Tricyclic Janus kinase 1 inhibitors, their compositions, and methods.

Abstract

To provide compounds that are safe and effective Janus kinase 1 inhibitors and useful in treatment of various diseases and disorders (e.g., inflammatory diseases, immune-mediated diseases or cancer).SOLUTION: The invention provides specific compounds having a tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine substructure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 754,029, filed on November 1, 2018, which is incorporated in its entirety by reference.

[0002] Technical field of the present invention This invention generally relates to novel compounds and methods for their therapeutic applications. More specifically, the invention relates to a novel class of therapeutic agents that are safe and effective Janus kinase 1 inhibitors. The invention also relates to pharmaceutical compositions of these compounds, as well as methods for producing them and their use in the treatment of various diseases and disorders (e.g., inflammatory diseases, immune-mediated diseases, or cancer). [Background technology]

[0003] Background Art of the Invention Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the Janus kinase-signaling transcription factor (JAK-STAT) pathway. The human JAK family of enzymes comprises four families: JAK1, JAK2, JAK3, and TYK2. These families are defined by the presence of two adjacent kinase domains, JH1 and JH2, of which JH1 is phosphorylated in pathway activation, while JH2 modulates JH1 function (Thomas, et al., 2015 British Journal of Cancer 113, 365-371).

[0004] These cytoplasmic tyrosine kinases bind to membrane cytokine receptors, such as common gamma chain receptors, and to the transmembrane protein glycoprotein 130 (gp130) (Murray, et sl. 2007 Immunol. 178(5):2623-2629). Approximately 40 cytokine receptors are transmitted through combinations of these four JAKs and their seven downstream substances (STAT family members) (Ghoreschi et al. 2009 Immunol Rev. 228(l):273-287).

[0005] The JAK-STAT signaling pathway plays a major role in many fundamental biological processes, such as apoptosis and inflammation, by facilitating transcriptional gene activation through the communication of chemical signals from the extracellular space to the cell nucleus. Abnormalities in the JAK-STAT pathway can lead to many diseases, such as cancer and diseases affecting the immune system.

[0006] JAK1 and JAK3 are components of a common gamma-chain cytokine receptor complex, and blocking either inhibits signaling by inflammatory cytokines (interleukin (IL)-2, 4, 7, 9, 15, and 21) (Ghoreschi et al. 2009 Immunol Rev. 228(l):273-287). In contrast, other pathologically relevant cytokines (e.g., IL-6) are independently dependent on JAK1 (Guschin et al., EMBO J. 14(7): 1421-1429, 1995), and clinical effects in rheumatoid arthritis have been demonstrated by blocking IL-6 with the IL-6 receptor neutralizing antibody tocilizumab (Maini et al. 2006 Arthritis Rheum. 54(9):28 17-2829).

[0007] Previous studies have shown that JAK1 is essential for the development, function, and homeostasis of the immune system, and that JAK1 deficiency is lethal before birth (Schindler, et al. 2007 J. Biol Chem. 282(28):20059-20063). JAK2 deficiency in mice is also lethal due to deletion during lung development, and JAK2 embryos die between 12 and 13 days postimplantation (Neubauer et al. 1998 Cell 93(3):397-409). JAK3 deficiency has been reported in humans and presents with severe combined immunodeficiency in the first few months of life, along with symptoms such as developmental delays, severe and recurrent infections, thrush, and diarrhea. Infants with JAK3 deficiency show the absence of circulating T cells and NK cells as well as abnormal B cell function. Furthermore, TYK2 deficiency has been reported in humans, presenting with impaired antimicrobial response, elevated serum IgE levels, and atopic dermatitis (Minegishi, et al, 2006 Immunity 25(5):745-755).

[0008] Anticytokine therapy has become standard in the treatment of rheumatoid arthritis and other autoimmune diseases. Multiple clinical trials have demonstrated statistically significant efficacy in rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Kremer, et al. 2009 Arthritis Rheum. 60(7):1895-1905; Riese, et al. 2010 Best Pract. Res. Clin. Rheumatol. 24(4):5 13-526; Fleischmann, et al., Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open 2017; 3:e000546.).

[0009] Despite a variety of treatment options, many patients with autoimmune diseases fail to achieve a significant reduction in disease activity. While studies have shown that JAK blockade may be effective in controlling the disease and achieving remission, first-generation JAK inhibitors (e.g., tofacitinib and baricitinib) have not reached their full potential, at least in part, due to their tolerability and safety issues that limit dosage (Fleischmann et al, Curr. Opin. Rheumatol. 24:335-341, 2012; Riese et al, Best Pract. Res. Clin. Rheumatol. 24:513-526, 2010). Even though these two compounds exhibit higher selectivity for JAK than other kinase families, these inhibitors may not be the optimal choice for kinase within the JAK family. These effects can be enhanced by inhibition of EPO and IL-15 signaling by JAK2 and JAK3, respectively (Jost, et al. 2013 Annu. Rev. Immunol. 31:163-194; Kennedy, et al. 2000 J. Exp. Med. 191:771-780; Richmond, et al. 2005 Trends Cell Biol. 15:146-155). The regulation of immune activity by inhibiting JAK1 kinase activity can be shown to be useful in treating various immune disorders while evading JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Murray 2007 J. Immunol. 178, 2623-2629; Kisseleva, et al. 2002 Gene, 285, 1-24; O' Shea, et al. 2002 Cell 109, S121-S131; Neubauer, et al. 1998 Cell 93(3), 397-409; Parganas, et al. 1998 Cell 93(3), 385-95).

[0010] Therefore, there is an urgent unmet need for a new, potent, selective JAK1 inhibitor with fewer side effects and improved efficacy compared to existing therapeutic agents, despite the current availability of therapeutic options for inflammatory diseases, immune-mediated diseases, cancer, and other diseases related to JAK1. Summary of the Invention

[0011] Summary of the Invention The present invention provides a series of novel orally and / or topically available, selective, and potent JAK1 inhibitors with improved safety and / or efficacy profiles compared to currently available therapeutic agents. The present invention also provides pharmaceutical compositions of these compounds, as well as methods for their manufacture and therapeutic use.

[0012] In one aspect, the present invention generally relates to a structural formula (I):

Chemical formula

[0013] In another embodiment, the present invention generally relates to structural formula (VII): [ka] (VII) [In the formula, R 1 is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR’, COOR’, and CONR’R’’; Each R 3 is independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR’, COOR’, and CONR’R’’; R 4 is a group selected from hydrogen (e.g., F, Cl), halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR’, and NHR’; R4] 5 is R x or NR x R y where each of R x and R y is independently selected from H, alkyl (e.g., C1-C6 alkyl), cycloalkyl (e.g., C3-C 10 cycloalkyl), heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 aryl), heteroaryl (e.g., C3-C9 heteroaryl), and R x and R y may together form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and each of R x and R y is optionally substituted with one or more of halogen (e.g., F, Cl), CN, OR’, NR’R’’, alkyl (e.g., C1-C6 alkyl), haloalkyl (e.g., CHF2, CF3), cyanoalkyl (e.g., CH2CN), hydroxyalkyl (e.g., CH2OH), and alkoxyalkyl (e.g., CH2O-alkyl); provided that when R 5 is R x then R x is not H (i.e., R 5 is not H); Each R L is independently (CH2) mand m is independently 0, 1, 2 or 3, and when m is 0, each crosslink is absent; each R’ and R’’ is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl, and R’ and R’’ may together form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] relates to a compound as shown or a pharmaceutically acceptable form or isotope derivative thereof.

[0014] In yet another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound according to the invention disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent, which is effective for the treatment or alleviation of one or more diseases or disorders in mammals (including humans).

[0015] In yet another aspect, the present invention generally relates to Structural Formula (I):

Chemical formula

[0016] In yet another embodiment, the present invention generally relates to structural formula (VII): [ka] (VII) [In the formula, R 1 This is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 These are independently selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4This group is selected from hydrogen, halogen, CN, C1-C6 unsubstituted or substituted alkyl, OR', and NHR'; R 5 R x or NR x R y And R x and R y Each of them is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and R x and R y These may together form a 3- to 7-membered ring, and R x and R y Each of these may be appropriately substituted with one or more of halogens, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; however, R 5 R x If R x It is not H; Each R L (CH2) m And m is independently 0, 1, 2, or 3, and when m is 0, each bridge is nonexistent; Each R' and R'' is independently selected from hydrogen, as well as from C1-C6 unsubstituted and substituted alkyl groups, and R' and R'' may together form a 3-7 membered ring; and n is either 1 or 2. This relates to a pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0017] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, which is effective in treating or alleviating one of inflammatory diseases, immune-mediated diseases and cancer, or related diseases or disorders in mammals (including humans), structural formula (I): [ka] (I) [wherein, R 1 is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR’, COOR’, and CONR’R’’; R 2 is selected from C3-C 10 cycloalkyl, bicycloalkyl, spiro ring or bridged cycloalkyl, and is substituted with NR’C(=O)R x , NR’C(=O)OR x , NR’C(=O)NR x [RR y , C(=O)NR x [RR y , NR’SO2R x , NR’SO2NR x [RR y , CR’R’’SO2R x , or CR’R’’SO2NR x [RR y ; each R 3 is independently selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR’, COOR’, and CONR’R’’; R 4 is a group selected from hydrogen, halogen, CN, C1-C6 unsubstituted or substituted alkyl, OR’, and NHR’; R x and each of R y is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and R x and R y may together form a 3- to 7-membered ring, and each of R x and R y may be optionally substituted with one or more of halogen, CN, OR’, NR’R’’, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; Each of R’ and R’’ is independently selected from hydrogen and C1-C6 unsubstituted and substituted alkyl, and R’ and R’’ may together form a 3- to 7-membered ring; and n is 1 or 2] A method for administering to a subject in need thereof a pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable form or isotope derivative thereof.

[0018] In yet another aspect, the present invention generally provides a method for treating or alleviating a disease or disorder, which is effective for the treatment or alleviation of one of inflammatory diseases, immune-mediated diseases and cancers, or related diseases or disorders in mammals (including humans), of structural formula (VII):

Chemical formula

[0019] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, characterized by administering a pharmaceutical composition comprising a compound disclosed herein to a subject in need thereof, wherein the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases and cancer, or related diseases or disorders.

[0020] In yet another embodiment, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents in the manufacture of therapeutic agents for diseases or disorders. [Modes for carrying out the invention]

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. General principles of organic chemistry, as well as specific functional parts and reactions, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0022] Some compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all such compounds, including cis and trans isomers, atrop isomers, R and S enantiomers, diastereomers, (d) isomers, (l) isomers, racemic mixtures thereof, and other mixtures thereof. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are considered to be included in the present invention.

[0023] Isomer mixtures containing various isomer ratios may be used in the present invention. For example, when only two isomers are combined, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 may be included in the present invention. Those skilled in the art will readily understand that similar ratios are encompassed for more complex isomer mixtures.

[0024] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary group, the resulting mixture of diastereoisomers is separated, the auxiliary group is cleaved, and the pure, desired enantiomer is provided. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), the diastereomer salt is formed with a suitable optically active acid or base, the diasteomer is then separated by fractional crystallization or chromatography, which are well known in the art, and the pure enantiomer is subsequently recovered.

[0025] Solvates and polymorphs of the compounds of the present invention are also included herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0026] The specific definitions of functional groups and chemical terms are described in more detail below. When a numerical range is given, it is assumed that each value and subrange within that range are included. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to contain alkyl groups.

[0027] When substituents are identified by their general chemical formulas written from left to right, chemically identical substituents written from right to left are equivalent; for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0028] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group can be substituted with one or more of many substituents, such substitutions are selected to confer a compound that conforms to the principles of chemical bonding, is not inherently unstable, and / or is likely to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions), which is not known to those skilled in the art.

[0029] As used herein, the term "alkyl" refers to a group of 1 to 10 carbon atoms (e.g., C 1-10This means a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having an alkyl group and containing no unsaturated atoms. Where used herein, a numerical range such as "1 to 10" means each integer within a given range; for example, "1 to 10 carbon atoms" means that the alkyl group may contain up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on. This definition also includes the use of the term "alkyl" without specifying a numerical range. In some embodiments, "alkyl" means C 1-6 It may be an alkyl group. In one embodiment, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Typical saturated linear alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl group is bonded to the parent molecule by a single bond. Unless otherwise specified herein, alkyl groups are independently acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphophosphate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a, -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R a [These are independently hydrogen, alkyl, haloalkyl, carbocyryl, carbocyrylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be appropriately substituted by one or more substituents as defined herein.] In non-limiting embodiments, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0030] As used herein, the term "alkoxy" refers to a molecule with 1 to 10 carbon atoms (C) bonded to the parent molecule structure by oxygen. 1-10This refers to the -O-alkyl group, including linear, branched, saturated cyclic structures and combinations thereof. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, etc. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms. In one embodiment, C 1-3 Alkoxy groups are alkoxy groups that include both linear and branched alkyl groups with 1 to 3 carbon atoms. Unless otherwise specified herein, alkoxy groups are independently acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphophosphate, phosphine, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a -C(O)ORa, -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(Ra ), or -OP(=O)(ORa)2[wherein each R a [These are independently hydrogen, alkyl, haloalkyl, carbocyryl, carbocyrylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these parts may be appropriately substituted with one or more substituents as defined herein.]

[0031] As used herein, the terms “aromatic” or “aryl” mean a group having 6 to 14 ring atoms (e.g., C) having at least one ring (e.g., phenyl, fluorenyl, and naphthyl) having a conjugated pi-electron system of carbon rings. 6-14 Aromatic or C 6-14 It means aryl. In one embodiment, the aryl is C 6-10This refers to aryl groups. For example, a divalent group formed from a substituted benzene derivative and having free valence on the ring atom is called a substituted phenylene group. In other embodiments, divalent groups derived from monovalent polycyclic hydrocarbon groups ending in "-yl" by removing one hydrogen atom along with its free valence from a carbon atom are named by adding "-idene" to the name of the corresponding monovalent group; for example, a naphthyl group having two bond points is called naphthylidene. Where used herein, numerical ranges such as "6-14 aryl" mean each integer within a given range; for example, "6-14 ring atoms" means that the aryl group may consist of ring atoms containing up to 14, such as 6 ring atoms, 7 ring atoms, etc. The terms include monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include dicyclic, tricyclic, tetracyclic, etc. Since only one ring is required to be aromatic in a polycyclic group, groups such as indanyl are included in the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenantrenyl, anthracenyl, fluorenyl, indolyl, and indanyl. Unless otherwise specified herein, the aryl moiety can independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphophosphate, phosphine, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(ORa)2[wherein each R a [These are independently hydrogen, alkyl, haloalkyl, carbocyryl, carbocyrylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these parts may be appropriately substituted with one or more substituents as defined herein.]

[0032] As used herein, the terms “cycloalkyl” and “carbocyclyl” mean monocyclic or polycyclic groups, respectively, that consist only of carbon and hydrogen and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups may be called “cycloalkenyl” if their carbocyclic ring contains at least one double bond, or “cycloalkynyl” if their carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3-13This includes cycloalkyl groups. Where used herein, numerical ranges such as "3 to 10" mean each integer within a given range; for example, "3 to 13 carbon atoms" means that a cycloalkyl group may consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and so on. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Polycyclic aryl groups include dicyclic, tricyclic, tetracyclic, and so on. In some embodiments, "cycloalkyl" means C 3-8 It can be a cycloalkyl group. In one embodiment, "cycloalkyl group" is C 3-5 It can be a cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, C 3-6 Examples of carbocyclyl groups, though not limited to them, include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-7 Examples of carbocyclyl groups include norbornyl (C7). 3-8 As an example of a carbocyric group, the above C 3-7 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3-13 Examples of a carbocyric group include the aforementioned C 3-8Examples include carbocykyl groups, as well as octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, etc. Unless otherwise specified herein, cycloalkyl groups are independently acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphophosphate, phosphine, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R aThe terms "cycloalkenyl" and "cycloalkynyl" are similar to the above description of "cycloalkyl," except that the prefix "alk" is replaced with "alken" or "alkyn," respectively, and the parent terms "alkenyl" or "alkynyl" are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group may have 5 to 13 ring atoms.

[0033] As used herein, the term “halogen” means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term “halide” or “halo” means fluoro, chloro, bromo, or iodine. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may be further substituted as appropriate, as defined herein.

[0034] As used herein, the term “heteroatom” means oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0035] As used herein, the term “heteroalkyl” means an alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. For example, C 1-4 A numerical range is assigned to represent the total chain length of heteroalkyl groups, which in this example is the length of four atoms. For example, the -CH2OCH2CH3 group is referred to as a "C4" heteroalkyl group, and the description of the atomic chain length includes the heteroatom center. Bonding to the parent molecular structure can be via either heteroatoms or carbon atoms in the heteroalkyl chain. For example, a nitrogen-containing heteroalkyl group means a group in which at least one of the skeletal atoms is a nitrogen atom. One or more heteroatoms in the heteroalkyl group may be oxidized as appropriate. One or more nitrogen atoms may also be quaternized as appropriate, if present. For example, a heteroalkyl group may also include a skeletal chain substituted with one or more nitrogen oxide (-O-) substituents. Examples of heteroalkyl groups include, but are not limited to, ethers such as methoxyethanyl (-CH2CH2OCH3), ethoxymethanyl (-CH2OCH2CH3), (methoxymethoxy)ethanyl (-CH2CH2OCH2OCH3), (methoxymethoxy)methanyl (-CH2OCH2OCH3), and (methoxyethoxy)methanyl (-CH2OCH2CH2OCH3); and amines such as (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3)).

[0036] As used herein, the terms “heteroaryl” or “heteroaromatic” mean a 5- to 18-membered monocyclic or polycyclic (e.g., dicyclic, tricyclic, tetracyclic, etc.) aromatic ring group ("5- to 18-membered heteroaryl") having a ring carbon atom and 1 to 6 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur) in an aromatic ring group (e.g., having 6, 10, or 14π electrons shared in a cyclic structure). A heteroaryl polycyclic ring group may contain one or more heteroatoms in one or both rings. Where used herein, numerical ranges such as “5-18” mean each integer within a given range; for example, “5-18 ring atoms” means that the heteroaryl group may consist of ring atoms containing up to 18, such as 5 ring atoms, 6 ring atoms, etc. In some examples, a heteroaryl may have 5 to 14 ring atoms. In one embodiment, the heteroaryl group is derived from a monovalent heteroaryl group with the suffix "-yl" by removing one hydrogen atom along with the free valence from an atom, for example. A divalent group is named by adding "-ene" to the name of the corresponding monovalent group. For example, a pyridyl group having two bonding sites is pyridylene.

[0037] For example, the N-containing "heteroaromatic" or "heteroaryl" moiety means an aromatic group in which at least one of the ring's skeletal atoms is a nitrogen atom. One or more heteroatoms in the heteroaryl group may be oxidized as appropriate. One or more nitrogen atoms may also be quaternized as appropriate, if present. The heteroaryl also includes a ring group substituted with one or more nitrogen oxide (-O-) substituents, such as pyridine N-oxide. The heteroaryl is bonded to the parent molecule structure via any atom of the ring.

[0038] "Heteroaryl" also includes ring groups in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site to the parent molecule structure is on the aryl or heteroaryl ring, or ring groups in which the heteroaryl ring defined above is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site to the parent molecule structure is on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site to the parent molecule structure can be either a ring containing a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl). In one embodiment, the heteroaryl group is a 5-10 membered aromatic ring group having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring group, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heteroaryl"). In one embodiment, the heteroaryl group is a 5-8 membered aromatic ring group having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring group, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In another embodiment, the heteroaryl group is a 5-6 membered aromatic ring group having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring group, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In another embodiment, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In yet another embodiment, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In yet another embodiment, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0039] Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzoxazolyl, benzopyranil, benzopyranonil, benzof Ranyl, benzopyranonil, benzoflazanil, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinil, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinil, carbazolyl, cinnolinil, cyclopenta[d]pyrimidinil, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinil, 5,6-dihydrobenzo[h]quinazolinil, 5,6-dihydrobenzo[h]cinnolinil, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2 -c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, 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, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazoli Lu, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinol, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, prinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d] Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, 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] These include thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranil, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyrimidinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl moieties are independently acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphophosphate, phosphine, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R, a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NRa )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R a [These are independently hydrogen, alkyl, haloalkyl, carbocyryl, carbocyrylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these parts may be appropriately substituted with one or more substituents as defined herein.]

[0040] As used herein, the term “administer” means oral administration, suppository administration, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, subarachnoid, intracerebral, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a mini osmotic pump. The appropriate route of administration for a particular patient depends on the characteristics and severity of the disease or illness being treated, the characteristics of the treatment used, and the characteristics of the active compound.

[0041] Administration may be by any suitable route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracerebral. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patches.

[0042] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after, the administration of one or more further treatments.

[0043] The compounds of the present invention can be administered to patients alone or in combination. Combination involves administering the compounds separately or in combination (one or more compounds or drugs) simultaneously or sequentially. Thus, the formulations can also be combined with other active substances (for example, to reduce metabolic degradation) if desired.

[0044] The compositions of the present invention can be delivered transdermally via local routes and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, topical applications, powders, and aerosols. Oral formulations suitable for patient ingestion include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, suppositories, gels, syrups, slurries, and suspensions. Solid formulations include powders, tablets, pills, capsules, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, emulsions, and gels, such as water or water / propylene glycol solutions.

[0045] The compositions of the present invention may further include components for sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and micropharmaceutical carriers. These components are described in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated by reference in their entirety for all purposes. The compositions of the present invention may also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered by intradermal injection of microspheres containing drugs that are released subcutaneously with a delay (see Rao, 1995 J. Biomater Sci. Polym. Ed. 7:623-645); as biodegradable and injectable gel formulations (see, for example, Gao 1995 Pharm. Res. 12:857-863); or as orally administered microspheres (see, for example, Eyles 1997 J. Pharm. Pharmacol. 49:669-674).

[0046] As used herein, the terms “disease,” “illness,” and “disorder” are interchangeable herein and mean a condition or health condition of a patient or subject that is treated or can be treated by the compounds, pharmaceutical compositions, or methods provided herein.

[0047] As used herein, the term “effective dose” of an active agent means an amount sufficient to produce a desired biological response. As will be understood by those skilled in the art, the effective dose of the compounds of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient.

[0048] As used herein, terms relating to the interaction between a biological target (e.g., JAK) and an inhibitor, such as “inhibition,” “inhibit,” and “inhibiting,” mean a negative effect (e.g., reduction) on the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means a negative effect (e.g., reduction) on the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition means a reduction in the disease or symptoms of a disease. In embodiments, inhibition means a decrease in the activity of a particular protein target. Inhibition includes interfering, reducing, hindering, or delaying the activity of at least some, partly, or entirely, or inactivating, desensitizing, or downmodulating signaling or enzymatic activity or the amount of a protein. In embodiments, inhibition means a decrease in the activity of a target protein resulting from a direct interaction (e.g., an inhibitor that binds to the target protein). In embodiments, inhibition means a decrease in the activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby inhibiting the activation of the target protein).

[0049] As used herein, the terms “isolated” or “purified” typically mean a substance that substantially or essentially does not contain the components that naturally accompany it. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0050] As used herein, “pharmaceutically acceptable forms” of the disclosed compounds include, but are not limited to, their pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives. In one embodiment, “pharmaceutically acceptable forms” include, but are not limited to, their pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives. In one embodiment, “pharmaceutically acceptable forms” include, but are not limited to, their pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives.

[0051] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” means a salt that is within reasonable medical judgment suitable for use in contact with a subject without excessive toxicity, irritation, or allergic reaction, and that balances out with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds provided herein include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, e.g., ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonic acid, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, p-toluenesulfonate, undecanoate, and valerate.In one embodiment, organic acids from which the salt may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic 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.

[0052] The salts can be prepared in stew during the isolation and purification of the disclosed compound, or separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Medicinally acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Alkyl) 4 salts are included. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins), such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium.

[0053] In one embodiment, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” means a compound further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. The solvate may be of the disclosed compound or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” is understood to encompass the compound and its solvates, as well as mixtures thereof.

[0054] In one embodiment, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) means a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the said compound. A prodrug is inactive when administered to a subject but is converted in vivo to an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physiological and / or delivery properties compared to the parent compound. Compared to the parent compound, a prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by enabling increased absorption into the blood after oral administration) or enhance delivery to a biological structure of interest (e.g., the brain or lymphatic system). Exemplary prodrugs include derivatives of the disclosed compound that have increased water solubility or active transport across the enteric membrane compared to the parent compound.

[0055] The aforementioned prodrug compounds often offer advantages in terms of solubility, histocompatibility, or delayed release within mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Descriptions of prodrugs are provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0056] Prodrug forms often offer advantages in terms of solubility, histocompatibility, or sustained release within mammals (see Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985, and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs generally known in the art include well-known acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, amides prepared by reacting a parent acid compound with an amine, and basic groups reacted to form acylated base derivatives. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. Thus, those skilled in the art will understand that certain disclosed compounds having free amino, amide, hydroxy, or carboxyl groups can be converted into prodrugs. Prodrugs include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the substituents disclosed herein.

[0057] Exemplary advantages of prodrugs include, but are not limited to, their physiological properties, such as higher water solubility for parenteral administration at physiological pH compared to the parent compound, the ability to enhance absorption from the gastrointestinal tract, or improved drug stability for long-term storage.

[0058] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance related to transporting or carrying from one organ or part of body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Examples of substances that can be used as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer, as well as colorants, release agents, coating agents, sweeteners, fragrances, and flavorings, preservatives, and oxidizing agents may also be present in the composition.

[0059] As used herein, the term “subject” means any animal (e.g., mammal) including, but not limited to, humans, non-human primates, rodents, etc. (which are recipients of a particular treatment). Subjects to which administration is envisioned include, but not limited to, humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)), and / or other non-human animals, e.g., non-human mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques); commercially relevant mammals, e.g., cattle, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice), etc. In some embodiments, the non-human animal is a mammal. The non-human animal may be male or female at any developmental stage. The non-human animal may be a genetically modified animal. Typically, the terms “subject” and “patient” are used interchangeably herein with respect to human subjects.

[0060] As used herein, the terms “treatment” of a disease or disorder, or “to treat” a disease or disorder, mean a method of reducing, delaying, or alleviating its condition before or after its onset. Treatment may be directed towards one or more effects or symptoms of the disease and / or its underlying pathological condition. Treatment may be any reduction, but may also be the complete elimination of the disease or its symptoms. Thus, treating or treating means signs of success in treating or alleviating an injury, disease, disorder, or condition, including any objective or subjective parameter, e.g., reduction; alleviation; reducing symptoms or making the injury, lesion, or condition tolerable to the patient; slowing the rate of degeneration or decline; not diminishing the endpoint of degeneration; or improving the patient’s physical or mental health. Treatment or alleviation of symptoms may be based on objective or subjective parameters, e.g., the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Compared to an equivalent untreated control, the degree of such reduction or mitigation, when measured by any standard technique, may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%.

[0061] The treatment method involves administering a therapeutically effective dose of the compounds described herein to a target. The administration step may be a single administration or a series of administrations. The length of the treatment period depends on various factors such as the severity of the disease, the patient's age, the concentration of the compound, the activity of the composition used in treatment, or a combination thereof. It is also understood that the effective dose of the drug used in treatment may be increased or decreased throughout the course of a particular treatment plan. Changes in dose can be determined and clarified by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the composition is administered to the target in an amount and duration sufficient to treat the patient.

[0062] Detailed description of the present invention This invention is based on unexpected findings of a novel class of selectively potent JAK1 therapeutic agents available orally and / or topically. The invention also provides pharmaceutical compositions of these compounds, as well as methods for their manufacture and use. The JAK1 inhibitors disclosed herein have shown remarkably superior potency and selectivity profiles.

[0063] More specifically, the novel JAK1 inhibitors disclosed herein benefit from improved efficacy, indicated by their superior binding affinity to JAK1 (e.g., IC50 values ​​of approximately 3-4 nM), and the potential for reduced hematopoietic side effects, indicated by their superior specificity (e.g., IC50 values ​​of JAK2 > 20xJAK1).

[0064] In one embodiment, the present invention generally relates to structural formula (I): [ka] (I) [In the formula, R 1 This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'C(=O)R x , NR'C(=O)OR x NR'C(=O)NR x R y , C(=O)NR x R y NR'SO2R x NR'SO2NR x R y ,CR'R''SO2R x , or CR'R''SO2NR x R y Replaced by; Each R 3These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, as well as R x and R y Each of these may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); Each of R' and R'' is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. This relates to the compound indicated by or its pharmaceutically acceptable form or isotopic derivative.

[0065] In one embodiment of formula (I), R 4 is H, and the compound has the structural formula (II): [ka] (II) This is shown.

[0066] In one embodiment of formula (II), n is 1, and the compound has structural formula (III): [ka] (III) This is shown.

[0067] In one embodiment of formula (I), R 1 is H, and the compound has the structural formula (IV): [ka] (IV) This is shown.

[0068] In some embodiments of formulas (I), (II), (III), and (IV), R 1 and R 4 Both are H.

[0069] In some embodiments of formulas (I), (II), (III), and (IV), R 1 It is methyl, and R 4 H is H.

[0070] In some embodiments of equations (I), (II), (III), and (IV), n is 1.

[0071] One reason, R 3 H is H.

[0072] In an exemplary embodiment, R 1 H is R 4 The compound in which is H and n is 1 has the structural formula (V): [ka] (V) This is shown.

[0073] In a further exemplary embodiment of equation (V), R 3 is H, and the compound has the structural formula (VI): [ka] (VI) This is shown. R 2 C3-C 10 (For example, C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl may be selected, and NR'C(=O)R x , NR'C(=O)OR x NR'C(=O)NR x R y , C(=O)NR x R y NR'SO2R x NR'SO2NR x R y ,CR'R''SO2R x , or CR'R''SO2NR x R y Substituted with a group selected from R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y Each of these may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls), as well as R x and R yThey may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring. Each of R' and R'' is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups. R' and R'' may together form a 3- to 7-membered ring.

[0074] Together with R' and R'', or R x and R y It should be noted that the 3- to 7-membered (e.g., 3 or 4-membered) rings that may be appropriately formed together may also have hetero-3- to 7-membered (e.g., 3 or 4-membered) rings having 0-3 carbon atoms substituted by one or more heteroatoms selected from N, O, S, and P.

[0075] Heterocycloalkyls (e.g., C2-C9 heterocycloalkyls) and heteroaryls (e.g., C3-C9 heteroaryls) may have 1 to 4 carbon atoms substituted with one or more heteroatoms selected from N, O, S, and P.

[0076] One reason, R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'C(=O)R x It will be replaced by this.

[0077] One reason, R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring or crosslinked cycloalkyl, and NR'C(=O)OR x It will be replaced by this.

[0078] One reason, R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'C(=O)NRx R y It will be replaced by this.

[0079] One reason, R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and C(=O)NR x R y It will be replaced by this.

[0080] One reason, R 2 C3-C 10 Selected from (for example, C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'SO2R x It will be replaced by this.

[0081] One reason, R 2 C3-C 10 Selected from (for example, C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, NR'SO2NR x R y It will be replaced by this.

[0082] One reason, R 2 C3-C 10 Selected from (for example, C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and CR'R''SO2R x It will be replaced by this.

[0083] One reason, R 2 C3-C 10 Selected from (for example, C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and CR'R''SO2NR x R y It will be replaced by this.

[0084] In one embodiment, R2 is the following part: [ka] [In the formula, each R L (CH2) m And m is independently 0, 1, 2, or 3, and if m is 0, each bridge does not exist; however, at least one of m is not 0. Includes.

[0085] In one embodiment, m is not 0 (i.e., each m is independently 1, 2, or 3).

[0086] In one embodiment, if m is one or less, then it is 0 (i.e., if R is one or less). L (It is non-existent).

[0087] In one embodiment, each m is independently 1, 2, or 3.

[0088] In one embodiment, all m are identical integers selected from 1, 2, and 3.

[0089] In one embodiment, all m are not identical integers selected from 1, 2, and 3.

[0090] In one embodiment, each m is 1 (i.e., forming a [1.1.1]-biring portion).

[0091] In one embodiment, each m is 2 (i.e., forming a [2,2,2]-biring portion).

[0092] One reason, R2, [ka] [In the formula, R 5 R x or NR x R y And R x and R yEach of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, as well as R x and R y Each of these may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); however, R 5 However, R x And R x However, it is not H (i.e., R 5 (This is not H) The following are included: Each of R' and R'' is independently selected from hydrogen and C1-C6 unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring.

[0093] One reason, R 5 R x That is the case.

[0094] One reason, R 5 This is a C1-C6 alkyl (e.g., C1-C3 alkyl) which may be appropriately substituted with one or more halogens (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxy, CN, or amino groups.

[0095] One reason, R 5 These are C1-C6 alkyl groups (for example, C1-C3 alkyl groups).

[0096] One reason, R 5 These are halogens (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxys, or C1-C6 alkyls substituted with CN (e.g., C1-C3 alkyls).

[0097] One reason, R 5 This is a C1-C6 alkyl group substituted with CN (for example, a C1-C3 alkyl group).

[0098] One reason, R x These are linear or branched C1-C6 alkyl groups.

[0099] One reason, R x These are linear or branched C2-C4 alkyl groups.

[0100] One reason, R x It is either n-propyl or isopropyl.

[0101] One reason, R 5 , NR x R y That is the case.

[0102] One reason, R x and R y One of them is H.

[0103] One reason, R 5 , NR x R y And R x and R y Each of these is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups.

[0104] One reason, R 5 , NR x R y And R x and R y , NRx R y Together with N in the above, it may form a 3- to 7-membered (e.g., 3, 4, or 5-membered) heterocyclic group which may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls).

[0105] In one embodiment, the heterocyclic group is a four-membered heterocyclic group.

[0106] One reason, R 5 , NR x R y And R x and R y Each of these is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted alkyl groups.

[0107] One reason, R 5 , NR x R y And R x and R y These combine to form a CN-substituted 3- or 4-membered cycloalkyl ring.

[0108] One way of doing this is for each R L This is CH2.

[0109] One way of doing this is for each R L It is (CH2)2.

[0110] In another embodiment, the present invention generally relates to structural formula (VII): [ka] (VII) [In the formula, R 1This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen, halogens (e.g., F, Cl), CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl groups, OR', and NHR'; R 5 R x or NR x R y And R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, and may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); however, R 5 R x If R x It is not H (i.e., R 5 It is not H; Each R L (CH2) m And m is independently 0, 1, 2, or 3, and when m is 0, each bridge is nonexistent; Each R' and R'' is independently selected from hydrogen, as well as from C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. This relates to the compound indicated by or its pharmaceutically acceptable form or isotopic derivative.

[0111] In one embodiment of (VII), one or fewer m are 0 (i.e., one or fewer R L (It is non-existent).

[0112] In one embodiment of (VII), m is not 0 (i.e., each m is independently 1, 2, or 3).

[0113] In one embodiment of (VII), all m are identical integers selected from 1, 2, and 3.

[0114] In one embodiment of (VII), all m are not identical integers selected from 1, 2, and 3.

[0115] In one embodiment of (VII), each m is 1 (i.e., forming a [1.1.1]-biring portion).

[0116] In one embodiment of (VII), each m is 2 (i.e., forming a [2,2,2]-biring portion).

[0117] (VII) In one embodiment, R 4 H is H.

[0118] (VII) In one embodiment, R 1 H is H.

[0119] (VII) In one embodiment, R 1 It is methyl.

[0120] In one embodiment of (VII), n is 1.

[0121] (VII) In one embodiment, R 4 is H, n is 1, and the compound has the structural formula (VIII): [ka] (VIII) This is shown.

[0122] In one embodiment (VIII), R 1 It is methyl, and R 3 H is H.

[0123] In one embodiment (VIII), R 1 and R 3 Both are H, and structural formula (IX): [ka] (IX) This is shown.

[0124] In one embodiment (VIII), each R L It is CH2, and the compound has the structural formula (X): [ka] (X) This is shown.

[0125] In one embodiment of (X), R 5 R x That is the case.

[0126] In one embodiment of (X), R x This is a linear or branched C1-C6 (e.g., C1-C3) alkyl group which may be appropriately substituted with one or more halogens (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxy, CN, or amino groups.

[0127] In one embodiment of (X), R x These are linear or branched C2-C4 alkyl groups.

[0128] In one embodiment of (X), R x It is either n-propyl or isopropyl.

[0129] In one embodiment of (X), R 5 , NR x R y That is the case.

[0130] In one embodiment of (X), R x and R y One of them is H.

[0131] One reason, R x and R y , NR x R y Together with N in the , it forms a 3- to 5-membered (e.g., 3, 4, or 5-membered) heterocyclic group which may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls).

[0132] In one embodiment, the heterocyclic group is a four-membered heterocyclic group.

[0133] Table 1 lists non-limiting examples of the compounds of the present invention. Table 1. Exemplary Compounds [ka] [ka]

[0134] In one embodiment, the compound is represented by the structural formula of compound 1. In one embodiment, the compound is represented by the structural formula of compound 4. In one embodiment, the compound is represented by the structural formula of compound 5. In one embodiment, the compound is represented by the structural formula of compound 6. In one embodiment, the compound is represented by the structural formula of compound 21. In one embodiment, the compound is represented by the structural formula of compound 23. In one embodiment, the compound is represented by the structural formula of compound 31. In one embodiment, the compound is represented by the structural formula of compound 32. In one embodiment, the compound is represented by the structural formula of compound 45. In one embodiment, the compound is represented by the structural formula of compound 46. In one embodiment, the compound is represented by the structural formula of compound 48. Table 1A. Exemplary Compounds [Table 1] [Table 2]

[0135] As described herein, isotopic derivative compounds having one or more hydrogen atoms substituted with deuterium atoms are included in the present invention. In some embodiments, the compounds of the present invention have one or more hydrogen atoms substituted with deuterium atoms. In some embodiments, the compounds of the present invention have one hydrogen atom substituted with a deuterium atom. In some embodiments, the compounds of the present invention have one or more hydrogen atoms substituted with deuterium atoms.

[0136] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a compound according to the invention described herein, as well as a pharmaceutically acceptable excipient, carrier, or diluent, which is generally effective in treating or alleviating one or more diseases or disorders in mammals (including humans).

[0137] In yet another embodiment, the present invention generally relates to structural formula (I): [ka] (I) [In the formula, R 1 This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'C(=O)R x , NR'C(=O)OR x NR'C(=O)NR x R y , C(=O)NR x R y NR'SO2R x NR'SO2NR x R y ,CR'R''SO2R x , or CR'R''SO2NR x R y Replaced by; Each R 3 These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, as well as R xand R y Each of these may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); Each of R' and R'' is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. This relates to a pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0138] In yet another embodiment, the present invention generally relates to structural formula (VII): [ka] (VII) [In the formula, R 1 This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen, halogens (e.g., F, Cl), CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl groups, OR', and NHR'; R 5 R x or NR x R y And R x and R yEach of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, and may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); however, R 5 R x If R x It is not H (i.e., R 5 It is not H; Each R L (CH2) m And m is independently 0, 1, 2, or 3, and when m is 0, each bridge is nonexistent; Each R' and R'' is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. This relates to a pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0139] In one embodiment, the pharmaceutical compositions disclosed herein are suitable for oral administration.

[0140] In one embodiment, the pharmaceutical composition of the present invention is suitable for topical administration.

[0141] In one embodiment, the pharmaceutical compositions disclosed herein are effective in treating or alleviating one or more of the following conditions or disorders: inflammatory diseases, immune-mediated diseases, and cancer, or related diseases or disorders.

[0142] In one embodiment, the pharmaceutical compositions disclosed herein are effective in treating or alleviating one or more autoimmune diseases or related diseases or disorders.

[0143] In one embodiment of the pharmaceutical composition, the disease or disorder is asthma, allergy, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain Barre syndrome, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, psoriasis vulgaris, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, graft rejection (allograft rejection), graft-versus-host disease (GVDH), or related diseases or disorders.

[0144] In yet another embodiment, the present invention generally relates to unit formulations comprising the pharmaceutical compositions disclosed herein.

[0145] In one embodiment, the unit formulation is in the form of a solid dosage form, such as a capsule, tablet, pill, powder, or granule. In one embodiment, the formulation is a tablet. In one embodiment, the formulation is a capsule.

[0146] In one embodiment, the unit formulation is in the form of a liquid formulation, such as an emulsion, solution, suspension, syrup, or elixir.

[0147] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, which is effective in treating or alleviating one or more of the inflammatory diseases, immune-mediated diseases and cancers, or related diseases or disorders in mammals (including humans), structural formula (I): [ka] (I) [In the formula, R 1 This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 C3-C 10 (For example, selected from C3-C6) cycloalkyl, bicycloalkyl, spiro ring, or crosslinked cycloalkyl, and NR'C(=O)R x , NR'C(=O)OR x NR'C(=O)NR x R y , C(=O)NR x R y NR'SO2R x NR'SO2NR x R y ,CR'R''SO2R x , or CR'R''SO2NR x R y Replaced by; Each R 3 These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, as well as R x and R y Each of these may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); Each of R' and R'' is independently selected from hydrogen, as well as C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. The present invention relates to a method characterized by administering a pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need of it.

[0148] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, which is effective in treating or alleviating one or more of the inflammatory diseases, immune-mediated diseases and cancers, or related diseases or disorders in mammals (including humans), structural formula (VII): [ka] (VII) [In the formula, R 1 This is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 These are independently selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4 This group is selected from hydrogen (e.g., F, Cl), halogens, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl groups, OR', and NHR'; R 5 R x or NR x R y And R x and R y Each of these can independently be H, alkyl (e.g., C1-C6 alkyl), or cycloalkyl (e.g., C3-C 10 Cycloalkyl, heterocycloalkyl (e.g., C2-C9 heterocycloalkyl), aryl (e.g., C4-C 10 Selected from aryls, heteroaryls (e.g., C3-C9 heteroaryls), and R x and R y They may together form a 3- to 7-membered (e.g., 3 or 4-membered) ring, and may be appropriately substituted with one or more of the following: halogens (e.g., F, Cl), CN, OR', NR'R'', alkyls (e.g., C1-C6 alkyls), haloalkyls (e.g., CHF2, CF3), cyanoalkyls (e.g., CH2CN), hydroxyalkyls (e.g., CH2OH), and alkoxyalkyls (e.g., CH2O-alkyls); however, R 5 R x If R x It is not H (i.e., R 5 It is not H; Each R L(CH2) m And m is independently 0, 1, 2, or 3, and when m is 0, each bridge is nonexistent; Each R' and R'' is independently selected from hydrogen, as well as from C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl groups, and R' and R'' together may form a 3- to 7-membered (e.g., 3 or 4-membered) ring; and n is either 1 or 2. The present invention relates to a method characterized by administering a pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, to a subject requiring it.

[0149] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, characterized by administering a pharmaceutical composition comprising a compound disclosed herein to a subject in need thereof, wherein the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases and cancer, or related diseases or disorders.

[0150] In one embodiment, the method of the present invention is effective in treating or alleviating autoimmune diseases.

[0151] In one embodiment, the disease or disorder is asthma, allergy, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, and Guillain-Barré syndrome. Selected from syndromes, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, psoriasis vulgaris, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, graft rejection (allograft rejection), graft-versus-host disease (GVDH), or related diseases or disorders.

[0152] In one embodiment, the method of the present invention is effective in treating or alleviating inflammatory diseases or related diseases or disorders.

[0153] In one embodiment, the method of the present invention is effective in treating or alleviating autoimmune diseases or related diseases or disorders.

[0154] In one embodiment, the method of the present invention is effective in treating or alleviating immune-mediated diseases or related diseases or disorders.

[0155] In one embodiment, the method of the present invention is effective in treating or alleviating cancer or related diseases or disorders.

[0156] In one embodiment, the method of the present invention is effective in treating or alleviating one or more of the following conditions: rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, DES, vitiligo, alopecia areata, and complete alopecia.

[0157] In yet another embodiment, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents in the manufacture of therapeutic agents for diseases or disorders.

[0158] In one embodiment of such use, the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases, and cancers.

[0159] In one embodiment of such use, the disease or disorder is an autoimmune disease.

[0160] In embodiments of such use, the disease or disorder is asthma, allergy, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barré syndrome, etc.). Selected from Reye's syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, psoriasis vulgaris, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, graft rejection (allograft rejection), graft-versus-host disease (GVDH), or related diseases or disorders.

[0161] In one embodiment of such use, the disease or disorder is one or more of rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, DES, vitiligo, alopecia areata, and complete alopecia.

[0162] In one embodiment of the use described above, the drug is intended for oral administration.

[0163] In one embodiment of the use described above, the drug is for local administration.

[0164] The term "inflammatory disease" means a disease or illness characterized by an abnormality of inflammation, such as an increased level of inflammation compared to a control, such as a healthy person without the disease. Examples of inflammatory diseases that may be treated with the compounds, pharmaceutical compositions, or methods described herein include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, and autoimmune thyroiditis. These include Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, graft rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These diseases are frequently and closely associated with other diseases, disorders, and illnesses. For example, non-exclusive descriptions of inflammation-related diseases, disorders, and illnesses that may be caused by inflammatory cytokines include arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, disorders, and conditions for which the compounds of this disclosure may be particularly effective (for example, due to limitations of current treatments) are described in more detail below.

[0165] The term "autoimmune disease" refers to a disease or illness in which the immune system of a subject exhibits an abnormal immune response to a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with the compounds, pharmaceutical compositions, or methods described herein include acne vulgaris, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, Eicardi-Goutier syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, and autoimmune inner ear. Diseases, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neurological neuropathy, Balo's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic atypical neutrophilic cutaneous disease syndrome with lipodystrophy and fever (CANDLE), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Chrg's disease Trauss syndrome, pemphigoid scarring / pemphigoid benign mucosalis, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest syndrome, Cushing's disease, demyelinating neuropathy, depression, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler syndrome, dry eye syndrome (DES - keratoconjunctivitis sicca), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome Fibromyalgia, alveolitis fibrous, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, graft-versus-host disease (GVDH), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes zoster of pregnancy, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosing disease, inflammatory bowel disease (IBD), immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis,Juvenile diabetes mellitus (Type 1 diabetes mellitus), juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytosis-destructive vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease, lupus, Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohren's ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis, pediatric autoimmune streptococcal neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg disease, Personage-Turner syndrome, ciliary uveitis (peripheral uveitis), pemphigus, peripheral neuropathy , perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), polyglandular autoimmune syndrome type I, II and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, psoriasis vulgaris, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity (sperm These include testicular autoimmunity, Stiff-Man syndrome, infant-onset interferon-stimulating factor (STING)-associated vasculitis (SAVI), subacute bacterial endocarditis, Suzac syndrome, sympathetic ophthalmitis, systemic lupus erythematosus (SLE), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, graft rejection (allogeneic graft rejection), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous diseases, vitiligo, or Wegener's granulomatosis.

[0166] The term "immune-mediated disease" refers to chronic inflammatory diseases that are perpetuated by antibody and cellular immunity. Immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease. This includes diseases such as thyroiditis, Guillain-Barré syndrome, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, psoriasis vulgaris, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, graft rejection (allograft rejection), and graft-versus-host disease (GVDH).

[0167] As used herein, the term “cancer” means all types of cancer, neoplasms, or malignant tumors found in mammals (e.g., humans), including blood cancers such as leukemia, as well as lymphoma, T-ALL, and solid tumors such as carcinomas and sarcomas. Exemplary cancers include blood cancers, brain cancers, gliomas, glioblastomas, neuroblastomas, prostate cancers, colorectal cancers, pancreatic cancers, cervical cancers, stomach cancers, ovarian cancers, lung cancers, and head cancers. Exemplary cancers include thyroid cancers, endocrine cancers, brain cancers, breast cancers, cervical cancers, colon cancers, head and neck cancers, liver cancers, kidney cancers, lung cancers, non-small cell lung cancers, melanomas, mesotheliomas, ovarian cancers, sarcomas, stomach cancers, uterine cancers, medulloblastomas, colorectal cancers, and pancreatic cancers. Further examples include myeloproliferative neoplasms, thyroid cancer, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, tumors of the pancreatic endocrine or exocrine part, medullary thyroid carcinoma, medullary cell carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0168] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, “isotope-labeled compound” or “isotope derivative” means a compound of the disclosure (including its pharmaceutically acceptable salts and prodrugs, as described herein) in which one or more atoms are substituted by atoms having an atomic weight or mass number different from that which is normally found in nature. Examples of isotopes that can be incorporated into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O,31 P, 32 P, 35 S, 18 F, and 36 Cl is included.

[0169] By isotope labeling the compounds of this disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritium ( 3 H) and carbon-14 ( 14 Compounds labeled with C) are particularly preferred due to their ease of preparation and detection. Furthermore, deuterium ( 2 Substitution with heavier isotopes, such as H), can yield certain therapeutic benefits resulting from higher metabolic stability, e.g., increased in vivo half-life or reduced dose requirements, and may therefore be preferred under certain circumstances. The isotope-labeled compounds of this disclosure (including their pharmaceutically acceptable salts, esters, and prodrugs) can be prepared by any method known in the art.

[0170] Furthermore, hydrogen is usually abundant 1 By substituting H) with a heavier isotope (e.g., deuterium), certain therapeutic benefits can be obtained, such as improvements in absorption, distribution, metabolism, and / or excretion (ADME) properties, resulting in the creation of drugs with improved efficacy, safety, and / or tolerability. The benefits are also usually abundant. 12 C 13 This can also be obtained by substituting with C (see WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0171] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemics, diastereomers, and other mixtures of such isomers, are within the scope of this disclosure.

[0172] The compounds of the present invention, after their preparation, are preferably isolated and purified to obtain a composition containing up to 95% or more ("substantially pure") by weight, and then used or formulated as described herein. In some embodiments, the compounds of the present invention are 99% or more pure.

[0173] Solvates and polymorphs of the compounds of the present invention are also included herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0174] General descriptions of the formulation and / or manufacture of pharmaceutical compositions or drugs can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0175] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacy. Generally, such preparation methods include the steps of conjugating the compounds described herein ("active ingredients") with a carrier and / or one or more other auxiliary ingredients, and then, as necessary and / or desired, shaping the product into desired single or multi-dose units and / or packaging it.

[0176] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose and / or as multiple single-dose unit doses. As used herein, “unit dose” refers to an individual amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equivalent to the dose of the active ingredient administered to a subject, and / or a convenient division of such a dose, for example, half or one-third of such a dose.

[0177] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds or derivatives described herein may be used in conjunction with at least one inert common excipient (or carrier), e.g., sodium citrate or calcium hydrogen phosphate, or (i) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, e.g., carboxymethylcellulose, alginic acid (alignate), gelatin, polyvinylpyrrolidone, sucrose, and acacia; (iii) humectants, e.g., glycerol; (iv) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicic acids, and sodium carbonate; (v) solution retarders, e.g., paraffin; (vi) absorption enhancers. (vii) an accelerator, for example, a quaternary ammonium compound; (viii) a wetting agent, for example, cetyl alcohol and glycerol monostearate; (viii) an adsorbent, for example, kaolin and bentonite; and (ix) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets, and pills, the formulation may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules with excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc. Solid formulations, for example, tablets, sugar-coated tablets, capsules, pills, and granules, can be prepared using coatings and shells, for example, enteric coatings and other agents known in the art.

[0178] Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid formulation may also contain inactivating diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof. In addition to such inactivating diluents, the composition may also contain further agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, or fragrances.

[0179] The relative amounts of any of the active ingredients, pharmaceutically acceptable excipients, and / or further components in the pharmaceutical compositions of this disclosure may vary depending on the specificity, size, and / or condition of the target being treated, and further on the route by which the composition is administered. For example, the composition may contain 0.1(w / w)% to 100(w / w)% of the active ingredient.

[0180] The exact amount of compound required to achieve an effective dose varies from subject to subject, depending on factors such as the type of subject, age, and overall condition, the severity of side effects or disease, the specific compound, and the mode of administration. The desired dose can be delivered three times a day, twice a day, once a day, every two days, every three days, every week, every two weeks, every three weeks, or every four weeks. In one embodiment, the desired dose can be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more doses).

[0181] In one embodiment, an effective dose of the compound for administration once or more daily to a 70 kg adult human may contain approximately 0.001 mg to approximately 3,000 mg of the compound per unit formulation (for example, approximately 0.001 mg to approximately 2,000 mg, approximately 0.001 mg to approximately 1,000 mg, approximately 0.001 mg to approximately 500 mg, approximately 0.001 mg to approximately 100 mg, approximately 0.001 mg to approximately 50 mg, approximately 0.001 mg to approximately 10 mg, approximately 0.01 mg to approximately 1,000 mg, approximately 0.1 mg to approximately 1,000 mg, approximately 1 mg to approximately 1,000 mg, approximately 10 mg to approximately 1,000 mg, approximately 1 mg to approximately 500 mg, approximately 5 mg to approximately 250 mg).

[0182] In one embodiment, the compounds described herein are administered daily (once or more) at a dose of approximately 0.001 mg / kg to approximately 1,000 mg / kg of the subject's body weight (e.g., approximately 0.01 mg / kg to approximately 1,000 mg / kg, approximately 0.1 mg / kg to approximately 1,000 mg / kg, approximately 1 mg / kg to approximately 1,000 mg / kg, approximately 0.001 mg / kg to approximately 1 mg / kg) to obtain the desired therapeutic effect. It can be administered at dose levels sufficient to deliver the drug at approximately 00 mg / kg, approximately 0.001 mg / kg to approximately 10 mg / kg, approximately 0.001 mg / kg to approximately 1 mg / kg, approximately 0.1 mg / kg to approximately 40 mg / kg, approximately 0.5 mg / kg to approximately 30 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, or approximately 1 mg / kg to approximately 25 mg / kg.

[0183] In one embodiment, the medication plan may last for several days, weeks, months, or years.

[0184] The dose ranges described herein are understood to provide guidelines for the administration of pharmaceutical compositions intended for adults. For example, the amount to be administered to children or young people can be determined by a healthcare professional or a person skilled in the art and may be lower than or the same as the amount administered to adults.

[0185] It is also understood that the compounds or pharmaceutical compositions described herein may be administered in combination with one or more further therapeutic agents. In some embodiments, the compounds or pharmaceutical compositions provided herein are administered in combination with one or more further therapeutic agents that improve their bioavailability in the body, reduce and / or regulate their metabolism, inhibit their excretion, and / or modulate their distribution. It is also understood that the treatments used may achieve the desired effect on the same disease, and / or achieve different effects.

[0186] The compound or pharmaceutical composition may be administered simultaneously with, before, or after, one or more additional therapeutic agents. Generally, each agent is administered in a dose and / or time schedule determined for that agent. It is further understood that the additional therapeutic agents used in this combination may be administered together in a single composition or separately in different compositions. The specific combination used in the drug regimen takes into account the compatibility of the compound being administered with the additional therapeutic agents and / or the desired therapeutic effect to be achieved. Generally, it is expected that the additional therapeutic agents used in a combination will be used at levels that do not exceed the levels used individually. In some embodiments, the levels used in a combination are lower than the levels used individually.

[0187] Exemplary further therapeutic active agents include, but are not limited to, small organic molecules, e.g., drug compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, protein-binding small molecules, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0188] The substances, compositions, and components disclosed herein may be used for the disclosed methods and compositions, used in combination with the disclosed methods and compositions, used in the manufacture of the disclosed methods and compositions, or are products of the disclosed methods and compositions. While specific references to various individual and overall combinations and permutations of these compounds may not be explicitly disclosed, where combinations, subsets, interactions, groups, etc., of these substances are disclosed, each is understood to be expressly intended and described herein. For example, where a method is disclosed and described, and many possible modifications to many molecules included in the method are described, then all combinations and permutations of the method and each possible modification are expressly intended, unless otherwise indicated as being inconsistent. Similarly, any subset or combination of these is also expressly intended and described. This concept applies to all aspects of the disclosure, including, but not limited to, steps in methods using the compounds or compositions of the disclosure. Therefore, where various further steps may be performed, each of these further steps may be performed in any specific step or combination of steps of the disclosed method, and each such combination or subset of combinations should be understood as being specifically intended and disclosed.

[0189] Certain compounds of the present invention may exist in geometric or stereoisomeric form. The present invention encompasses all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are considered to be included in the present invention.

[0190] Isomer mixtures containing various isomer ratios may be used in the present invention. For example, when only two isomers are combined, mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 may be included in the present invention. Those skilled in the art will readily recognize that similar ratios are included for more complex isomer mixtures.

[0191] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary group, the resulting mixture of diastereoisomers is separated, the auxiliary group is cleaved, and the pure desired enantiomer is provided. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), the diastereomer salt is formed with a suitable optically active acid or base, the diasteomer is then separated by fractional crystallization or chromatography, which are well known in the art, and the pure enantiomer is subsequently recovered.

[0192] The following embodiments are illustrative of the embodiments of the present invention and are not intended to be limiting in any way. [Examples]

[0193] Abbreviation Certain abbreviations are listed below. methanol: MeOH Dichloromethane: DCM Petroleum ether: PE Acetyl acetate: acetyl acetate Triethylamine:TEA Sodium hydroxide: NaOH Nitrogen: N2 Diphenyl phosphate azide: DPPA Thin-layer chromatography: TLC High-performance liquid chromatography (HPLC) N,N-diisopropylethylamine: DIPEA N,N-dimethylformamide:DMF 4-Methylbenzene-1-sulfonyl chloride:TsCl Room temperature: RT Hours:

[0194] Typical Prep-HPLC method: (Flow rate and gradient may vary) An example of a Prep-HPLC method is provided below. Method A: NH4HCO3: (Column: XBrige Prep C18 5μm OBD 19) * 150 mm, PN186002979; Mobile phase: CH3CN in 20%-60% water (0.1% NH4HCO3), flow rate: 15 mL / min. Method B: (Column: XBridge Prep C18 5μm OBD 19) * 150mm, PN186002979; Mobile phase: CH3CN in 15%-40% water (0.1% formic acid), Flow rate: 15mL / min)

[0195] Typical HPLC analysis methods Method 1: Analysis was performed using the Agilent 1260 series HPLC-6120MS. UHPLC Long Gradient Equivalent: Acetonitrile in 5%-95% water (containing 0.02% NH4OAc) at a flow rate of 1.5 mL / min for 6.5 minutes. XBridge C18 column (5 μm, 4.6 * A 50mm (PN186003113) was used at a temperature of 40°C.

[0196] Method 2: Analysis was performed using an Agilent 1200 series HPLC-6120MS. UHPLC Long Gradient Equivalent: Acetonitrile (containing 0.1% trifluoroacetic acid) in 5%-95% water, flow rate 1.5 mL / min, flow time 6.5 minutes. XBridge C18 column (5 μm, 4.6 * A 50mm (PN186003113) was used at a temperature of 40°C.

[0197] Method 3: Analysis was performed using the Agilent 1260 series HPLC-6120MS. UHPLC Long Gradient Equivalent: Acetonitrile in 5%-95% water (containing 0.02% NH4OAc) at a flow rate of 2 mL / min for 6.5 minutes. Diamonsil Plus C18 column (5 μm, 4.6 * A 30mm (catalog #99436) was used at a temperature of 40°C.

[0198] Example 1 [ka] Step 1. 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1b) Compound 1a (30 g, 0.2 mol) and TsCl (45 g, 0.24 mol) were dissolved in a mixture of acetone and water (600 mL, V:V = 5:1), followed by the addition of NaOH (11.8 g, 0.29 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour, concentrated to 100 mL of solvent, and cooled with ice water. The resulting solid was filtered and dried to obtain the title product as a white solid (52 g, yield 86%). 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 5.2 Hz, 1H), 6.69 (d, J = 4.0 Hz, 1H), 2.37 (s, 3H).

[0199] Step 2. 4-Chloro-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1c) To a mixture of compound 1b (5.0 g, 16.3 mmol) and 75 mL of DCM, tetrabutylammonium nitrate (2.9 g, 21.3 mmol) was added gradually at 0°C, followed by the slow addition of trifluoroacetic anhydride (3.14 mL, 22.2 mmol). The mixture was stirred at room temperature for 16 hours, and additional amounts of tetrabutylammonium nitrate (0.58 g, 4.23 mmol) and trifluoroacetic anhydride (0.8 mL, 5.7 mmol) were added at 0°C. The mixture was warmed to room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (150 mL), washed with water (30 mL x 2), and then concentrated until dry. The residue was triturated in MeOH to obtain the title product as a white solid (3.15 g, yield 55%). LC-MS (Method 2): t R = 1.76 min, m / z (M+H) + = 351.8.

[0200] Step 3. Tert-butyl 3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)bicyclo[1.1.1]pentan-1-carboxylate(1d) Compound 1c (500 mg, 1.42 mmol), tert-butyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (313 mg, 1.71 mmol), and DIPEA (276 mg, 2.13 mmol) were dissolved in isopropanol (5 mL). The solution was stirred at 120 °C for 2 hours. After cooling, the formed solid was collected by filtration and dried to obtain the title product as a brown solid (612 mg, yield 86%). 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 9.11 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 5.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 5.6 Hz, 1H), 2.48 (s, 6H), 2.40 (s, 3H), 1.47 (s, 9H).

[0201] Step 4. Tert-butyl 3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)bicyclo[1.1.1]pentan-1-carboxylate(1e) Compound 1d (600 mg, 1.22 mmol) was dissolved in MeOH (6 mL), and then Pd / C (48 mg, 10% wt) was added all at once. The mixture was hydrogenated at room temperature for 16 hours (1 atm). The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (PE:siRNA = 1:1) to obtain the title product as a white solid (258 mg, yield 46%). LC-MS (Method 2): t R = 1.64 min, m / z (M+H) + = 469.0.

[0202] Step 5. Tert-butyl 3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-carboxylate(1f) Compound 1e (258 mg, 0.55 mmol), triethyl orthoformate (204 mg, 1.37 mmol), and p-toluenesulfonic acid (10 mg, 0.05 mmol) were dissolved in toluene (6 mL). The mixture was stirred at 120 °C for 16 hours. After cooling, the mixture was concentrated until dry. The residue was purified by chromatography on silica gel (eluent:PE:Â=1:1) to obtain the title product as a brown solid (191 mg, yield 73%). 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.27-7.25 (m, 2H), 6.83 (d, J = 4.4 Hz, 1H), 2.71 (s, 6H), 2.35 (s, 3H), 1.51 (s, 9H).

[0203] Step 6.3 - (6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-carboxylic acid (1g) To a solution of compound 1f (191 mg, 0.40 mmol) in DCM (2 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 16 hours and concentrated until dry to obtain the crude title product as a brown solid (170 mg, yield 100%). LC-MS (Method 2): t R = 1.47 min, m / z (M+H) + = 423.0

[0204] Step 7. Tert-butyl (3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(1h) To a mixture of 1 g (153 mg, 0.36 mmol) of the compound in tert-butanol (7.2 mL), DPPA (130 mg, 0.47 mmol) and TEA (73 mg, 0.72 mmol) were added under N2. The mixture was stirred at room temperature for 30 minutes, then raised to 90°C and stirred for a further 16 hours. After cooling, the mixture was concentrated until dry. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 50:1) to obtain the title product as a brown solid (160 mg, yield 89%). LC-MS (Method 2): t R = 1.71 min, m / z (M+H) + = 494.0.

[0205] Step 8. Tert-butyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(1i) To a solution of 160 mg (0.32 mmol) of the compound in MeOH (3 mL) and water (3 mL), NaOH (300 mg, 7.5 mmol) was added. The mixture was stirred at room temperature for 4 hours and concentrated. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined and concentrated until dry, and the residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 20:1) to obtain the title product as a white solid (60 mg, yield 55%). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.81 (s, 1H), 7.80 (s, 1H), 7.39 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 4.4 Hz, 1H), 5.30 (br s, 1H), 2.80 (s, 6H), 1.50 (s, 9H).

[0206] Step 9.3 - (Imidazou[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetate(1j) To a solution of compound 1i (60 mg, 0.18 mmol) in DCM (2 mL), TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated until dry to obtain the crude title product as a brown solid (100 mg, yield 100%). LC-MS (Method 2): t R = 0.309 min, m / z (M+H) + = 240.0

[0207] Step 10. N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(1) To a solution of compound 1 joule (40 mg, 0.16 mmol) and TEA (51 mg, 50 mmol) in DMF (1 mL), propane-1-sulfonyl chloride (28 mg, 0.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours, diluted with water (20 mL), and extracted with  (20 mL x 3). The organic layers were combined and concentrated until dry. The residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (10 mg, yield 18%). LC-MS (Method 1): t R = 2.71 min, m / z (M+H) + = 346.0. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 6.70 (d, J = 1.6 Hz, 1H), 3.08 (d, J = 8.8 Hz, 2H), 2.70 (s, 6H), 1.74 - 1.72 (m, 2H), 1.73 (d, J = 6.0 Hz, 3H).

[0208] Example 2 [ka] Step 1. Tert-butyl (cis-3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutyl)carbamate (2a) Compound 2a (380 mg) was synthesized in 89% yield using compound 1c (300 mg, 0.85 mmol) and tert-butyl (cis-3-aminocyclobutyl)carbamate (191 mg, 1.02 mmol) as starting materials, by the same preparation method as in step 3 of Example 1. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 9.04 (d, J = 6.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 4.4 Hz, 1H), 4.73 (br s, 1H), 4.07 (br s, 1H), 3.04 - 2.92 (m, 2H), 2.41 (s, 3H), 2.03 - 1.94 (m, 2H), 1.40 (s, 9H).

[0209] Step 2. Tert-butyl (cis-3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutyl)carbamate(2b) Compound 2b (300 mg) was synthesized in 84% yield using compound 2a (380 mg, 0.76 mmol) as the starting material and the same preparation method as in step 4 of Example 1. LC-MS (Method 1): t R = 1.63 min, m / z (M+H) + = 472.2

[0210] Step 3. Tert-butyl (cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)carbamate (2c) Compound 2c (260 mg) was synthesized in 85% yield using compound 2b (300 mg, 0.64 mmol) and triethoxymethane (236 mg, 1.59 mmol) as starting materials, by the same preparation method as in step 5 of Example 1. 1 H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 4.0 Hz, 1H), 4.73 (br s, 1H), 4.73 - 4.69 (m, 1H), 4.16 - 4.14 (m, 1H), 3.18 - 3.12 (m, 2H), 2.47 - 2.44 (m, 2H), 2.34 (s, 3H), 1.45 (s, 9H).

[0211] Step 4. Tert-butyl (cis-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)carbamate (2d) Compound 2d (165 mg) was synthesized in 93% yield using compound 2c (260 mg, 0.54 mmol) as the starting material, by the same preparation method as in step 8 of Example 1. LC-MS (Method 1): t R = 1.47 min, m / z (M+H) + = 328.1.

[0212] Step 5. cis-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutanamine 2,2,2-trifluoroacetate(2e) Compound 2e (199 mg, crude) was synthesized in 87% yield using compound 2d (165 mg, 0.50 mmol) as the starting material, by the same preparation method as in step 9 of Example 1. LC-MS (Method 1): t R = 0.22 min, m / z (M+H) + = 228.0.

[0213] Step 6. N-(cis-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)propan-1-sulfonamide(2) Example 2 (28.8 mg) was synthesized in 25% yield using compound 2e (160 mg, crude, 0.35 mmol) and propane-1-sulfonyl chloride (60 mg, 0.42 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.84 min, m / z (M+H) + = 334.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.58 (dd, J = 3.6, 2.0 Hz, 1H), 4.95 - 4.90 (m, 1H), 3.86 - 3.80 (m, 1H), 3.10 - 3.24 (m, 2H), 3.00 - 2.96 (m, 2H), 2.54 - 2.47 (m, 2H), 1.73 - 1.67 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0214] Example 3 [ka] Step 1. Tert-butyl (trans-3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutyl)carbamate (3a) Compound 3a (0.64 g) was synthesized in 89% yield using compound 1c (500 mg, 1.42 mmol) and tert-butyl (trans-3-aminocyclobutyl) carbamate (318 mg, 1.71 mmol) as starting materials, by the same preparation method as in step 1 of Example 2. 1 H NMR (400 MHz, CDCl3) δ 9.16 (d, J = 5.2 Hz, 1H), 9.11 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 4.0 Hz, 1H), 4.81 (br s, 1H), 4.50 (br s, 1H), 4.33 (br s, 1H), 2.57 - 2.46 (m, 4H), 2.40 (s, 3H), 1.45 (s, 9H).

[0215] Step 2. Tert-butyl (trans-3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutyl)carbamate(3b) Compound 3b (0.45 g) was synthesized in 75% yield using compound 3a (0.64 g, 1.28 mmol) as the starting material and the same preparation method as in step 2 of Example 2. LC-MS (Method 1): t R = 1.61 min, m / z (M+H) + = 472.2.

[0216] Step 3. Tert-butyl (trans-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)carbamate(3c) Compound 3c (160 mg) was synthesized in 35% yield using compound 3b (0.45 g, 0.95 mmol) and triethoxymethane (432 mg, 2.91 mmol) as starting materials, by the same preparation method as in step 3 of Example 2. 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.11 - 8.07 (m, 3H), 7.79 (d, J = 4.0 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.70 (d, J = 4.0 Hz, 1H), 5.21- 5.14 (m, 1H), 4.90 (br s, 1H), 4.37 (br s, 1H), 2.93 - 2.86 (m, 2H), 2.79 - 2.73 (m, 2H), 2.35 (s, 3H), 1.46 (s, 9H).

[0217] Step 4. Tert-butyl (trans-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)carbamate(3d) Compound 3d (100 mg) was synthesized in 92% yield using compound 3c (160 mg, 0.33 mmol) as the starting material, by the same preparation method as in step 4 of Example 2. LC-MS (Method 1): t R = 1.32 min, m / z (M+H) + = 328.2.

[0218] Step 5. Trans-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutanamine 2,2,2-trifluoroacetate(3e) Compound 3e (60 mg, crude) was synthesized in 43% yield using compound 3d (100 mg, 0.31 mmol) as the starting material, by the same preparation method as in step 5 of Example 2. The crude product was used in the next step without further purification.

[0219] Step 6. N-(trans-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)propane-1-sulfonamide(3) Example 3 (29.6 mg) was synthesized in 34% yield using compound 3e (60 mg, 0.26 mmol) and propane-1-sulfonyl chloride (45 mg, 0.31 mmol) as starting materials, by the same preparation method as in the final step of Example 2. LC-MS (Method 1): t R = 2.68 min, m / z (M+H) + = 334.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 6.72 (dd, J = 3.2, 2.0 Hz, 1H), 5.34 - 5.27 (m, 1H), 4.10 - 4.05 (m, 1H), 3.02 - 2.90 (m, 4H), 2.73 - 2.66 (m, 2H), 1.73 - 1.64 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0220] Example 4 [ka] 3-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-sulfonamide(4) Example 4 (22.6 mg) was synthesized in 28% yield using compound 1j (50 mg, 0.21 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (45 mg, 0.25 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.01 min, m / z (M+H) + = 384.1. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.68 (dd, J = 1.6, 3.2 Hz, 1H), 4.07 (t, J = 8.4 Hz, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.81 - 3.77 (m, 1H), 2.70 (s, 6H).

[0221] Example 5 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-2-methylpropane-1-sulfonamide(5) Example 5 (6.9 mg) was synthesized in 11% yield using compound 1j (43 mg, 0.18 mmol) and 2-methylpropane-1-sulfonyl chloride (34 mg, 0.22 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.10 min, m / z (M+H) + = 360.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.54 (t, J = 3.6 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 3.04 (d, J = 8.4 Hz, 2H), 2.73 (s, 6H), 2.22 - 2.13 (m, 1H), 1.10 (d, J = 8.8 Hz, 6H).

[0222] Example 6 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-2-methoxyethanesulfonamide(6) Example 6 (21.1 mg) was synthesized in 31% yield using compound 1j (45 mg, 0.19 mmol) and 2-methoxyethanesulfonyl chloride (36 mg, 0.23 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.48 min, m / z (M+H) + = 362.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.11 (s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.69 (dd, J = 1.6, 3.2 Hz, 1H), 3.72 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.37 (s, 3H), 2.70 (s, 6H).

[0223] Example 7 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclopropanesulfonamide(7) Example 7 (15.5 mg) was synthesized in 25% yield using compound 1j (43 mg, 0.18 mmol) and cyclopropanesulfonyl chloride (30 mg, 0.21 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.02 min, m / z (M+H) + = 344.1. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.69 (dd, J = 1.6, 3.2 Hz, 1H), 2.71 (s, 6H), 2.69 - 2.67 (m, 1H), 1.05 - 1.00 (m, 4H).

[0224] Example 8 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methylbutanamide(8) Example 8 (17.3 mg) was synthesized in 26% yield using compound 1j (50 mg, 0.21 mmol) and 3-methylbutanoyl chloride (38 mg, 0.31 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.43 min, m / z (M+H) + = 324.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 6.69 (dd, J = 2.0, 3.6 Hz, 1H), 2.72 (s, 6H), 2.00 - 1.99 (m, 3H), 0.90 (d, J = 6.4 Hz, 6H).

[0225] Example 9 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)butylamide(9) Example 9 (12.4 mg) was synthesized in 14% yield using compound 1j (50 mg, 0.21 mmol) and butyryl chloride (53 mg, 0.32 mmol) as starting materials, by the same preparation method as in the final step of Example 1. The final compound was purified by Prep-HPLC (Method B). LC-MS (Method 1): t R = 3.06 min, m / z (M+H) + = 310.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 7.63 (s, 1H), 6.82 (s, 1H), 2.75 (s, 6H), 2.09 (t, J = 7.6 Hz, 2H), 1.58 - 1.49 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0226] Example 10 [ka] Isobutyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(10) Example 10 (2.3 mg) was synthesized in 3% yield using compound 1j (50 mg, 0.21 mmol) and isobutyl carbonochloride (31 mg, 0.230 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.38 min, m / z (M+H) + = 340.2. 1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.03 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.76 (s, 1H), 3.77 (s, 2H), 2.72 (s, 6H), 1.91 - 1.78 (m, 1H), 0.88 (d, J = 5.2 Hz, 6H).

[0227] Example 11 [ka] Step 1.3-(6-(triisopropylsilyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-amine(11a) To a solution of 1 joule (200 mg, 0.84 mmol) of the compound in DMF (2 mL), NaH (100 mg, 2.56 mmol, 60% in mineral oil) was added at 0°C. The mixture was stirred at 0°C for 1 hour. TIPSCl (240 mg, 1.28 mmol) was added to the reaction mixture at 0°C. The mixture was stirred for 4 hours, diluted with H2O (30 mL), and extracted with ELISA (50 mL). The organic layer was separated and concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title product as a colorless oil (150 mg, yield 45%). LC-MS (Method 3): t R = 1.94 min, m / z (M+H) + = 396.2.

[0228] Step 2.2-Cyano-N-(3-(6-(triisopropylsilyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)acetamide(11b) To a solution of compound 11a (150 mg, 0.39 mmol) and 2-cyanoacetic acid (65 mg, 0.76 mmol) in DMF (2 mL), HATU (433 mg, 1.14 mmol) and DIPEA (147 mg, 1.14 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title compound (150 mg, yield 83%) as a white solid. LC-MS (Method 3): t R = 1.87 min, m / z (M+H) + = 463.2.

[0229] Step 3.2-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)acetamide(11) To a solution of compound 11b (150 mg, 0.32 mmol) in THF (4 mL), TBAF (0.49 mL, 0.49 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (33 mg, yield 34%). LC-MS (Method 1): t R = 2.89 min, m / z (M+H) + = 307.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.18 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.69 (dd, J = 2.0, 3.6 Hz, 1H), 3.70 (s, 2H), 2.75 (s, 6H).

[0230] Example 12 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclopropanecarboxamide(12) Example 12 (6 mg) was synthesized in 9% yield using compound 1j (50 mg, 0.21 mmol) and cyclopropane carbonyl chloride (33 mg, 0.31 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.23 min, m / z (M+H) + = 308.1. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.97 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 6.70 (dd, J = 1.6, 3.2 Hz, 1H), 2.73 (s, 6H), 1.58 - 1.54 (m, 1H), 0.74 - 0.69 (m, 4H).

[0231] Example 13 [ka] 2-Cyclopropyl-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)acetamide(13) To a solution of 2-cyclopropylacetic acid (200 mg, 2.0 mmol) in DCM (2 mL), DMF (1 drop) and oxalate chloride (508 mg, 4.0 mmol) were added dropwise at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-cyclopropylacetyl chloride (236 mg, crude) as a white solid.

[0232] To a solution of compound 1j (50 mg, 0.21 mmol) and DIPEA (270 mg, 2.1 mmol) in DMF (1 mL), 2-cyclopropylacetyl chloride (37.2 mg, 0.315 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was purified by Prep-HPLC (Method B) to obtain the title compound (30 mg, yield 44%) as a white solid. LC-MS (Method 1): t R = 2.96 min, m / z (M+H) + = 322.2; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 7.61 (t, J = 2.8 Hz, 1H), 6.81 (s, 1H), 2.76 (s, 6H), 2.03 (d, J = 7.2 Hz, 2H), 1.01 - 0.95 (m, 1H), 0.48 - 0.44 (m, 2H), 0.13 (dd, J1= 5.2 Hz, J2= 10.0 Hz, 2H).

[0233] Example 14 [ka] 3-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propanamide(14) Example 14 (8.8 mg) was synthesized in 13% yield using compound 1j (50 mg, 0.21 mmol) and 3-cyanopropanoic acid (69 mg, 0.69 mmol) as starting materials, by the same preparation method as in Example 13. LC-MS (Method 1): t R = 2.84 min, m / z (M+H) + = 321.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 7.50 (t, J = 2.4 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 2.74 (s, 6H), 2.66 (t, J = 7.2 Hz, 2H), 2.44 - 2.39 (m, 2H).

[0234] Example 15 [ka] 4-Chloro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)benzamide(15) Example 15 (15 mg) was synthesized in 19% yield using compound 1j (50 mg, 0.21 mmol) and 4-chlorobenzoyl chloride (54 mg, 0.31 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.48 min, m / z (M+H) + = 378.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.41 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 3.2 Hz, 1H), 6.73 (dd, J = 1.6, 3.2 Hz, 1H), 2.84 (s, 6H).

[0235] Example 16 [ka] Isopropyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(16) Example 16 (15.3 mg) was synthesized in 21% yield using compound 1j (55 mg, 0.23 mmol) and isopropyl chloroformate (0.23 mL, 1 mol / L, 0.23 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.79 min, m / z (M+H) + = 326.2. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 8.07 (br s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 6.68 (dd, J = 1.6, 3.2 Hz, 1H), 4.83 - 4.77 (m, 1H), 2.67 (s, 6H), 1.21 (d, J = 5.6 Hz, 6H).

[0236] Example 17 [ka] 3,3-Difluoro-N-(3-(Imidazou[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclobutanecarboxamide(17) Example 17 (3.7 mg) was synthesized in 4% yield using compound 1j (50 mg, 0.21 mmol) and 3,3-difluorocyclobutane carbonyl chloride (49 mg, 0.32 mmol) as starting materials, by the same preparation method as in the final step of Example 1. The title compound was purified by Prep-HPLC (Method B). LC-MS (Method 1): t R = 3.11 min, m / z (M+H) + = 358.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.49 (t, J = 2.8 Hz, 1H), 6.70 (dd, J = 1.6, 3.2 Hz, 1H), 2.89 - 2.87 (m, 1H), 2.76 - 2.68 (m, 10H).

[0237] Example 18 [ka] 4,4,4-Trifluoro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)butanamide(18) Example 18 (29.9 mg) was synthesized in 39% yield using compound 1j (50 mg, 0.21 mmol) and 4,4,4-trifluorobutanoic acid (60 mg, 0.42 mmol) as starting materials, by the same preparation method as in Example 13. LC-MS (Method 1): t R = 2.82 min, m / z (M+H) + = 364.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.91 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.49 (t, J = 2.8 Hz, 1H), 6.69 (dd, J = 2.0 Hz, 3.6 Hz, 1H), 2.73 (s, 6H), 2.57 - 2.52 (m, 2H), 2.42 - 2.39 (m, 2H).

[0238] Example 19 [ka] Cyclopropylmethyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(19) Cyclopropylmethanol (30 mg, 0.42 mmol) and TEA (63 mg, 0.63 mmol) were dissolved in THF (1 mL). The resulting solution was cooled to -30°C, and then a solution of bis(trichloromethyl)carbonate (124 mg, 0.42 mmol) in THF (1 mL) was added dropwise at the same temperature. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Next, a solution of compound 1j (50 mg, 0.21 mmol) and TEA (63 mg, 0.63 mmol) in THF / DMSO (1 mL / 0.5 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour, diluted with DCM (10 mL), and washed with saline solution (5 mL). The organic layer was separated and concentrated to obtain a residue, which was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (2.4 mg, 3% yield). LC-MS (method 1): t R = 8.49 min, m / z (M+H) + = 338.2. 1 H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.12 (s, 1H), 7.47 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H), 3.92 (s, 2H), 2.81 (s, 6H), 1.17 - 1.15 (m, 1H), 0.59 - 0.57 (m, 2H), 0.32 - 0.30 (m, 2H).

[0239] Example 20 [ka] 3-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)pyrrolidine-1-sulfonamide(20) Compound 20a (100 mg, 0.76 mmol) and TEA (267 mg, 2.64 mmol) were dissolved in DCM (2 mL), and then a solution of SO2Cl2 (122 mg, 0.91 mmol) in 6.0 mL of DCM was added dropwise at -78°C. The mixture was stirred at -78°C for 30 minutes and then warmed to room temperature. HCl aqueous solution (1 N, 10 mL) and saline solution (10 mL) were added to the solution. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated until dry to obtain a brown oily substance. This was then dissolved in DCM (0.5 mL). The resulting solution was added at room temperature to a mixture of compound 1j (80 mg, 0.335 mmol) and DIPEA (130 mg, 1.005 mmol) in THF (2 mL) and DMSO (0.4 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with siRNA (30 mL x 3). The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated until dry to obtain the residue, which was purified by Prep-HPLC (Method A) to obtain the title product as a yellow solid (12 mg, 9% yield). LC-MS (Method 1): t R = 2.96 min, m / z (M+H) + = 398.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.51 - 7.49 (m, 1H), 6.68 - 6.67 (m, 1H), 3.52 - 3.49 (m, 2H), 3.44 - 3.41 (m, 1H), 3.29 - 3.27 (m, 2H), 2.71 - 2.68 (m, 6H), 2.34 - 2.29 (m, 1H), 2.22 - 2.16 (m, 1H).

[0240] Example 21 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methoxyazetidine-1-sulfonamide(21) Example 21 (13 mg) was synthesized in 16% yield using compound 1j (50 mg, 0.21 mmol) and compound 21a (150 mg, 1.21 mmol) as starting materials, by the same preparation method as in Example 20. LC-MS (Method 1): t R = 2.87 min, m / z (M+H) + = 389.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 6.67 (s, 1H), 4.18 (s, 1H), 3.95 (d, J = 6.4 Hz, 2H), 3.66- 2.65 (m, 2H), 3.23 (s, 3H), 2.69 (s, 6H).

[0241] Example 22 [ka] 3-Fluoro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-sulfonamide(22) Example 22 (13 mg) was synthesized in 16% yield using compound 1j (50 mg, 0.21 mmol) and compound 22a (200 mg, 1.79 mmol) as starting materials, by the same preparation method as in Example 20. LC-MS (Method 1): t R = 2.88 min, m / z (M+H) + = 377.1. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 7.51 (t, J = 3.2 Hz, 1H), 6.67 (d, J = 0.8 Hz, 1H), 5.47 - 5.44 (m, 0.5H), 5.32 - 5.30 (m, 0.5H), 4.15 - 4.06 (m, 2H), 3.93 - 3.84 (m, 2H), 2.69 (s, 6H).

[0242] Example 23 [ka] 3,3-Difluoro-N-(3-(Imidazol[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-sulfonamide(23) Example 23 (8.0 mg) was synthesized in 10% yield using compound 1j (50 mg, 0.21 mmol) and compound 23a (200 mg, 1.54 mmol) as starting materials, by the same preparation method as in Example 20. LC-MS (Method 1): t R = 3.15 min, m / z (M+H) + = 395.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.93 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.51 (t, J = 2.8 Hz, 1H), 6.67 (dd, J = 1.6, 3.2 Hz, 1H), 4.29 (t, J = 12.8 Hz, 4H), 2.68 (s, 6H).

[0243] Example 24 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-N'-dimethyl-1-sulfonamide(24) To a solution of compound 1j (60 mg, 0.25 mmol) and DIPEA (130 mg, 1.00 mmol) in THF (1.5 mL) and DMSO (0.5 mL), a solution of dimethylsulfamoyl chloride (36 mg, 0.25 mmol) in 0.5 mL of THF was added dropwise at 0°C. The mixture was stirred at 25°C for 14 hours. The mixture was diluted with H2O (15 mL) and extracted by DCM (20 mL x 2). The organic layers were combined, concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (15 mg, yield 17%). LC-MS (Method 1): t R = 2.59 min, m / z (M+H) + = 347.1. 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.02 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.2 Hz, 1H), 2.73 (s, 6H), 2.68 (s, 6H).

[0244] Example 25 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-N'-methyl-N'-ethyl-1-sulfonamide(25) A mixture consisting of compound 1j (70 mg, 0.29 mmol), Et3N (148 mg, 1.46 mmol), K2CO3 (404 mg, 2.93 mmol), and ACN (3 mL) was added dropwise to 0.5 mL of a solution of ethyl (methyl)sulfamoyl chloride (46.0 mg, 0.29 mmol) in ACN at 0°C. The mixture was stirred at 30°C for 14 hours. The mixture was diluted with H2O (20 mL) and extracted by DCM (40 mL x 2). The organic layers were combined and concentrated until dry. The residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (8.0 mg, 9% yield). LC-MS (Method 1): t R = 2.96 min, m / z (M+H) + = 361.1. 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.02 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 3.17 (q, J = 7.2 Hz, 2H), 2.75 (s, 3H), 2.68 (s, 6H), 1.14 (t, J = 7.2 Hz, 3H).

[0245] Example 26 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methoxypropane-1-sulfonamide(26) Example 26 (15 mg) was synthesized in 12% yield using compound 1j (80 mg, 0.33 mmol) and 3-methoxypropane-1-sulfonyl chloride (58 mg, 0.33 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.11 min, m / z (M+H) + = 376.1. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.50 (s, 1H), 6.69 (s, 1H), 3.45 (s, 4H), 3.09 (s, 3H), 2.68 (s, 6H), 1.93 (s, 2H).

[0246] Example 27 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)ethanesulfonamide(27) Example 27 (11 mg) was synthesized in 16% yield using compound 1j (50 mg, 0.21 mmol) and ethanesulfonyl chloride (35 mg, 0.27 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.36 min, m / z (M+H) + = 332.1. 1 H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.68 (s, 1H), 7.73 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 3.16 (q, J = 7.2 Hz, 2H), 2.90 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H).

[0247] Example 28 [ka] 4-Chloro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide(28) Example 28 (12.4 mg) was synthesized in 14% yield using compound 1j (50 mg, 0.21 mmol) and 4-chlorobenzene-1-sulfonyl chloride (58 mg, 0.27 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.94 min, m / z (M+H) + = 414.0. 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 2.52 (s, 6H).

[0248] Example 29 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-1-methyl-1H-pyrazole-4-sulfonamide(29) Example 29 (5.5 mg) was synthesized in 7% yield using compound 1j (50 mg, 0.21 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (49 mg, 0.27 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.41 min, m / z (M+H) + = 384.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 6.59 - 6.58 (m, 1H), 3.91 (s, 3H), 2.56 (s, 6H).

[0249] Example 30 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-2-sulfonamide(30) Example 30 (3.4 mg) was synthesized in 5% yield using compound 1j (50 mg, 0.21 mmol) and propane-2-sulfonyl chloride (39 mg, 0.27 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.50 min, m / z (M+H) + = 346.1. 1 H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 7.53 (t, J = 2.7 Hz, 1H), 6.72 (d, J = 1.2 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.72 (s, 6H), 1.32 (d, J = 6.9 Hz, 6H).

[0250] Example 31 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)butan-1-sulfonamide(31) Example 31 (10 mg) was synthesized in 13% yield using compound 1j (50 mg, 0.21 mmol) and butane-1-sulfonyl chloride (66 mg, 0.42 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.13 min, m / z (M+H) + = 360.1. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J = 3.6 Hz, 1H), 6.85 (d, J = 3.2 Hz, 1H), 3.18 - 3.14 (m, 2H), 2.84 (s, 6H), 1.86 - 1.80 (m, 2H), 1.58 - 1.52 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

[0251] Example 32 [ka] 3,3,3-trifluoro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(32) Example 32 (4.7 mg) was synthesized in 6% yield using compound 1j (50 mg, 0.21 mmol) and 3,3,3-trifluoropropane-1-sulfonyl chloride (62 mg, 0.32 mmol) as starting materials, by the same preparation method as in the final step of Example 1. The final compound was purified by Prep-HPLC (Method B) to obtain the title compound. LC-MS (Method 1): t R = 3.17 min, m / z (M+H) + = 400.1. 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.41 (s, 1H), 7.55 (d, J = 3.6 Hz, 1H), 6.92 (d, J = 3.6 Hz, 1H), 3.31 - 3.27 (m, 2H), 2.79 (s, 6H), 2.67 - 2.61 (m, 2H). 19 F NMR (376 MHz, CD3OD) δ -67.55.

[0252] Example 33 [ka] 1-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide(33) Example 33 (4.5 mg) was synthesized in 6% yield using compound 1j (50 mg, 0.21 mmol) and cyanomethanesulfonyl chloride (45 mg, 0.32 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 3.32 min, m / z (M+H) + = 343.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.75 - 6.74 (m, 1H), 4.87 (s, 2H), 2.75 (s, 6H).

[0253] Example 34 [ka] 1-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-propylurea(34) To a well-stirred solution consisting of compound 1j (50 mg, 0.21 mmol), THF (0.6 mL), and DMSO (0.2 mL), 1-isocyanatopropane (36 mg, 0.42 mmol) was added. The mixture was stirred at 30°C for 3 hours. The mixture was concentrated until dry to produce a residue, which was purified by Prep-HPLC (Method A) to obtain the title product (27.3 mg, 40% yield) as a pale yellow solid. LC-MS (Method 1): t R = 2.80 min, m / z (M+H) + = 325.2. 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 7.48 (t, J = 2.8 Hz, 1H), 6.75 - 6.70 (m, 2H), 5.91 (t, J = 5.6 Hz, 1H), 2.99 - 2.94 (m, 2H), 2.66 (s, 6H), 1.42 - 1.37 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0254] Example 35 [ka] 1-Cyclopropyl-3-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)urea(35) Example 35 (29.6 mg) was synthesized in 44% yield using compound 1j (50 mg, 0.21 mmol) and isocyanatocyclopropane (35 mg, 0.42 mmol) as starting materials, by the same preparation method as in Example 34. LC-MS (Method 1): t R = 2.83 min, m / z (M+H) + = 323.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 6.77 (s, 1H), 6.71 (dd, J = 2.0 Hz, 3.6 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 2.67 (s, 6H), 2.45- 2.41 (m, 1H), 0.60 - 0.56 (m, 2H), 0.38 - 0.34 (m, 2H).

[0255] Example 36 [ka] 1-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-isobutylurea(36) Example 36 (17.4 mg) was synthesized in 25% yield using compound 1j (50 mg, 0.21 mmol) and 1-isocyanato-2-methylpropane (41 mg, 0.42 mmol) as starting materials, by the same preparation method as in Example 34. LC-MS (Method 1): t R = 3.23 min, m / z (M+H) + = 339.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 7.48 (t, J = 3.2 Hz, 1H), 6.73 (s, 1H), 6.72 (dd, J = 1.6, 3.2 Hz, 1H), 5.95 (t, J = 5.6 Hz, 1H), 2.84 (t, J = 6.4 Hz, 2H), 2.66 (s, 6H), 1.67 - 1.61 (m, 1H), 0.84 (d, J = 6.8 Hz, 6H).

[0256] Example 37 [ka] 3,3-difluoro-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-carboxamide(37) To a well-stirred solution consisting of compound 1j (50 mg, 0.21 mmol), TEA (74 mg, 0.73 mmol), DCM (1.0 mL), and DMSO (0.5 mL), CDI (68 mg, 0.42 mmol) was added all at once. The mixture was stirred at room temperature for 2 hours. The resulting reaction solution was added to a solution of 3,3-difluoroazetidine hydrochloride (95 mg, 0.73 mmol) and TEA (84 mg, 0.84 mmol) in DCM (1 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (1.1.1 mg, yield 15%). LC-MS (Method 1): t R = 2.79 min, m / z (M+H) + = 359.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 6.67 (s, 1H), 4.25 (t, J = 12.8 Hz, 4H), 2.69 (s, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -99.31.

[0257] Example 38 [ka] N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methoxyazetidine-1-carboxamide(38) Example 38 (26.6 mg) was synthesized in 36% yield using compound 1j (50 mg, 0.21 mmol) and 3-methoxyazetidine hydrochloride (90 mg, 0.73 mmol) as starting materials, by the same preparation method as in Example 37. LC-MS (Method 1): t R = 2.77 min, m / z (M+H) + = 353.2. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.14 (br s, 1H), 4.01 - 3.98 (m, 2H), 3.65 - 3.61 (m, 2H), 3.20 (s, 3H), 2.66 (s, 6H).

[0258] Example 39 [ka] 3-Cyano-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)pyrrolidine-1-carboxamide(39) Example 39 (12 mg) was synthesized in 16% yield using compound 1j (50 mg, 0.21 mmol) and pyrrolidine-3-carbonitride hydrochloride (97 mg, 0.73 mmol) as starting materials, by the same preparation method as in Example 37. LC-MS (Method 1): t R = 2.82 min, m / z (M+H) + = 362.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.49 (t, J = 3.2 Hz, 1H), 7.25 (s, 1H), 6.68 (dd, J = 1.6, 3.2 Hz, 1H), 3.60 - 3.56 (m, 1H), 3.49 - 3.34 (m, 4H), 2.69 (s, 6H), 2.27 - 2.22 (m, 1H), 2.16 - 2.11 (m, 1H).

[0259] Example 40 [ka] 1-(2-cyano-2-methylpropyl)-3-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)urea(40) Example 40 (21.4 mg) was synthesized in 28% yield using compound 1j (50 mg, 0.21 mmol) and 3-amino-2,2-dimethylpropanenitrile 4-methylbenzenesulfonate (198 mg, 0.73 mmol) as starting materials, by the same preparation method as in Example 37. LC-MS (Method 1): t R = 3.26 min, m / z (M+H) + = 364.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 7.49 (s, 1H), 6.96 (s, 1H), 6.72 (s, 1H), 6.38 - 6.35 (m, 1H), 3.22 (d, J = 6.4 Hz, 2H), 2.68 (s, 6H), 1.26 (s,6H).

[0260] Example 41 [ka] 1-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-(2,2,2-trifluoroethyl)urea(41) Example 41 (19.6 mg) was synthesized in 21% yield using compound 1j (60 mg, 0.25 mmol) and 2,2,2-trifluoroethaneamine (87 mg, 0.88 mmol) as starting materials, by the same preparation method as in Example 37. LC-MS (Method 1): t R = 3.09 min, m / z (M+H) + = 365.1. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.58 (s, 1H), 8.10 (s, 1H), 7.49 (t, J = 2.8 Hz, 1H), 7.17 (s, 1H), 6.71 (dd, J = 1.6, 3.2 Hz, 1H), 6.58 (t, J = 6.4 Hz, 1H), 3.88 - 3.79 (m, 2H), 2.68 (t, J = 8.0 Hz, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -71.54.

[0261] Example 42 [ka] 2-Cyano-2-methylpropyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate(42) Example 42 (2.2 mg) was synthesized in 3% yield using compound 1j (50 mg, 0.21 mmol) and 3-hydroxy-2,2-dimethylpropanenitrile (50 mg, 0.73 mmol) as starting materials, by the same preparation method as in Example 19. LC-MS (Method 1): t R = 3.23 min, m / z (M+H) + = 365.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.49 (s, 1H), 6.69 (s, 1H), 4.04 (s, 2H), 2.71 (s, 6H), 1.35 (s, 6H).

[0262] Example 43 [ka] 1-(2-cyanoethyl)-3-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)urea(43) Example 43 (12.8 mg) was synthesized in 18% yield using compound 1j (50 mg, 0.21 mmol) and 3-aminopropanenitrile (51 mg, 0.73 mmol) as starting materials, by the same preparation method as in Example 37. LC-MS (Method 1): t R = 2.60 min, m / z (M+H) + = 336.2. 1 H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 8.13 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 3.6 Hz, 1H), 3.43 (t, J = 6.4 Hz, 2H), 2.84 (s, 6H), 2.68 (t, J = 6.8 Hz, 2H).

[0263] Example 44 [ka] Step 1. Methyl cis-3-aminocyclobutane-1-carboxylate TFA(44b) To a solution of compound 44a (500 mg, 2.18 mmol) in 5 mL of DCM, TFA (2.5 mL) was added at 0°C. The solution was stirred at 0°C to 5°C for 1.5 hours. The solution was concentrated to obtain the title product as a colorless oil (530 mg, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (br s, 2H), 3.62 - 3.59 (m, 4H), 3.02 - 2.93 (m, 1H), 2.46 - 2.39 (m, 2H), 2.29 - 2.21 (m, 2H).

[0264] Step 2. Methyl cis-3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutanecarboxylate (44c) Compound 44c (760 mg) was synthesized in 78% yield using 4-chloro-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (765 mg, 2.18 mmol) and compound 44b (530 mg, 2.18 mmol) as starting materials, by the same preparation method as in step 3 of Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.87 (m, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 4.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 4.0 Hz, 1H), 4.59 - 4.53 (m, 1H), 3.61 (s, 3H), 3.04 - 2.97 (m, 1H), 2.75 - 2.68 (m, 2H), 2.36 (s, 3H), 2.33 - 2.26 (m, 2H).

[0265] Step 3. Methyl cis-3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)cyclobutanecarboxylate (44d) Compound 44d (640 mg) was synthesized in 92% yield using compound 44c (750 mg, 1.69 mmol) as the starting material, by the same preparation method as in step 4 of Example 1. LC-MS (Method 3): t R = 1.55 min, m / z (M+H) + = 415.1.

[0266] Step 4. Methyl cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutanecarboxylate (44e) Compound 44e (550 mg) was synthesized in 84% yield using compound 44d (640 mg, 1.54 mmol) and triethoxymethane (571 mg, 3.86 mmol) as starting materials, by the same preparation method as in step 5 of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 3.6 Hz, 1H), 5.22 - 5.17 (m, 1H), 3.34 (s, 3H), 3.19 - 3.12 (m, 1H), 2.89 - 2.82 (m, 2H), 2.74 - 2.66 (m, 2H), 2.32 (m, 3H).

[0267] Step 5. (Cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methanol (44f) To a solution of compound 44e (550 mg, 1.30 mmol) in 5 mL of dry THF, LiAlH4 (73.9 mg, 1.94 mmol) was added at 0°C. The mixture was stirred at room temperature for 1.5 hours. After cooling to 0°C, the reaction mixture was quenched with 0.1 mL of water, 0.2 mL of 10% NaOH solution, and then 0.3 mL of water. The mixture was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the crude title product as a white solid (450 mg, yield 88%). LC-MS (Method 3): t R = 1.43 min, m / z (M+H) + = 397.1.

[0268] Step 6. (Cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methylmethanesulfonate (44g) Compound 44f (450 mg, 1.13 mmol) and Et3N (344 mg, 3.40 mmol) were dissolved in DCM (15 mL), followed by the addition of MsCl (196 mg, 1.70 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was diluted with water (100 mL) and extracted with ELISA (150 mL). The organic layer was separated, washed with saline solution (40 mL), dried over Na2SO4, and filtered. The filtrate was concentrated until dry to obtain the crude title compound (539 mg, 100% yield) as a yellow solid. LC-MS (Method 3): t R = 1.35 min, m / z (M+H) + = 475.1.

[0269] Step 7. S-((cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methyl)ethanethioate (44h) 44 g (535 mg, 1.13 mmol) of the compound and potassium thioacetate (386 mg, 3.38 mmol) were mixed in DMF (16 mL) and then heated at 50°C for 5 hours. The reaction mixture was diluted with water (100 mL) and extracted with ELISA (150 mL). The organic layer was separated and concentrated. The residue was purified by reverse-phase chromatography (ACN in water (5-95%)) to obtain the crude title compound (338 mg, yield 66%) as a yellow solid. LC-MS (Method 3): t R = 1.53 min, m / z (M+H) + = 455.1.

[0270] Step 8. (Cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methanesulfonic acid (44i) A 0.55 mL, 30% aqueous hydrogen peroxide solution was added dropwise to a stirred suspension of the compound (330 mg, 0.73 mmol) in 4 mL of formic acid. The resulting mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated to obtain the title compound (334 mg, 100% yield) as a white solid. LC-MS (Method 3): t R = 0.81 min, m / z (M+H)+ = 461.1.

[0271] Step 9. (Cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methanesulfonyl chloride (44j) A mixture of compound 44i (330 mg, 0.73 mmol) in DCM (50 mL) and DMF (1.0 mL) was mixed with thionyl chloride (930 mg, 7.82 mmol). The reaction mixture was then heated at 50°C for 3 hours. The mixture was concentrated to obtain the title compound (334 mg, 100%) as a yellow solid. A small amount of the reaction solution was mixed with MeOH for analysis. LC-MS (Method 3): t R = 1.60 min, m / z (M+H) + = 475.1.

[0272] Step 10. N-methyl-1-(cis-3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methanesulfonamide (44k) Compound 44j (200 mg, 0.42 mmol) was added at 0°C to a solution consisting of CH3NH2·HCl (34 mg, 0.50 mmol), TEA (127 mg, 1.25 mmol), and DCM (2 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL). The separated organic layer was washed with water (30 mL x 2) and concentrated to obtain the crude title product as a white solid (25 mg, yield 13%). LC-MS (Method 3): t R = 1.43 min, m / z (M+H) + = 474.1.

[0273] Step 11.1-(cis-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)-N-methylmethanesulfonamide (44) Compound 44k (22 mg, 0.05 mmol) and LiOH·H2O (10 mg, 0.05 mmol) were dissolved in a mixture of i-PrOH and H2O (2.5 mL, V:V=4:1). The solution was stirred at 60°C for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (20 mL). The separated organic layer was concentrated, and the residue was purified by Prep-HPLC (Method A) to obtain the title compound (3.7 mg, yield 25%) as a white solid. LC-MS (Method 1): t R = 2.37 min, m / z (M+H) + = 320.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.42 (s, 1H), 7.46 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 3.6 Hz, 1H), 5.26 - 4.86 (m, 1H), 3.38 - 3.33 (m, 2H), 3.09 - 3.02 (m, 2H), 2.86 - 2.80 (m, 1H), 2.76 (s, 3H), 2.54 - 2.47 (m, 2H).

[0274] Example 45 [ka] Step 1.1-(((Cis-3-(6-Tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methyl)sulfonyl)azetidine-3-carbonitride(45a) Compound 45a (80 mg) was synthesized in 64% yield using compound 44j (120 mg, 0.25 mmol) and azetidine-3-carbonitride hydrochloride (32 mg, 0.26 mmol) as starting materials, by the same preparation method as in step 10 of Example 44. LC-MS (Method 3): t R = 1.50 min, m / z (M+H) + = 525.1.

[0275] Step 2.1-(((Cis-3-(Imidazol[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)cyclobutyl)methyl)sulfonyl)azetidine-3-carbonitride(45) A mixture of compound 45a (40 mg, 0.08 mmol) and Mg powder (73 mg, 3.05 mmol) in MeOH (2 mL) was placed in an ultrasonic bath for 1.5 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC (Method A) to obtain the title product as an off-white solid (1.4 mg, 5% yield). LC-MS (Method 1): t R = 3.04 min, m / z (M+H) + = 371.1. 1 H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.42 (s, 1H), 7.46 (d, J = 3.6 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 5.28 - 4.86 (m, 1H), 4.29 - 4.24 (m, 2H), 4.16 - 4.13 (m, 2H), 3.75 - 3.69 (m, 1H), 3.50 - 3.43 (m, 2H), 3.07 - 3.01 (m, 2H), 2.89 - 2.85 (m, 1H), 2.56 - 2.48 (m, 2H).

[0276] Example 46 [ka] Step 1. (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate (46b) A mixture of (3,3-difluorocyclobutyl)methanol (1 g, 8.19 mmol), DMAP (100 mg, 0.82 mmol), and TEA (1.24 g, 12.29 mmol) in DCM (10 mL) was mixed with TsCl (889 mg, 9.83 mmol) at 0°C and warmed to room temperature. The mixture was stirred overnight at room temperature, diluted with 20 mL of DCM, washed with water (10 mL) and saline solution (10 mL), and dried over Na₂SO₄. The mixture was filtered, and the filtrate was concentrated to obtain the crude title compound (1.89 g of crude product, yield 79%) as a yellow oil.

[0277] Step 2. Benzyl ((3,3-difluorocyclobutyl)methyl)sulfane (46c) A mixture of compound 46b (100 mg, 0.36 mmol) and benzyl carbaminimidothionate hydrochloride (88 mg, 0.43 mmol) in DMF (0.5 mL) was mixed with NaOH (36 mg, 0.90 mmol) in H2O (0.5 mL). The mixture was stirred overnight at 60°C. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 80:1) to obtain the crude title product as a yellow oil (82 mg, 99% yield). 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 5H), 3.70 (s, 2H), 2.71 - 2.60 (m, 2H), 2.55 (d, J = 7.2 Hz, 2H), 2.32 - 2.14 (m, 3H).

[0278] Step 3.1-(3,3-difluorocyclobutyl)-N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide(46) A mixture consisting of compound 46c (82 mg, 0.36 mmol), DCM (1.5 mL), and H2O (0.4 mL) was mixed with SO2Cl2 (418 mg, 3.09 mmol) at -5°C. The mixture was stirred at 0°C for 30 minutes. Subsequently, ice water (15 mL) was added, and the mixture was extracted with DCM (20 mL x 2). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (0.5 mL), and this solution was added at 0°C to a mixture of compound 1j (100 mg, 0.44 mmol) and DIPEA (170 mg, 1.31 mmol) in THF (1.5 mL) and DMSO (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (15 mL) and extracted with ELISA (20 mL x 2). The organic layers were combined and concentrated. The residue was purified by prep-TLC (DCM:MeOH=25:1) and prep-HPLC (Method A) to obtain the title product as a yellow solid (14 mg, 8% yield). LC-MS (Method 1): t R = 2.98 min, m / z (M+H) + = 408.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.12 (s, 1H), 7.51 (t, J = 2.8 Hz, 1H), 6.71 (t, J = 1.6 Hz, 1H), 3.39 - 3.38 (m, 2H), 2.82 - 2.75 (m, 2H), 2.72 (s, 6H), 2.62 - 2.53 (m, 3H).

[0279] Example 47 [ka] Step 1. Tert-butyl (3-(propylsulfonamide)bicyclo[1.1.1]pentan-1-yl)carbamate (47b) To a solution of compound 47a (1.0 g, 5.04 mmol) and Et3N (1.5 g, 15.1 mmol) in DCM (1.5 mL), propane-1-sulfonyl chloride (1.0 g, 7.56 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours, diluted with water (100 mL), and extracted with DCM (100 mL x 2). The organic layers were combined, washed with brine (100 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated to obtain the title compound (1.45 g, yield 97%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.55 (s, 1H), 2.94 - 2.90 (m, 2H), 2.05 (s, 6H), 1.69 - 1.59 (m, 2H), 1.37 (s, 9H) 1.03 - 0.91 (m, 3H).

[0280] Step 2. N-(3-aminobicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(47c) To a solution of compound 47b (1.45 g, 4.77 mmol) in SiO2 (20 mL), HCl (g) in SiO2 (2 M, 20 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain the title compound (1.2 g, crude product, yield ~100%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 3H), 8.25 (s, 1H), 2.98 - 2.95 (m, 2H), 2.13 (s, 6H), 1.73 - 1.61 (m, 2H), 1.03 - 0.96 (m, 3H).

[0281] Step 3. N-(3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(47d) Compound 47d (2.4 g) was synthesized in 100% yield using compound 47c (1.2 g, 4.99 mmol) and compound 1c (1.6 g, 4.54 mmol) as starting materials, by the same preparation method as in step 3 of Example 1. LC-MS (Method 3): t R = 1.68 min, m / z (M+H) + = 520.1

[0282] Step 4. N-(3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(47e) To a solution consisting of compound 47d (2.4 g, 4.62 mmol), NH4Cl (1.2 g, 23.1 mmol), MeOH (900 mL), and H2O (300 mL), Fe powder (905 mg, 16.2 mmol) was added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (2.2 g, 95.6%, crude product) as a brown solid. LC-MS (Method 3): t R = 1.44 min, m / z (M+H) + = 490.1.

[0283] Step 5. (R)-N-(3-(2-(1-hydroxyethyl)-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propan-1-sulfonamide(47f) (R)-2-hydroxypropanamide (136 mg, 1.53 mmol) and triethyloxonium tetrafluoroborate (291 mg, 1.53 mmol) were dissolved in THF (5 mL), and the resulting mixture was stirred at room temperature under N2 for 30 minutes. Compound 47e (150 mg, 0.31 mmol) in EtOH (5 mL) was then added to the reaction mixture. The mixture was stirred at 85°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were combined, concentrated, and the residue was purified by prep-TLC (DCM:MeOH = 10:1) to obtain the desired compound (55 mg, yield 50%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 8.99 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 4.0 Hz, 1H), 5.53 (d, J = 7.2 Hz, 1H), 5.07 - 5.04 (m, 1H), 3.09 - 3.05 (m, 2H), 2.81 (s, 6H), 2.32 (s, 3H), 1.75 - 1.70 (m, 2H), 1.61 (d, J = 6.0 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).

[0284] Step 6. (R)-N-(3-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propan-1-sulfonamide(47) To a solution of compound 47f (55 mg, 0.10 mmol) in a mixture of MeOH and H2O (5.5 mL, V:V=1:5), NaOH (12 mg, 0.30 mmol) was added all at once. The mixture was stirred at 30°C for 25 hours, and the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL x 2). The separated aqueous layer was concentrated until dry, and the residue was purified by Prep-HPLC (Method A) to obtain the title compound (10 mg, yield 16%) as a white solid. LC-MS (Method 1): t R = 2.98 min, m / z (M+H) + = 390.2. 1 H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 7.48 (s, 1H), 6.88 (s, 1H), 5.26 (s, 1H), 3.13 (s, 2H), 3.00 (s, 6H), 1.89 - 1.88 (m, 2H), 1.78 (s, 3H), 1.12 (s, 3H).

[0285] Example 48 [ka] Step 1. N-(3-(2-methyl-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propan-1-sulfonamide(48a) Compound 48a (89 mg) was synthesized in 57% yield using compound 47e (150 mg, 0.31 mmol) and 1,1,1-triethoxyethane (124 mg, 0.76 mmol) as starting materials, by the same preparation method as in step 5 of Example 1. LC-MS (Method 3): t R = 1.52 min, m / z (M+H) + = 514.1.

[0286] Step 2. N-(3-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propan-1-sulfonamide(48) To a solution of compound 48a (85 mg, 0.17 mmol) in MeOH and H2O (3.3 mL, V:V=1:10), NaOH (20 mg, 0.50 mmol) was added all at once. The mixture was stirred at 30°C for 20 hours, and the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL x 2). The separated aqueous layer was concentrated until dry, and the residue was purified by Prep-HPLC (Method A) to obtain the title compound (5 mg, 8% yield) as a white solid. LC-MS (Method 1): t R = 3.22 min, m / z (M+H) + = 360.2. 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.37 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 3.05 - 3.01 (m, 2H), 2.84 (s, 6H), 2.62 (s, 3H), 1.80 - 1.75 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H).

[0287] Example 49 [ka] Step 1. 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (49b) Compound 49b (15 g) was synthesized in 92% yield using compound 49a (10 g, 65 mmol) and TsCl (14.8 g, 78 mmol) as starting materials, by the same preparation method as in Step 1 of Example 1. 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 4.0 Hz, 1H), 2.40 (s, 3H).

[0288] Step 2. Tert-butyl 3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-carboxylate(49c) Compound 49b (294 mg, 0.95 mmol), tert-butyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (210 mg, 1.14 mmol), and DIPEA (247 mg, 1.91 mmol) were dissolved in NMP (1.5 mL). The mixture was stirred at 160 °C for 6 hours under microwave irradiation. After cooling, the mixture was diluted with water (40 mL) and extracted with SiO (30 mL x 2). The organic layers were combined and concentrated until dry, and the residue was purified by chromatography on silica gel (eluent:PE:SiO = 3:1) to obtain the title product as a white solid (400 mg, yield 92%). 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 4.0 Hz, 1H), 5.34 (s, 1H), 2. 43 (s, 6H), 2.37 (s, 3H), 1.44 (s, 9H).

[0289] Step 3. Tert-butyl 3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-carboxylate(49d) To a solution of compound 49c (430 mg, 0.95 mmol) in dry THF (6 mL), LiHMDS (2.8 mL, 2.8 mmol, 1 M in THF) was added at -50°C. The mixture was stirred at 0°C for 30 minutes, and CH3I (268 mg, 1.89 mmol) was added to the solution. The mixture was stirred at 40°C for 1.5 hours. After cooling, the reaction mixture was quenched with saturated NH4Cl (20 mL) and water (20 mL). The mixture was extracted with  (30 mL x 2). The organic layers were combined and concentrated until dry, and the residue was purified by chromatography on silica gel (eluent:PE: = 1:1) to obtain the title product as a white solid (125 mg, yield 28%). 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 4.0 Hz, 1H), 3.25 (s, 3H), 2.47. (s, 6H), 2.37 (s, 3H), 1.46 (s, 9H).

[0290] Step 4.3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-carboxylic acid(49e) Compound 49e (154 mg) was synthesized in 100% yield using compound 49d (175 mg, 0.37 mmol) as the starting material, by the same preparation method as in step 6 of Example 1. LC-MS (Method 2): t R = 1.62 min, m / z (M+H) + = 412.9

[0291] Step 5. Tert-butyl (3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate(49f) Compound 49f (120 mg) was synthesized in 66% yield using compound 49e (154 mg, 0.37 mmol) as the starting material, by the same preparation method as in step 7 of Example 1. LC-MS (Method 2): t R = 1.85 min, m / z (M+H) + = 484.2.

[0292] Step 6. Tert-butyl (3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (49g) Compound 49 g (40 mg) was synthesized in 49% yield using compound 49f (120 mg, 0.25 mmol) as the starting material, by the same preparation method as in step 8 of Example 1. LC-MS (Method 2): t R = 1.50 min, m / z (M+H) + = 330.2.

[0293] Step 7.N 1 -methyl-N 1 -(7H-pyrrolo[2,3-d]pyrimidine-4-yl)bicyclo[1.1.1]pentan-1,3-diamine 2,2,2-trifluoroacetate (49h) Compound 49h (55 mg, crude) was synthesized in 100% yield using compound 49 g (40 mg, 0.12 mmol) as the starting material and the same preparation method as in step 9 of Example 1. LC-MS (Method 2): t R = 0.22 min, m / z (M+H) + = 230.0.

[0294] Step 8. N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide(49) Compound 49 (1.8 mg) was synthesized in 4% yield using compound 49h (55 mg, crude, 0.12 mmol) and propane-1-sulfonyl chloride (21 mg, 0.15 mmol) as starting materials, by the same preparation method as in the final step of Example 1. LC-MS (Method 1): t R = 2.72 min, m / z (M+H) + = 336.1. 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.07 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 3.40 (s, 3H), 3.06 - 3.02 (m, 2H), 2.53 (s, 6H), 1.86 - 1.79 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H).

[0295] Example 50 [ka] Step 1. Benzyl (cis-3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclobutyl)carbamate (50a) Compound 49b (420 mg, 1.36 mmol), benzyl ((cis)-3-(methylamino)cyclobutyl)carbamate hydrochloride (350 mg, 1.50 mmol), and DIPEA (614 mg, 4.76 mmol) were dissolved in i-PrOH (7 mL). The mixture was stirred at 75°C for 7 hours. Subsequently, the mixture was filtered. The filtered cake was washed with i-PrOH and dried to obtain the title product as a white solid (580 mg, yield 88%). LC-MS (Method 2): t R = 1.79 min, m / z (M+H) + =506.2.

[0296] Step 2. Sys-N 1 -methyl-N 1 -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)cyclobutan-1,3-diamine hydrobromide (50b) Compound 50a (250 mg, 0.49 mmol) was dissolved in HBr (7 mL, 33% in CH3COOH) and CH3COOH (2 mL). The solution was stirred at 90°C for 0.5 hours. The mixture was concentrated until dry to obtain the crude title product as a brown solid (170 mg, crude, yield 65%). LC-MS (Method 2): t R = 1.34 min, m / z (M+H) + =372.1.

[0297] Step 3. N-(cis-3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclobutyl)propan-1-sulfonamide (50c) A mixture of 50b (170 mg, crude, 0.46 mmol) and DIPEA (614 mg, 4.76 mmol) in DCM (8 mL) was inoculated at 0°C to obtain 3-cyanoazetidine-1-sulfonyl chloride (163 mg, 1.14 mmol). The mixture was stirred at room temperature for 3 hours, diluted with water (70 mL), and extracted with DCM (50 mL). The separated organic layer was concentrated until dry to obtain the crude title product as a brown solid (218 mg, 100% yield). LC-MS (Method 2): t R = 1.58 min, m / z (M+H) + =478.1.

[0298] Step 4. N-(cis-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)cyclobutyl)propan-1-sulfonamide(50) Compound 50c (215 mg, 0.45 mmol) was dissolved in i-PrOH and H2O (5.8 mL, V:V=25:4), followed by the addition of LiOH·H2O (95 mg, 2.25 mmol) all at once. The mixture was stirred at 60°C for 13 hours, diluted with water (30 mL), and then extracted with ELISA (50 mL). The separated organic layer was concentrated until dry. The residue was purified by Prep-HPLC (Method A) to obtain the title product as a white solid (50.0 mg, yield 35%). LC-MS (Method 1): t R= 2.80 min, m / z (M+H) + = 324.1; 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.10 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.15 - 7.14 (m, 1H), 6.63 (d, J = 1.2 Hz, 1H), 4.92 - 4.88 (m, 1H), 3.60 - 3.54 (m, 1H), 3.25 (s, 3H), 2.94 (t, J = 7.6 Hz, 2H), 2.62 - 2.60 (m, 2H), 2.26 - 2.19 (m, 2H), 1.73 - 1.64 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0299] Biochemical assay JAK activity was investigated by microfluidic assay in reaction buffer (50 mM HEPES, 0.01% Brij35, 10 mM MgCl2, 2 mM DTT). Phosphorylation of FAM-labeled peptide substrates was monitored using a Caliper EZ Reader II (Perkin Elmer). Measurement conditions for each batch of enzyme (Carna Biosciences) were optimized to achieve a 10% conversion rate of the peptide substrate.

[0300] The test compound was dissolved in DMSO at a storage concentration of 10 mM. The compound, serially diluted 3-fold at a maximum concentration of 5 μM, was pre-incubated with JAK1, JAK2, or TYK2 at ambient temperature for 10 minutes. The final DMSO concentration of the assay mixture was 1%. The kinase reaction was initiated at 28°C by sequentially adding FAM-labeled peptide substrate (final concentration 3 μM) and ATP (Km concentration or 1 mM). The reaction was stopped by adding 50 mM EDTA.

[0301] Wells in the test plate that did not contain the enzyme were defined as 100% inhibition. Wells that did not contain the compound but contained the same amount of DMSO were defined as no inhibition. The inhibition percentage was calculated using the following formula. Inhibition % = (Conversion rate)最大 - Conversion rate サンプル ) / (conversion rate 最大 - Conversion rate 最小 )*100 Conversion rate 最大 This refers to the conversion rate in the positive well where no compound has been added. Conversion rate 最小 This refers to the conversion rate in wells where no enzyme was added. Conversion rate サンプル This represents the conversion rate of the test compound.

[0302] Dose-response (inhibition percentage) curves were plotted, and IC50 values ​​were determined using GraphPad software. The IC50 values ​​for the test compounds are listed in Table 2. Table 2 [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0303] Antiproliferative assay A dimerized domain of the Tel protein, fused with a JAK kinase domain, was persistently introduced into BaF3 cells, and the proliferation of these cells became dependent on JAK activity in the absence of IL-3 induction. Using these created BaF3-Tel-JAK cells, the JAK inhibitory activity of compounds in the cells was monitored.

[0304] BaF3-Tel-JAK cells were cultured in RPMI-1640 (Corning) containing 10% fetal bovine serum. Cells were seeded at a rate of 2000 cells / well in a white, flat-bottomed, 96-well plate. A well containing only culture medium was used as a background control. After 24 hours of growth, the cells were treated with a compound. The test compound was dissolved in DMSO to a 10 mM storage concentration. The compound was then added to each well in nine sequentially diluted concentrations (3-fold) at a maximum concentration of 10 μM. The final DMSO concentration was 0.2%. The cells were grown for 72 hours after compound treatment at 37°C with 5% CO2. Cell viability was measured by cell ATP assay using the Cell-Titer Glo-luciferase reagent (Promega). Luminescence values ​​were recorded using a multi-label reader, Envision (PerkinElmer). The values ​​were converted to inhibition percentages using the following formula. Inhibition %=(Read value) 最大 -Read value サンプル ) / (read value 最大 -Read value 最小 )*100 Wells that do not contain the compound but contain the same amount of DMSO, reading 最大 It was stipulated as follows. Wells containing only DMSO, similar to the culture medium, are read. 最小 It was stipulated as follows.

[0305] Dose-response (inhibition percentage) curves were plotted, and the GI50 value (concentration that produces 50% growth inhibition) was determined using GraphPad software. The GI50 values ​​of the test compounds are shown in Table 3. Table 3 [Table 12]

[0306] Human liver microsome stability test: Commercially available human liver microsomes (supplier: Corning) were used in the Phase 1 stability test of the test substance.

[0307] Microsomes were pre-incubated with the test compound or control compound in 100 mM potassium phosphate buffer (pH 7.4, 3.3 mM MgCl2) at 37°C for 10 minutes. The reaction was initiated by adding 80 μL of NADPH regeneration system to 320 μL of each incubation mixture at time points. The final incubation conditions were 0.5 mg / mL of microsomal protein, 1 μM of test substance / positive control, 1.3 mM NADP, 3.3 mM glucose-6-phosphate, and 0.6 U / mL of glucose-6-phosphate dehydrogenase. Samples at minute 0 were prepared by precipitating the protein by adding a fixed amount of 80 μL of each incubation mixture to 400 μL of quench reagent. Subsequently, a fixed amount of 20 μL of NADPH regeneration system was added. At 10, 30, and 90 minutes, the reaction was stopped by adding cold acetonitrile solutions (tolbutamide and propanolol) used as internal standards. Samples collected at all time points were centrifuged at 4000 × g for 15 minutes. 160 μL of ultrapure water was pre-added to 80 μL of supernatant collected in a 96-well assay plate, and the mixture was then analyzed by LC / MS / MS (Shimadzu LC30AD & API4000 / API5000).

[0308] The concentrations of the test substance and control compound in the sample were determined using LC / MS / MS. Chromatographic plotting and peak area integration were performed using Analyst (AB Sciex).

[0309] In determining the in vitro disappearance constant (ke) of the control compound, the analyte / internal standard peak area ratio is expressed by the following formula: [Table 13] Convert to remaining percentage (remaining%) using this method.

[0310] The CLint of microsomes was calculated using the formula: CLint(mic) = 0.693 / T1 / 2 / mg microsomal protein (per mL). An example of the results is summarized in Table 4. Table 4 [Table 14]

[0311] Pharmacokinetic studies in rats: The pharmacokinetic profiles of the test substance were evaluated using fasted Sprague Dolly rats. Typically, rats were administered 1 mg / kg and 2 mg / kg via intravenous injection and oral tube feeding, respectively. Blood samples were collected at various time points after administration. For the IV injection group, time points were set at 5, 15, and 30 minutes post-administration, followed by 1, 2, 4, 8, and 24 hours. For the oral tube feeding group, time points were set at 15 and 30 minutes post-administration, followed by 1, 2, 4, 8, and 24 hours. Blood was collected in appropriately labeled tubes containing K2EDTA as an anticoagulant. Plasma was obtained within 1 hour of blood collection by centrifugation at 8000 × g for 6 minutes at 4°C and stored at -20°C until analysis by LC / MS / MS for quantification.

[0312] PK parameter values ​​(including, but not necessarily limited to, maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and area under the plasma concentration curve (AUC) from 0 to 24 hours (AUC0-24h)) were determined using the WinNonlin program. Example results are summarized in Table 5. Table 5 [Table 15]

[0313] Conclusion: Examples 1 and 4 exhibit excellent pharmacokinetic profiles in rats. The applicant's disclosure is described herein in preferred embodiments with reference to drawings in which similar figures represent the same or similar configurations. Throughout this specification, the terms “one embodiment,” “embodiment,” or similar terms refer to a particular feature, structure, or property described in relation to an embodiment that is included in at least one embodiment of the present invention. Thus, the terms “one embodiment,” “embodiment,” and similar terms in this specification refer to the same embodiment, but not all of them.

[0314] The features, structures, or properties described in the applicant's disclosure may be combined with any suitable method in one or more embodiments. Many specific details are provided herein to provide an understanding of embodiments of the invention. However, those skilled in the art will understand that the applicant's compositions and / or methods may be carried out without using one or more specific details, or using other methods, structures, materials, etc. In other examples, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of this disclosure.

[0315] In this specification and in the claims, the singular forms "a," "an," and "the" include multiple subjects unless the context specifically indicates otherwise.

[0316] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Methods and substances similar to or equivalent to those described herein may also be used in the present practice or experiment, but preferred methods and substances are described herein. The methods described herein may be performed in any logically possible order, in addition to the specific order disclosed herein.

[0317] Import by reference This publication is referenced and cited in other literature, including patents, patent applications, patent publications, journals, books, articles, and web content. All such literature is incorporated herein by reference in its entirety for any purpose. Any substance or part thereof that is incorporated herein by reference but conflicts with existing definitions, descriptions, or other disclosed substances expressly provided herein is incorporated only to the extent that it does not create a conflict between the incorporated substance and the substances of this disclosure. Where such a conflict exists, the conflict should be resolved by prioritizing this disclosure as the preferred disclosure.

[0318] Equal portions The aforementioned representative embodiments are intended to illustrate the present invention and are not intended to limit the scope of the invention, nor should they be construed as limiting it. In fact, various modifications of the invention and many further embodiments are apparent to those skilled in the art from the entirety of this specification, including the examples and references to scientific and patent documents included herein, in addition to those shown and described herein. The aforementioned embodiments contain important further information, examples, and inducements that enable the application of the invention to its various embodiments and equivalents.

Claims

1. Structural formula (I): 【Chemistry 1】 (I) [In the formula, R １ is hydrogen, C １ -C ６ The group is selected from unsubstituted or substituted alkyl groups, OR', COOR', and CONR'R''; R ２ teeth, 【Chemistry 2】 [In the formula, each R Ｌ This is CH2. And, R2 is NR'C(=O)R ｘ , NR'C(=O)OR ｘ , NR'C(=O)NR ｘ R ｙ , C(=O)NR ｘ R ｙ , CR'R''SO ２ R ｘ , or CR'R''SONR ２ R ｘ R ｙ and is substituted by; Each R ３ These are, independently, hydrogen and C １ -C ６ The group is selected from unsubstituted or substituted alkyl groups, OR', COOR', and CONR'R''; R ４ Hydrogen, halogen, CN, C １ -C ６ The group is selected from unsubstituted or substituted alkyl groups, OR', and NHR'; R ｘ and R ｙ Each of these is independently a group selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or R ｘ and R ｙ They may together form a 3- to 7-membered ring, and also, R ｘ and R ｙ Each of these may be appropriately substituted with one or more of the following: halogen, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; Each of R' and R'' is independently hydrogen, and C １ -C ６ The group is selected from unsubstituted or substituted alkyl groups, or R' and R'' may together form a 3- to 7-membered ring; and n is either 1 or 2. The compound indicated by or its pharmaceutically acceptable salt or isotopic derivative.

2. R ４ However, it is H, structural formula (II): 【Transformation 3】 (II) The compound according to claim 1, as shown by [the formula].

3. R １ However, it is H, structural formula (IV): 【Chemistry 4】 (IV) The compound according to claim 1, as shown by [the formula].

4. R １ and R ４ The compound according to claim 1, wherein both are H.

5. R １ However, it is methyl, and R ４ The compound according to claim 1, wherein H is present.

6. R ３ The compound according to claim 4, wherein H is present.

7. R ３ The compound according to claim 5, wherein H is present.

8. A pharmaceutical composition comprising the compound according to claim 1, which is effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

9. A unit formulation comprising the pharmaceutical composition described in claim 8.

10. The use of the compound according to claim 1, and a pharmaceutically acceptable excipient or carrier, in the manufacture of a pharmaceutical product for treating a disease or disorder related to Janus kinase 1 (JAK1).

11. The use according to claim 10, wherein the disease or disorder is one or more inflammatory diseases, immune-mediated diseases, or cancer.

12. The use according to claim 11, wherein the disease or disorder is selected from asthma, allergy, arthritis, inflammatory bowel disease, endocrine disorders, neurodegenerative diseases, autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases, skin diseases, Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, graft rejection, or related diseases or disorders.

13. The use according to claim 12, wherein the disease or disorder is one or more of rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, DES, vitiligo, alopecia areata, and complete alopecia.

Images