, providing a mixture of two regiosisomeric bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-ones 19, which may be used as is as illustrated in Schemes 6 and 7. The mixture of two regiosisomers may also be separated by HPLC, for example, using a chiral column, to provide (5-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one and 6-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one; 19a and 19b, respectively), which may then be utilized individually to prepare products of Formula II.Scheme 8CF3(25) o1919a 19bIsotopes and Isotopically Labeled Compounds

[0172] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. Accordingly, reference to a certain element is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes isotopes thereof. For example, hydrogen has three naturally occurring isotopes, denoted 'H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0173] The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds. An "isotopically" or "radio-labeled" compound may be a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in some embodiments, in the compounds described herein hydrogen atoms are replaced or substituted by one or more deuterium or tritium.

[0174] Certain isotopically labeled compounds of this disclosure, for example, those incorporating a radioactive isotope, may be useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon 14, i.e.,14C, may be particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. In some embodiments, the compound comprises at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Suitable isotopes that may be incorporated in compounds described herein include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),nC,13C,14C,13N,15N,150,170,18O,18F,35S,36C1,82Br,75Br,76Br,77Br,1231,1241,125I, and131I. Substitution with positron emitting isotopes, such asnC,18F,15O, and13N, can be useful in Positron Emission Topography (PET) studies.

[0175] Isotopically labelled versions of the compounds disclosed herein can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.Isomers

[0176] In some embodiments, compounds of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein. An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or at least 75, at least 80, at least 85, at least 90, at least 95, at least 96, at least 97, at least 98, at least 99, at least 99.5 or even 100 mol percent. In some embodiments, the compounds described herein enriched in one enantiomer may be substantially free of the other enantiomer, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the compound mixture. For example, if a compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2 mol percent of the second enantiomer.

[0177] In some embodiments, the compounds of the disclosure may be enriched to provide predominantly one diastereomer of a compound disclosed herein. A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or at least 75, at least 80, at least 85, at least 90, at least 95, at least 96, at least 97, at least 98, at least 99, at least 99.5, or even 100 mol percent. In some embodiments, the compounds described herein enriched in one diastereomer may be substantially free of other diastereomers, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of other diastereomers, e.g., in the compound mixture.

[0178] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column. Also, some of the compounds of the disclosure may be atropisomers or rotameric forms and are considered as part of this disclosure.Metabolites

[0179] The disclosure herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure may include compounds produced by a process comprising administering a compound of this disclosure to a subject, e.g., a mammal, for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to subject, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.Salts and Solvates

[0180] The present disclosure further provides pharmaceutically acceptable salts, solvates (e.g., hydrates), and combinations thereof of any of the compounds as disclosed herein. The use of the terms "salt," "hydrate," "solvate," and the like, is intended to equally apply to the salt, hydrate, or solvate of enantiomers, diastereomers, isomers, stereoisomers, rotamers, tautomers, positional isomers, or racemates of the disclosed compounds.

[0181] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. In some embodiments, the "pharmaceutically acceptable salts" may include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, l,l-methene-bis-2-hydroxy-3-naphthoate, einbonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0182] Suitable anionic salt forms include, but are not limited to acetate, benzenesulfonate, benzoate, benzylate, bicarbonate, bitartrate, bitartrate, bromide, calcium edetate, camsylateh, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionatei, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate and diphosphate, polygalacturonate, salicylate and disalicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate, and the like.

[0183] Suitable cationic salt forms include, but are not limited to aluminum, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, zinc, and the like. Suitable cationic salt forms include, but are not limited to benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like.

[0184] In some embodiments, the salt is selected from the group consisting of acetate, ascorbate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, etoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate,palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0185] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0186] Compounds of the disclosure, including their stereoisomers and tautomers, as well as salts of any thereof, may exist as solvates. Often, crystallizations produce a solvate of the compound of the disclosure. As used herein, the term "solvate" may refer to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds and salts of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the disclosure may be true solvates, while in other cases the compound of the disclosure may merely retain adventitious water or be a mixture of water plus some adventitious solvent.Pharmaceutical Formulations and Compositions

[0187] A compound of the present disclosure, as well as its salts, solvates, isomers, and the like, can be administered to the subject by itself or in a pharmaceutical composition where it is mixed with one or more biologically suitable and pharmaceutically acceptable carriers or excipients. The compositions can be in various forms, including, but not limited to, oral formulations, injectable formulations, suppository formulations, and topical, dermal, or subdermal formulations. Selection of an appropriate formulation of a compound as provided herein may be based, e.g., on the physicochemical properties of the compound (and any other optional active agent to be administered), the type of animal being treated, the condition of the animal being treated, and cost.

[0188] Pharmaceutical compositions can comprise at least the compounds or salts described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and / or thickening agents. The particular components and the relative amounts of each will vary depending on, for example, the intended route of administration. The compositions can be formulated to contain a single daily dose or a convenient fraction of a daily dose in a dosage unit (e.g., a single tablet, single capsule, convenient volume of liquid / ointment, etc.). The amount of the compound of the formula provided above included within a given composition for use in animal and human health can vary widely. The compound is typically included within a composition in an amount likely to induce the desired effect. Compositions that will be administered to a subject or patient commonly take the form of one or more dosage units, where forexample, a tablet may be a single dosage unit, and a container of one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, in aerosol form may hold a plurality of dosage units.

[0189] Pharmaceutical compositions for use in accordance with the present disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in " Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991). In general, pharmaceutical compositions of the disclosed compounds may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The techniques for formulation may be found in references well known to one of ordinary skill in the art, such as " Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Oral dose forms

[0190] The compositions described herein can be formulated for oral administration. When intended for oral administration, pharmaceutical compositions of the present disclosure typically are either solid or liquid form, where semi solid, semi liquid, suspension and gel forms may be included within the forms considered herein as either solid or liquid.

[0191] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials disclosed herein, a liquid carrier such as polyethylene glycol or oil.

[0192] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycolsand the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. In some embodiments, a capsule (a hard capsule or a soft capsule), e.g., a gelatin capsule comprising a compound according to a formula as described herein is provided. A hard gelatin capsule, in some embodiments, can a compound according to a formula as described herein admixed with an inert solid diluent, e.g., a starch, powdered cellulose (e.g., crystalline or microcrystalline cellulose), a sugar (e.g., fructose, mannitol, or sucrose), a grain flour, calcium carbonate, calcium phosphate, and / or kaolin, enclosed in a capsule. A soft or liquid gelatin capsule, in some embodiments, can comprise a compound according to a formula as described herein mixed with water or a solvent such as propylene glycol, polyethylene glycol (PEG), and / or ethanol or mixed with an oil medium, e.g., peanut oil, liquid paraffin, or olive oil, enclosed within a capsule. In some embodiments, such capsules are microcapsules.

[0193] In some embodiments, a composition in tablet form is provided, comprising a compound according to a formula as described herein in combination with one or more pharmaceutically acceptable excipients. Tablets are generally prepared via direct compression (e.g., wet granulation or dry granulation of ingredients). Excipients known to be suitable for the manufacture of tablets are generally known and include, for example, inert diluents (e.g., starches, lactose, mannitol, powdered sugar, powdered cellulose derivatives, kaolin, calcium carbonate, sodium carbonate, lactose, calcium phosphate, calcium sulfate, sodium phosphate, and / or inorganic salts such as sodium chloride); granulating and disintegrating agents (e.g., starch such as com or potato starch, clay, cellulose, methylcellulose, carboxymethyl cellulose, algins, and / or alginic acid, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, guar gum, citrus pulp, and / or sodium lauryl sulfate); binding agents (e.g., starch, gelatin, sugars (e.g., lactose, fructose, glucose, and the like), natural or synthetic gums such as acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like), polyethylene glycol, ethyl cellulose, and / or waxes; and lubricating agents, (e.g., magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, and / or talc). Tablets may be uncoated or may be coated by known techniques (which can serve to delay disintegration and absorption in the gastrointestinal tract and thereby provide for sustained action over a longer period of time). For example, in some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Tablets may also be optionally coated by techniques described in U. S. Patent Nos. 4,256,108 to Theeuwes; 4,166,452 to Generales Jr.; and 4,265,874 to Bonsen et al., which are all incorporated herein by reference with respect to the preparation of osmotic therapeutic tablets for controlled release. Troches are an example of tablets, and are typically formulated as small, hard tablets which dissolve slowly when placed under the tongue. Tablets canoptionally be coated, e.g., with sugar as a flavorant and sealant or with film-forming protecting agents to modify the dissolution properties of the tablet.

[0194] Pharmaceutical compositions of the disclosure may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, pharmaceutical compositions of the disclosure typically contain, in addition to one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer.

[0195] In some embodiments, a composition comprising a compound according to a formula as described herein is provided in the form of an emulsion, e.g., in the form of an oil-in-water or a water-in-oil emulsion. The oily phase of the emulsion may be a vegetable oil, e.g., olive oil or arachis oil or may be a mineral oil, e.g., liquid paraffin, or a mixture of any such oils. In some embodiments, the oily phase is formed from unsaturated polyglycosylated glycerides, triglycerides, (e.g., medium-chain triglycerides, such as C8-C10 caprylic / capric triglycerides), or combinations thereof. The aqueous phase can comprise water or glycol derivatives (e.g., propylene glycol, glycol ether, polyethylene glycol, or glycerol). Specific examples include, but are not limited to, propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, and mixtures thereof. Suitable emulsifying agents may include, e.g., naturally occurring phosphatides, e.g., soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g., sorbitan monoleate, and condensation products of the referenced partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. The emulsions may also optionally contain sweetening agents, bittering agents, flavoring agents, and / or preservatives. In one embodiment, the emulsion is in the form of a microemulsion (composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or of microdroplets of the oily phase in the aqueous phase). Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a co-surfactant. They are translucent and isotropic liquids. The size of these microdroplets is less than 200 nm (in contrast to microdroplets with sizes of about 1000 run to 100,000 nm for emulsions). In some embodiments, the oily phase will represent a % v / v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v / v of the microemulsion. Generally, the aqueous phase will represent a proportion from about 1 to about 4% v / v in the microemulsion. The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously. Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, the co-surfactants include short-chain alcohols, such as ethanol and propanol. Some compounds are common to the three components discussed above, i.e., aqueous phase, surfactant and co-surfactant.However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment, the co-surfactant to surfactant ratio will be from about 1 / 7 to about 1 / 2. In another embodiment, there will be from about 25 to about 75% v / v of surfactant and from about 10 to about 55% v / v of co-surfactant in the microemulsion.

[0196] In some embodiments, a composition comprising a compound according to a formula as described herein is provided in the form of a suspension, generally comprising the compound (optionally along with other ingredients) dispersed in a liquid. The compound is typically in the form of a dispersible powder or granule; dispersible powders and granules suitable for preparation of a suspension generally provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, bittering, flavoring, and coloring agents, may also be present. The liquid can be oily or aqueous. Oily suspensions may be formulated by suspending the compound in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid, or other known preservatives. Aqueous suspensions contain the compound in admixture with excipients suitable for the manufacture of aqueous suspensions. For example, such aqueous suspensions may comprise excipients that are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and / or bittering agents, such as those set forth above. Aqueous suspensions may comprise, e.g., juice (such as apple or orange juice).

[0197] In some embodiments, a composition comprising a compound according to a formula as described herein is provided in the form of a syrup or elixir. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and / or coloring agent(s).

[0198] In some embodiments, a composition comprising a compound according to a formula as described herein is in paste form. Examples of embodiments in a paste form include but are not limited to those described in U. S. Pat. Nos. 6,787,342 to Chen; 7,001,889 to Freehauf et al.; and 7,563,773 to Freehauf, each of which is incorporated herein by reference in its entirety. In addition to the compound(s) of the invention, the paste can also contain components including, e.g., fumed silica; a viscosity modifier (e.g., selected from PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80), and polyoxamers (e.g., Pluronic L 81)); a carrier (e.g., a hydrophilic carrier selected from triacetin, a monoglyceride, a diglyceride, and a triglyceride); optionally, an absorbent (e.g., selected from magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives); and optionally, a colorant (e.g., selected from the group consisting of titanium dioxide iron oxide, and FD& C Blue #1 Aluminum Lake), stabilizer, surfactant, and / or preservative.

[0199] Sustained-release preparations can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound or salt, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(–)-3-hydroxybutyric acid.Injectable forms

[0200] The compositions described herein can be formulated for administration as an injection. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included. Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0201] For parenteral administration, the compounds or salts can be formulated in a unit dosage injectable form (e.g., use letter solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic, and non-therapeutic. Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixedoils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0202] Liquid pharmaceutical compositions of the disclosure, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. In some embodiments, the adjuvant is physiological saline. In some embodiments, the injectable pharmaceutical composition is sterile.Other dosage forms

[0203] Pharmaceutical compositions of the disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration.

[0204] In some embodiments, a composition suitable for topical, dermal, and / or subdermal formulation comprising a compound according to the formula(s) described herein is provided. Topical, dermal, and subdermal formulations can include, e.g., emulsions, creams, ointments, gels, pastes, powders, patches, shampoos, pour-on formulations, ready-to-use formulations, spray formulations, and spot-on formulations. Such formulations can be, e.g., concentrated solutions, suspensions, microemulsions, or emulsions. Topical application can, in some embodiments, allow for the active compound(s) to be distributed through the glands (e.g., sebaceous glands) of the animal and / or allow the active compound(s) to achieve a systemic effect (plasma concentration) and / or allow for distribution throughout the haircoat. Certain suitable formulations for topical, dermal, and / or subdermal application include, but are not limited to, those disclosed in U. S. Pat. No. 6,395,765 to Etchegaray, which is incorporated herein by reference in its entirety.

[0205] Spot-on compositions are typically applied in a localized region which refers to an area other than the entire animal. Spot-on compositions are generally used by administering the composition at a particular location of an animal (e.g., between the shoulders). Another embodiment of a localized region is a stripe, e.g., a stripe from head to tail of the animal. Such compositions can be administered, e.g., via pipettes, squeeze-ons, or drop-ons.

[0206] The carrier can be a liquid carrier vehicle as described in U. S. Pat. No. 6,426,333, which is incorporated herein by reference in its entirety. For example, in one embodiment, a spot-on formulation comprises a solvent and a co-solvent wherein the solvent is selected from the group consisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters, such as the diethyl ester or diisobutyl adipate, and a mixture of at least two of these solvents and the co-solvent is selected from the group consisting of absolute ethanol, isopropanol or methanol. The liquid carrier vehicle can optionally contain a crystallization inhibitor selected from the group consisting of an anionic surfactant, a cationic surfactant, a non-ionic surfactant, an amine salt, an amphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, and acrylic derivatives, or a mixture of these crystallization inhibitors.

[0207] Pour-on compositions are generally used by pouring the composition along an animal’s backline (e.g., from the neck to the tail). The pour-on formulations are advantageously oily, and generally comprise a diluent or vehicle and also a solvent (e.g., an organic solvent) for the active ingredient if the latter is not soluble in the diluent. Certain non-limiting pour-on compositions are disclosed, for example, in U. S. Patent Nos. 6,010,710 to Etchegaray and 8,097,266 to Gogolewski et al., which are incorporated herein by reference in their entireties.

[0208] Spray-on compositions are generally used by spraying a composition along an animal’s backline (e.g., from the neck to the tail). Each of these compositions can involve application, e.g., of a concentrated solution, suspension, microemulsion or emulsion.

[0209] Such topical compositions (e.g., spot-on, spray-on, and pour-on compositions) can generally comprise the compound as provided herein in combination with one or more diluents / vehicles and / or one or more solvents. Diluents / vehicles include, but are not limited to, plant oils (e.g., soybean oil, groundnut oil, castor oil, com oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.); mineral oils (e.g., petrolatum, paraffin, silicone, etc.); aliphatic or cyclic hydrocarbons; medium-chain (such as C8 to C12) triglycerides, and combinations thereof. Solvents (e.g., organic solvents) that can be added in some embodiments include, but are not limited to, acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethyleneglycol and diethyl phthalate, and mixtures of two or more thereof. In some embodiments, an emollient and / or spreading and / or film-forming agent is included in the composition. An emollient and / or spreading and / or filmforming agent can be, for example, selected from the group consisting of: polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example those containing silanol functionalities, or a 45V2 oil, anionic surfactants such as alkaline stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulphosuccinate; fatty acids (e.g. those derived from coconut oil), cationic surfactants such as water-soluble quaternary ammonium salts of formula N+R'R" R'" R"", Y- in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y-is an anion of a strong acid such as the halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used, amine salts of formula N+R'R" R'" in which the radicals R are optionally hydroxylated hydrocarbon radicals (e.g., octadecylamine hydrochloride), nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as the substituted lauryl compounds of betaine; and mixtures of at least two of these agents.

[0210] Pharmaceutical compositions of the disclosure may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. Compositions for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases may include, without limitation, lanolin, cocoa butter and polyethylene glycol.

[0211] Pharmaceutical compositions of the disclosure may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the compositions may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.Dosing

[0212] The dosage to be administered of a compound of Formula I or Formula II as described herein will vary according to the particular compound, the subject and the physical condition thereof, the nature and severity of the disease, and the selected route of administration. Accordingly, the amount of compound or composition administered to an animal in need of treatment can vary widely. The amount of compound administered can depend, e.g., on such factors as the efficacy of the compound, the type of animal being treated, the animal’sbody weight, the animal’s age, the desired effect, and the nature and severity of the disease. It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the disorders or diseases being treated. One of skill in the art will be able to discern a specific efficacious dose. Generally, a therapeutically effective amount is the amount of compound or composition sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the subject to whom the compound or composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. Also, it is to be understood that an initial, higher dosage (i.e., one or more loading doses) may be administered in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation (i.e., dose titration).

[0213] Administration of the compounds or compositions provided herein may vary in frequency and duration. Administration may, for example, be intermittent in time and can be administered daily, weekly, biweekly, monthly, bimonthly, quarterly, or even for longer durations of time. In some embodiments, the administration is daily for a period of time of at least about one week, two weeks, three weeks, a month, or two months, and up to six months, a year, or multiple years, including for the lifetime of the subject.

[0214] In some embodiments, administration of the desired dose may be presented as a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete, loosely spaced administrations, such as multiple oral dose forms.

[0215] It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound as described herein or a composition comprising the compound as described herein will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and condition of the particular subject being treated, and that a physician will ultimately determine appropriate dosages, frequency and treatment duration to be used. The selected dosage may be repeated as often as appropriate. If side effects develop the amount and / or frequency of the dosage can be altered or reduced, in accordance with normal clinical practice. One of skill in the art will be able to develop a specific administration protocol for a particular situation.Method of Treating Canine Atopic Dermatitis and / or Pruritis

[0216] Provided herein is a method of treating canine atopic dermatitis and / or pruritis. The method generally comprises administering an effective amount of a compound of the disclosure, a salt, or solvate thereof, or a composition comprising the compound or salt or solvate thereof. Without wishing to be bound by any particulartheory, it is believed that the potency and selectivity of the disclosed compounds in inhibiting Janus Kinase 1 (JAK-1; e.g., canine JAK-1 (cJAK-1)) provides efficacy and tolerability, which, together with a long half-life, allows for once-daily dosing.

[0217] The pathogenesis of canine atopic dermatitis is complex. Percutaneous sensitization to environmental allergens (e.g., dust mites, pollen, mold) and / or allergens from food induces skin infiltration by various inflammatory cells, activation of resident cells, and local production of inflammatory / itch mediators. Various factors can exacerbate canine atopic dermatitis, including ectoparasites, particularly fleas, environmental factors, cutaneous colonization / infection by bacteria and yeast, and epidermal barrier dysfunction.

[0218] The JAK / STAT signaling pathway has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, and autoimmune diseases such as rheumatoid arthritis, JAK1 inhibition blocks the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, and IL- 15, which are known contributors to inflammatory disorders such as atopic dermatitis. Accordingly, inhibition of JAK signaling, and particularly JAK-1 signaling, has been proposed for treatment of immune-mediated disorders such as atopic dermatitis. In addition to the anti-inflammatory activity of JAK- 1 inhibitors, it has been reported that type 2 cytokines, IL-4 and IL- 13, directly stimulate sensory neurons and that chronic itch is dependent on neuronal IL-4Ra and JAK1 signaling (see, e.g., US Patent Application Publication No.2021 / 0338812). Further, as discussed herein above, oclacitinib (APOQUEL®) has been approved by the FDA for treatment canine atopic dermatitis, lending further support to the concept of utilizing JAK inhibitors for the treatment of pruritis / immune / allergic disorders in companion animals. (Gonzales et al., J. Vet. Pharmacol Ther. 2014 Aug; 37(4): 317-24).

[0219] Oclacitinib is most potent at inhibiting JAK-1 (IC50 = 10 nM), and also inhibits the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL- 13) as well as pruritus (IL-31) at IC50's ranging from 36 to 249 nM. (Gonzales et al., 2014). Oclacitinib has been characterized as a targeted therapy that selectively inhibits JAK 1 -dependent cytokines involved in allergy, inflammation, and pruritus with the suggestion that these are the mechanisms by which oclacitinib controls clinical signs associated with allergic skin disease in dogs.

[0220] It has now been found that the selectivity of oclacitinib toward cJAK-2, cJAK-3, and cJAK-4 relative to cJAK-1 is, in fact, relatively low. It is believed that this lack of selectivity is responsible for the dose limiting emesis observed in dogs and is likely cJAK-2 related. As noted herein above, it would be desirable in the art to provide a cJAK inhibitor with efficacy in treating canine atopic dermatitis and the related symptoms while allowing for the potential for once daily (QD) dosing.

[0221] Accordingly, disclosed herein are compounds having selectivity for JAK-1 over JAK-2 inhibition (canine, human, or both) on the order of 10-fold or greater, and methods of treating canine atopic dermatitis, pruritis, or both using such compounds. The methods of treatment generally comprise administering atherapeutically effective amount of the compound of Formula I or Formula II, a salt or solvate thereof, or a composition comprising the compound, salt, or solvate.

[0222] Generally, the method comprises administering a compound of the present disclosure or its pharmaceutical compositions orally, parenterally, topically, rectally, or transmucosally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Topical administrations include the treatment of skin or organs readily accessible by local application, for example, ears. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. In some embodiments, the route of administration is oral or parenteral. In specific embodiments, the route of administration is oral.

[0223] As described herein above, the frequency of dosing may vary based on the individual compound, the subject, the nature and severity of the dermatitis, and the like. In some embodiments, the compound or composition is administered orally on a daily basis. Also as described herein above, in some embodiments, the compound of the present disclosure has pharmacological and pharmacokinetic properties amenable to once daily dosing. Accordingly, in some embodiments, the administration is once daily.Combination Therapy

[0224] One or more compounds disclosed herein or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers of any of these, may be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy may include administration of a single pharmaceutical dosage formulation that contains one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, and one or more additional active agents, as well as administration of one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, and each active agent in its own separate pharmaceutical dosage formulation. For example, one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, and the other active agent can be administered to the subject together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, and one or more additional active agents can be administered at essentially the same time, e.g., concurrently, or at separately staggered times, e.g., sequentially; combination therapy is understood to include all these regimens.

[0225] Suitable therapeutic agents for combination therapy with the disclosed compounds include those which modulate a mammalian immune system, antihistamines, and anti-inflammatory agents. These agents may include but are not limited to cyclosporin A (e.g., Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g., Cellcept®, azathioprine (e.g., Imuran®), daclizumab (e.g.,Zenapax®), 0KT3 (e.g., Orthocolone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and antiinflammatory steroids (e.g., prednisolone or dexamethasone). These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[0226] Although the technology herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present technology. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present technology without departing from the spirit and scope of the technology. Thus, it is intended that the present technology include modifications and variations that are within the scope of the appended claims and their equivalents. Accordingly, the disclosure is not limited except as by the appended claims.

[0227] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Any ranges cited herein are inclusive.

[0228] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0229] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0230] Many modifications and other embodiments of the disclosure will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0231] Reagent / reactant names given are as named on the commercial bottle or as generated by IUPAC conventions, ChemDraw 19.0 (CAMBRIDGESOFT®; PerkinElmer). Compounds designated as salts (e.g., hydrochloride, acetate, sulfate) may include more than one molar equivalent of the acid.EXEMPLIFICATION

[0232] Aspects of the present disclosure are more fully illustrated by the following examples, which are set forth to illustrate certain aspects of the present invention and are not to be construed as limiting thereof. The technology is capable of other embodiments and of being practiced or being carried out in various ways. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, further compounds within the scope of the present disclosure by using appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.Example 1. Synthesis of N-[2,4-dichloro-3-(methylsulfamoyl)phenyl]-2-(piperazin-l-yl)propenamide- HC1 (Intermediate 1).Step A. Synthesis of 2,6-dichloro-N-methylbenzenesulfonamide

[0233] To a solution of 2,6-dichlorobenzenesulfonyl chloride (4 g, 16.30 mmol, 1 equiv) in DCM (50 mL) under nitrogen atmosphere was added TEA (4.12 g, 40.75 mmol, 2.50 equiv). Then methylamine (3.37 g, 32.60 mmol, 2 equiv) was added and the mixture was stirred at 30°C for 1 hour. The reaction mixture was treated with water (100 mL), extracted by DCM (100 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (3.35 g, 77%) as a white solid.[M+H]+=240;242.Step B. Synthesis of 3-bromo-2,6-dichloro-N-methylbenzenesulfonamide

[0234] To a solution of 2,6-dichlorobenzenesulfonamide (2.50 g, 10.40 mmol,l equiv) in H2SO4 (25 mL) under nitrogen atmosphere, cooled to 0°C, N-bromosuccinimide (1.85 g, 10.40 mmol, 1 equiv) was added over 2 mins. The reaction mixture was poured on to ice (300 g), extracted by EtOAc (150 mL x 3), and the combinedorganic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (2.80 g, 76%) as a white solid. [M+H]+=318;320. ‘H NMR (400 MHz, DMSO-d6): δ 2.55 (d, J = 4.8 Hz, 3H), 7.59 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.09-8.13 (m, 1H).Step C. Synthesis of tert-butyl N- [2, 4-dichloro-3-(methylsulfamoyl)phenyl] carbamate

[0235] A mixture of 3-bromo-2,6-dichloro-N-methylbenzenesulfonamide (1.30 g, 4.10 mmol, 1 equiv), tertbutyl carbamate (0.72 g, 6.15 mmol, 1.50 equiv), CS2CO3 (3.34 g, 10.25 mmol, 2.50 equiv), XantPhos (0.52 g, 0.90 mmol, 0.22 equiv) and Pd2dba3 (0.41 g, 0.45 mmol, 0.11 equiv) in 1,4-dioxane (40 mL) under nitrogen atmosphere was stirred at 105°C for 22 hours. The reaction mixture was treated with water (100 mL), extracted with EA (80 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EA / PE=0-80%) to give the title compound (0.89 g, 51%) as a yellow solid. [M+H]+=355.Step D. Synthesis of 3-amino-2,6-dichloro-N-methylbenzenesulfonamide

[0236] To a solution of tert-butyl N-[2,4-dichloro-3-(methylsulfamoyl)phenyl]carbamate (400 mg, 1.13 mmol, 1 equiv ) in DCM (15 mL) under nitrogen atmosphere was added TFA (5 mL) and the reaction mixture was stirred at 30°C for 3 hours. The reaction mixture was concentrated and purified by flash chromatography (MeOH / DCM=0-10%) to give the titled compound (280 mg, 88%) as a yellow oil. [ M+H]+=255.Step E. Synthesis of tert-butyl 4-(l-{[2,4-dichloro-3-(methylsulfamoyl)phenyl]carbamoyl}ethyl)piperazine-l-carboxylate

[0237] To a solution of 2-{4-[(tert-butoxy)carbonyl]piperazin-l-yl}propanoic acid (354 mg, 1.37 mmol, 1 equiv), 3-amino-2,6-dichloro-N-methylbenzenesulfonamide (350 mg, 1.37 mmol, 1 equiv) in pyridine (12 mL) under nitrogen atmosphere at 0°C was added POCI3 (567 mg, 3.70 mmol, 2.70 equiv) over 2 mins. The mixture was stirred at 30°C for 2 hours. The reaction mixture was treated with aqueous NaHCCL (50 mL), extracted by EA (40 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EA / PE= 10-80%) to give the title compound (340 mg, 45%) as a yellow solid. [M+H]+=495.Step F. Synthesis of N-[2,4-dichloro-3-(methylsulfamoyl)phenyl]-2-(piperazin-l-yl)propenamide (HC1 salt)

[0238] To a solution of tert-butyl 4-(l-{[2,4-dichloro-3- (methylsulfamoyl)phenyl]carbamoyl}ethyl)piperazine-l-carboxylate (150 mg, 0.30 mmol, 1 equiv) in MeOH (0.60 mL)and DCM (6 mL) under nitrogen atmosphere, 4M HC1 in 1,4-dioxane (3 mL) was added, and the mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated to give the title compound (181 mg, 95%) as a light yellow solid. [M+H]+=395.Example 2. Synthesis of N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)-2-(piperazin-l-yl)acetamide (Intermediate 2).Et3N Pd2(dba)3, XPhos, Cs2CO3 TFA, DCM0°C to r.t., 2 h DCM, 0°C, 1 h Dioxane, 100°C, overnightDIEA, DCM, rt, 2 hHCl / dioxane 0°C to r.t., 3 hStep A. Synthesis of 5-bromo-2-fluoro-N, N-dimethylbenzenesulfonamide

[0239] To a solution of 5-bromo-2-fluorobenzenesulfonyl chloride (2 g, 7.30 mmol, 1.0 equiv) in DCM (20 mL) was added EtzN (2.03 mL, 14.6 mmol, 2 equiv) and dimethylamine (3.65 mL, 2M, 7.30 mmol, equiv) at 0°C and the mixture was stirred at 25 °C for Ih. The mixture was concentrated, diluted with water and extracted with EA. The combined organic layers were dried over Na2SO4, concentrated in vacuo to afford crude 5-bromo-2-fluoro-N, N-dimethylbenzenesulfonamide (1.90 g, 92%) as brown solid. [M+H]+=282.Step B. Synthesis of tert-butyl (3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)carbamate

[0240] To a solution of 5-bromo-2-fluoro-N, N-dimethylbenzenesulfonamide (1.90 g, 6.70 mmol, 1 equiv) in dioxane (20 mL) was added tert-butyl carbamate (1.18 g, 10 mmol, 1.50 equiv), Pd2(dba)3 (0.31 g, 0.34 mmol, 0.05 equiv), Xphos (0.32 g, 0.67 mmol, 0.10 equiv), Cs2CO3 (4.37g, 13.40 mmol, 2 equiv) and mixture was stirred at 100°C under nitrogenatmosphere for 16h. The mixture was filtered and the filtrated was concentrated to afford a residue. The residue was purified by silica gel column chromatography (eluting with PE / EA = 5: 1~2: 1) to afford the title compound (2 g, 94%) as brown oil. [M+H]+=319.Step C. Synthesis of methyl 5-amino-2-fluoro-N, N-dimethylbenzenesulfonamide

[0241] To a solution of tert-butyl N-[3-(dimethylsulfamoyl)-4-fluorophenyl]carbamate (1 g, 3.10 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL) at 0°C and the mixture was stirred at 25 °C for 16h. The mixture was poured into saturated solution of NaHCCL, extracted with EA. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound (1.10 g, 97%) as brown solid. [M+H]+=219. Step D. Synthesis of methyl 2-chloro-N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)acetamide

[0242] To a solution of a 5-amino-2-fluoro-N, N-dimethylbenzenesulfonamide (1.10 g, 5 mmol) in DMF (20 mL) was added 2-chloroacetyl chloride (1.13 g 10.0 mmol, 2.0 equiv), DIEA (1.29 g, 10 mmol, 2 equiv) and the mixture was stirred at 25°C for 3h. The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with H2O and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na₂SO₄, concentrated and purified by silica gel column chromatography (eluting with PE / EA = 5: 1~2: 1) to afford the title compound (1.35 g, 92%) as brown solid. [M+H]+=295.Step E. Synthesis of tert-butyl 4-(2-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine-l-carboxylate

[0243] To a solution of 2-chloro-N-[3-(dimethylsulfamoyl)-4-fluorophenyl]acetamide (1.35 g, 4.60 mmol, 1 equiv) in MeCN (25 mL) was added tert-butyl piperazine- 1 -carboxylate (1.71 g, 9.20 mmol, 2 equiv), DIEA (1.19 g, 9.20 mmol, 2 equiv) and the mixture was stirred at 85°C for 3h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (eluting with PE / EA = 5: 1—2: 1) to afford tert-butyl 4-(2-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine-l-carboxylate (1.51 g, 74%) as brown oil. [M+H]+=445.Step F. Synthesis of N-(3-(N, N-dimethylsulfamoyl)-4-fhiorophenyl)-2-(piperazin-l-yl)acetamide

[0244] To a solution of tert-butyl tert-butyl 4-(2-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine- 1 -carboxylate (200 mg, 0.45 mmol, 1 equiv) in DCM (6 mL) was added 1,4-dioxane / HCl (4M, 2 mL) at 0°C and the mixture was stirred at 25°C for 2h. The mixture was poured into a saturated solution of NaHCCh and extracted with DCM. The combined organic layers were dried over Na₂SO₄, concentrated in vacuo to afford the crude title compound (140 mg, 90%) as brown oil. [M+H]+=345.Example 3. Synthesis of 2-bromo-N-(3-fluoro-4-(N-methylsulfamoyl)Dhenyl)butanamide (Intermediate 3).o25°C Step A. Synthesis of 2-fluoro-N-methyl-4-nitrobenzenesulfonamide

[0245] A solution of MeNH₂ in THF (37.6 mL, 75.20 mmol, 4 equiv) in dry THF (40 mL) was cooled to -10°C. A solution of 2-fluoro-4-nitrobenzenesulfonyl chloride (4.50 g, 18.80 mmol, 1 equiv) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to remain at -10°C and stirred for Ih, then added HC1 (2 M) to pH ~ 5, concentrated, and extracted with DCM (3 x 10 mL). The extracts were concentrated to provide crude 2-fluoro-N-methyl-4-nitrobenzenesulfonamide (4.60 g, purity: 90%, yield: 94%, brown solid). LCMS: [M+H]+=233.Step B. Synthesis of 4-amino-2-fluoro-N-methylbenzenesulfonamide

[0246] To a solution of 2-fluoro-N-methyl-4-nitrobenzenesulfonamide (4.6 g, 0.020 mol, 1 equiv), NH4CI (10.48 g, 0.196 mmol, lO. Oequiv) in EtOH (90 mL) and H₂O (30 mL), stirred under at 50°C was added Fe power (5.47 g, 0.10 mol, 5equiv). The reaction mixture was stirred at 80°C for Ih. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated and adjusted to pH = 7-8 with NaHCO₃. The residue was extracted with EA (5 x 20 mL). The combined organic layers were washed with brine and concentrated in vacuo to get the crude 4-amino-2-fluoro-N-methylbenzenesulfonamide (3.75 g, purity: 90%, yield: 84%, brown solid). LCMS: [M+H]+=204.Step C. Synthesis of 2-bromo-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide

[0247] To a stirred solution of 2-bromobutanoic acid (368 mg, 2.20 mmol, 1.50 equiv) in DCM (10 mL), HATU (1.68 g, 4.41 mmol, 3 equiv) and pyridine (465 mg, 5.88 mmol, 4 equiv) were added. The reaction mixture was kept under nitrogen at 25°C for 0.5h, then a solution of 4-amino-2-fluoro-N-methylbenzenesulfonamide (300 mg, 1.47 mmol, 1 equiv) was added dropwise. The reaction mixture was allowed to 25°C and stirred for 16 h. The mixture was diluted with ice water (10 mL), extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine and concentrated in vacuo. The crude was purified by flash chromatography (PE / EA=3 / 1) to give the title product (460 mg, purity: 90%, yield: 80%, off-white solid). LCMS: [M+H]+=353.Example 4. Synthesis of 4-amino-N-(pyridin-4-yl)benzenesulfonamide (Intermediate 4).Pd / C, H2MeOHStep A. Synthesis of 4-nitro-N-(pyridin-4-yl)benzenesulfonamide

[0248] A solution of pyridin-4-amine (500 mg, 5.31 mmol, 1 equiv) in dry pyridine (3 mL) was cooled to 0°C. A solution of 4-nitrobenzenesulfonyl chloride (1.40 g, 6.38 mmol, 1.20 equiv) in anhydrous pyridine (4 mL) was added dropwise and the mixture was stirred at 0°C for 2h. The reaction mixture was allowed to warm to ambient temperature and stirred for 16h. Water (5 mL) was added. The solution was filtered, filter cake was collected, involved addition of MeOH / DCM for precipitation. The solution was filtered and the filtrate was concentrated under reduced pressure to give the title product (870 mg, purity: 90%, yield: 59%, yellow solid). LCMS: [M+H]+=278.Step B. Synthesis of 4-amino-N-(pyridin-4-yl)benzenesulfonamide

[0249] A solution of 4-nitro-N-(pyridin-4-yl)benzenesulfonamide (870 mg, 3.12 mmol, lequiv), Pd / C (10%, 332 mg) in MeOH (15 mL) was stirred at 25°C for 16h under 1 atm of H₂. The solution was filtered, and filtratewas collected. The reaction mixture was concentrated under reduced pressure to give the title product (460 mg, purity:90%, 66%, white solid). LCMS: [M+H]+=251.Example 5. Synthesis of 2-chloro-N-(4-(N-cvclopropylsulfamoyl)phenyl)acetamide (Intermediate 5),[x*- NH2Fe, NH4CIDIEA, DCM EtOH / water16h, O°C~rt 80°C, 1hClStep A. Synthesis of N-cyclopropyl-4-nitrobenzenesulfonamide

[0250] To a solution of 4-nitrobenzenesulfonyl chloride (10 g, 0.045 mol, 1 equiv) and cyclopropanamine (3.09 g, 0.054 mol, 1.20 equiv) in DCM (15 mL) was added DIEA (8.74 g, 0.068 mol, 1.50 equiv). The mixture was stirred at room temperature for 16h. The residue was extracted with DCM and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated to get the N-cyclopropyl-4-nitrobenzenesulfonamide (10.40 g, 9%) as off-white solid. [M+H]+=243.0.Step B. Synthesis of 4-amino-N-cyclopropylbenzenesulfonamide

[0251] To a solution of N-cyclopropyl-4-nitrobenzenesulfonamide (2.80 g, 0.012 mol, 1 equiv) in EtOH / water (30 mL / 5 mL) was added Fe (6.48 g, 0.12 mol, 10 equiv) and NH4CI (3.10 g, 0.058 mol, 5 equiv). The mixture was stirred at 80°C for Ih. The mixture was filtered and the filtrate was extracted with DCM and washed with water. The organic layer was dried over Na₂SO₄ and concentrated to provide the title compound (2.44 g, 99%) as gray solid. [M+H]+=213.1.Step C. Synthesis of 2-chloro-N-(4-(N-cyclopropylsulfamoyl)phenyl)acetamide

[0252] To a solution of 4-amino-N-cyclopropylbenzenesulfonamide (1.8 g, 8.48 mmol, 1 equiv), pyridine (1.34 g, 16.96 mmol, 2 equiv) in DCM (20 mL) was added 2-chloroacetyl chloride (1.25 g, 11.02 mmol, 1.30 equiv). The mixture was stirred at room temperature for Ih. The residue was extracted with DCM and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated to provide the title compound (2.35 g, 96%) as gray solid. [M+H]+=289.0.Example 6. Synthesis of 3-amino-2-chloro- / V-methyl benzenesulfonamide (Intermediate 6).CISO2OH TEA, CH3NH2 L X '9 Fe, NH4CI 50-110’C, 4 h DCM, 0 °C - r.t., 30 min O2N^V>NTHF, EtOH, H2O, 80 °C, 1 hH2NI > NCl O H Cl o HStep A. Synthesis of 2-chloro-3-nitrobenzenesulfonyl chloride

[0253] Chlorosulfonic acid (14.30 g, 0.12 mol, 3.87 equiv) was to added melted l-chloro-2-nitrobenzene (5 g, 0.032 mol, 1 equiv) dropwise at 50°C. Then the reaction mixture was heated to 110 °C and stirred for 4 h.The reaction mixture was cooled to RT and added dropwise to ice-water (40 mL), then extracted with EtOAc (40 mL x 2). The organic layer was evaporated in vacuo to afford crude 2-chloro-3-nitrobenzenesulfonyl chloride (8.10 g, 100%) as brown oil, which was used directly in the next step without further purification.Step B. Synthesis of 2-chloro-N-methyl-3-nitrobenzenesulfonamide

[0254] To a stirred solution of 2-chloro-3-nitrobenzenesulfonyl chloride (8.10 g, 0.032 mol, 1 equiv) in DCM (60 mL) were added a solution of triethylamine (9.59 g, 0.095 mol, 3 equiv) and methanamine (30% in MeOH, 5.1 g, 0.049 mol, 1.56 equiv) in DCM (20 mL) dropwise at 0 °C. Then the reaction mixture was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo, the resulting residue was purified by column chromatography on silica gel (0 ~ 25% EtOAc in petroleum ether) to afford 2-chloro-N-methyl-3-nitrobenzenesulfonamide (2.97 g, 36%) as a yellow solid. [M-H]+= 249.Step C. Synthesis of 3-amino-2-chloro-N-methyl benzenesulfonamide

[0255] To a solution of 2-chloro-N-methyl-3-nitrobenzenesulfonamide (1 g, 040 mol, 1 equiv) in THF (6 mL), EtOH (6 mL) and H2O (2 mL) were added Fe (1.12 g, 0.020 mol, 5 equiv) and NH4CI (0.64 g, 0.012 mol, 3 equiv) at RT. Then the reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was filtered via a pad of diatomaceous earth and the filtrate was evaporated in vacuo. The resulting residue was diluted with EtOAc (10 mL), washed with saturated aqueous solution of NaHCO₃ (30 mL), and extracted with EtOAc (30 mL x 2). The organic layer was evaporated in vacuo to afford crude 3-amino-2-chloro-N-methylbenzenesulfonamide (0.88 g, 95%) as yellow oil. [M-H]+= 219.Example 7. Synthesis of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 7).Step A. Synthesis of 4-nitro-N-(pyridin-2-yl)benzenesulfonamide

[0256] A solution of pyridin-2-amine (1.50 g, 15.90 mmol, 1.00 equiv) in DCM (10 mL) was cooled to 0°C.4-nitrobenzenesulfonyl chloride (3.52 g, 15.90 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise and the mixture was stirred at 25°C for 4h. The crude material was added to a silica gel column and was eluted with PE / EtOAc (2: 1). The mixture was concentrated under reduced pressure to give the title product (1.70 g, 90% purity, 59% yield, off-brown solid). LCMS: [M+H]+=280.Step B. Synthesis of 4-amino-N-(pyridin-2-yl)benzenesulfonamide

[0257] To a solution of 4-nitro-N-(pyridin-2-yl)benzenesulfonamide (1.70 g, 6.10 mmol, 1.00 equiv) in EtOH / H2O=1:1 (5 mL) was added Fe (2.04 g, 36.60 mmol, 5.00 equiv) and NH4CI (1.96 g, 36.60 mmol, 5.00 equiv), stirred at 80°C for Ih. The organic phase was washed with water (5 mL). The reaction mixture was concentrated under pressure at 50°C. The crude material was added to a silica gel column and was eluted withPE / EtOAc (1:1). The reaction mixture was concentrated under reduced pressure to get the title product (1.05 g, 90 % purity, 62 %, yield, brown solid). LCMS: [M+H]+=250.Example 8. Synthesis of 4-amino-2-fhioro-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 8),Zn AcOH / Water / THF60°C,4h Step A. Synthesis of 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide

[0258] To a solution of pyridin-2-amine (1002 mg, 10.64 mmol) in THF (30 mL) stirred under nitrogen at -50°C was added a solution of LiHMDS (10.60 mL, 10.64 mmol). The reaction mixture was stirred at -50°C for Ih. Then was added 2-fluoro-4-nitrobenzenesulfonyl chloride at -50°C for 2h. Saturated aqueous HC1 (20 mL) was added. The residue was extracted with EA (3 x 30 mL). Solvent was dried over sodium sulphate and evaporated in vacuo to give the crude product 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide (1200 mg, 30% purity) as light-yellow oil. [M+H]+=298.Step B. Synthesis of 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide

[0259] To a solution of 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide (900 mg, 3.03 mmol) and AcOH (1818 mg, 30.30 mmol) in THF / H2O=1: 1 (30 mL) stirred under nitrogen at 30°C was added Zn (1970 mg, 30.30 mmol). The reaction mixture was stirred at 80°C for 2h. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure 70°C. The residue was purified via flash chromatography eluting with ACN / H₂O (Ratios: 2:8; Pressure: 2.5 bar) to give the title product (140 mg, 95% purity, 16% yield) as light-yellow oil. [M+H]+=268.Example 9. Synthesis of 4-bromo-2,6-difluoro-N-methylbenzenesulfonamide (Intermediate 9).MeNH2 / H2OTHF,0°C

[0260] To a solution of 4-bromo-2,6-difluorobenzenesulfonyl chloride (800 mg, 2.74 mmol, 1.00 equiv) in THF (10 mL) at 0°C was added MeNH₂ / H₂O (759 mg, 1.95 mmol, 2.50 equiv, 40 Wt%). The reaction mixture was stirred at 0°C for 0.5 h and 25 °C for 0.5 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 4-bromo-2,6-difluoro-N-methylbenzenesulfonamide (650 mg, 75%) as white solid. [M+H]+=286.Example 10. Synthesis of 4-bromo-2-chloro-6-fluoro-N-methylbenzenesulfonamide (Intermediate 10).— NH2in H2OTHF, r.t., 1h

[0261] To a solution of 4-bromo-2-chloro-6-fluorobenzenesulfonyl chloride (650 mg, 2.1 mmol, 1.00 equiv) in THF (10 mL) stirred at 0°C was added a solution of methylamine (656 mg, 21.1 mmol, 10.00 equiv) in H2O dropwise. The reaction mixture was stirred at 0°C for Ih. Quenched the reaction with HC1 aq. (1 N). The mixture was concentrated and extracted from H2O with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. This resulted in 4-bromo-2-chloro-6-fluoro-N-methylbenzenesulfonamide (603 mg, yield 94%) as yellow solid. [M-H]+=301.Example 11. Synthesis of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (Intermediate 11).Step A. Synthesis of 4-nitro-N-(pyrimidin-5-yl)benzenesulfonamide

[0262] A solution of pyrimidin-5 -amine (1.00 g, 10.50 mmol, 1.00 equiv) and DIEA (2.71 g, 21.00 mmol, 2.00 equiv) in DCM (10 mL) was cooled to 0°C. A solution of 4-nitrobenzenesulfonyl chloride (2.33 g, 10.50 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise and the mixture was stirred at 25 °C for 4h. The crude material was added to a silica gel column and was eluted with PE / EtOAc (2: 1). The mixture was concentrated under reduced pressure to get the title product (0.85 g, 90% purity, 26% yield, brown solid). LCMS: [M+H]+= 281.Step B. Synthesis of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide

[0263] To a solution of 4-nitro-N-(pyrimidin-5-yl)benzenesulfonamide (850 mg, 3.03 mmol, 1.00 equiv) in EtOH / H2O=1:1 (5 mL) was added Fe (847 mg, 15.15 mmol, 5.00 equiv) and NH4CI (811 mg, 15.15 mmol, 5.00 equiv), stirred at 80°C for Ih. The organic phase was washed with water (5 mL). The reaction mixture was concentrated under pressure 50°C. The crude material was added to a silica gel column and was eluted with PE / EtOAc (1:1). The reaction mixture was concentrated under reduced pressure to get the title compound (263 mg, 90% purity, 31% yield, brown solid). LCMS: [M+H]+=251.Example 12. Synthesis of (R)-and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (Intermediates 12 and 13).HCI / dioxane12 13Step A. Synthesis of tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate

[0264] To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.63 g, 49.70 mmol, 1.00 equiv) in n-BuOH (30 mL) was added tert-butyl piperazine- 1 -carboxylate (9.31 g, 49.70 mmol, 1.00 equiv) and DIEA (19.27 g, 149.10 mmol, 3.00 equiv), stirred at 90°C for 16h. The reaction mixture was concentrated under pressure at 50°C. The crude material was added to a silica gel column and was eluted with PE / EtOAc (2:1) to get the product tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate (12.79 g, 90% purity, 76% yield, white solid). LCMS: [M+H]+=304.Step B. Synthesis of 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0265] To a solution of tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate (6.00 g, 19.70 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added 1,4-dioxane / HCl (15 mL) and stirred at 25 °C for 5h.The reaction mixture was concentrated under pressure 50°C to give the title product (6.03 g, 90% purity, 88% yield, white solid). LCMS: [M+H]+=204.Step C. Synthesis of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate

[0266] To a solution of 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.00 g, 13.10 mmol, 1.00 equiv) in DMF (30 mL) was added tert-butyl 2-bromopropanoate (2.74 g, 13.10 mmol, 1.00 equiv), K2CO3 (3.62 g, 26.20 mmol, 2.00 equiv) and KI (2.17 g, 13.10 mmol, 1.00 equiv), stirred at 50°C for 16h. The residue was extracted with EA (10 x 3 mL). The solution was filtered and the filtrate was collected. The reaction mixture was concentrated and the residue was triturated with PE (5 mL) to give the title product (3.50 g, 95% purity, 76% yield, white solid). LCMS: [M+H]+=332.Step D. Chiral separation

[0267] Racemic tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (3.40 g) was subjected to chiral chromatography to provide two enantiomers. The first eluting enantiomer (1.60 g) was arbitrarily assigned the (R)-configuration and the second eluting enantiomer (1.6 g) was assigned the (S)-configuration.Step E. Synthesis of (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (Intermediate 12; HC1 Salt)

[0268] To a stirred solution of (R)-tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yljpropanoate (90 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25 °C for 3h. The reaction mixture was concentrated to give the title product (HC1 Salt) (89 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Step F. Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (Intermediate 13; HC1 Salt)

[0269] To a stirred solution of (S)-tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yljpropanoate (193 mg, 0.59 mmol) in dioxane (6 mL) was added HCl / dioxane (6 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the title product (163 mg, yield: >95%, 92% purity, white solid). LCMS: [M+H]+=276.Example 13. Synthesis of (R)- and (S)-2-bromo-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propenamide (Intermediates 14 and 15).MeNH2 / H2O Fe, NH4CI DCM / H2On.. EtOH / H2O n. D T °2N80°C, 2 hStep A. Synthesis of 2-chloro-N-methyl-4-nitrobenzenesulfonamide

[0270] To a solution of 2-chloro-4-nitrobenzenesulfonyl chloride (1 g, 0.78 mmol, lequiv) in DCM (15 mL) at 0°C was added MeNH₂ / H₂O (759 mg, 1.95 mmol, 2.50equiv, 40 Wt%). The reaction mixture was stirred at 0°C for 0.5 h and 25°C for 0.5 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the product 2-chloro-N-methyl-4-nitrobenzenesulfonamide (860 mg, 70 %) as yellow solid. [M+H]+=251.Step B. Synthesis of 4-amino-2-chloro-N-methylbenzenesulfonamide

[0271] To a solution of 2-chloro-N-methyl-4-nitrobenzenesulfonamide (837 mg, 3.34 mmol, lequiv) in EtOH (12 mL) and water (4 mL) was added Fe powder (933 mg, 16.70 mmol, 5equiv) and NH4CI (1786 mg, 33.39 mmol, 10 equiv). The reaction mixture was stirred at 80°C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the product 4-amino-2-chloro-N-methylbenzenesulfonamide (614 mg, 75%) as yellow solid. [M+H]+=221.Step C. Synthesis of 2-bromo-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propanamide

[0272] To a solution of 4-amino-2-chloro-N-methylbenzenesulfonamide (300 mg, 1.36 mmol, lequiv) and 2-bromopropanoic acid (250 mg, 1.63 mmol, 1.20equiv) in DCM (15 mL) was added pyridine (216 mg, 2.72 mmol, 2 equiv) and HATU (776 mg, 2.04 mmol, 1.50equiv). The reaction mixture was stirred at 30°C for 16 h. The mixture was extracted with DCM and washed with water. The organic layer was dried over Na₂SO₄ and concentrated. The mixture was purified by flash chromatography (EA / PE=l / 3~l / 2) to give the product 2-bromo-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propanamide (370 mg, 69 %) as yellow oil. [M+H]+=355 / 357.Step D. Synthesis of tert-butyl 4-(l-((3-chloro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0273] To a solution of 2-bromo-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propanamide (260 mg, 0.73 mmol, lequiv) and DIEA (284 mg, 2.19 mmol, 3equiv) in ACN (10 mL) was added tert-butyl piperazine-1-carboxylate (164 mg, 0.88 mmol, 1.20equiv). The reaction mixture was stirred at 80°C for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (EA / PE=1 / 2~1 / 1) to give theproduct tert-butyl 4-( 1 -((3 -chloro-4-(N-methylsulfamoyl)phenyl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carboxylate (196 mg, 52%) as yellow oil. [M+H]+= 461.Step E. Chiral separation

[0274] Tert-butyl 4-( l-((3-chloro-4-(N-methylsulfamoyl)phenyl)amino)- l-oxopropan-2-yl)piperazine- 1-carboxylate (336 mg) was subjected to chiral chromatography to provide two enantiomers ((R)-first eluting: 158 mg, and (S)-, second eluting; 148 mg). Absolute configurations were not determined and stereochemistry was randomly assigned.Step F. Synthesis of (R)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1)

[0275] To a solution of (R)-tert-butyl 4-(l-((3-chloro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yljpiperazine- 1 -carboxylate (75 mg, 0.16 mmol, lequiv) in DCM (4 mL) at 0°C was added 4 MHCl / dioxane (1 mL). The reaction mixture was stirred at 30°C for 1 h. The mixture was concentrated in vacuo to give crude (R)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1) (70 mg, 95%) as yellow solid. [M+H]+= 361.Step G. Synthesis of N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1)

[0276] To a solution of (S)-tert-butyl 4-(l-((3-chloro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yljpiperazine- 1 -carboxylate (70 mg, 0.15 mmol, lequiv) in DCM (4 mL) at 0°C was added 4M HCl / dioxane (1 mL). The reaction mixture was stirred at 30°C for 1 h. The mixture was concentrated in vacuo to give crude (S)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1) (73 mg, >100%) as yellow solid, which was used to next step directly. [M+H]+= 361.Example 14. Synthesis of (R)- and (S)-N-(3.5-dichloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yllpropenamide (intermediates 17 and 18).Step A. Synthesis of tert-butyl 4-(l-((3,5-dichloro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0277] To a solution of 4-bromo-2,6-dichloro-N-methylbenzenesulfonamide (479 mg, 1.50 mmol, 1 equiv), tert-butyl 4-(l-carbamoylethyl)piperazine-l-carboxylate (386 mg, 1.50 mmol, 1 equiv) and CS2CO3 (978 mg, 3 mmol, 2 equiv) in 50 ml of 1,4-dioxane stirred under nitrogen at 25°C was added 138 mg of Pd2(dba)3 and174 mg of xantphos. The reaction mixture was stirred at 103°C for 16 hours. The mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column (PE: EA=1: 1-1:2) to afford tert-butyl 4-(l-((3,5-dichloro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl) piperazine- 1 -carboxylate (440 mg, 59%) as yellow solid. [M+H]+=495.Step B. Chiral separation

[0278] The product of Step A (440 mg) of product was subjected to chiral chromatography to provide two enantiomers (first eluting: 210 mg, (R); and second eluting; 190 mg, (S)). Absolute configurations were not determined and stereochemistry was randomly assigned.Step C. Synthesis of (R)-N-(3,5-dichloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide

[0279] (R)-tert-butyl 4-(l-((3,5-dichloro-4-(N-methylsulfamoyl)phenyl)amino)- l-oxopropan-2-yljpiperazine- 1 -carboxylate (210 mg) was dissolved in 20 ml of DCM: TFA=1: 1. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give the titled product (410 mg, 93%) as yellow oil. [M+H]+=395Step D. Synthesis of (S)-N-(3,5-dichloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide

[0280] (S)-tert-butyl 4-(l-((3,5-dichloro-4-(N-methylsulfamoyl) phenyl)amino)-l-oxopropan-2-yljpiperazine- 1 -carboxylate (190 mg) was dissolved in 20 ml of DCM: TFA=1: 1. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give the title product (395 mg, 99%) as yellow oil.[M+H]+=395Example 15. Synthesis of (R)-2-(4-(7H-nvi olo|2.3-dlr)yrimidin-4-yl)ninerazin-l-yl)-N-(2.4-dichloro-3-(N-methylsulfamovDphenyl)propenamide and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-vD-N-(2,4-dichloro-3-(N-methylsulfamovDphenyl)propenamide (Compounds 1 and 2).Step A. Synthesis of racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(2,4-dichloro-3-(N-methylsulfamoyl)phenyl)propenamide

[0281] To a solution of N-[2,4-dichloro-3-(methylsulfamoyl)phenyl]-2-(piperazin-l-yl)propanamide (Intermediate 1, Example 1; 181 mg, 0.37 mmol, 1 equiv) and4-chloro-7H-pyrrolo[2,3-d]pyrimidine (56 mg, 0.37 mmol, 1 equiv) in 1-butanol (10 mL) under nitrogen atmosphere, DIEA (237 mg, 1.83 mmol, 5 equiv)was added and the mixture was stirred at 98°C for 16 hours. The reaction mixture was concentrated and purified by flash chromatography (MeOH / DCM=0-10%) to provide the title product.Step B. Chiral separation

[0282] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)-N-(2,4-dichloro-3-(N-methylsulfamoyl)phenyl)propenamide was subjected to chiral chromatography to provide two enantiomers. The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned. The first eluting enantiomer was (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(2,4-dichloro-3-(N-methylsulfamoyl)phenyl)propanamide (Compound 1) (38 mg, 20%) as a light yellow solid.[M+H]+=512. 'HNMR (400 MHz, DMSO-d6): δ 1.23 (d, J = 7.2 Hz, 3H), 2.54 (s, 3H), 2.65-2.76 (m, 4H), 3.52-3.57 (m, 1H), 3.98 (br, 4H), 6.63 (d, J= 3.6 Hz, 1H), 7.20 (d, J= 3.6 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 8.16 (s, 1H), 8.41 (d, J= 9.2 Hz, 1H), 10.45 (s, 1H), 11.73 (s, 1H).

[0283] The second eluting enantiomer was (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(2,4-dichloro-3-(N-methylsulfamoyl)phenyl)propanamide (Compound 2) (45 mg, 24%) as a light yellow solid.[M+H]+=512. 'HNMR (400 MHz, DMSO-d6): δ 1.23 (d, J = 6.8 Hz, 3H), 2.54 (s, 3H), 2.65-2.76 (m, 4H), 3.52-3.57 (m, 1H), 3.98 (br, 4H), 6.63 (d, J= 3.6 Hz, 1H), 7.20 (d, J= 3.6 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 8.16 (s, 1H), 8.41 (d, J= 8.8 Hz, 1H), 10.45 (s, 1H), 11.73 (s, 1H).Example 16. Synthesis of (R)- and (S)-2-(4-(7 / / -pyrrolo|2.3-d|pyrimidin-4-yl)piperazin-l-yl)-N-(2-chloro-3-(N-methylsulfamoyl)phenyl)propenamide (Compounds 3 and 4).H2N HCl / dioxane Cl O H DCM MeOH, rt, 30 minStep A. Synthesis of tert-butyl 4-(l-((2-chloro-3-( / V-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0284] To a solution of 3-amino-2-chloro-A''-mcthylbcnzcncsiilfonamidc (Intermediate 6, Example 6; 300 mg, 1.36 mmol, 1 equiv) in DCE (10 mL) were added 2- {4- [(tert-butoxy)carbonyl]piperazin-l-yl [propanoic acid (358 mg, 1.39 mmol, 1.02 equiv), pyridine (441 mg, 5.57 mmol, 4.10 equiv) and T3P (50% in EtOAc,2.60 g, 4.08 mmol, 3 equiv) successively at RT (~ 30 °C). Then the reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was evaporated in vacuo, the resulting residue was purified by column chromatography on silica gel (MeOH / DCM=0 ~ 5%) to afford tert-butyl 4-(l-((2-chloro-3-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (460 mg, 67%) as brown oil.[M+H]+= 461.Step B. Synthesis of / V-(2-chloro-3-( / V-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide hydrochloride

[0285] To a stirred solution of tert-butyl 4-( 1 -((2-chloro-3-(A-methylsulfamoyl)phenyl)amino)- 1 -oxopropan-2-yl)piperazine-l -carboxylate (570 mg, 1.24 mmol, 1 equiv) in DCM (8 mL) and MeOH (1 mL) was added HCl / dioxane (4 M, 3 mL, 12 mmol, 9.71 equiv) at RT. Then stirring was continued at RT for 30 min. The reaction mixture was evaporated in vacuo to afford A-(2-chloro-3-(A-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide hydrochloride (490 mg, 91%). [M+H]+= 361.Step C. Synthesis of 2-(4-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)rtV-(2-chloro-3-(A-methylsulfamoyl)phenyl)propenamide

[0286] To a mixture of A-(2-chloro-3-(A-methylsulfamoyl)phenyl)-2-(piperazin- l-yl)propanamide hydrochloride (490 mg, 1.23 mmol, 1 equiv) in n-BuOH (8 mL) were added DIEA (1.02 g, 7.89 mmol, 6.40 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (189 mg, 1.23 mmol, 1 equiv) successively at RT. Then the reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was evaporated in vacuo, the resulting residue was purified by reverse chromatography (0 ~ 30% CH3CN in water) to afford 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(2-chloro-3-(N-methylsulfamoyl)phenyl)propenamide (204 mg, 33%) as a yellow solid. [M+H]+= 478.Step D. Chiral separation

[0287] Racemic 2-(4-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)-N-(2-chloro-3-(N-methylsulfamoyl)phenyl)propenamide (204 mg) was subjected to chiral chromatography (ACN-IPA-DEA) to afford two enantiomers. The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned. The first eluting enantiomer was purified by using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4. HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 60% B in 10 min, Wavelength: 214 nm. This afforded (R)-2-(4-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(2-chloro-3-(N-methylsulfamoyl)phenyl)propenamide (Compound 3; 26.23 mg) as white solid. [M+H]+= 478.1H NMR (400 MHz, DMSO-de): 5 1.23 (d, J= 6.8 Hz, 3H), 2.44 (d, J= 3.2 Hz, 3H), 2.64-2.76 (m, 4H), 3.53-3.60 (m, 1H), 3.92-4.04 (m, 4H), 6.62-6.65 (m, 1H), 7.18-7.22 (m, 1H), 7.50 (dd, J= 2.4 Hz, 8.4 Hz, 1H), 7.60-7.66 (m, 1H), 7.78 (d, J= 8.8 Hz, 1H), 8.16 (s, 1H), 8.74 (d, J= 2.0 Hz, 1H), 10.36 (s, 1H), 11.72 (s, 1H).

[0288] The second eluting enantiomer was purified by using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4. HCO3), MobilePhase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 60% B in 10 min, Wavelength: 214 nm. This afforded 2-(4-(7 / / -pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)-N-(2-chloro-3-(N-methylsulfamoyl)phenyl)propenamide Compound 4 (33.40 mg) as white solid. [M+H]+= 478.1H NMR (400 MHz, DMSO-de): 5 1.23 (d, J = 7.2 Hz, 3H), 2.44 (d, J = 4.0 Hz, 3H), 2.64-2.76 (m, 4H), 3.53-3.60 (m, 1H), 3.92-4.04 (m, 4H), 6.62-6.65 (m, 1H), 7.18-7.22 (m, 1H), 7.50 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.60-7.66 (m, 1H), 7.78 (d, J= 8.4 Hz, 1H), 8.16 (s, 1H), 8.74 (d, J= 2.0 Hz, 1H), 10.36 (s, 1H), 11.72 (s, 1H).Example 17. Synthesis of (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3,5-dichloro-4- (N-methylsulfamoyl)phenyl)propenamide (Compound 5).DIEA ACN,100°C

[0289] To a solution of 2,6-dichloro-N-methyl-4-[2-oxo-3 -(piperazin- l-yl)pyrrolidin-l-yl] benzene sulfonamide (Intermediate 16, Example 14, 410 mg, 0.42 mmol, 1 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (111 mg, 0.72 mmol, 1.70 equiv) in 10 ml of n-BuOH stirred in air at 25°C was added DIEA (425 mg, 3.29 mmol, 7.80 equiv) dropwise. The reaction mixture was stirred at 100°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by using Prep-HPLC with the following conditions (Column: XBridge C18 SN. Column, 19*150 mm, 5pm, 16min; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 70% B in 10 min; Wavelength: 214 nm) to give the title product Compound 5 (103 mg, 29%) as a white solid. [M+H]+= 512. 'HNMR (400 MHz, DMSO-d6): δ 1.21 (d, J = 6.8Hz, 3H), 2.50 (s, 3H), 2.59-2.68 (m, 4H), 3.36-3.38 (m, 1 H), 3.89-3.93 (m, 4H), 6.61 (s, 1H), 7.17-7.19 (m, 1H), 7.76-7.79 (m, 1H), 8.01 (s, 2H), 8.14 (s, 1H), 10.40 (s, 1H), 11.69 (s, 1H).Example 18. Synthesis of (SI- 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3,5-dichloro-4-(N-methylsulfamoyl)phenyl)propenamide (Compound 6).DIEAACN,100°C

[0290] To a solution of 2,6-dichloro-N -methyl-4- [2-oxo-3 -(piperazin- 1 -yl)pyrrolidin- 1 -yl] benzene sulfonamide (Intermediate 17, Example 14, 395 mg, 0.38 mmol, 1 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (107 mg, 0.70 mmol, 1.80 equiv) in 10 ml of n-BuOH stirred in air at 25°C was added DIEA (409 mg, 3.17 mmol, 8.34 equiv) dropwise. The reaction mixture was stirred at 100°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by using Prep-HPLC with the following conditions (Column: XBridge C18 SN. Column, 19*150 mm, 5 pm, 16 min; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 30% B to 60% B in 10 min; Wavelength: 214 nm) to give the product (2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3,5-dichloro-4-(N-methylsulfamoyl)phenyl)propenamide, Compound 6, 75 mg, 22%) as a white solid. [M+H]+= 512.1HNMR (400 MHz, DMSO-d6): δ 1.21 (d, J = 6.8Hz, 3H), 2.50 (s, 3H), 2.59-2.68 (m, 4H), 3.36-3.38 (m, 1 H), 3.89-3.93 (m, 4H), 6.61 (s, 1H), 7.17-7.19 (m, 1H), 7.76-7.79 (m, 1H), 8.01 (s, 2H), 8.13 (s, 1H), 10.40 (s, 1H), 11.69 (s, 1H).Example 19. Synthesis of (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propenamide (Compound 7).7

[0291] To a solution of N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1) (Intermediate 14, Example 13, 70 mg, 0.19 mmol, 1 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (45 mg, 0.29 mmol, 1.50equiv) in n-BuOH (8 mL) was added DIEA (126 mg, 0.97 mmol, 5equiv). The reaction mixture was stirred at 95°C for 16 h. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP -PREP-11 Xbridge C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 5%B to 70% B in 10 min; Wavelength: 214 nm. This afforded (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propenamide (Compound 7, 33 mg, 33%) as a white solid. [M+H]+= 478. ‘H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J = 6.8 Hz, 3H), 2.43 (d, J = 4.8 Hz, 3H), 2.60-2.70 (m, 4H), 3.36-3.41 (m, 1H), 3.91-3.93 (m, 4H), 6.61 (s, 1H), 7.17-7.19 (m, 1H), 7.53-7.57 (m, 1H), 7.77-7.91 (m, 2H), 8.08 (s, 1H), 8.14 (s, 1H), 10.36 (s, 1H), 11.69 (s, 1H).Example 20. Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propenamide (Compound 8).

[0292] To a solution of N-(3-chloro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1) (Intermediate 15, Example 13, 73 mg, 0.15 mmol, lequiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (35 mg, 0.23 mmol, 1.50equiv) in n-BuOH (8 inL) was added DIEA (97 mg, 0.75 mmol, 5 equiv). The reaction mixture was stirred at 95°C for 16 h. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP-PREP-11 Xbridge Cl 8 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 60% B in 10 min; Wavelength: 214 nm. This afforded 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-4-(N-methylsulfamoyl)phenyl)propenamide (Compound 8, 35 mg, 34%) as a white solid.[M+H]+= 478. ’H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J = 6.8 Hz, 3H), 2.43 (d, J = 4.8 Hz, 3H), 2.60-2.70 (m, 4H), 3.37-3.39 (m, 1H), 3.91-3.93 (m, 4H), 6.61 (s, 1H), 7.17-7.19 (m, 1H), 7.53-7.57 (m, 1H), 7.77-7.91 (m, 2H), 8.08 (s, 1H), 8.14 (s, 1H), 10.36 (s, 1H), 11.69 (s, 1H).Example 21. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-4-fluor ophen vDacetamide (Compound 9).

[0293] To a solution of N-[3-(dimethylsulfamoyl)-4-fluorophenyl]-2-(piperazin-l-yl)acetamide (Intermediate 2, Example 2; 100 mg, 0.29 mmol, 1 equiv) in MeCN (5 mL) was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (67 mg, 0.44 mmol, 1.50 equiv), DIEA (75 mg, 0.58 mmol, 2 equiv) and the mixture was stirred 100°C for 3h. The resulted solution was purified using Prep-HPLC with the following conditions: Column: RP-PREP-5 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 60% B in 10 min; Wavelength: 214 nm. This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)-N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)acetamide (Compound 9; 44 mg, 33%) as a white solid. [M+H]+= 461. ’H NMR (400 MHz, DMSO-d6): δ 2.63-2.66 (t, J = 4.8 Hz, 4H), 2.74 (s, 6H), 3.23 (s, 2H), 3.93-3.96 (t, J= 4.4 Hz, 4H), 6.62 (s, 1H), 7.18-7.20 (t, J= 2.8 Hz, 1H), 7.44-7.49 (t, J= 9.6 Hz, 1H), 7.98-8.02 (m, 1H), 8.15 (s, 1H), 8.17-8.19 (m, 1H), 10.19 (s, 1H).Example 22. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (Compounds 10 and 11).

[0294] A solution of 2-bromo-N-[3-fluoro-4-(methylsulfamoyl)phenyl]butanamide (Intermediate 3, Example 3; 400 mg, 1.13 mmol, lequiv), 1-{7H- pyrrolo[2,3-d]pyrimidin-4-yl}piperazine (253 mg, 1.25 mmol, 1.10equiv) and K2CO3 (469 mg, 3.40 mmol, 3equiv) and KI (188 mmol, 1.13 mmol, lequiv) in ACN (4 mL) was stirred at 25°C for 16h. The mixture was concentrated and the residue was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 25% B to 60% B in 12min; Wavelength: 214 nm. This provided 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (150 mg, yield: 26%, white solid).

[0295] The racemic (7H-pyrrolo [2, 3 -d]pyrimidin-4-y l)piperazin- 1 -yl)-N-(3 -fluoro-4-(N -methylsulfamoyl)phenyl)butanamide (150 mg) was subjected to chiral chromatography to provide two enantiomers: Compound 10 (40 mg) and Compound 11 (45 mg). Absolute configurations were not determined and configurational assignments were arbitrary. Compound 10: LCMS: [M+H]+=476.1. ’H NMR (400 MHz, DMSO-d6): δ 0.90 (3H, t, J = 7.2 Hz), 1.67-1.70 (2H, m), 2.45-2.50 (3H, m), 2.63-2.76 (4H, m), 3.17-3.20 (1H, m), 3.87 (4H, s), 6.60 (1H, s), 7.17 (1H, s), 7.50-7.58 (2H, m), 7.71 (1H, t, J= 8.8 Hz), 7.82-7.85 (1H, m), 8.12 (1H, s), 10.49 (1H, s), 11.63 (1H, s). Compound 11: LCMS: [M+H]+=476.1. ‘H NMR (400 MHz, DMSO-d6): δ 0.90 (3H, t, J = 7.2 Hz), 1.68-1.71 (2H, m), 2.46-2.50 (3H, m), 2.63-2.77 (4H, m), 3.17-3.20 (1H, m), 3.87 (4H, s), 6.60 (1H, s), 7.17 (1H, s), 7.50-7.58 (2H, m), 7.71 (1H, t, J= 8.8 Hz), 7.82-7.85 (1H, m), 8.12 (1H, s), 10.49 (1H, s), 11.63 (1H, s).Example 23. Synthesis of (R)- and (S)- 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-3-methoxypropanamide (Compounds 12 and 13).Step A. Synthesis of tert-butyl 4-(l,3-dimethoxy-l-oxopropan-2-yl) piperazine-l-carboxylate

[0296] To a solution of methyl 2-bromo-3-methoxypropanoate (1000 mg, 5.08 mmol, lequiv) in ACN (10 mL) was added tert-butyl piperazine-l-carboxylate (1418 mg, 7.61 mmol, 1.50equiv) and K2CO3 (1052 mg, 7.61 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was evaporated in vacuo, the resulting residue was purified by column chromatography on silica gel (0~25% EtOAc in petroleum ether) to afford tert-butyl 4-( 1,3 -dimethoxy- l-oxopropan-2-yl) piperazine-l-carboxylate (970 mg, 40%) as a white solid. [M+H]+= 303.4.Step B. Synthesis of methyl 3-methoxy-2-(piperazin-l-yl) propanoate

[0297] To a solution of tert-butyl 4-(l,3-dimethoxy-l-oxopropan-2-yl) piperazine- 1 -carboxylate (950 mg, 3.14 mol, 1 equiv) in DCM (10 mL) were added a solution of TFA (ImL) at room temperature. The resulting mixture was stirred at room temperature for 30 mins. The reaction mixture was evaporated in vacuo to afford methyl 3 -methoxy -2-(piperazin-l-yl) propanoate (800 mg, crude) as a yellow oil. [M-H]+= 203.2Step C. Synthesis of methyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoate

[0298] To a mixture of methyl 3-methoxy-2-(piperazin-l-yl) propanoate (800 mg, 3.95 mmol, lequiv) in n-BuOH (15 mL) were added DIEA (3067 mg, 27.73 mmol, 6equiv) and 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (729 mg, 4.74 mmol, 1.20equiv) successively at RT (~30 °C). Then the reaction mixture was stirred at 110 °C for 15 hrs. The reaction mixture was evaporated in vacuo, the resulting residue was purified by column chromatography on silica gel (0 ~ 50% EtOAc in petroleum ether) to afford methyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoate (900 mg, 71%) as a yellow solid. [M+H]+= 320.4 Step D. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoic acid

[0299] To a solution of methyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoate (400 mg, 1.25 mmol, lequiv) in MeOH (8 mL) and H2O (2 mL) under nitrogen atmosphere was added LiOH.H2O (105 mg, 2.51 mmol, 2equiv) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was treated with 2N HC1 to PH=3-4 and concentrated to afford 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoic acid (350 mg, 87%) as a white solid. [M+H]+=306.3.Step E. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-3-methoxypropanamide

[0300] To 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-3-methoxypropanoic acid (200 mg, 0.66 mmol, 1 equiv) in pyridine (4 mL) was added 4-amino-2-fluoro-N-methylbenzenesulfonamide (Example 3, 135 mg, 0.66 mmol, lequiv) and HATU (374 mg, 0.98 mmol, 1.50 equiv) successively at RT (~30°C). Then the reaction mixture was stirred at RT (~30°C) for 30 mins. The reaction mixture was evaporated in vacuo and the resulting residue was purified by reverse chromatography (0~30% CH3CN in water) to afford 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-3-methoxypropanamide (60 mg, 18%) as a white solid. [M+H]+= 424.3.Step F. Chiral separation

[0301] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-3-methoxypropanamide (60 mg) was subjected to chiral chromatography (ACN-IPA-DEA) to provide two enantiomers. The first eluting enantiomer was Compound 12 (22 mg, white solid). The second eluting enantiomer was Compound 13 (18 mg, white solid). The absolute configurations were not determined and configurations were arbitrarily assigned. Compound 12: [M+H]+= 424.1H NMR (400 MHz,DMSO-de): 52.46 (s, 3H), 2.47-2.69 (m, 2H), 2.79-2.82 (m, 2H), 3.26 (s, 3H) 3.14-3.44 (m, 1H), 3.50-3.54 (m, 1H), 3.65-4.69 (m, 1H), 3.80-3.81 (m, 4H), 6.60 (d, J= 1.6 Hz, 1H), 7.17-7.18 (m, 1H), 7.54-7.59 (m, 2H), 7.58-7.74 (m, 1H), 7.86 (d, J= 12.8 Hz, 1H), 8.13 (s, 1H), 10.50 (s, 1H), 11.69 (s, 1H). Compound 13: [M+H]+= 424. ‘H NMR (400 MHz, DMSO-de): 52.46 (s, 3H), 2.47-2.69 (m, 2H), 2.79-2.82 (m, 2H), 3.26 (s, 3H) 3.14-3.44 (m, 1H), 3.50-3.54 (m, 1H), 3.65-4.69 (m, 1H), 3.80-3.81 (m, 4H), 6.60 (d, J= 1.6 Hz, 1H), 7.17-7.18 (m, 1H), 7.54-7.59 (m, 2H), 7.58-7.74 (m, 1H), 7.86 (d, J= 12.8 Hz, 1H),8.13 (s, 1H), 10.51 (s, 1H), 11.69 (s, 1H).Example 24. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo|2.3-d|pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N- (pyridin-4-yl)sulfamoyl)phenyl)propenamide (Compound 14 and 15).IM 12 IM1315Synthesis of (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-4-yl)sulfamoyl)phenyl)propenamide (Compound 14)

[0302] To a solution of TCFH (290 mg, 1.03 mmol, 4 equiv), NMI (255 mg, 3.10 mmol, 12 equiv) in dry ACN (lOmL) was added (R)-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, 90 mg, 0.26 mmol, lequiv) in anhydrous NMP (1 mL) and 4-amino-N-(pyridin-4-yl)benzenesulfonamide (Intermediate 12, Example 12, 645 mg, 0.26 mmol, 1.0 equiv) in NMP (1 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep Cl 8 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 50% B in 12 min; Wavelength: 214 nm. This afforded Enantiomer P 1:2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-4-yl)sulfamoyl)phenyl)propanamide (14; 22 mg, 17%, white solid). LCMS: [M+H]+=507.1. ‘H NMR (400 MHz, DMSO-6): 5 1.21 (d, J= 6.4 Hz, 3H), 2.50-2.63 (m, 4H), 3.36-3.38(m, 1H), 3.89-3.91 (m, 4H), 6.60-6.61 (m, 1H), 6.91 (d, J= 6.8 Hz, 2H), 7.17 (t, J= 2.4 Hz, 1H), 7.73-7.79 (m, 4H), 8.02 (s, 2H), 8.13 (s, 1H), 10.14 (s, 1H), 11.69 (s, 1H).Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-4-yl)sulfamoyl)phenyl)propenamide (Compound 15)

[0303] To a solution was added TCFH (290 mg, 1.03 mmol, 4 equiv), NMI (255 mg, 3.10 mmol, 12 equiv) in dry ACN (10 mL). (S)-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, 90 mg, 0.26 mmol, lequiv) in anhydrous NMP (1 mL) and 4-amino-N-(pyridin-4-yl)benzenesulfonamide (Intermediate 13, Example 12, 65 mg, 0.26 mmol, 1.0 equiv) in NMP (1 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep Cl 8 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0. 1% NH HCO3). Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 30% B to 50% B in 12 min; Wavelength: 214 nm. This afforded the title product (Compound 15, 28 mg, 20%, white solid). LCMS: [M+H]+=507.1. 'HNMR (400 MHz, DMSO-6): 5 1.21 (d, J= 6.4 Hz, 3H), 2.50-2.63 (m, 4H), 3.33-3.38 (m, 1H), 3.89-3.91 (m, 4H), 6.60-6.61 (m, 1H), 6.91 (d, J= 6.8 Hz, 2H), 7.17 (t, J = 2.4 Hz, 1H), 7.73-7.79 (m, 4H), 8.02 (s, 2H), 8.13 (s, 1H), 10.14 (s, 1H), 11.69 (s, 1H).Example 25. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d1pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (Compounds 16 and 17).Step A. Synthesis of ethyl 2-bromo-4,4,4-trifluorobutanoate

[0304] To a solution of ethyl 4,4,4-trifluorobutanoate (3.40 g, 20.0 mmol) in THF (100 mL) stirred under nitrogen at -50°C was added a solution of LiHMDS (12.00 mL, 24.00 mmol) in THF (12 mL). The reaction mixture was stirred at -50°C for Ih. Then was added N-Bromosuccinimide (4.27 g, 24.00 mmol) at -50°C and the reaction mixture was stirred at 25°C for 3h. Saturated aqueous HC1 (100 mL) was added. The residue was extracted with EA (3 x 100 mL). Solvent was dried over sodium sulphate and evaporated in vacuo to give the product ethyl 2-bromo-4,4,4-trifluorobutanoate (4.50 g, 20% purity) as light-yellow oil. [M+H]+=249. Step B. Synthesis of benzyl 4-(l-ethoxy-4,4,4-trifhioro-l-oxobutan-2-yl)piperazine-l-carboxylate

[0305] To a solution of ethyl 2-bromo-4,4,4-trifluorobutanoate (4.50 g, 18.10 mmol) and benzyl piperazine-1-carboxylate (3.99 g, 18.10 mmol) in THF (100 mL) stirred under nitrogen at 30°C was added DIEA (4.68 g, 36.20 mmol). The reaction mixture was stirred at 30°C for 16h. H2O (100 mL) was added and was then extracted with EA (3 x 100 mL). Solvent was dried over sodium sulphate and evaporated in vacuo to give the crude product. The crude material was added to a silica gel column and was eluted with PE / EA (2: 1) to give the product benzyl 4-(l -ethoxy-4, 4, 4-trifluoro-l-oxobutan-2-yl)piperazine-l -carboxylate (400 mg, 80% purity, 5% yield) as yellow oil. [M+H]+=389.Step C. Synthesis of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid

[0306] To a solution of benzyl 4-(l-ethoxy-4,4,4-trifluoro-l-oxobutan-2-yl)piperazine-l -carboxylate (200 mg, 0.52 mmol) in MeOH / H2O=4:1 (10 mL) stirred under nitrogen at 30°C was added LiOH (15 mg, 0.62 mmol). The reaction mixture was stirred at 30°C for 16h. The reaction mixture was concentrated under pressure at 50°C to give the product 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid (180 mg, 95% purity, 92% yield) as off-yellow solid. [M+H]+=361.Step D. Synthesis of benzyl 4-(4,4,4-trifluoro-l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxobutan-2-yl)piperazine-l-carboxylate

[0307] To a solution of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid (180 mg, 0.50 mmol), 4-amino-2-fluoro-N-methylbenzenesulfonamide (102 mg, 0.50 mmol) and DIEA (129 mg, 1.00 mmol) in DCM (20 mL) stirred under nitrogen at 30°C was added HATU (285 mg, 0.75 mmol). The reaction mixture was stirred at 30°C for 16h. The reaction mixture was concentrated under pressure at 45°C. The residue was purified via Flash Chromatography and was eluted with ACN / H2O (Ratios:4:6; Pressure:2 bar) and to give the product benzyl 4-(4,4,4-trifluoro- l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)- l-oxobutan-2-yl)piperazine- 1 -carboxylate (68 mg, 95% purity, 24% yield) as light-yellow solid. [M+H]+=547.Step E. Synthesis of 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butan amide

[0308] To a solution of benzyl 4-(4,4,4-trifluoro-l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxobutan-2-yl)piperazine-l-carboxylate (68 mg, 0.12 mmol) in i-PrOH (10 mL) stirred under H2 at 30°C wasadded Pd / C (53 mg, 0.025 mmol). The reaction mixture was stirred at 30°C for 16h. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure at 60°C to give the product 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butanamide (50 mg, 95% purity, 93% yield) as light-yellow oil. [M+H]+=413.Step F. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifhioro-N-(3-fhioro-4-(N-methylsulfamoyl)phenyl)butanamide (Compounds 16 and 17)

[0309] To a solution of 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butanamide (50 mg, 0.12 mmol) and 4-chloro-7H-pyrrolo[2,3- d]pyrimidine (19 mg, 0.12 mmol) in n-BuOH (10 mL) stirred under nitrogen at 30°C was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (19 mg, 0.12 mmol). The reaction mixture was stirred at 90°C for 16h. The reaction mixture was concentrated under pressure at 70°C. The residue was purified by Prep-HPLC with the following conditions: Column: Prep- 11 Xbrige C18 5um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 60% B in 16 min; Wavelength: 214 nm. This resulted in racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (31 mg, 95% purity, 46% yield) as white solid. The racemic material was subjected to chiral chromatography to provide two enantiomers. The first eluting enantiomer (16, 7 mg) was arbitrarily assigned the ((R)-configuration and the second eluting enantiomer (17; 7 mg) was arbitrarily assigned the (S)-configuration. Compound 16:[M+H]+=530. 'HNMR (400 MHz, DMSO-6): 52.44-2.45 (d, J= 4.0 Hz, 3H), 2.67-2.78 (m, 3H), 2.89-2.94 (m, 3H), 3.74-3. 82 (m, 4H), 3.93-3.99 (m, 1H), 6.58 (s, 1H), 7.17 (s, 1H), 7.40-7.42 (d, J= 8.4 Hz, 1H), 7.55-7.56 (m, 1H), 7.69-7.78 (m, 2H), 8.12 (s, 1H), 10.66 (s, 1H), 11.68 (s, 1H). Compound 17: [M+H]+=530. 'HNMR (400 MHz, DMSO-6): 52.45 (d, J= 2.8 Hz, 3H), 2.67-2.78 (m, 3H), 2.89-2.94 (m, 3H), 3.75-3. 82 (m, 4H), 3.93-3.99 (m, 1H), 6.58 (s, 1H), 7.17 (s, 1H), 7.39-7.41 (d, J= 8.4 Hz, 1H), 7.55-7.56 (m, 1H), 7.69-7.78 (m, 2H), 8.12 (s, 1H), 10.65 (s, 1H), 11.68 (s, 1H).Example 26. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fhioro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 18).

[0310] To a stirred solution of (R)-tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Intermediate 12, Example 12, 72 mg, 0.22 mmol) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (60 mg, yield: >95%, 92% purity, white solid). LCMS: [M+H]+=276. To a solution of the (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (60 mg, 0.22 mmol), 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 8, Example 8; 58 mg, 0.22 mmol) and pyridine (103 mg, 1.31 mmol) in DCE (20 mL) stirred under nitrogen at 25°C was added T3P in EA (693 mg, 2.20 mmol). The reaction mixture was stirred at 60°C for 16h. The reaction mixture was concentrated under pressure at 60°C. The residue was purified via Genal-Prep-HPLC with the following conditions: Column: Prep- 11 Xbrige Cl 8 5um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide Compound 18; 25 mg, 95% purity) as white solid. [M+H]+=525. 'HNMR (400 MHz, DMSO-6): 5 1.19-1.21 (d, J= 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.36-3.38 (m, 1H), 3.89-3.91 (m, 4H), 6.59 (s, 1H), 6.81-6.84 (m, 1H), 7.14-7.18 (m, 2H), 7.53-7.56 (m, 1H), 7.71-7.75 (m, 2H), 7.83-7.87 (t, J= 8.4 Hz, 1H), 7.92-7.94 (d, J= 5.2 Hz, 1H), 8.13 (s, 1H), 10.33 (s, 1H), 11.70 (s, 1H), 12.59 (s, 1H).Example 27. Synthesis of an enantiomer of 2-(4-(7H-nyrrolo|2.3-dlr)yrimidin-4-yl)ninerazin-l-yl)-N-(3-fluoro-4-(N-(pyridin-2-vDsulfamoyl)phenvDpropenamide (Compound 19).O

[0311] To a solution of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (Intermediate 13, Example 12, 163 mg, 0.59 mmol), 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 8, Example 8; 95 mg, 0.59 mmol) and pyridine (280 mg, 3.54 mmol) in DCE (20 mL) stirred under nitrogen at 25°C was added T3P in EA (1859 mg, 5.90 mmol). The reaction mixture was stirred at 60°C for 16h. The reaction mixture was concentrated under pressure 60°C. The residue was purified via Genal-Prep-HPLC with the following conditions: Column: Prep- 11 Xbrige C18 5um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 50% B in 16 min; Wavelength:214 nm. This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 19; 20 mg, 95% purity) as white solid. [M+H]+=525. 'HNMR (400 MHz, DMSO-6): 5 1.19-1.21 (d, J= 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.36-3.38 (m, 1H), 3.89-3.91 (m, 4H), 6.59 (s, 1H), 6.81-6.84 (m, 1H), 7.14-7.18 (m, 2H), 7.53-7.56 (m, 1H), 7.71-7.75 (m, 2H), 7.83-7.87 (t, J = 8.4 Hz, 1H), 7.92-7.94 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H), 10.33 (s, 1H), 11.70 (s, 1H), 12.58 (s, 1H).Example 28. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo|2.3-d|pyrimidin-4-yl)piperazin-l-yl)-N-(4- (N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 20).T3P, Py, DCE, 60°C, 16h

[0312] To a solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 7, Example 7, 50 mg, 0.20 mmol, 1.00 equiv) in DCE (5 mL) was added (R)- 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, Example 26, Step A, 70 mg, 0.20 mmol, 1.00 equiv), T3P in EA (255 mg, 0.80 mmol, 4.00 equiv) and pyridine (79 mg, 1.00 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title product (Compound 20; 26 mg, 25% yield, white solid). LCMS: [M+H]+=507.1.1H NMR (400 MHz, DMSO-6): 5 1.21 (d, J= 6.8 Hz, 3H), 2.57-2.70 (m, 4H), 3.36 (s, 1H), 3.89-3.91 (m, 4H), 6.60 (d, J= 2 Hz, 1H), 6.868 (t, J= 5.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.68-7.72 (m, 1H), 7.79-7.84 (m, 4H), 8.01 (s, 1H), 8.13 (s, 1H), 10.19 (s, 1H), 11.70 (s, 1H).Example 29. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo|2.3-d|pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 21).Step A. Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0313] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Intermediate 13, Example 12, 90 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)propanoic acid (HC1 Salt) (P2: 90 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Step B. Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 21)

[0314] To a solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (Intermediate 7, Example 7, 60 mg, 0.24 mmol, 1.00 equiv) in DCE (5 mL) was added (S)-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, 84 mg, 0.24 mmol, 1.00 equiv), T3P in EA (306 mg, 0.96 mmol, 4.00equiv) and pyridine (95 mg, 1.20 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep Cl 8 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title product (Compound 21; 9 mg, 7% yield, white solid). LCMS: [M+H]+=507.1. ‘H NMR (400 MHz, DMSO-6): 5 1.21 (d, J= 7.2 Hz, 3H), 2.59-2.68 (m, 4H), 3.34-3.36(m, 1H), 3.89-3.91 (m, 4H), 6.60-6.61 (m, 1H), 6.83 (t, J = 5.6 Hz, 1H), 7.11-7.18 (m, 2H), 7.65-7.70 (m, 1H), 7.76 (d, J= 7.2 Hz, 4H), 8.03 (s, 1H), 8.13 (s, 1H), 10.19 (s, 1H), 11.70 (s, 1H).Example 30. Synthesis of an enantiomer of 2-(4-(7H-Dyrrolo[2,3-d]Dyrimidin-4-yl)DiDerazin-l-yl)-N-(4-(N-(pyrimidin-5-yl)sulfamoyl)phenyl)propanamide (Compound 22).

[0315] To a solution of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (Intermediate 11, Example 11 1160 mg, 0.24 mmol, 1.00 equiv) in DCE (5 mL) was added (R)-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-1- yl)propanoic acid HC1 salt (Intermediate 12, Example 12,, 83 mg, 0.24 mmol, 1.00 equiv), T3P in EA (305 mg, 0.96 mmol, 4.00 equiv) and pyridine (95 mg, 1.20 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 45% B in 16 min; Wavelength: 214 nm. This resulted in the title product (Compound 22, 2 mg, 2% yield, white solid). LCMS: [M+H]+=508.1.1HNMR(400 MHz, DMSO-6): 5 1.21 (d, J= 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.49-3.58(m, 1H), 3.90 (t, J= 4.4 Hz, 4H), 6.61(s, 1H), 7.17 (s, 1H), 7.73 (d J= 8.8 Hz, 2H), 7.82 (d, J= 8.8 Hz, 2H), 8.13 (s, 1H), 8.44 (s, 2H), 8.77 (s, 1H), 10.24 (s, 1H), 11.70 (s, 1H).Example 31. Synthesis of an enantiomer of -2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyrimidin-5-yl)sulfamoyl)phenyl)propanamide (Compound 23).

[0316] To a solution of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (Intermediate 11, Example 11, 64 mg, 0.26 mmol, 1.00 equiv) in DCE (5 mL) was added (S)-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid HC1 salt (Intermediate 13, Example 12, 89 mg, 0.26 mmol, 1.00 equiv), T3P in EA (325 mg, 1.02 mmol, 4.00 equiv) and pyridine (101 mg, 1.28 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 5% B to 40% B in 16 min; Wavelength:214 run. This resulted in the title product (Compound 23, 15 mg, 11% yield, white solid). LCMS: [M+H]+=508.1. ‘H NMR (400 MHz, DMSO-6): 5 1.21 (d, J= 6.8 Hz, 3H), 2.59-2.69 (m, 4H), 3.36 (d, J= 10.8 Hz, 1H), 3.90 (s, 4H), 6.60 (d, J= 1.6 Hz, 1H), 7.18 (d, J= 2.8 Hz, 1H), 7.75 (d, J= 8.8 Hz, 2H), 7.85 (d, J= 8.8 Hz, 2H), 8.13 (s, 1H), 8.50 (s, 2H), 8.87 (s, 1H), 10.28 (s, 1H), 10.75 (s, 1H), 11.70 (s, 1H).Example 32. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3- (N, N-dimethylsulfamoyl)-4-fluorophenyl)propanamide (Compound 24 and 25).HCI DCM, rt, 3h 1-Butanol, DIEA Cs2CO3, 1,4-dioxane 100°C, 16h 100°C, 16hStep A. Synthesis of tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0317] To a solution of 5-bromo-2-fluoro-N, N-dimethylbenzenesulfonamide (Example 2, 350 mg, 1.24 mmol, 1.00 equiv), tert-butyl 4-(l -amino- l-oxopropan-2-yl)piperazine-l -carboxylate (351 mg, 1.36 mmol, 1.10 equiv) and cesium carbonate (808 mg, 2.48 mmol, 2.00 equiv) in 1,4-dioxane stirred under nitrogen was added a solution of Pd2(dba)3(114 mg, 0.12 mmol, 0.10 equiv) and Xantphos (144 mg, 0.25 mmol, 0.20 equiv). The reaction mixture was stirred at 100°C for 16h. The mixture was concentrated, and the residue was purified by silica gel chromatography (100% EA). This resulted in tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-l-oxopropan-2-yl)piperazine-l -carboxylate (253 mg, 45%) as gray solid. [M+H]+=459.3.Step B. Synthesis of N-(3-(N, N-dimethylsulfamoyl)-4-fhiorophenyl)-2-(piperazin-l-yl)propanamide (HCI salt)

[0318] To a solution of tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (253 mg, 0.55 mmol, 1.00 equiv) in of DCM (5 mL) was added 2 mL of HCI (4M in 1,4-dioxane). The mixture was stirred at room temperature for 3h. The mixture was concentrated to get theN-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)-2-(piperazin-l-yl)propanamide (HC1 salt) (235 mg, >100%) as gray solid. [M+H]+=359.1.Step C. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)propan amide

[0319] To a solution of N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)-2-(piperazin-l-yl)propanamide (HC1 salt) (235 mg, 0.60 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (91 mg, 0.60 mmol, 1.00 equiv) in 1-butanol (5 mL) was added DIEA (231 mg, 1.79 mmol, 3.00 equiv). The mixture was stirred at 100°C for 16 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (DCM: MeOH=10:l). This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)propanamide (140 mg, 50%) as white solid. [M+H]+=476.1.Step D. Chiral separation

[0320] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)propanamide (140 mg) was subjected to chiral chromatography to provide 30 mg of a first eluting enantiomer (Compound 24) and 29 mg of a second eluting enantiomer (Compound 25). Absolute configurations were not determined and were arbitrarily assigned. Compound 24: [M+H]+=476.1. ’H NMR (400 MHz, DMSO-6): 5 1.23 (d, J= 6.8 Hz, 3H), 2.59-2.73 (m, 10H), 3.32-3.37 (m, 1H), 3.92 (t, J= 4.6 Hz, 4H), 6.61 (s, 1H), 7.18 (s, 1H), 7.45 (t, J =9.6 Hz, 1H), 7.98-8.02 (m, 1H), 8.13-8.18 (m, 2H), 10.24 (s, 1H), 11.69 (s, 1H). Compound 25: [M+H]+=476.1. ‘H NMR (400 MHz, DMSO-6): 5 1.23 (d, J = 6.8 Hz, 3H), 2.60-2.73 (m, 10H), 3.32-3.38 (m, 1H), 3.92 (t, J= 4.4 Hz, 4H), 6.61 (s, 1H), 7.17-7.18 (m, 1H), 7.45 (t, J =9.4 Hz, 1H), 7.98-8.02 (m, 1H), 8.13-8.18 (m, 2H), 10.24 (s, 1H), 11.69 (s, 1H).Example 33. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3,5-difluoro-4-(N-methylsulfamoyl)phenyl)propenamide (Compounds 26 and 27)Pd2(dba)3, Xantphos,Cs2CO3, dioxane, 100°CStep A. Synthesis of tert-butyl 4-(l-((3,5-difluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0321] To a solution of 4-bromo-2,6-difluoro-N-methylbenzenesulfonamide (Intermediate 9, Example 9, 200 mg, 0.6991 mmol, 1.00 equiv), tert-butyl 4-(l-carbamoylethyl)piperazine-l-carboxylate (216 mg, 0.84 mmol, 1.20 equiv) and CS2CO3 (456 mg, 1.40 mmol, 2.00 equiv) in dioxane (12 mL) stirred under nitrogen at R. T. was added Xantphos (81 mg, 0.14 mmol, 0.20 equiv) and Pd2(dba)3 (64 mg, 0.07 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C for 16 h under N2. The mixture was extracted with EtOAc and washed with water. The organic layer was dried over Na2SO4and concentrated. The residue was purified by flash chromatography (EA / PE=80%~100%) to give the product tert-butyl 4-(l-((3,5-difluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (142 mg, 40%) as a yellow solid.[M+H]+=463.Step B. Synthesis of N-(3,5-difhioro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1 salt)

[0322] To a solution of tert-butyl 4-(l-((3,5-difluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (142 mg, 0.31 mmol, 1.00 equiv) in DCM (4 mL) stirred at R. T. was added 4N HCl / dioxane (2 mL). The reaction mixture was stirred at 25°C for Ih. The mixture was finished. The mixture was concentrated under reduced pressure to give the product N-(3,5-difluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1 salt) (130 mg, 100%) as yellow solid. [M+H]+=363.Step C. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3,5-difluoro-4-(N-methylsulfamoyl)phenyl)propenamide

[0323] To a solution of N-(3,5-difluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propenamide (HC1 salt) (crude 130 mg, 0.31 mmol, l. OOequiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.36 mmol, I.16 equiv) in n-BuOH (8 mL) at room temperature was added DIEA (232 mg, 1.80 mmol, 5.00 equiv). The reaction mixture was stirred at 100°C for 16 h. The mixture was concentrated and the resulting residue was purified using Prep-HPLC with the following conditions: Column: RP-PREP-11 xbrige C18, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 25% B to 55% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (75 mg, 47%) as a white solid.[M+H]+= 480.Step D. Chiral separation

[0324] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- l-yl)-N-(3,5-difluoro-4-(N-methylsulf amoyl)phenyl)propenamide (75 mg) was subjected to chiral HPLC to give two enantiomers. The first eluting enantiomer (Compound 26; 22 mg) was arbitrarily assigned the (R)-configuration, and the second eluting enantiomer (Compound 27; 20 mg) was arbitrarily assigned the (S)-configuration. Compound 26:[M+H]+= 480. ’H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J= 7.2 Hz, 3H), 2.52-2.59 (m, 3H), 2.61-2.68 (m, 4H), 3.36-3.41 (m, 1H), 3.91-3.93 (m, 4H), 6.60-6.61 (m, 1H), 7.18 (dd, J= 2.4 and 3.6 Hz, 1H), 7.61 (d, J = 11.2 Hz, 2H), 7.87 (d, J= 4.4 Hz, 1H), 8.13 (s, 1H), 10.48 (s, 1H), 11.69 (s, 1H). Compound 27: [M+H]+= 480. ‘H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J= 6.8 Hz, 3H), 2.52-2.59 (m, 3H), 2.61-2.68 (m, 4H), 3.36-3.41 (m, 1H), 3.91-3.94 (m, 4H), 6.60-6.61 (m, 1H), 7.17-7.18 (m, 1H), 7.61 (d, J= 11.2 Hz, 2H), 7.85 (s, 1H), 8.13 (s, 1H), 10.48 (s, 1H), 11.69 (s, 1H).Example 34. Synthesis of (R)- and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)propenamide (Compounds 28 and 29).Pd2(dba)3Cs2CO3Dio, 100°C18h2829Step A. Synthesis of tert-butyl 4-(l-((3-chloro-5-fhioro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0325] To a solution of 4-bromo-2-chloro-6-fluoro-N-methylbenzenesulfonamide (Intermediate 10, Example 10, 200 mg, 0.66 mmol, 1.00 equiv), tert-butyl 4-(l-amino-l-oxopropan-2-yl)piperazine-l-carboxylate (171 mg, 0.66 mmol, 1.00 equiv) and CS2CO3 (431 mg, 1.32 mmol, 2.00 equiv) in dioxane (10 mL) stirred under nitrogen at 25°C was added Pd₂(dba)₃ (61 mg, 0.06 mmol, 0.10 equiv)and Xantphos (77 mg, 0.13 mmol, 0.20 equiv). The reaction mixture was stirred at 100°C for 18h. The mixture was concentrated and the resulted solution was purified by flash chromatography (ACN / H2O = 3:1). This resulted in tert-butyl 4-(l-((3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (171 mg, yield 54%) as yellow solid. [M+H]+=479.Step B. Synthesis of N-(3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propan amide

[0326] The solution of tert-butyl 4-(l-((3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l -carboxylate (196 mg, 0.41 mmol, 1.00 equiv) in DCM / TFA (5 mL) stirred at 25°C for Ih. The mixture was concentrated. This resulted in N-(3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (190 mg, yield >100%) as yellow oil. [M+H]+=379.Step C. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-fhioro-4-(N-methylsulfamoyl)phenyl)propanamide

[0327] To a solution of N-(3-chloro-5-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (190 mg, 0.50 mmol, 1.00 equiv) and 4-chloro-lH-pyrrolo[3,2-c]pyridine (77 mg, 0.50 mmol, 1.00 equiv) in " BuOH (5 mL) stirred at 25°C was added DIEA (130 mg, 1.00 mmol, 2.00 equiv). The reaction mixture wasstirred at 100°C for 18h. The mixture was concentrated and the residue was purified using Chiral Prep-HPLC and Prep-HPLC with the following conditions: Xbrige C18 5um 19* 150mm, 16min-15-60% B, A: H2O (0.1%NH4HCO3), B: ACN, UV: 214 run, flow rate 15ml / min. The first eluting enantiomer (Compound 28, 16 mg) was arbitrarily assigned the ((R)-configuration, and the second eluting enantiomer (Compound 29; 22 mg) was arbitrarily assigned the (S)-configuration. Compound 28: [M+H]+= 497. ’H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J= 6.8 Hz, 3H), 2.51-2.55 (m, 3H) 2.56-2.72 (m, 4H), 3.34-3.42 (m, 1H), 3.85-3.99 (m, 4H), 6.58-6.63 (m, 1H), 7.14-7.21 (m, 1H), 7.73-7.86 (m, 3H), 8.14 (s, 1H), 10.44 (s, 1H), 11.69 (s, 1H).Compound 29: ‘H NMR (400 MHz, DMSO-d6): δ 1.22 (d, J= 6.8 Hz, 3H), 2.51-2.55 (m, 3H) 2.56-2.72 (m, 4H), 3.34-3.42 (m, 1H), 3.85-3.99 (m, 4H), 6.58-6.63 (m, 1H), 7.14-7.21 (m, 1H), 7.73-7.86 (m, 3H), 8.14 (s, 1H), 10.44 (s, 1H), 11.69 (s, 1H)Example 35. Synthesis of 2-(l-(7H-pyrrolo[2,3-d1pyrimidin-4-yl)piperidin-4-yl)-N-(4-(N-cvclopropylsulfamovDphenvDacetamide (Compound 30).30Step A. Synthesis of tert-butyl 4-(2-((4-(N-cyclopropylsulfamoyl)phenyl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0328] To a solution of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (190 mg, 0.78 mmol, 1.50 equiv) in DCM (8 mL) stirred under nitrogen at 25°C was added oxalyl chloride (99 mg, 0.78 mmol, 1.50 equiv) and DMF (1 drop). The reaction mixture was stirred at 25°C for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in DCM (4 mL). The above solution was dropwise into a solution of 4-amino-N-cyclopropylbenzenesulfonamide (Intermediate 5, Example 5, 110 mg, 0.52 mmol, 1.50 equiv) and pyridine (123 mg, 1.55 mmol, 3 equiv) in DCM (10 mL). The reaction mixture was stirred at 25°C for 16 h. The mixturewas added water (15 mL), extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to give the title product (crude 330mg, >100%) as yellow oil.[M+H-100]+= 338.Step B. Synthesis of N-(4-(N-cyclopropylsulfamoyl)phenyl)-2-(piperidin-4-yl)acetamide (TFA salt)

[0329] To a solution of tert-butyl 4-(2-((4-(N-cyclopropylsulfamoyl)phenyl)amino)-2-oxoethyl)piperidine-l-carboxylate (330 mg, 0.75 mmol, lequiv) in DCM (6 mL) was added TFA (1 mL). The reaction mixture was stirred at 25°C for 1 h. The mixture was concentrated in vacuo to give the crude N-(4-(N-cyclopropylsulfamoyl)phenyl)-2-(piperidin-4-yl)acetamide (TFA salt) (crude 360 mg, 100%) as yellow oil.[M+H]+= 338.Step C. Synthesis of 2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-(N-cyclopropylsulfamoyl)phenyl)acetamide (Compound 30)

[0330] To a solution of N-(4-(N-cyclopropylsulfamoyl)phenyl)-2-(piperidin-4-yl)acetamide (TFA salt) (330 mg, 0.59 mmol, lequiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (91 mg, 0.59 mmol, lequiv) in n-BuOH (10 mL) was added DIEA (380 mg, 2.93 mmol, 5 equiv). The reaction mixture was stirred at 100°C for 16 h. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP-PREP-8 SunFire C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 5% B to 40% B in 13 min; Wavelength: 214 nm. This afforded the title product (Compound 30, 63 mg, 22%) as a white solid. [M+H]+= 455. ’H NMR (400 MHz, DMSO-d6): δ 0.34-0.49 (m, 4H), 1.20-1.30 (m, 2H), 1.81 (d, J= 10.8 Hz, 2H), 2.06-2.18 (m, 2H), 2.32 (d, J= 6.8 Hz, 2H), 2.32 (t, J= 11.8 Hz, 2H), 4.69 (d, J= 13.2 Hz, 2H), 6.57-6.58 (m, 1H), 7.15-7.17 (m, 1H), 7.72-7.81 (m, 5H), 8.12-8.15 (m, 1H), 10.29 (s, 1H), 11.65 (s, 1H).Example 36. Synthesis of (R)- and (S)- 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (Compounds 31 and 32).o o Boc-NH2HCI in dioxane Pd2(dba)3, Xantphos, DCM, rt CS2CO3, dioxane, 100°CEt3N, DCM DMF, DIEA 40°Cchiral separationo HCI in Dioxane DCM, rtoStep A. Synthesis of tert-butyl (l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate

[0331] To a solution of 5-bromo-2-[5-(trifluoromethyl)-l,3-thiazol-2-yl]-3H-isoindol-l-one (Example 37, 130 mg, 0.36 mmol, 1 equiv), tert-butyl carbamate (84 mg, 0.72 mmol, 2 equiv) and Pd₂(dba)₃ (33 mg, 0.04 mmol, 0.10 equiv) in 1,4-dioxane (10 mL) stirred at 100°C was added Xantphos (21 mg, 0.04 mmol, 0.10 equiv) and CS2CO3 (340 mg, 1.07 mmol, 3 equiv). The reaction mixture was stirred at 100°C for 16 h. The mixture was concentrated, diluted with NaHC’CL solution and then extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel chromatography on Combiflash (EA: PE=1:3) to afford tert-butyl (l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate (120 mg, 75.5%) as a yellow solid. [M+H]+=400.Step B. Synthesis of 5-amino-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one (HCI salt)

[0332] To a solution of tert-butyl (l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate (120 mg, 0.30 mmol, 1 equiv) in MeOH (6 mL) stirred at 25°C was added HCI in 1,4-dioxane (4M, 3 mL). Thereaction mixture was stirred at 25°C for 16 h. The mixture was concentrated to afford 5-amino-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one(HCl salt) (85 mg, 95%) as off-white solid. [M+H]+=300. Step C. Synthesis of 2-bromo-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide

[0333] To a solution of 5-amino-2-[5-(trifluoromethyl)-l,3-thiazol-2-yl]-3H-isoindol-l-one 85 mg, 0.28 mmol, 1 equiv) and 2-bromopropanoyl chloride (58 mg, 0.34 mmol, 1.20 equiv) in DCM (5 mL) stirred at 25°C was added triethylamine (72 mg, 0.56 mmol, 2 equiv). The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel chromatography on Combiflash (EA: PE=1:3) to afford 2-bromo-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (75 mg, 61%) as colorless oil. [M+H]+=434.Step D. Synthesis of tert-butyl 4-(l-oxo-l-((l-oxo-2-(5-(trifhioromethyl)thiazol-2-yl)isoindolin-5-yl)amino)propan-2-yl)piperazine-l-carboxylate

[0334] To a solution of 2-bromo-N-{l-oxo-2-[5-(trifhroromethyl)-l,3-thiazol-2-yl]-3H-isoindol-5-yl}propanamide (75 mg, 0.17 mmol, 1 equiv) and tert-butyl piperazine- 1 -carboxylate (35 mg, 0.19 mmol, 1.10 mmol) in DMF (5 mL) stirred at 25 °C was added DIEA (44 mg, 0.34 mmol, 2 equiv). The reaction mixture was stirred at 40°C for 2 h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography on Combiflash (EA: PE=1:4) to give the title product (80 mg, 87%) as white solid.Step E. Chiral separation

[0335] Racemic tert-butyl 4-(l-oxo-l-((l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)amino)propan-2-yl)piperazine-l-carboxylate (80 mg) was separated by chiral HPLC to afford two enantiomers. The first eluting enantiomer (32 mg) was arbitrarily assigned the ((R)-configuration and the second eluting enantiomer (30 mg) was arbitrarily assigned the (S)-configuration.Step F. Synthesis of (R)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin-l-yl)propenamide (HC1 salt)

[0336] To a solution of (R)-tert-butyl 4-(l-oxo-l-((l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)amino)propan-2-yl)piperazine-l-carboxylate (32 mg, 0.06 mmol, 1 equiv) in MeOH (3 mL) stirred at 25 °C was added HC1 in 1,4-dioxane (4M, 1 mL). The reaction mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford (R)-N-( 1 -oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin- 1-yl)propenamide(HCl salt) (26 mg, 100%) as off-white solid.Step G. Synthesis of (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide (Compound 31)

[0337] To a solution of (R)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin-l-yl)propenamide (HC1 salt) (26 mg, 0.05 mmol, 1 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9 mg, 0.06mmol, 1.10 equiv) in t-BuOH (3 mL) stirred at 25°C was added DIEA (13 mg, 0.10 mmol, 2 equiv). The reaction mixture was stirred at 105 °C for 16 h. The resulted solution was purified using Prep-HPLC with the following conditions: Column: xbrige C18 SN.315, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 80% B in 16 min; Wavelength: 214 nm. This afforded (R)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (Compound 31; 1.26 mg, 0.5%) as white solid.[M+H]+= 557. ’H NMR (400 MHz, DMSO-6): 5 1.24 (t, J= 3.8 Hz, 4H), 2.69 (d, J= 16.8 Hz, 3H), 3.44 (s, 1H), 3.93 (s, 4H), 5.18 (s, 2H), 6.62 (s, 1H), 7.19 (s, 1H), 7.83 (dd, Ji = 8.4 Hz, J2= 36.0 Hz, 2H), 8.18 (d, J= 27.2 Hz, 3H), 10.39 (s, 1H), 11.71 (s, 1H).Step H. Synthesis of (S)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin-l-yl)propenamide (HC1 salt)

[0338] To a solution of (S)-tert-butyl 4-(l-oxo-l-((l-oxo-2-(5-(trifhroromethyl)thiazol-2-yl)isoindolin-5-yl)amino)propan-2-yl)piperazine-l-carboxylate (30 mg, 0.06 mmol, 1 equiv) in MeOH (3 mL) stirred at 25 °C was added HC1 in 1,4-dioxane (4M, 1 mL). The reaction mixture was stirred at 25 °C for 3h. The mixture was concentrated to afford (S)-N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin-l-yl)propenamide(HCl salt) (25 mg, 100%) as off-white solid.Step I. Synthesis of (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(l-oxo-2-(5- (trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide (Compound 32)

[0339] To a solution of N-(l-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)-2-(piperazin-l-yl)propenamide(HCl salt) (25 mg, 0.05 mmol, 1 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9 mg, 0.06 mmol, 1.10 equiv) in t-BuOH (3 mL) stirred at 25°C was added DIEA (13 mg, 0.10 mmol, 2 equiv). The reaction mixture was stirred at 105 °C for 16h. The resulted solution was purified using Prep-HPLC with the following conditions: xbrige C18 SN.315, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 80% B in 16 min; Wavelength: 214 nm. This afforded (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(l-oxo-2-(5- (trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (Compound 32; 6.47 mg, 2%) as white solid.[M+H]+= 557. ‘H NMR (400 MHz, DMSO-6): 5 1.25 (t, J= 6.8 Hz, 4H), 2.63-2.73 (m, 3H), 3.43 (d, J= 6.8 Hz, 1H), 3.93 (s, 4H), 5.18 (s, 2H), 6.62 (s, 1H), 7.18 (s, 1H), 7.83 (dd, Ji = 8.8 Hz, J2= 34.8 Hz, 2H), 8.14 (s, 1H), 8.22 (s, 2H), 10.40 (s, 1H), 11.71 (s, 1H).Example 37. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide (Compound 33).BOCNH2, Pd2(dba)3, Xantphos, Cs2CO3dioxane, 100°C Py, DCMStep A. Synthesis of (Z)-5-bromo-N,2-bis(5-(trifhioromethyl)thiazol-2-yl)isoindolin-l-imine and (E)-6-bromo-N,2-bis(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-imine

[0340] To a solution of 4-bromophthalaldehyde (980 mg, 4.60 mmol, 1 equiv) and 5-(trifluoromethyl)thiazol-2-amine (1547 mg, 9.20 mmol, 2 equiv) in toluene (20 mL) was added AcOH (0.5 mL). The reaction mixture was stirred at 110°C for 5 h. The resulting mixture was concentrated to afford (Z)-5-bromo-N,2-bis(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l -imine and (E)-6-bromo-N,2-bis(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l -imine (2800 mg, 47%) as yellow solid, which was used to next step directly. [M+H]+=513 / 515.Step B. Synthesis of 5-bromo-2-(5-(trifhioromethyl)thiazol-2-yl)isoindolin-l-one and 6-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one

[0341] To a solution of mixture of (Z)-5-bromo-N,2-bis(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-imine and (E)-6-bromo-N,2-bis(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-imine (1670 mg, 3.25 mmol, 1 equiv) in EtOH (30 mL) and water (8 mL) was added sulphuric acid (6 mL). The reaction mixture was stirred at 90°C for 16 h. The mixture was cooled to R. T. and then filtered. The filter cake was collected and dried under reduced pressure to give the mixture 5-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one and 6-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one. Then the mixture was separated by chiral SFC-HPLC to give two products: 5-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one (280 mg) and 6-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one (460 mg). LCMS:363[M+H] / 365.Step C. Synthesis of tert-butyl (3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate

[0342] To a solution of 6-bromo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one (50 mg, 0.14 mmol, 1 equiv), tert-butyl carbamate (33 mg, 0.27 mmol, 2 equiv) and CS2CO3 (90 mg, 0.27 mmol, 2 equiv) in dioxane (10 mL) stirred under nitrogenwas added Xantphos (16 mg, 0.03 mmol, 0.20 equiv) and Pd₂(dba)₃ (13 mg, 0.014 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C for 16 h under nitrogen. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EA / PE=13%~15%) to give the product tert-butyl (3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate (61 mg, 89%) as red solid. [M+H]+=400.Step D. Synthesis of 6-amino-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one

[0343] A solution of tert-butyl (3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)carbamate (50 mg, 0.13 mmol, 1 equiv) in 4M HCl / dioxane (4 mL) was stirred at 25 °C for 3h. The mixture was concentrated in vacuo to give the crude 6-amino-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-l-one (50 mg, 100%) as yellow solid, which was used to next step directly. [M+H]+=300.Step E. Synthesis of 2-bromo-N-(3-oxo-2-(5-(trifhioromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide

[0344] To a solution of crude 6-amino-2-(5-(trifhroromethyl)thiazol-2-yl)isoindolin-l-one (50 mg, 0.16 mmol, 1 equiv) in DCM (8 mL) was added Pyridine (53 mg, 0.66 mmol, 4 equiv) and 2-bromopropanoyl chloride (32 mg, 0.18 mmol, 1.10 equiv) in THF (1 mL). The reaction mixture was stirred at 25°C for 2 h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, to give the product 2-bromo-N-(3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (44 mg, 63%) as red solid. [M+H]+=434.Step F. Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide (Compopund 33)

[0345] To a solution of 2-bromo-N-(3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propanamide (44 mg, 0.10 mmol, 1 equiv), 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine (25 mg, 0.12 mmol, 1.20 equiv) and TEA (31 mg, 0.30 mmol, 3 equiv) in DMF (5 mL) was added KI (2 mg, 0.01 mmol, 0.10 equiv). The reaction mixture was stirred at 90°C for 16h. The mixture was concentrated in vacuo. The resulted solution was purified using Prep-HPLC with the following conditions: Column: RP-PREP-8 SunFire C18 5um 19* 150mm; Mobile Phase A: Water (0.2%FA), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 45% B in 10 min; Wavelength: 214 nm. This afforded 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-oxo-2-(5-(trifluoromethyl)thiazol-2-yl)isoindolin-5-yl)propenamide (Compound 33); 7 mg, 12%) as a white solid. [M+H]+= 557. ‘H NMR (400 MHz, DMSO-d6): δ 0.84-0.87 (m, 3H), 1.97-2.03 (m, 1H), 2.62-2.74 (m, 4H), 3.94 (t, J= 4.6 Hz, 4H), 5.16 (s, 2H), 6.61-6.63 (m, 1H), 7.17-7.18 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.96-7.99 (m, 1H), 8.14 (s, 1H), 8.23-8.34 (m, 2H), 10.25 (s, 1H), 11.69 (s, 1H).Example 38. Synthesis of (R) and (S)-4-(2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanamido)-N-(pyrimidin-2-yl) benzamide (Compounds 34 and 35).Fe, HCI EtOH, H2O 70°CHCI in dioxane dioxane ACN, K2C03,0~80°CEnantiomer 2 Synthesis of 4-nitro-N-(pyrimidin-2-yl) benzamide

[0346] To a solution of pyrimidin-2-amine (0.50 g, 5.30 mmol, l. OOequiv) in pyridine (5 mL), cooled to 0°C, added 4-nitrobenzoyl chloride (1.48 g, 7.95 mmol, 1.50equiv) in pyridine (10 mL) dropwise slowly at 0°C, heated to 50°C, stirred at 50°C for 16h. Concentrated and extracted with DCM, washed with water and brine, dried over Na₂SO₄, filtered and concentrated. Purified by SGC (DCM: MeOH=0%-10%) to get the product 4-nitro-N-(pyrimidin-2-yl) benzamide (1.02 g, 75.12%) as yellow solid. [M+H]+=245.0Synthesis of 4-amino-N-(pyrimidin-2-yl) benzamide

[0347] To a solution of 4-nitro-N-(pyrimidin-2-yl) benzamide (1.02 g, 4.20 mmol, l. OOequiv) in EtOH / H2O (60mL), added HCI (1.5mL) and Fe (0.94 g, 16.80 mmol, 4.00equiv), heated to 70°C, stirred at 70°C for 6h. Checked by LCMS, Ms is ok, filtered and concentrated, adjusted pH=8 by 2N NaiCCK concentrated and washed with DCM and MeOH to get the product 4-Amino-N-(pyrimidin-2-yl) benzamide (0.96g, 95.24%) as yellow solid. [M+H]+=215.0.

[0348] Synthesis of tert-butyl 4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl} piperazine-l-carboxylate

[0349] To a solution of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (5.00 g, 32.60 mmol, l. OOequiv) in DMF (50 mL), added DIEA (16.85 g, 130.40 mmol, 4.00equiv) and tert-butyl piperazine- 1 -carboxylate (7.29 g, 39.12mmol, 1.20equiv), heated to 90°C, stirred at 90°C for 6h. Checked by LCMS, Ms is ok, concentrated and extracted with DCM, washed with water and brine, dried over Na2SO4. filtered and concentrated. Purified by SGC (DCM: MeOH=0%-4%) to get the product tert-butyl 4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl} piperazine-1-carboxylate (7.05g, 67.79%) as white solid. [M+H]+=304.0.Synthesis of l-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazine

[0350] To a solution of tert-butyl 4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazine- 1 -carboxylate (7.00 g, 23.10 mmol, l. OOequiv) in dioxane (30 mL), cooled to 0°C, added 4N HC1 in dioxane (30mL), stirred at r.t for 2h. Checked by LCMS, Ms is ok, concentrated to get the product l-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazine (5.20g, 99.57%) as crude white solid. [M+H]+=204.1.Synthesis of tert-butyl 4-(l-((3-chloro-4-(N-methylsulfamoyl) phenyl) amino)-l-oxopropan-2-yl) piperazine-l-carboxylate

[0351] To a solution of l-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazine (2.35 g, 11.60 mmol, l. OOequiv) in ACN (60 mL), cooled to 0°C, added K2CO3 (4.01 g, 29.00 mmol, 2.50equiv), stirred at 0°C for 10 minutes, added tert-butyl 2-bromopropanoate (2.67 g, 12.76 mmol, LlOequiv), heated to 80°C, stirred at 80°C for 6h. Concentrated and extracted with DCM, washed with water and brine, dried over Na2SO4 filtered and concentrated. Purified by SGC (DCM: MeOH=0%-5%) to get the product (2.25 g, 55.17%), [M+H]+=332.0. This was subjected to chiral chromatography to obtain a first eluting enantiomer (Enantiomer 1, 1.02 g) and second eluting enantiomer (Enantiomer 2, 1.05 g), both as white solids. The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1)

[0352] To a solution of tert-butyl-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propanoate (Enantiomer 1) (0.20 g, 0.60 mmol, l. OOequiv) in dioxane (2 mL), cooled to 0°C, added 4N HC1 in dioxane (8 mL), stirred at r.t for 16h. Concentrated to get the product 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1) (0.20g, 96.30%) as crude white solid. [M+H]+=276.0Synthesis of an enantiomer of 4-(2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanamido)-N-(pyrimidin-2-yl) benzamide (Compound 34)

[0353] To a solution of TCFH (366.69 mg, 1.31 mmol, 3.50equiv) in ACN (lOmL), cooled to 0°C, added NMI (122.64 mg, 1.49 mmol, 4.00equiv), stirred at 0°C for 0.5h. The solution was added into 2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propanoic acid (102.80 mg, 0.37 mmol, l. OOequiv) and 4-Amino-N-(5-fluoropyrimidin-2-yl) benzene sulfonamide (80.00 mg, 0.37 mmol, l. OOequiv) in DMF (10 mL), stirred at r.t for 3.5h. Concentrated and extracted with DCM, washed with water and brine, dried over Na2SO4. filtered and concentrated. The resulting residue was purified using Prep-HPLC with the following conditions:Column: RP-PREP-8 Sunfire C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.2% FA), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 2% B to 20% B in 11 min; Wavelength: 214 nm. This resulted in the title compound (16.73 mg, 9.03%) as white solid. [M+H]+= 472.1. ’H NMR (400 MHz, DMSO-d6): 5 1.24 (d, J=6.8 Hz, 3H), 2.62-2.73 (m, 4H), 3.37-3.42 (m, 1H), 3.93 (t, J =4.6 Hz, 4H), 6.62 (t, J=1.6 Hz, 1H), 7.18 (t, J=3.0 Hz, 1H), 7.25 (t,.7=4.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 8.14 (s, 1H), 8.72 (d,.7 =5.2 Hz, 2H), 10.18 (s, 1H), 10.89 (s, 1H), 11.71 (s, 1H).Synthesis of 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1)

[0354] To a solution of tert-butyl-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propanoate (Enantiomer 2) (0.20 g, 0.60 mmol, l. OOequiv) in dioxane (2 mL), cooled to 0°C, added 4N HC1 in dioxane (8 mL), stirred at r.t for 16h. Concentrated to get the title product (0.20 g, 96.30%) as crude white solid. [M+H]+=276.0Synthesis of enantiomer of 4-(2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanamido)-N-(pyrimidin-2-yl) benzamide (Compound 35)

[0355] To a solution of TCFH (366.69 mg, 1.31 mmol, 3.50equiv) in ACN (10 mL), cooled to 0°C, added NMI (122.64 mg, 1.49 mmol, 4.00equiv), stirred at 0°C for 0.5h. The solution was added into 2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propanoic acid (102.80 mg, 0.37 mmol, l. OOequiv) and 4-Amino-N-(5-fluoropyrimidin-2-yl) benzene sulfonamide (80.00 mg, 0.37 mmol, l. OOequiv) in DMF (10 mL), stirred at r.t for 3.5h. Checked by LCMS, Ms is ok, concentrated and extracted with DCM, washed with water and brine, dried over NazSCh, filtered and concentrated. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP- PREP-8 Sunfire C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.2% FA), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 2% B to 20% B in 11 min; Wavelength: 214 nm. This resulted in the title compound (12.10 mg, 6.53%) as white solid. [M+H]+= 472.1. ‘H NMR (400 MHz, DMSO-6): 5 1.24 (d, J =6.8 Hz, 3H), 2.64-2.71 (m, 4H), 3.34-3.40 (m, 1H), 3.93 (t, J =4.6 Hz, 4H), 6.62 (m, 1H), 7.18 (t, J =2.8 Hz, 1H), 7.25 (t, J =4.8 Hz, 1H), 7.80 (d, J =8.8 Hz, 2H), 7.96 (d, J =8.8 Hz, 2H), 8.14 (s, 1H), 8.72 (d,.7=4.4 Hz. 2H), 10.17 (s, 1H), 10.89 (s, 1H), 11.70 (s, 1H).Example 39. Synthesis of (R) and (S)-N-[4-[(5-fluoropyrimidin-2-yl) sulfamoyl] phenyl}-2-(4-[7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propenamide (Compounds 36 and 37)-I ll-Synthesis of N-(4-methylpyrimidin-2-yl)-4-nitrobenzene sulfonamide

[0356] To a solution of 4-methylpyrimidin-2-amine (0.5 g, 4.60 mmol, 1.00 equiv) in pyridine (5 mL), stirred at 0 °C was added 4-nitrobenzenesulfonyl chloride (1.33 g, 5.98 mmol, 1.30 equiv) in pyridine (10 mL). The reaction mixture was stirred at 70 °C for 16h. Concentrated and added water, the solid was formed, filtered and washed with water, dried to get the product N-(4-methylpyrimidin-2-yl)-4-nitrobenzene sulfonamide (1.14 g, 67.65%) as brown solid. [M+H]+=294.9.Synthesis of 4-amino-N-(4-methylpyrimidin-2-yl) benzene sulfonamide

[0357] To a solution of N-(4-methylpyrimidin-2-yl)-4-nitrobenzene sulfonamide (1.04 g, 3.50 mmol, 1.00 equiv) in EtOH (50 mL) stirred under H2 at 25°C was added Pd / C (0.3 g). The reaction mixture was stirred at 60°C for 48 h. Filtered and purified by SGC (PE: EA=20%-70%) to get the product 4-Amino-N-(4-methylpyrimidin-2-yl) benzene sulfonamide (537.17 mg, 51.43%) as yellow oil. [M+H]+=265.0.Synthesis of tert-butyl 4-(l-((4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl) amino)-l-oxopropan-2-yl) piperazine-l-carboxylate

[0358] To a solution of 4-amino-N-(4-methylpyrimidin-2-yl) benzene sulfonamide (537.17 mg, 2.03 mmol, 1.05 equiv) and 2-(4-(tert-butoxycarbonyl) piperazin-l-yl) propanoic acid (0.5 g, 1.94 mmol, 1.00 equiv) in DMF (15 mL) was added pyridine (459.32 mg, 5.81 mmol, 3.00 equiv) and HATU (1.10 g, 2.90 mmol, 1.50 equiv). The reaction mixture was stirred at 40°C for 16 h. Concentrated and purified by SGC (PE: EA=20%~100%) to get the product (1.23 g, 88.22%) as yellow solid. [M+H]+=505.0.

[0359] Then in total 400 mg tert-butyl 4-(l-((4-(N-(4-methylpyrimidin-2-yl)sulfamoyl) phenyl) amino)-l-oxopropan-2-yl)piperazine-l -carboxylate was used to separate two enantiomers (first eluting, Enantiomer 1,239 mg) and second eluting (Enantiomer 2, 108 mg). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl)-2-(piperazin-l-yl) propanamide (HC1)

[0360] To a solution of tert-butyl 4-(l-((4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl) amino)-l-oxopropan-2-yl) piperazine- 1 -carboxylate (239.00 mg, 0.47 mmol, l. OOequiv) in dioxane (2mL) stirred at 20 °C was added 4N HC1 in dioxane (4mL). The reaction mixture was stirred at 20 °C for Ih. concentrated to get the product N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl)-2-(piperazin-l-yl) propanamide (HC1) (0.32 g, 85.09%) as yellow oil. [M+H]+=405.0.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl)-N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl) propenamide (Compound 36)

[0361] To a solution of N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl)-2-(piperazin-l-yl) propanamide (HC1) (324.00 mg, 0.80 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (135.31 mg, 0.88 mmol, 1.10 equiv) in n-BuOH (5mL) was added DIEA (1.04 g, 8.01 mmol, 10.00 equiv). The reaction mixture was stirred at 80°C for 16 h. LCMS showed the desired mass was found. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP-PREP-11 Xbridge C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 5% B to 40% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (39.00 mg, 9.15%) as a white solid. [M+H]+= 522.1. ’H NMR (400 MHz, DMSO-d6): 5 1.21 (d,.7=6.8 Hz, 3H), 2.31 (s, 3H), 2.59-2.70 (m, 4H), 3.36-3.39 (m, IH), 3.90 (t,.7=4.6 Hz, 4H), 6.60-6.61 (m, IH), 6.88 (d, J =4.8 Hz, IH), 7.17 (t,.7=3.0 Hz, IH), 7.82 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 8.13 (s, IH), 8.30 (d,.7=4.8 Hz, IH), 10.22 (s, IH), 11.56 (brs, IH), 11.70 (s, IH).Synthesis of 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1)

[0362] To a solution of tert-butyl 4-(l-((4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl) amino)-l-oxopropan-2-yl) piperazine- 1 -carboxylate (108.00 mg, 0.21 mmol, 1.00 equiv) in dioxane (2 mL) stirred at 20 °C was added 4N HC1 in dioxane (2 mL). The reaction mixture was stirred at 20 °C for Ih. concentrated to get the product N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl)-2-(piperazin-l-yl) propanamide (HC1) (0.14 g, 82.62%) as white solid. [M+H]+=405.0Synthesis of enantiomer of N-{4-[(5-fhioropyrimidin-2-yl) sulfamoyl] phenyl}-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propenamide (Compound 37)

[0363] To a solution of N-(4-(N-(4-methylpyrimidin-2-yl) sulfamoyl) phenyl)-2-(piperazin-l-yl) propanamide (HC1) (143.00 mg, 0.35 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (81.43 mg, 0.53 mmol, 1.50 equiv) in n-BuOH (3 mL) was added DIEA (456.86 mg, 3.53 mmol, 10.00 equiv). The reaction mixture was stirred at 80°C for 16 h. LCMS showed the desired mass was found. The mixture wasconcentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP-PREP-11 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 5% B to 40% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (24.00 mg, 12.5%) as a white solid. [M+H]+= 522.1. ’H NMR (400 MHz, DMSO-d6): 5 1.21 (d, J=6.8 Hz, 3H), 2.31 (s, 3H), 2.59-2.70 (m, 4H), 3.34-3.38 (m, 1H), 3.90 (t,.7=4.6 Hz, 4H), 6.60-6.61 (m, 1H), 6.89 (d, J =5.2 Hz, 1H), 7.17 (t, J =3.0 Hz, 1H), 7.82 (d,.7=8.4 Hz, 2H), 7.92 (d, J =9.2 Hz, 2H), 8.13 (s, 1H), 8.30 (d,.7=5.2 Hz, 1H), 10.22 (s, 1H), 11.58 (brs, 1H), 11.70 (s, 1H).Example 40. Synthesis of (R) and (S)-N-!4-|(5-fluoropyrimidin-2-yl) sulfamoyl] phenyl}-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin- 1-yl) propenamide (Compounds 38 and 39)Fe.conc HCI EtOH, H2O 70°CEnantiomer 1 HCIEnantiomer 2 HCISynthesis of N-(5-fluoropyrimidin-2-yl)-4-nitrobenzenesulfonamide

[0364] To a solution of 5-fluoropyrimidin-2-amine (0.50 g, 4.40 mmol, l. OOequiv) in pyridine (5 mL), cooled to 0°C, added 4-nitrobenzenesulfonyl chloride (1.46 g, 6.60 mmol, 1.50equiv) in pyridine (10 mL) dropwise slowly at 0°C, heated to 50°C, stirred at 50°C for 16h. Checked by LCMS, Ms is ok, concentrated and extracted with DCM, washed with water and brine, dried over Na₂SO₄, filtered and concentrated. Purified by SGC (DCM: MeOH = 0%-10%) to get the product N-(5-fluoropyrimidin-2-yl)-4-nitrobenzenesulfonamide (0.70 g, 50.00%) as yellow solid. [M-H]+=296.9Synthesis of 4-Amino-N-(5-fluoropyrimidin-2-yl) benzenesulfonamide

[0365] To a solution of N-(5-fluoropyrimidin-2-yl)-4-nitrobenzenesulfonamide (0.70 g, 2.35 mmol, l. OOequiv) in EtOH / HzO (60 mL), added HC1 (1.0 mL) and Fe (524.32 mg, 9.39 mmol, 4.00equiv), heated to 70°C, stirred at 70°C for 6h. Filtered and concentrated, adjusted pH=8 by 2N NazCCf. concentrated and washed with DCM and MeOH to get the product 4-Amino-N-(5-fluoropyrimidin-2-yl) benzenesulfonamide (615.70 mg, 88.01%) as yellow solid. [M-H]+=267.0.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1)

[0366] To a solution of tert-butyl-2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl) propanoate (Enantiomer 1; Example 38; 0.20 g, 0.60 mmol, 1.00 equiv) in dioxane (2 mL), cooled to 0°C, added 4N HC1 in dioxane (8mL), stirred at r.t for 16h. Concentrated to get the product 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1) (0.20 g, 96.30%) as crude white solid. [M+H]+=276.0 Synthesis of enantiomer of N-{4-[(5-fluoropyrimidin-2-yl) sulfamoyl] phenyl}-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propenamide (Compound 38)

[0367] To a solution of TCFH (366.10 mg, 1.30 mmol, 3.50equiv) in ACN (10 mL), cooled to 0°C, added NMI (122.44 mg, 1.49 mmol, 4.00equiv), stirred at 0°C for 0.5h. The solution was added into 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl) propanoic acid (102.63 mg, 0.37 mmol, l. OOequiv) and 4-Amino-N-(5-fluoropyrimidin-2-yl) benzene sulfonamide (100.00 mg, 0.37 mmol, l. OOequiv) in DMF (10 mL), stirred at r.t for 3.5h. Checked by LCMS, Ms is ok, concentrated and extracted with DCM, washed with water and brine, dried over NazSCh, filtered and concentrated. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP -PREP-11 Xbrige C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 30% B in 10 min; Wavelength: 214 nm. This resulted in the title compoound (18.51 mg, 8.99%) as white solid. [M+H]+= 526.1.1HNMR(400 MHz, DMSO-d6): 5 1.22 (d, J=5.4 Hz, 3H), 2.61-2.67 (m, 4H), 3.36-3.38 (m, 1H), 3.90 (t,.7=4.6 Hz, 4H), 6.60-6.61 (m, 1H), 7.17 (t, J =3.0 Hz, 1H), 7.83-7.92 (m, 4H), 8.13 (s, 1H), 8.60 (s, 2H), 10.26 (s, 1H), 11.70 (s, 1H), 11.83 (br s, 1H).Synthesis of 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) piperazin-l-yl) propanoic acid (HC1)

[0368] To a solution of tert-butyl-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propanoate (Enantiomer 2; Example 38, 0.20 g, 0.60 mmol, l. OOequiv) in dioxane (2 mL), cooled to 0°C, added 4N HC1 in dioxane (8 mL), stirred at r.t for 16h. Concentrated to get the product 2-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)piperazin-l-yl) propanoic acid (HC1) (0.20 g, 96.30%) as crude white solid. [M+H]+=276.0 Synthesis of enantiomer of N-{4-[(5-fluoropyrimidin-2-yl)sulfamoyl]phenyl}-2-(4-{7H-pyrrolo[2,3-d] pyrimidin-4-yl} piperazin-l-yl) propenamide (Compound 39)

[0369] To a solution of TCFH (366.10 mg, 1.30 mmol, 3.50equiv) in ACN (10 mL), cooled to 0°C, added NMI (122.44 mg, 1.49 mmol, 4.00equiv), stirred at 0°C for 0.5h. The solution was added into 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl) propanoic acid (102.63 mg, 0.37 mmol, l. OOequiv) and 4-Amino-N-(5-fluoropyrimidin-2-yl) benzene sulfonamide (100.00 mg, 0.37 mmol, l. OOequiv) in DMF (10 mL), stirred at r.t for 3.5h. Concentrated and extracted with DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP- RP-PREP-11 Xbrige C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 30% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (16.02 mg, 7.78%) as white solid. [M+H]+= 526.1. 'H NMR (400 MHz, DMSO-d6): 5 1.22 (d, J =5.6 Hz, 3H), 2.62-2.68 (m, 4H), 3.36-3.38 (m, 1H), 3.90 (t, J =4.6 Hz, 4H), 6.60-6.61 (t, J=1.8 Hz, 1H), 7.17 (t, J=3.0 Hz, 1H), 7.83-7.92 (m, 4H), 8.13 (s, 1H), 8.60 (s, 2H), 10.26 (s, 1H), 11.70 (s, 1H), 11.82 (br s, 1H).Example 41. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4- (N-phenylsulfamoyl)phenyl)propanamide (Compound 40)Synthesis of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate

[0370] To a stirred solution of tert-butyl 2-bromopropanoate (1.30 g, 6.20 mmol, l. OOequiv), 1-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazine (1.40 g, 6.90 mmol, l.lOequiv) and K2CO3 (1.43 g, 10.35 mmol, 1.67equiv) in DMF (10 mL)was placed in oil bath heated to 50°C for 16 h. The reaction mixture was concentrated under pressure 50 °C. H2O (10 mL) was added. The residue was extracted with EA (10x3mL). The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure 45°C. The residue was triturated with PE (5 mL) to give the product tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (0.92 g, purity:85%, yield:44.8%, yellow solid). LCMS: [M+H]+=332.Chiral separation

[0371] Racemic tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (660.00 mg) was separated by chiral to get two enantiomers: first eluting (329.00 mg Enantiomer 1) and second eluting(315.00 mg, Enantiomer 2). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0372] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 2, 160.00 mg, 0.48 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 8 mL). The mixture was continuously stirred under 25°C of 3 h. The reaction mixture was concentrated to give the title product (186.00 mg, yield: >95%, purty: 90%, white solid). LCMS: [M+H]+=276.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-phenylsulfamoyl)phenyl)propanamide (Compound 40)

[0373] To a solution was added TCFH (225.59 mg, 0.80 mmol, 4.00 equiv), NMI (198.05 mg, 2.40 mmol, 12.00 equiv) in dry ACN (10 mL). 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, 70.00 mg, 0.20 mmol, l. OOequiv) in anhydrous NMP (1 mL) and 4-amino-N-phenylbenzenesulfonamide (47.41 mg, 0.20 mmol, l. Oequiv) in NMP (1 mL) was added in. The reaction mixture was allowed to warm to ambient temperature and stirred for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep Cl 8 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 25% B to 65% B in 16 min; Wavelength: 214 nm. This resulted in Compound 40 (20.70 mg, yield: 20.5%, white solid). LCMS: [M+H]+=506.1. 'HNMR (400 MHz, DMSO-6): 5 1.20 (d, J= 6.8 Hz, 3H), 2.50-2.69 (m, 4H), 3.35-3.37 (m, 1H), 3.86-3.91 (m, 4H), 6.59-6.60 (m, 1H), 6.99 (t, J= 7.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 2H), 7.16-7.22 (m, 3H), 7.69 (d, J= 9.2 Hz, 2H), 7.79 (d, J= 9.2 Hz, 2H), 8.13 (s, 1H), 10.16 (br, 1H), 10.20(s, 1H), 11.69 (s, 1H).Example 42. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)propanamide (Compound 41)chiral Pd2(dba)3, Xantphos, separation Cs2CO3, dioxane, 100°C, 16 hBoc Enantiomer 1HCI / dioxaneBoc Enantiomer 2Synthesis of tert-butyl 4-(l-((4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0374] To a solution of 5-bromo-2-chloro-N, N-dimethylbenzenesulfonamide (500.00 mg, 1.67 mmol, 1.00 equiv), tert-butyl 4-(l -amino- l-oxopropan-2-yl)piperazine-l -carboxylate (475.00 mg, 1.84 mmol, 1.10 equiv) and CS2CO3 (1092.00 mg, 3.35 mmol, 2.00 equiv) in dioxane (20 mL) stirred under nitrogen at 25 °C was added Xantphos (194.00 mg, 0.34 mmol) and Pd2(dba)3 (154.00 mg, 0.17 mmol). The reaction mixture was stirred at 100°C for 16 h under N2. LCMS showed the desired mass was found. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (EA / PE=l / l~l / 0) to give the product tert-butyl 4-(l-((4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (490.00 mg, 55.44%) as yellow solid. [M+H]+= 475. Then in total 170 mg tert-butyl 4-(l-((4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l -carboxylate was used to separate two enantiomers: first eluting (Enantiomer 1: 65.00 mg) and second eluting (Enantiomer 2:71.00 mg). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of N-(4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1)

[0375] To a solution of tert-butyl 4-(l-((4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (Enantiomer 2) (68.00 mg, 0.13 mmol, 1.00 equiv) in DCM (4 mL) at 0°C was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at 30°C for 1 h. LCMS showed the reaction was finished. The mixture was concentrated in vacuo to give the crude N-(4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1) (75.00 mg, >100%) as yellow oil, which was used to next step directly. [M+H]+= 375.

[0376] Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)propanamide (Compound 41)

[0377] To a solution of N-(4-chloro-3-(N, N-dimethylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1) (65.00 mg, 0.17 mmol, l. OOequiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (27.00 mg, 0.17 mmol, l. OOequiv) in n-BuOH (8 mL) was added DIEA (112.00 mg, 0.87 mmol, 5.00equiv). The reaction mixture was stirred at 95°C for 16 h. LCMS showed the desired mass was found. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP -PREP- 11 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 30% B to 55% B in 10 min; Wavelength: 214 nm. This resulted the title compound (29.00 mg, 33.33%) as a white solid. [M+H]+= 492. ‘H NMR (400 MHz, DMSO-d6): 5 1.23 (d, J = 6.4 Hz, 3H), 2.59-2.72 (m, 4H), 2.81 (s, 6H), 3.33-3.36 (m, 1H), 3.90-3.93 (m, 4H), 6.61 (s, 1H), 7.17-7.18 (m, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.95-7.98 (m, 1H), 8.13 (s, 1H), 8.35 (s, 1H), 10.33 (s, 1H), 11.70 (s, 1H).Example 43. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-2-cvclopropyl-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)acetamide (Compounds 42 and 43)Synthesis of benzyl 4-(l-cyclopropyl-2-ethoxy-2-oxoethyl)piperazine-l-carboxylate

[0378] To a solution of ethyl 2-bromo-2-cyclopropylacetate (1.00 g, 4.80 mmol, 1.00 equiv) in ACN (15 mL) was added benzyl piperazine-l-carboxylate (1.06 g, 4.80 mmol, 1.00 equiv), K2CO3 (1.99 g, 14.40 mmol, 3.00 equiv) and KI (0.96 g, 5.70 mmol, 1.20 equiv), stirred at 50°C for 4h. The solution was filtered, filtrate was collected. The crude material was added to a silica gel column and was eluted with PE / EtOAc (3:1). The reaction mixture was concentrated under pressure 50°C to get the product benzyl 4-( 1 -cyclopropyl -2 -ethoxy -2-oxoethyl)piperazine-l -carboxylate (1.50 g, 90% purity, 81.25% yield, white solid). [M+H]+= 347.Synthesis of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-cyclopropylacetic acid

[0379] To a solution of benzyl 4-(l-cyclopropyl-2-ethoxy-2-oxoethyl)piperazine-l -carboxylate (0.80 g, 2.30 mmol, 1.00 equiv) in MeOH / H2O=3:l (8 mL) was added LiOH (0.55 g, 2.30 mmol, 1.00 equiv), stirred at 25°C for 5h. The reaction mixture was concentrated under pressure 45 °C. The mixture was adjusted to pH= 8-9 with HC1, then was filtered, filtrate cake was collected. The reaction mixture was concentrated under pressure 50°C to 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-cyclopropylacetic acid (0.70 g, 90% purity, 86.96% yield, off-white solid). [M+H]+= 319.Synthesis of benzyl 4-(l-cyclopropyl-2-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-2-oxoethyl)piperazine-l-carboxylate

[0380] To a solution of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-cyclopropylacetic acid (0.65 g, 2.04 mmol, 1.00 equiv) in DCM (15 mL) was added 4-amino-2-fluoro-N-methylbenzenesulfonamide (0.42 g, 2.04mmol, 1.00 equiv), HATU (1.64 g, 3.06 mmol, 1.50 equiv) and pyridine (0.32 g, 4.08 mmol, 2.00 equiv), stirred at 25 °C for 5h. The residue was extracted with EA (3x10 mL). The crude material was added to a silica gel column and was eluted with PE / EtOAc (3:1). The mixture was concentrated under pressure 50°C to get benzyl 4-( 1 -cyclopropyl -2-((3 -fluoro-4-(N-methylsulfamoyl)phenyl)amino)-2-oxoethyl)piperazine- 1 -carboxylate (0.26 g, 90% purity, 22.98% yield, white solid). [M+H]+= 505.Synthesis of 2-cyclopropyl-N-(3-fhioro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)acetamide

[0381] To a solution of benzyl 4-(l-cyclopropyl-2-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-2-oxoethyl)piperazine- 1 -carboxylate (0.26 g, 0.52 mmol, 1.00 equiv) in IPA (8 mL) was added Pd / C (0.11 g, 1.03 mmol, 2.00 equiv), stirred at 40°C for 16h. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure 50°C to get the product 2-cyclopropyl-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)acetamide (0.16 g, 90% purity, 75.43% yield, white solid).[M+H]+=371.Synthesis of enantiomers of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-2-cyclopropyl-N-(3-fhioro-4-(N-methylsulfamoyl)phenyl)acetamide (Compounds 42 nd 43)

[0382] To a solution of 2-cyclopropyl-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)acetamide (0.10 g, 0.27 mmol, 1.00 equiv) in n-BuOH (20 mL) was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (41.45 mg, 0.27 mmol, 1.00 equiv) and DIEA (104.65 mg, 0.81 mmol, 3.00 equiv), stirred at 100°C for 16h. The solution was purified using Prep-HPLC with the following conditions: Column: SunFire Prep C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 22% B in 18 min; Wavelength: 214 nm. This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-2-cyclopropyl-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)acetamide (35.00 mg).Chiral separation:

[0383] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-2-cyclopropyl-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)acetamide (35.00 mg) was separated by chiral HPLC to get two enantiomers: first eluting (Enantiomer 1: 6.93 mg, Compound 42) and second eluting (Enantiomer 2: 8.16 mg, Compound 43). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned. Compound 42: LCMS: [M+H]+= 488.1.1HNMR (400 MHz, DMSO-6): 50.30 (d, J= 9.2 Hz, 1H), 0.38 (d, J = 9.6 Hz, 1H), 0.48 (d, J= 8.4 Hz, 1H), 0.71 (d, J= 7.2 Hz, 1H), 1.127 (t, J= 7.2 Hz, 1H), 2.22 (d, J= 9.6 Hz, 1H), 2.46 (d, J= 4.8 Hz, 3H), 2.59-2.63 (m, 2H), 2.85-2.89 (m, 2H), 3.92 (s, 4H), 6.62-6.63 (m, 1H), 7.18 (t, J= 2.8 Hz, 1H), 7.58-7.61 (m, 2H), 7.70-7.74 (m, 1H), 7.86-7.89 (m, 1H), 8.14 (s, 1H), 10.39 (s, 1H), 11.71 (s, 1H). Compound 43: LCMS: [M+H]+= 488.1. 'HNMR (400 MHz, DMSO-6): 5 0.30 (d, J = 9.2 Hz, 1H), 0.38 (d, J= 9.6 Hz, 1H), 0.48 (d, J= 8.4 Hz, 1H), 0.71 (d, J= 3.6 Hz, 1H), 1.12-1.23 (m, 1H), 2.2 (d, J= 9.6 Hz, 1H), 2.46 (d, J= 4.8 Hz, 3H), 2.59-2.63 (m, 2H), 2.85-2.89 (m, 2H), 3.92 (s, 4H), 6.62 (t, J= 1.6 Hz, 1H), 7.18 (t,.7= 2.8 Hz, 1H), 7.58-7.61 (m, 2H), 7.70-7.74 (m, 1H), 7.88 (t, J= 12.8 Hz, 1H), 8.14 (s, 1H), 10.39 (s, 1H), 11.71 (s, 1H).Example 44. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d1pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)propanamide (Compounds 44 and 45)Synthesis of N-(5-methoxypyrimidin-2-yl)-4-nitrobenzenesulfonamide

[0384] To a solution of 5-methoxypyrimidin-2-amine (900.00 mg, 7.19 mmol, 1.00 equiv) in pyridine (12.00 mL) stirred under nitrogen at 0 °C was added a solution of 4-nitrobenzenesulfonyl chloride (2391.01 mg, 10.79 mmol, 1.50 equiv) in pyridine (8.00 mL) dropwise. The reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was concentrated and purified by flash chromatography (DCM: MeOH =20:1) to afford product N-(5-methoxypyrimidin-2-yl)-4-nitrobenzenesulfonamide (600.00 mg, 26.00%) as yellow solid.[M+H]+=311.Synthesis of 4-amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide

[0385] To a solution of N-(5-methoxypyrimidin-2-yl)-4-nitrobenzenesulfonamide (575.00 mg, 1.85 mmol, 1.00 equiv) in EtOH / H2O (10.00 / 2.00 mL) stirred in air at 25 °C were added iron powder (206.99 mg, 3.71 mmol, 2.00 equiv) and ammonium chloride (198.24 mg, 3.71 mmol, 2.00 equiv). The reaction mixture was stirred at 70 °C for 3 h. Filtered, concentrated and extracted by EA (30.00 mL x 3). Then concentrated to affordproduct 4-amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide (420.00 mg, crude product) as an orange solid, which was gone to next step without further purification. [M+H]+=281.Synthesis of tert-butyl 4-(l-((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0386] To a solution of 4-amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide (420.00 mg, 1.49 mmol, 1.00 equiv), 2-{4-[(tert-butoxy)carbonyl]piperazin-l-yl}propanoic acid (503.18 mg, 1.95 mmol, 1.30 equiv) and pyridine (237.05 mg, 2.98 mmol, 2.00 equiv) in DMF (9.00 mL) stirred under nitrogen at 25 °C was added HATU (683.68 mg, 1.80 mmol, 1.20 equiv) portionwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O and extracted with EA. The combined organic layers were dried over Na₂SO₄, concentrated and purified by flash chromatography (DCM: MeOH =20: 1) to afford product tertbutyl 4-(l-((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (810.00 mg, 86.00%) as yellow oil. [M+H]+=521.Synthesis of Enantiomers of tert-butyl 4-(l-((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0387] Racemic tert-butyl 4-( 1 -((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carboxylate (100.00 mg) was purified by chiral separation (Column: IG, Column, 4.6mm*250mm 5um; Mobile Phase A: Hex, Mobile Phase B: EtOH (0.10% DEA); Flow rate: 1 mL / min; Gradient: 30% B to 70% B in 20 min; Wavelength: 254 nm.) to afford a first eluting (Enantiomer 1, 47.00 mg, 47.00%) and second eluting enantiomer (Enantiomer 2, 46.00 mg, 46.00%) as white solids. [M+H]+ =521. The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of Enantiomer 1 of N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)-2-(piperazin-l-yl)propan amide

[0388] To a solution of tert-butyl 4-(l-((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l -carboxylate Enantiomer 1 (47.00 mg, 0.09 mmol, 1.00 equiv) in DCM (2.50 mL) stirred in air was added a solution of HC1 in dioxane (1.00 mL, 4 N in dioxane) dropwise at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated to afford product Enantiomer 1 (58.00 mg, crude product) as a white solid, which was gone to next step without further purification. [M+H]+ =421.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)propanamide (Compound 44)

[0389] To a solution of N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide Enantiomer 1 (58.00 mg, 0.14 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21.20 mg, 0.14 mmol, 1.00 equiv) in n-BuOH (2.50 mL) stirred under nitrogen at 25 °C was added DIEA(71.34 mg, 0.56 mmol, 4.00 equiv). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated, then purified by Pre-HPLC (Column: RP-PREP-5 Xbridge C 18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.10% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 35% B to 65% B in 10 min; Wavelength: 254 nm) to afford the title compound (14.83 mg, 40%) as a white solid.[M+H]+=538. 'HNMR (400 MHz, DMSO-d6): 5 1.21 (d, J= 5.6 Hz, 3H), 2.58-2.70 (m, 4H), 3.35-3.39 (m, 1H), 3.78 (s, 3H), 3.89-3.91 (m, 4H), 6.59-6.60 (m, 1H), 7.16-7.18 (m, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 8.8 Hz, 2H), 8.12 (s, 1H), 8.27 (s, 2H), 10.23 (s, 1H), 11.39 (s, 1H), 11.70 (s, 1H).Synthesis of Enantiomer 2 of N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)-2-(piperazin-l-yl)propan amide

[0390] To a solution of tert-butyl-4-(l-((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l -carboxylate Enantiomer 2 (46.00 mg, 0.09 mmol, 1.00 equiv) in DCM (2.50 mL) stirred in air was added a solution of HC1 in dioxane (1.00 mL, 4 N in dioxane) dropwise at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated to afford product Enantiomer 2 (56.00 mg, crude product) as a white solid, which was gone to next step without further purification. [M+H]+ =421.Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)propanamide (Compound 45)

[0391] To a solution of N-(4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide Enantiomer 2 (40.00 mg, 0.09 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.48 mg, 0.10 mmol, 1.10 equiv) in n-BuOH (2.50 mL) stirred under nitrogen at 25 °C was added DIEA (49.16 mg, 0.36 mmol, 4.00 equiv). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated, then purified by Pre-HPLC (Column: RP-PREP-5 Xbridge C 18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.10% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 35% B to 65% B in 10 min; Wavelength: 254 nm) to afford the title compound (19.04 mg, 36%) as a white solid.[M+H]+=538. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J = 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.35-3.39 (m, 1H), 3.78 (s, 3H), 3.89-3.91 (m, 4H), 6.59-6.60 (m, 1H), 7.16-7.18 (m, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 8.8 Hz, 2H), 8.12 (s, 1H), 8.27 (s, 2H), 10.23 (s, 1H), 11.39 (s, 1H), 11.70 (s, 1H).Example 45. Synthesis of (R) and (S)- 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(4- (trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propenamide (Compounds 46 and 47)Synthesis of 4-nitro-N-(4-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide

[0392] To a solution of 4-(trifluoromethyl)pyrimidin-2-amine (950.00 mg, 5.82 mmol, 1.00 equiv) in DMF (10.00 mL) was added NaH (698.95 mg, 17.47 mmol, 3.0 equiv) at 0 °C and the mixture was stirred at 0 °C for 30 min. Next, the 4-nitrobenzenesulfonyl chloride (1.94 g, 8.74 mmol, 1.50 equiv) was added at 0 °C and the mixture was warmed to 25 °C, then stirred at 25 °C for 16 h. When the reaction finished, the mixture was diluted with water and extracted with EA. The combined organic layers were dried over NazSCfi, concentrated in vacuo to afford a residue. Then the residue was purified by silica gel column chromatography (eluting with PE: EA = 5:1~2:1) to afford 4-nitro-N-(4-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (1.35 g, 66.55%) as brown solid. [M-H+] =347.Synthesis of 4-amino-N-(4-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide

[0393] To a solution of 4-nitro-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzenesulfonamide (1.35 g, 3.90 mmol, 1.00 equiv) in EtOH (30.00 mL) was added Fe powder (0.65 g, 11.70 mmol, 3.00 equiv), NH4CI (0.63 g, 11.70 mmol, 3.00 equiv) and the mixture was stirred at 70 °C for 3 h. When the reaction finished, the mixture was filtered and the filtrate was concentrated in vacuo to afford a crude tert-butyl (3-(N, N-dimethylsulfamoyl)-4-fluorophenyl)carbamate (0.64 g, 51.28%) as yellow solid. [M+H]+=319.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid

[0394] To a solution of tert-butyl 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoate (Enantiomer 1) (250.00 mg, 0.75 mmol, 1.00 equiv) in dioxane (2 mL) was added HC1 (4 mL, 4 M in dioxane) at 0 °C and the mixture was stirred at 25 °C for 6 h. When the reaction finished, the mixture was concentrated in vacuo to afford a crude 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (160.00 mg, 96.30%) as white solid. [M+H]+=276.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(4-(trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propenamide (Compound 46)

[0395] To a solution of TCFH (570.76 mg, 2.03 mg, 3.50 equiv) in MeCN (5.00 mL) was added NMI (190.89 mg, 2.32 mmol, 4.00 equiv) at 0 °C and the mixture was stirred at 0 °C for 30 min, then the solution of 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (160.00 mg, 0.58 mmol, 1.00 equiv) and 4-amino-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzenesulfonamide (184.98 mg, 0.58 mmol, 1.00 equiv) in DMF (5 mL) was added, and the mixture was stirred at 25 °C for 24 h. The resulted solution was purified using Prep-HPLC with the following conditions: Column: RP-PREP-5 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 60% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (23.21 mg, 6.93%) as a white solid. ’H NMR (400 MHz, DMSO-6): 3 1.21 (d, J= 6.8 Hz, 3H), 2.60-2.70 (m, 4H), 3.35-3.40 (m, 1H), 3.91 (s, 4H), 6.61 (s, 1H), 7.17-7.18 (m, 1H), 7.48 (d, J= 4.0 Hz, 1H), 7.85 (d, J= 8.8 Hz, 2H), 7.94 (d, J =8.8 Hz, 2H), 8.13 (s, 1H), 8.84 (d, J= 4.8 Hz, 1H), 10.26 (s, 1H), 11.71 (s, 1H), 12.26 (s, 1H)Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid

[0396] To a solution of tert-butyl 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoate (Enantiomer 2) (250 mg, 0.75 mmol, 1.00 equiv) in dioxane (2 mL) was added HC1 (4 mL, 4 M in dioxane) at 0 °C and the mixture was stirred at 25 °C for 6 h. When the reaction finished, the mixture was concentrated in vacuo to afford a crude 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (170.00 mg) as white solid. [M+H]+=276.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(4-(trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propenamide (Compound 47)

[0397] To a solution of TCFH (581.46 mg, 2.03 mmol, 3.50 equiv) in MeCN (5.00 mL) was added NMI (194.47 mg, 2.36 mmol, 4.00 equiv) at 0 °C and the mixture was stirred at 0 °C for 30 min, then the solution of 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (163.00 mg, 0.59 mmol, 1.00 equiv) and 4-amino-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzenesulfonamide (188.45 mg, 0.59 mmol, 1.00 equiv) in DMF (5 mL) was added, and the mixture was stirred at 25 °C for 24 h. The resulted solution was purified using Prep-HPLC with the following conditions: Column: RP-PREP-5 Xbridge C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 60% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (19.81 mg, 5.81%) as a whitesolid.1H NMR δ 1.21 (d, J= 6.8 Hz, 3H), 2.60-2.70 (m, 4H), 3.35-3.40 (m, 1H), 3.90 (s, 4H), 6.60 (s, 1H), 7.17-7.18 (m, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.94 (d, J =8.8 Hz, 2H), 8.13 (s, 1H), 8.84 (d, J = 4.8 Hz, 1H), 10.26 (s, 1H), 11.70 (s, 1H), 12.26 (s, 1H).Example 46. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5- (trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propanamide (Compounds 48 and 49)Fe, NH4CI, EtOH / H2O, 70 °C, 3 hSynthesis of 4-nitro-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide

[0398] Sodium hydride (1312.54 mg, 32.81 mmol, 5.00 equiv.) was suspended in NMP (9.00 mL). At 0 °C, a solution of 5-(trifluoromethyl)pyrimidin-2-amine (1077.00 mg, 6.56 mmol, 1.00 equiv.) in NMP (3.00 mL) was added slowly dropwise. After stirring at room temperature for 30 minutes, it was again cooled to 0 °C before the slow dropwise addition of 4-nitrobenzenesulfonyl chloride (1890.74 mg, 8.53 mmol, 1.30 equiv.) in NMP (4.00 mL). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with NH4CI (30.00 mL) at 0 °C, then extracted with EA. The combined organic layers were dried over NazSCL, and concentrated. The reaction mixture was purified by flash by flash chromatography (PE: EA = 20:1) to afford product 4-nitro-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (1680.00 mg, 66.00% ) as a yellow solid, which was gone to next step without further purification. [M-H]+=347.Synthesis of 4-amino-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide

[0399] To a solution of 4-nitro-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (680.00 mg, 1.95 mmol, 1.00 equiv.) in EtOH / H2O (10.00 / 2.00 mL) stirred in air at 25 °C were added iron (218.11 mg, 3.90 mmol, 2.00 equiv.) and ammonium chloride (208.89 mg, 3.90 mmol, 2.00 equiv.). The reaction mixture was stirred at 70 °C for 3 h. Filtered, concentrated and extracted by EA (30.00 mL x 3). Then concentrated to afford product 4-amino-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (550.00 mg, crude product) as an orange solid, which was gone to next step without further purification. [M-H]+=317.Synthesis of Enantiomer 1-12-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid

[0400] To a solution of Enantiomer 1 of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (50.00 mg, 0.15 mmol, 1.00 equiv.) in HC1 in dioxane (3.60 mL, 4 N in dioxane) stirred in air at 25 °C. The reaction mixture was stirred at 25 °C for 6 h. The reaction was concentrated to afford product Enantiomer 1 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (58.00 mg, crude product) as a white solid, which was gone to next step without further purification. [M+H]+= l.Synthesis of enantiomer of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5-(trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propenamide (Compound 48)

[0401] To a solution of 4-amino-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (59.00 mg, 0.18 mmol, 1.00 equiv.), Enantiomer 1 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (50.88 mg, 0.18 mmol, 1.00 equiv.) and pyridine (58.47 mg, 0.74 mmol, 4.00 equiv.) in DCE (2.50 mL) stirred under nitrogen at 25 °C was added T3P (176.40 mg, 0.54 mmol, 50% in EA, 3.00 equiv.) portionwise. The reaction mixture was stirred at 60 °C for 16 h. Concentrated, the reaction residue was purified by Pre-HPLC (Column: RP-PREP-5 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.10% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 35% B to 65% B in 10 min; Wavelength: 254 nm) to afford the title product (6.08 mg, 5.00%) as a white solid. [M+H]+=576. 'HNMR (400 MHz, DMSO-de): 5 1.21 (d, J= 6.8 Hz, 3H), 2.50-2.70 (m, 4H), 3.36-3.40 (m, 1H), 3.89-3.94 (m, 4H), 6.59-6.60 (m, 1H), 7.16-7.18 (m, 1H), 7.85 (d, J= 8.8 Hz, 2H), 7.93 (d, J= 8.8 Hz, 2H), 8.12 (s, 1H), 8.90 (s, 2H), 10.27 (s, 1H), 11.70 (s, 1H), 12.36 (s, 1H).Synthesis of Enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid

[0402] To a solution of Enantiomer 2 tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (140.00 mg, 0.42 mmol, 1.00 equiv.) in HC1 in dioxane (5.60 mL, 4 N in dioxane) stirred in air at 25 °C. The reaction mixture was stirred at 25 °C for 6 h. The reaction was concentrated to afford product Enantiomer 2 (182.00 mg, crude product) as a white solid, which was gone to next step without further purification. [M+H]+= l.Synthesis of enantiomer of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(5-(trifluoromethyl)pyrimidin-2-yl)sulfamoyl)phenyl)propanamide (Compound 49)

[0403] To a solution of 4-amino-N-(5-(trifluoromethyl)pyrimidin-2-yl)benzenesulfonamide (100.00 mg, 0.31 mmol, 1.00 equiv.), Enantiomer 2 (103.47 mg, 0.37 mmol, 1.20 equiv.) and pyridine (161.91mg, 1.24 mmol, 4.00 equiv.) in DCE (3.60 mL) stirred under nitrogen at 25 °C was added T3P (357.26 mg, 0.93 mmol, 50% in EA, 3.00 equiv.) portionwise. The reaction mixture was stirred at 60 °C for 16 h. Concentrated, the reaction residue was purified by Pre-HPLC (Column: RP-PREP-5 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 35% B to 65% B in 10 min; Wavelength: 254 run) to afford the title product (15.74 mg, 6.00%) as a white solid. [M+H]+=576. 'HNMR (400 MHz, DMSO-d6): 5 1.21 (d, J= 6.8 Hz, 3H), 2.60-2.70 (m, 4H), 3.35-3.40 (m, 1H), 3.86-3.93 (m, 4H), 6.57-6.59 (m, 1H), 7.16-7.17 (m, 1H), 7.85 (d, J= 8.8 Hz, 2H), 7.93 (d, J= 8.8 Hz, 2H), 8.12 (s, 1H), 8.90 (s, 2H), 10.25 (s, 1H), 11.68 (s, 1H), 12.34 (s, 1H).Example 47. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)propenamide (Compounds 50 and 51)Synthesis of tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-5-fhiorophenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0404] To a solution of 3-bromo-5-fluoro-N, N-dimethylbenzenesulfonamide (200 mg, 0.71 mmol, 1.00 equiv), tert-butyl 4-(l -amino- l-oxopropan-2-yl)piperazine-l -carboxylate (182.42 mg, 0.71 mmol, 1.00 equiv) and CS2CO3 (461.95 mg, 1.42 mmol, 1.00 equiv) in dioxane (5 mL) stirred under nitrogen at 25°C was added Pd2(dba)3 (64.92 mg, 0.07 mmol, 0.10 equiv)and Xantphos (82.04 mg, 0.14 mmol, 0.20 equiv). The reaction mixture was stirred at 100°C for 18h. The reaction mixture was stirred at 100°C for 18h. The mixture was concentrated and the resulted solution was purified by flash chromatography (ACN / H2O = 3:1). This resultedin tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (296.00 mg, yield 91%) as yellow solid. [M+H]+=459.Synthesis of N-(3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)-2-(piperazin-l-yl)propenamide (TFA salt)

[0405] The solution of tert-butyl 4-(l-((3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (198.00 mg, 0.43 mmol, 1.00 equiv) in TFA / DCM (5 mL) was stirred at 25°C for Ih. The mixture was concentrated. This resulted in N-(3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)-2-(piperazin-l-yl)propanamide (213.00 mg, yield >100%) as yellow oil. [M+H]+=359.Synthesis of enantiomers of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)propan amide

[0406] To a solution of N-(3-(N, N-dimethylsulfamoyl)-5-fluorophenyl)-2-(piperazin-l-yl)propanamide (213.00 mg, 0.59 mmol, 1.00 equiv), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (91.27 mg, 0.59 mmol, 1.00 equiv) in n-BuOH (5 mL) stirred at 25 °C was added DIEA (153.61 mg, 1.19 mmol, 2.00 equiv). The reaction mixture was stirred at 100°C for 18h. The mixture was concentrated and the resulted solution was purified using Chiral Prep-HPLC and Prep-HPLC with the following conditions: Xbridge C185um 19* 150mm 16min-15-60% B, A: H2O (0.1% NH4HCO3), B: ACN, UV:214nm, Flowrate 15ml / min, GT10MIN. This resulted in racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- 1 -yl)-N -(3 -(N, N -dimethylsulfamoyl)-5 -fluorophenyl)propenamide (90 mg), which was separated by chiral-HPLC to give two enantiomers. The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Enantiomer 1 (first eluting, Compound 50): 39.40 mg, yield 14% as white solid. [M+H]+= 476. ’H NMR (400 MHz, DMSO-d6): 5 1.23 (d, J= 6.8 Hz, 3H), 2.57-2.75 (m, 10H), 3.35-3.41 (m, IH), 3.87-3.98 (m, 4H), 6.59-6.64 (m, IH), 7.15-7.29 (m, 2H), 7.92-8.02 (m, 2H), 8.14 (s, IH), 10.44 (s, IH), 11.71 (s, IH).Enantiomer 2 (Compound 51): 32.2 mg, yield 11% as a white solid. [M+H]+= 476. ’H NMR (400 MHz, DMSO-d6): 5 1.23 (d, J= 6.8 Hz, 3H), 2.57-2.75 (m, 10H), 3.35-3.41 (m, IH), 3.87-3.98 (m, 4H), 6.59-6.64 (m, IH), 7.15-7.29 (m, 2H), 7.92-8.02 (m, 2H), 8.14 (s, IH), 10.44 (s, IH), 11.71 (s, IH).Example 48. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-(N-methylsulfamoyl)phenyl)propanamide (Compounds 52 and 53)Synthesis of tert-butyl 4-(l-((3-chloro-5-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0407] To a solution of 3-bromo-5-chloro-N-methylbenzenesulfonamide (400.00 mg, 1.41 mmol, 1.00 equiv), tert-butyl 4-(l -amino- l-oxopropan-2-yl)piperazine-l -carboxylate (361.71 mg, 1.41 mmol, 1.00 equiv) and cesium carbonate (1374.02 mg, 4.21 mmol, 3.00 equiv) in 1,4-dioxane stirred under nitrogen was added a solution of Pd2(dba)3(64.36 mg, 0.07 mmol, 0.05 equiv) and Xantphos (81.34 mg, 0.14 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C for 16h. The mixture was concentrated, and the residue was purified by silica gel chromatography (100% EA). This resulted in tert-butyl 4-(l-((3-chloro-5-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate (333.00 mg, 51.38%) as off-white solid. [M+H-56]+=404.8.Synthesis of N-(3-chloro-5-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1 salt)

[0408] To a solution of tert-butyl 4-(l-((3-chloro-5-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (145.00 mg, 0.31 mmol, 1.00 equiv) in 5 mL of DCM was added 2 mL of HC1 (4M in 1,4-dioxane). The mixture was stirred at room temperature for 3h. The mixture was concentrated to get the N-(3-chloro-5-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1 salt) (145.00 mg, >100%) as white solid. [M+H]+=361.2.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-(N-methylsulfamoyl)phenyl)propanamide

[0409] To a solution of N-(3-chloro-5-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1 salt) (145.00 mg, 0.40 mmol, 1.00 equiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (61.27 mg, 0.40 mmol, 1.00 equiv) in 1-butanol (5 mL) was added DIEA (154.71 mg, 1.20 mmol, 3.00 equiv). The mixture was stirred at 100°C for 16 h. The mixture was concentrated, and the residue was purified by silica gel chromatography(DCM: MeOH=10:l). This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-(N-methylsulfamoyl)phenyl)propanamide (136.00 mg, 71.20%) as off-white solid. [M+H]+=478.2.Chiral separation

[0410] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-chloro-5-(N-methylsulfamoyl)phenyl)propanamide (136.00 mg) was separated by chiral HPLC to get two enantiomers (15.00 mg Enantiomer 1, first eluting, Compound 52) and 13.00 mg Enantiomer 2 (second eluyting, Compound 53). Compound 52: [M+H]+=478.0.1H NMR (400 MHz, DMSO-d6): δ 1.23 (d, J= 7.2 Hz, 3H), 2.45 (s, 3H), 2.60-2.70 (m, 4H), 3.34-3.38 (m, 1H), 3.93 (t, J= 4.4 Hz, 4H), 6.61-6.62 (m, 1H), 7.18 (t, J= 2.8 Hz, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 8.09-8.14 (m, 3H), 10.39 (s, 1H), 11.70 (s, 1H). Compound 53: [M+H]+=478.0.1H NMR (400 MHz, DMSO-d6): 5 1.23 (d, J= 6.8 Hz, 3H), 2.45 (s, 3H), 2.60-2.70 (m, 4H), 3.34-3.38 (m, 1H), 3.93 (t, J= 4.4 Hz, 4H), 6.61-6.62 (m, 1H), 7.18-7.19 (m, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 8.09-8.14 (m, 3H), 10.39 (s, 1H), 11.71 (s, 1H).Example 49. Synthesis of an enantiomer of 2-(4-(7H-pyrrolo|2.3-d|pyrimidin-4-yl)piperazin-l-yl)-N-(4-chloro-3-(N-methylsulfamoyl)phenyl)propanamide (Compound 54)chiral separation CS2CO3, dioxane, 100°C, 16 hBoc Enantiomer 1HCI / dioxaneSynthesis of tert-butyl 4-(l-((4-chloro-3-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate

[0411] To a solution of 5-bromo-2-chloro-N-methylbenzenesulfonamide (500.00 mg, 1.76 mmol, 1.00 equiv), tert-butyl 4-(l -amino- l-oxopropan-2-yl)piperazine-l -carboxylate (498.00 mg, 1.93 mmol, 1.10 equiv) and CS2CO3 (1145.00 mg, 3.51 mmol, 2.00 equiv) in dioxane (20 mL) stirred under nitrogen at 25°C was added Xantphos (203.00 mg, 0.35 mmol) and PdifdbaF (161.00 mg, 0.17 mmol). The reaction mixture was stirred at 100°C for 16 h under N2. LCMS showed the desired mass was found. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (EA / PE=l / l~l / 0) to give the product tert-butyl 4-(l-((4-chloro-3-(N-methylsulfamoyl)phenyl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carboxylate (420.00 mg, 45%) as yellow solid. [M+H]+= 461. Then in total 420 mg of racemic tert-butyl 4-(l-((4-chloro-3-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine-l-carboxylate was separated into two enantiomers (Enantiomer 1, first eluting: 197.00 mg and Enantiomer 2, second eluting: 188.00 mg). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of N-(4-chloro-3-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1)

[0412] To a solution of tert-butyl 4-(l-((4-chloro-3-(N-methylsulfamoyl)phenyl)amino)-l-oxopropan-2-yl)piperazine- 1 -carboxylate (Enantiomer 2) (82.00 mg, 0.18 mmol, l. OOequiv) in DCM (4 mL) at 0°C was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at 30°C for 1 h. LCMS showed the reaction was finished. The mixture was concentrated in vacuo to give the crude N-(4-chloro-3-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1) (75.00 mg, 99%) as yellow oil, which was used to next step directly. [M+H]+= 361.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-chloro-3-(N-methylsulfamoyl)phenyl)propanamide (Compound 54)

[0413] To a solution of N-(4-chloro-3-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)propanamide (HC1) (75.00 mg, 0.20 mmol, l. OOequiv) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (32.00 mg, 0.21 mmol, l. OOequiv) in n-BuOH (6 mL) was added DIEA (134.00 mg, 1.04 mmol, 5.00equiv). The reaction mixture was stirred at 95°C for 16 h. LCMS showed the desired mass was found. The mixture was concentrated in vacuo. The resulted residue was purified using Prep-HPLC with the following conditions: Column: RP -PREP- 11 Xbridge C18 Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 55% B in 10 min; Wavelength: 214 nm. This resulted in the title compound (32.00 mg, 31.57%) as a white solid. [M+H]+= 478.1H NMR (400 MHz, DMSO-d6): δ 1.23 (d, J = 6.8 Hz, 3H), 2.48 (s, 3H), 2.60-2.71 (m, 4H), 3.33-3.36 (m, 1H), 3.90-3.92 (m, 4H), 6.61 (s, 1H), 7.17 (s, 1H), 7.58-7.66 (m, 2H), 7.94-7.97 (m, 1H), 8.13 (s, 1H), 8.36 (s, 1H), 10.31 (s, 1H), 11.70 (s, 1H).Example 50. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (Compounds 55 and 56)Synthesis of ethyl 2-bromo-4,4,4-trifluorobutanoate

[0414] To a solution of ethyl 4,4,4-trifluorobutanoate (3.40 g, 20.0 mmol) in THF (100 mL) stirred under nitrogen at -50°C was added a solution of LiHMDS (12.00 mL, 24.00 mmol) in THF (12 mL). The reaction mixture was stirred at -50°C for Ih. Then added N-Bromosuccinimide (4.27 g, 24.00 mmol) at -50°C and stirred at 25 °C for 3h. Saturated aqueous HC1 (100 mL) was added. The residue was extracted with EA (3 x 100 mL). Solvent was dried over sodium sulphate and and evaporated in vacuo to give the product ethyl 2-bromo-4,4,4-trifluorobutanoate (4.50 g, 20% purity) as light-yellow oil. [M+H]+=249.Synthesis of benzyl 4-(l-ethoxy-4,4,4-trifhioro-l-oxobutan-2-yl)piperazine-l-carboxylate

[0415] To a solution of ethyl 2-bromo-4,4,4-trifluorobutanoate (4.50 g, 18.10 mmol) and benzyl piperazine-1-carboxylate (3.99 g, 18.10 mmol) in THF (100 mL) stirred under nitrogen at 30°C was added DIEA (4.68 g, 36.20 mmol). The reaction mixture was stirred at 30°C for 16h. Saturated aqueous H2O (100 mL) was added. The residue was extracted with EA (3 x 100 mL). Solvent was dried over sodium sulphateand evaporated in vacuo to give the crude product. The crude material was added to a silica gel column and was eluted with PE / EA (2:1) to give the product benzyl 4-(l -ethoxy-4, 4, 4-trifluoro-l-oxobutan-2-yl)piperazine-l -carboxylate (400.00 mg, 80% purity, 4.6% yield) as yellow oil. [M+H]+=389.Synthesis of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid

[0416] To a solution of benzyl 4-(l -ethoxy-4, 4, 4-trifluoro-l-oxobutan-2-yl)piperazine-l -carboxylate (200.00 mg, 0.52 mmol) in MeOH / H2O=4: 1 (10 mL) stirred under nitrogen at 30°C was added LiOH (14.80 mg, 0.62 mmol). The reaction mixture was stirred at 30°C for 16h. The reaction mixture was concentrated under pressure50°C to give the product 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid (180.00 mg, 95% purity, 92.2% yield) as off-yellow solid. [M+H]+=361.Synthesis of benzyl 4-(4,4,4-trifluoro-l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxobutan-2-yl)piperazine-l-carboxylate

[0417] To a solution of 2-(4-((benzyloxy)carbonyl)piperazin-l-yl)-4,4,4-trifluorobutanoic acid (180.00 mg, 0.50 mmol), 4-amino-2-fluoro-N-methylbenzenesulfonamide (102.01 mg, 0.50 mmol) and DIEA (129.11 mg, 1.00 mmol) in DCM (20 mL) stirred under nitrogen at 30°C was added HATU (284.89 mg, 0.75 mmol). The reaction mixture was stirred at 30°C for 16h. The reaction mixture was concentrated under pressure 45°C. The residue was purified via Flash Chromatography and was eluted with ACN / H2O (Ratios:4:6; Pressure:2 bar) and to give the product benzyl 4-(4,4,4-trifluoro-l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxobutan-2-yl)piperazine-l-carboxylate (68.00 mg, 95% purity, 23.7% yield) as light-yellow solid. [M+H]+=547.Synthesis of 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butanamide

[0418] To a solution of benzyl 4-(4,4,4-trifluoro-l-((3-fluoro-4-(N-methylsulfamoyl)phenyl)amino)-l-oxobutan-2-yl)piperazine-l-carboxylate (68.00 mg, 0.12 mmol) in i-PrOH (10 mL) stirred under H2 at 30°C was added Pd / C (52.95 mg, 0.025 mmol). The reaction mixture was stirred at 30°C for 16h. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure 60°C to give the product 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butanamide (50.00 mg, 95% purity, 92.6% yield) as light-yellow oil. [M+H]+=413.Synthesis of 2-(4-(7H-pyrr olo [2, 3-d] pyrimidin-4-yl)piperazin- l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (Compounds 55 and 56)

[0419] To a solution of 4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)-2-(piperazin-l-yl)butanamide (50.00 mg, 0.12 mmol) and 4-chloro-7H-pyrrolo[2,3- d]pyrimidine (18.61 mg, 0.12 mmol) in n-BuOH (10 mL) stirred under nitrogen at 30°C was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (18.61 mg, 0.12 mmol). The reaction mixture was stirred at 90°C for 16h. The reaction mixture was concentrated under pressure 70°C. The residue was purified via Genal-Prep-HPLC with the following conditions: Column: Prep-11 Xbrige C185um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 60% B in 16 min; Wavelength: 214 nm. This resulted in 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (31.00 mg, 95% purity, 45.9% yield) as white solid.Chiral separation

[0420] Racemic 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-4,4,4-trifluoro-N-(3-fluoro-4-(N-methylsulfamoyl)phenyl)butanamide (31.00 mg) was separated by chiral HPLC to get two enantiomers (Enantiomer 1: first eluting, 7.10 mg, Compound 55; and Enantiomer 2: second eluting, 7.20 mg,Compound 56). Compound 55: [M+H]+=530. 'HNMR (400 MHz, DMSO-6): 52.44-2.45 (d, J= 4.0 Hz, 3H), 2.67-2.78 (m, 3H), 2.89-2.94 (m, 3H), 3.74-3. 82 (m, 4H), 3.93-3.99 (m, IH), 6.58 (s, IH), 7.17 (s, IH), 7.40-7.42 (d, J= 8.4 Hz, IH), 7.55-7.56 (m, IH), 7.69-7.78 (m, 2H), 8.12 (s, IH), 10.66 (s, IH), 11.68 (s, IH).Compound 56: [M+H]+=530. 'HNMR (400 MHz, DMSO-6): 52.45 (d, J= 2.8 Hz, 3H), 2.67-2.78 (m, 3H), 2.89-2.94 (m, 3H), 3.75-3. 82 (m, 4H), 3.93-3.99 (m, IH), 6.58 (s, IH), 7.17 (s, IH), 7.39-7.41 (d, J= 8.4 Hz, IH), 7.55-7.56 (m, IH), 7.69-7.78 (m, 2H), 8.12 (s, IH), 10.65 (s, IH), 11.68 (s, IH).Example 51. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fhioro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compounds 57 and 58)F o H F ov. S >1 ^1 Zn THF, LiHMDS,-50°C £ Y 'b AcOH / Water / THF O2NX^^ 60°C,4h H2NSynthesis of 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide

[0421] To a solution of pyridin-2-amine (1001.59 mg, 10.64 mmol) in THF (30 mL) stirred under nitrogen at -50°C was added a solution of LiHMDS (10.60 mL, 10.64 mmol). The reaction mixture was stirred at -50°C for Ih. Then added 2-fluoro-4-nitrobenzene sulfonyl chloride at -50°C for 2h. Saturated aqueous HC1 (20 mL) was added. The residue was extracted with EA (3 x 30 mL). Solvent was dried over sodium sulphateand evaporated in vacuo to give the crude product 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide (1200.00 mg, 30% purity) as light-yellow oil. [M+H]+=298.Synthesis of 4-amino-2-fhioro-N-(pyridin-2-yl)benzenesulfonamide

[0422] To a solution of 2-fluoro-4-nitro-N-(pyridin-2-yl)benzenesulfonamide (900.00 mg, 3.03 mmol) and AcOH (1818.13 mg, 30.30 mmol) in THF / H2O=1:1 (30 mL) stirred under nitrogen at 30°C was added Zn (1969.52 mg, 30.30 mmol). The reaction mixture was stirred at 80°C for 2h. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure 70°C. The residue was purified via Flash Chromatography and was eluted with ACN / H2O (Ratios: 2:8; Pressure: 2.5 bar) and to give the product 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (140.00 mg, 95% purity, 16.4% yield) as light-yellow oil. [M+H]+=268.Synthesis of enantiomer 1 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0423] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 1: 72.00 mg, 0.22 mmol) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (Pl: 60.00 mg, yield: >95%, 91.8% purity, white solid). LCMS: [M+H]+=276.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 57)

[0424] To a solution of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (Pl) (60 mg, 0.22 mmol), 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (58.24 mg, 0.22 mmol) and pyridine (103.42 mg, 1.31 mmol) in DCE (20 mL) stirred under nitrogen at 25°C was added T3P in EA (693.31 mg, 2.20 mmol). The reaction mixture was stirred at 60°C for 16h. The reaction mixture was concentrated under pressure 60°C. The residue was purified via Genal-Prep-HPLC with the following conditions: Column: Prep-11 Xbrige C185um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (25.00 mg, 95% purity) as white solid. [M+H]+=525. 'HNMR (400 MHz, DMS0-< ): 5 1.19-1.21 (d, J= 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.36-3.38 (m, 1H), 3.89-3.91 (m, 4H), 6.59 (s, 1H), 6.81-6.84 (m, 1H), 7.14-7.18 (m, 2H), 7.53-7.56 (m, 1H), 7.71-7.75 (m, 2H), 7.83-7.87 (t, J= 8.4 Hz, 1H), 7.92-7.94 (d, J= 5.2 Hz, 1H), 8.13 (s, 1H), 10.33 (s, 1H), 11.70 (s, 1H), 12.59 (s, 1H).Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0425] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 2: 193.00 mg, 0.59 mmol) in dioxane (6 mL) was added HCl / dioxane (6 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (P2: 163.12 mg, yield: >95%, 92.1% purity, white solid). LCMS: [M+H]+=276.Synthesis of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(3-fluoro-4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 58)

[0426] To a solution of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (P2) (163.12 mg, 0.59 mmol), 4-amino-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (95.00 mg, 0.59 mmol) and pyridine (279.66 mg, 3.54 mmol) in DCE (20 mL) stirred under nitrogen at 25°C was added T3P in EA (1859.31 mg, 5.90 mmol). The reaction mixture was stirred at 60°C for 16h. The reaction mixture was concentrated under pressure 60°C. The residue was purified via Genal-Prep-HPLC with the following conditions: Column: Prep-11 Xbrige C185um 19* 150mm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 15% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (20.00 mg, 95% purity) as white solid. [M+H]+=525. 'HNMR (400 MHz, DMSO-6): 5 1.19-1.21 (d, J= 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.36-3.38 (m, 1H), 3.89-3.91 (m, 4H), 6.59 (s, 1H), 6.81-6.84 (m, 1H), 7.14-7.18 (m, 2H), 7.53-7.56 (m, 1H), 7.71-7.75 (m, 2H), 7.83-7.87 (t, J= 8.4 Hz, 1H), 7.92-7.94 (d, J= 5.2 Hz, 1H), 8.13 (s, 1H), 10.33 (s, 1H), 11.70 (s, 1H), 12.58 (s, 1H).Example 52. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N- (pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compounds 59 and 60)Enantiomer 1 Enantiomer 2Synthesis of 4-nitro-N-(pyridin-2-yl)benzenesulfonamide

[0427] A solution of pyridin-2-amine (1.50 g, 15.90 mmol, 1.00 equiv) in DCM (10 mL) was cooled to 0°C.4-nitrobenzenesulfonyl chloride (3.52 g, 15.90 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise and the mixture was stirred at 25°C for 4h. The crude material was added to a silica gel column and was elutedwith PE / EtOAc (2:1). The mixture was concentrated under reduced pressure to get the product 4-nitro-N-(pyridin-2-yl)benzenesulfonamide (1.70 g, 90% purity, 58.60% yield, off-brown solid). LCMS: [M+H]+=280.Synthesis of 4-amino-N-(pyridin-2-yl)benzenesulfonamide

[0428] To a solution of 4-nitro-N-(pyridin-2-yl)benzenesulfonamide (1.70 g, 6.10 mmol, 1.00 equiv) in EtOH / H2O=1:1 (5 mL) was added Fe (2.04 g, 36.60 mmol, 6.00 equiv) and NH4CI (1.96 g, 36.60 mmol, 6.00 equiv), stirred at 80°C for Ih. The organic phase was washed with water (5 mL). The reaction mixture was concentrated under pressure 50°C. The crude material was added to a silica gel column and was eluted with PE / EtOAc (1:1). The reaction mixture was concentrated under reduced pressure to get the product 4-amino-N-(pyridin-2-yl)benzenesulfonamide (1.05 g, 90 % purity, 62.30 %, yield, brown solid). LCMS: [M+H]+=250.Synthesis of tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate

[0429] To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.63 g, 49.70 mmol, 1.00 equiv) in n-BuOH (30 mL) was added tert-butyl piperazine- 1 -carboxylate (9.31 g, 49.70 mmol, 1.00 equiv) and DIEA (19.27 g, 149.10 mmol, 3.00 equiv), stirred at 90°C for 16h. The reaction mixture was concentrated under pressure 50°C. The crude material was added to a silica gel column and was eluted with PE / EtOAc (2: 1) to get the product tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate (12.79 g, 90% purity, 76.06% yield, white solid). LCMS: [M+H]+=304.Synthesis of 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0430] To a solution of tert-butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-l-carboxylate (6.00 g, 19.70 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added 1,4-dioxane / HCl (15 mL), stirred at 25 °C for 5h. The reaction mixture was concentrated under pressure 50°C to get the product 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine (6.03 g, 90% purity, 88.32% yield, white solid). LCMS: [M+H]+=204.Synthesis of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate

[0431] To a solution of 4-(piperazin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.00 g, 13.10 mmol, 1.00 equiv) in DMF (30 mL) was added tert-butyl 2-bromopropanoate (2.74 g, 13.10 mmol, 1.00 equiv), K2CO3 (3.62 g, 26.20 mmol, 2.00 equiv) and KI (2.17 g, 13.10 mmol, 1.00 equiv), stirred at 50°C for 16h. The residue was extracted with EA (10 x 3 mL). The solution was filtered, filtrate was collected. The reaction mixture was concentrated and the residue was triturated with PE (5 mL) to give the product tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (3.50 g, 95% purity, 76.34% yield, white solid). LCMS:[M+H]+=332.Chiral separation

[0432] Racemic tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (3.40 g) was separated by chiral HPLC to get two enantiomers (1.60 g first eluting, El and 1.60 g second eluting, E2). The absolute configurations were not determined, and stereochemistry of the enantiomers was arbitrarily assigned.Synthesis of enantiomer 1 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1Salt)

[0433] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 1: 90.00 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (1: 89.00 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Synthesis of enantiomer 1 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 59)

[0434] To a solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (50.00 mg, 0.20 mmol, 1.00 equiv) in DCE (5 mL) was added Pl: 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l- yl)propanoic acid (HC1 salt, 69.85 mg, 0.20 mmol, 1.00 equiv), T3P in EA (255.31 mg, 0.80 mmol, 4.00 equiv) and pyridine (79.34 mg, 1.00 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 20% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (26.00 mg, 25.32% yield, white solid). LCMS: [M+H]+=507.1.1H NMR (400 MHz, DMSO-d6): 5 1.21 (d, J = 6.8 Hz, 3H), 2.57-2.70 (m, 4H), 3.36 (s, 1H), 3.89-3.91 (m, 4H), 6.60 (d, J= 2 Hz, 1H), 6.868 (t, J= 5.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.68-7.72 (m, 1H), 7.79-7.84 (m, 4H), 8.01 (s, 1H), 8.13 (s, 1H), 10.19 (s, 1H), 11.70 (s, 1H).Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0435] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 2: 90.00 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (90.00 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)propanamide (Compound 60)

[0436] To a solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (60.00 mg, 0.24 mmol, 1.00 equiv) in DCE (5 mL) was added Pl: 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l- yl)propanoic acid (HC1 salt, 83.82 mg, 0.24 mmol, 1.00 equiv), T3P in EA (306.34 mg, 0.96 mmol, 4.00equiv) and pyridine (95.20 mg, 1.20 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15mL / min; Gradient: 10% B to 50% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (9.40 mg, 7.31% yield, white solid). LCMS: [M+H]+=507.1. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J= 7.2 Hz, 3H), 2.59-2.68 (m, 4H), 3.34-3.36(m, 1H), 3.89-3.91 (m, 4H), 6.60-6.61 (m, 1H), 6.83 (t, J= 5.6 Hz, 1H), 7.11-7.18 (m, 2H), 7.65-7.70 (m, 1H), 7.76 (d, J= 7.2 Hz, 4H), 8.03 (s, 1H), 8.13 (s, 1H), 10.19 (s, 1H), 11.70 (s, 1H).Example 53. Synthesis of (R) and (S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyrimidin-5-yl)sulfamoyl)phenyl)propanamide (Compounds 61 and 62)Fe, NH4Cl EtOH / H2O, 80°C,1hSynthesis of 4-nitro-N-(pyrimidin-5-yl)benzenesulfonamide

[0437] A solution of pyrimidin-5 -amine (1.00 g, 10.50 mmol, 1.00 equiv) and DIEA (2.71 g, 21.00 mmol, 2.00 equiv) in DCM (10 mL) was cooled to 0°C. 4-nitrobenzenesulfonyl chloride (2.33 g, 10.50 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise and the mixture was stirred at 25 °C for 4h. The crude material was added to a silica gel column and was eluted with PE / EtOAc (2: 1). The mixture was concentrated under reducedpressure to get the product 4-nitro-N-(pyrimidin-5-yl)benzenesulfonamide (0.85 g, 90% purity, 25.71% yield, brown solid). LCMS: [M+H]+= 281.Synthesis of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide

[0438] To a solution of 4-nitro-N-(pyrimidin-5-yl)benzenesulfonamide (850.00 mg, 3.03 mmol, 1.00 equiv) in EtOH / H2O=1:1 (5 mL) was added Fe (846.94 mg, 15.15 mmol, 5.00 equiv) and NH4Cl (811.15 mg, 15.15 mmol, 5.00 equiv), stirred at 80°C for Ih. The organic phase was washed with water (5 mL). The reaction mixture was concentrated under pressure 50°C. The crude material was added to a silica gel column and was eluted with PE / EtOAc (1:1). The reaction mixture was concentrated under reduced pressure to get the product 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (263.00 mg, 90% purity, 31.18% yield, brown solid). LCMS:[M+H]+=251.Synthesis of enantiomer 1 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0439] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 1: 90.00 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (Pl: 86.00 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Synthesis of enantiomer 1 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyrimidin- 5-yl)sulfamoyl)phenyl)propanamide (Compound 61)

[0440] To a solution of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (60.00 mg, 0.24 mmol, 1.00 equiv) in DCE (5 mL) was added Pl: 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l- yl)propanoic acid (HC1 salt, 83.47 mg, 0.24 mmol, 1.00 equiv), T3P in EA (305.07 mg, 0.96 mmol, 4.00 equiv) and pyridine (94.80 mg, 1.20 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19* 150 mm, 5 pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 15 mL / min; Gradient: 10% B to 45% B in 16 min; Wavelength: 214 nm. This resulted in the title compound (2.44 mg, 2.00% yield, white solid). LCMS: [M+H]+=508.1. ‘H NMR (400 MHz, DMSO-d6): 5 1.21 (d, J = 6.8 Hz, 3H), 2.58-2.69 (m, 4H), 3.49-3.58(m, IH), 3.90 (t, J= 4.4 Hz, 4H), 6.61(s, IH), 7.17 (s, IH), 7.73 (d J= 8.8 Hz, 2H), 7.82 (d, J= 8.8 Hz, 2H), 8.13 (s, IH), 8.44 (s, 2H), 8.77 (s, IH), 10.24 (s, IH), 11.70 (s, IH).Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt)

[0441] To a stirred solution of tert-butyl 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoate (Enantiomer 2: 90.00 mg, 0.27 mmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (3 mL). The mixture was continuously stirred under 25°C for 3h. The reaction mixture was concentrated to give the product2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)propanoic acid (HC1 Salt) (90.00 mg, yield: >95%, 90% purity, white solid). LCMS: [M+H]+=276.Synthesis of enantiomer 2 of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-l-yl)-N-(4-(N-(pyrimidin-5-yl)sulfamoyl)phenyl)propanamide (Compound 62)

[0442] To a solution of 4-amino-N-(pyrimidin-5-yl)benzenesulfonamide (64.00 mg, 0.26 mmol, 1.00 equiv) in DCE (5 ml) was added P2: 2-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperazin-l-yl)propanoic acid (HC1 salt, 89.00 mg, 0.26 mmol, 1.00 equiv), T3P in EA (325.43 mg, 1.02 mmol, 4.00 equiv) and pyridine (101.13 mg, 1.28 mmol, 5.00 equiv), stirred at 60°C for 16h. The mixture was concentrated under reduced pressure. The resulted solution was purified using Prep-HPLC with the following conditions: Column: XBridge Prep C18 Column, 19* 150 mm, 5 ...

Claims

1. CLAIMS2.What is claimed is:

1. A compound having a structure according to Formula (I):

5. 7.wherein:8.R1is H or CH3;9.R2 is H, C1-C4 alkyl, C3-C5 cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3; or10.R1and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O;11.R3is independently selected for each occurrence from the group consisting of F, Cl, -OCH3, CH3and -CF3;12.R4is H, CH3, -CH2CH3, -CH2CF3, cyclopropyl, or -CH2OCH3;13.Z is N or CH; and14.x is 0, 1 or 2.

2. The compound of claim 1, wherein Ri is H.

3. The compound of claim 1, wherein Ri is CH3.

4. The compound of any one of claims 1-3, wherein R2 is selected from the group consisting of C1-C4 alkyl, C3-C5 cycloalkyl, -CH2CH2OCH3, phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl, wherein said phenyl, 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, and 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

5. The compound of claim 2 or 3, wherein R2 is C1-C4 alkyl.

6. The compound of claim 1, wherein Ri and R2 are each CH3.

7. The compound of claim 2 or 3, wherein R2 is C3-C5 cycloalkyl.

8. The compound of claim 2 or 3, wherein R2is 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl, wherein said 2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 5-pyrimidinyl is optionally substituted with one or more substituents selected from the group consisting of F, -CH3, -CF3, and -OCH3.

9. The compound of any one of claims 1-3, wherein Ri and R2, together with the included N atom, form a 4-, 5- or 6-membered ring, wherein said 6-membered ring optionally includes one additional heteroatom selected from N and O.

10. The compound of any one of claims 1-9, wherein R4 is H.

11. The compound of any one of claims 1-9, wherein R4 is CH3.

12. The compound of any one of claims 1-9, wherein R4 is CH2OCH3.

13. The compound of any one of claims 1-9, wherein R4 is CH2CF3.

14. The compound of any one of claims 1-13, wherein Z is CH.

15. The compound of any one of claims 1-13, wherein Z is N.

16. A compound having a structure according to Formula (II):

30.

31. (II),32.wherein:33.R5is H, CH3, -CH2CH3, -CH2CF3, or -CH2OCH3; and34.Y is N or CH.

17. The compound of claim 16, wherein Z is CH.

18. The compound of claim 16, wherein Z is N.

19. The compound of any one of claims 16-18, wherein R5 is CH3.

20. The compound of claim 16, selected from the group consisting of:

39.

21. The compound of any one of claims 1-19, selected from Table 1.

22. A method for treating allergic reactions, allergic dermatitis, atopic dermatitis, eczema, or pruritus in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-21.

23. The method of claim 22, wherein the mammal is a companion animal.

24. The method of claim 23, wherein the companion animal is a dog.

25. The method of any one of claims 22-24, wherein the compound is administered orally, parenterally, or topically.

26. The method of any one of claims 22-25, wherein the compound is administered orally once daily.

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