Tricyclic Janus Kinase 1 Inhibitors and Compositions and Methods Thereof

Abstract

The present invention provides novel therapeutic agents that are safe and effective Janus kinase 1 inhibitors, as well as pharmaceutical compositions and methods for their preparation and use in the treatment of various diseases and disorders (e.g., inflammatory diseases, immune-mediated diseases, or cancer).

Description

[Technical field]

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

[0002] FIELD OF THE PRESENT ART The present invention relates generally to novel compounds and methods for their therapeutic use. More specifically, the present invention relates to a novel class of therapeutic agents that are safe and effective inhibitors of Janus kinase 1. The present invention also relates to pharmaceutical compositions of these compounds as well as methods for their preparation and use in the treatment of various diseases and disorders, such as inflammatory diseases, immune-mediated diseases, or cancer. [Background technology]

[0003] 2. Background of the Invention Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. There are four human JAK family enzymes: JAK1, JAK2, JAK3, and TYK2. The family is defined by the presence of two adjacent kinase domains, JH1 and JH2, of which JH1 is responsible for phosphorylation in pathway activation, while JH2 regulates 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 the common gamma chain receptor and the glycoprotein 130 (gp130) transmembrane protein (Murray, et al. 2007 Immunol. 178(5):2623-2629.). Approximately 40 cytokine receptors transduce through a combination of these four JAKs and their seven downstream products (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, through the communication of chemical signals from the outside of the cell to the cell nucleus, resulting in the activation of genes by transcription. Abnormalities in the JAK-STAT pathway can result in many diseases, such as cancer and diseases that affect the immune system.

[0006] JAK1 and JAK3 are components of a common gamma chain cytokine receptor complex, and blockade of 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 uniquely dependent on JAK1 (Guschin et al., EMBO J. 14(7): 1421- 1429, 1995), and clinical benefit in rheumatoid arthritis has been shown 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 required for immune system development, function and homeostasis, and JAK1 deficiency is prenatal lethal (Schindler, et al. 2007 J. Biol Chem. 282(28):20059-20063.). JAK2 deficiency in mice is also lethal due to loss during lung development, with JAK2 embryos dying between days 12 and 13 postimplantation (Neubauer et al. 1998 Cell 93(3):397-409.). JAK3 deficiency has been reported in humans, who display severe combined immunodeficiency in the first few months of life, with symptoms such as growth retardation, severe and recurrent infections, thrush, and diarrhea. JAK3-deficient infants display an absence of circulating T and NK cells, as well as abnormal B cell function. Furthermore, TYK2 deficiency has been reported in humans, showing impaired antibacterial responses, elevated serum IgE, and atopic dermatitis (Minegishi, et al, 2006 Immunity 25(5):745-755.).

[0008] Anti-cytokine therapy has become standard in the treatment of rheumatoid arthritis and other autoimmune diseases. Multiple clinical trials have shown 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 diverse treatment options, many autoimmune disease patients fail to undergo a significant reduction in disease activity. Although studies have shown that JAK blockade can be effective in controlling disease and achieving remission, first generation JAK inhibitors (e.g., tofacitinib and baricitinib) have failed to reach 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 have high selectivity for JAK over other kinase families, these inhibitors may not be the optimal choice for kinases within the JAK family. These effects can be increased 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.). Modulation of immune activity by inhibition of JAK1 kinase activity may prove useful in the treatment of various immune disorders while avoiding 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] Thus, despite current treatment options for inflammatory diseases, immune-mediated diseases or cancer and other diseases associated with JAK1, there exists an urgent unmet need for novel potent and selective JAK1 inhibitors with improved side effects and fewer side effects than existing therapeutics. Summary of the Invention

[0011] SUMMARY OF THE PRESENT APPLICATION 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 over currently available therapeutics. The present invention also provides pharmaceutical compositions of these compounds and methods for their preparation and therapeutic use.

[0012] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 with; Each R 3are 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, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R x and R y each of which may be 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., CHO-alkyl); Each of R' and R'' is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3-7 membered (e.g., 3 or 4 membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0013] In another aspect, the present invention generally provides a compound of 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 are 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'; R 5 is R x or NR x R y Where R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R x and R y each may be 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., CHO-alkyl); with the proviso that R 5 R x If R x is not H (i.e., R 5 is not H); Each R L are independently (CH2) mwherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge 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 be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0014] In yet another aspect, the present invention generally relates to pharmaceutical compositions comprising a compound according to the invention disclosed herein and a pharma- ceutical acceptable excipient, carrier, or diluent, which are effective in treating or ameliorating one or more diseases or disorders in a mammal, including a human.

[0015] In yet another aspect, the present invention generally provides a compound of structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 with; Each R3 are 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 R y is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R x and R y may be joined together to form a 3- to 7-membered ring, and R x and R y each of which 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 be joined together to form a 3- to 7-membered ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0016] In yet another aspect, the present invention generally provides a compound of structural formula (VII): [ka] (VII) [In the formula, R 1 is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 are independently selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 4is a group selected from hydrogen, halogen, CN, C1-C6 unsubstituted or substituted alkyl, OR', and NHR'; R 5 is R x or NR x R y Where R x and R y is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R x and R y may be joined together to form a 3- to 7-membered ring, and R x and R y each may be optionally substituted with one or more of halogen, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; provided that R 5 R x If R x is not H; Each R L are independently (CH2) m wherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge is absent; each R' and R'' is independently selected from hydrogen, and C1-C6 unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3- to 7-membered ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0017] In yet another aspect, the invention generally relates to a method for treating or ameliorating a disease or disorder, the method comprising administering to a mammal, including a human, a compound of structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 selected from cycloalkyl, bicycloalkyl, spirocyclic or bridged 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 with; Each R 3 are 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 R y is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R x and R y may be joined together to form a 3- to 7-membered ring, and R x and R y each of which 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 be joined together to form a 3- to 7-membered ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof to a subject in need thereof.

[0018] In yet another aspect, the present invention generally relates to a method for treating or ameliorating a disease or disorder, the method comprising administering to a mammal, including a human, a compound of structural formula (VII): [ka] (VII) [In the formula, R 1 is selected from hydrogen, C1-C6 unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 are 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 5 is R x or NR x R y Where R x and R y is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R x and R y may be joined together to form a 3- to 7-membered ring, and R x and R yeach may be optionally substituted with one or more of halogen, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; provided that R 5 R x If R x is not H; Each R L are independently (CH2) m wherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge is absent; each R' and R'' is independently selected from hydrogen, and C1-C6 unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3- to 7-membered ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutical composition comprising a pharma- ceutical acceptable excipient, carrier, or diluent to a subject in need thereof.

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

[0020] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharma- ceutically acceptable excipient, carrier, or diluent in the manufacture of a medicament for the treatment of a disease or disorder. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactions, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0022] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses within its scope all such compounds, including cis and trans isomers, atropisomers, R and S enantiomers, diastereomers, (d) isomers, (l) isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0023] Isomeric mixtures containing any of a variety of isomeric ratios may be used according to the present invention. For example, when only two isomers are combined, mixtures containing isomeric 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 isomeric mixtures.

[0024] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereoisomeric mixture separated, and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino group) or an acidic functional group (e.g., carboxyl group), a diastereomeric salt can be formed with a suitable optically active acid or base, and the diastereomers can then be resolved by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

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

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. When numerical ranges are given, each value and subrange within the range is intended to be included. For example, "C 1-6 Alkyl" is 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 include alkyl.

[0027] Where substituents are specified by their general chemical formula written from left to right, chemically identical substituents written from right to left in the structure are equivalently included, e.g., -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. Thus, when a group can be substituted with one or more of many substituents, such substitutions are selected to provide compounds that are compatible with the principles of chemical bonding and are not inherently unstable and / or are not known to those skilled in the art to be likely to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions).

[0029] As used herein, the term "alkyl" refers to an alkyl group having 1 to 10 carbon atoms (e.g., C 1-10As used herein, a numerical range such as "1-10" refers to each integer within the range; for example, "1-10 carbon atoms" means that the alkyl group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to and including 10 carbon atoms, and this definition also encompasses the description of the term "alkyl" without a numerical range specified. In certain embodiments, "alkyl" refers to a linear or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, without containing unsaturation. 1-6 It may be an alkyl group. In certain embodiments, the alkyl group has 1-10, 1-8, 1-6, or 1-3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched chain alkyls 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 is attached to the parent molecule by a single bond. Unless otherwise stated specifically in the specification, alkyl groups are independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, 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, phosphophate, 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 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted 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 an alkyl group having 1 to 10 carbon atoms (C 1-10"Alkoxy" refers to the group -O-alkyl, including straight chain, branched chain, saturated cyclic structures and combinations thereof. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In certain embodiments, C 1-3 Alkoxy is an alkoxy group that includes both straight and branched chain alkyl of 1 to 3 carbon atoms. Unless otherwise stated herein, alkoxy groups are independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, 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, phosphophate, 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)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 (wherein t is 1 or 2), -P(=O)(R a )(Ra ), or -OP(=O)(ORa)2 [wherein each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0031] As used herein, the term "aromatic" or "aryl" refers to a group having 6 to 14 ring atoms (e.g., C 6-14 Aromatic or C 6-14 In one embodiment, the aryl is 6-10It is an aryl group. For example, a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is referred to as a substituted phenylene group. In other embodiments, a divalent group derived from a monovalent polycyclic hydrocarbon group with the suffix "-yl" by removing one hydrogen atom with a free valence from a carbon atom is named by adding "-idene" to the name of the corresponding monovalent group, for example, a naphthyl group with two attachment points is referred to as naphthylidene. As described herein, a numerical range such as "6-14 aryl" refers to each integer within the range; for example, "6-14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, and so on up to and including 14 ring atoms. The term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and the like. In polycyclic groups, only one ring is required to be aromatic, so groups such as indanyl are included in the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless otherwise stated herein, aryl moieties can independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, 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, phosphophate, 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 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(ORa)2 [wherein each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0032] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic groups, respectively, that contain only carbon and hydrogen and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups may be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3-13As described herein, numerical ranges such as "3 to 10" refer to each integer within the range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and so on up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and the like. In certain embodiments, "cycloalkyl" refers to C 3-8 In some embodiments, "cycloalkyl" is a C 3-5 Examples of cycloalkyl groups include, but are not limited to, C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-7 Examples of carbocyclyl groups include norbornyl (C7). 3-8 Examples of the carbocyclyl group include the above-mentioned C 3-7 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. 3-13 Examples of carbocyclyl groups include those mentioned above. 3-8carbocyclyl groups, as well as octahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless otherwise stated herein, cycloalkyl groups are independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, 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, phosphophate, 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 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R aare independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. The 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 can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can be 5 to 13 ring atoms.

[0033] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term "halide" or "halo" refers to fluoro, chloro, bromo, or iodo. 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, 1-fluoromethyl-2-fluoroethyl, and the like. Each of the alkyl, alkenyl, alkynyl and alkoxy groups is as defined herein and can be further optionally substituted 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" refers to an alkyl group having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. For example, C 1-4 Numerical ranges are given to refer to the total chain length of a heteroalkyl, in this example, 4 atoms in length. For example, a -CH2OCH2CH3 group would be referred to as a "C4" heteroalkyl, with the heteroatom center included in the description of the chain length of atoms. The bond to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain. For example, an N-containing heteroalkyl moiety refers to a group in which at least one of the backbone atoms is a nitrogen atom. One or more heteroatoms in a heteroalkyl group may be optionally oxidized. One or more nitrogen atoms, if present, may also be optionally quaternized. For example, heteroalkyl also includes a backbone chain substituted with one or more nitrogen oxide (-O-) substituents. Example heteroalkyl groups include, but are not limited to, ethers, such as, for example, methoxyethanyl (-CH2CH2OCH3), ethoxymethanyl (-CHOCH2CH3), (methoxymethoxy)ethanyl (-CH2CH2OCH2OCH3), (methoxymethoxy)methanyl (-CH2OCH2OCH3), and (methoxyethoxy)methanyl (-CHOCH2CH2OCH3); amines, such as, for example, (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3)), and the like.

[0036] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring group ("5-18 membered heteroaryl") having ring carbon atoms and 1-6 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur) provided by an aromatic ring group (e.g., having 6, 10, or 14 π electrons shared in the ring structure). A heteroaryl polycyclic ring group can include one or more heteroatoms in one or both rings. As described herein, a numerical range such as "5-18" refers to each integer within the range; for example, "5-18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some examples, a heteroaryl can have 5-14 ring atoms. In certain embodiments, the heteroaryl is a divalent group derived from a monovalent heteroaryl group with the suffix "-yl" by removing one hydrogen atom along with the free valence from the atom, for example, the divalent group is named by adding "-ene" to the name of the corresponding monovalent group, e.g., a pyridyl group having two points of attachment is pyridylene.

[0037] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl group may be optionally oxidized. One or more nitrogen atoms, if present, may also be optionally quaternized. Heteroaryl also includes ring groups substituted with one or more nitrogen oxide (-O-) substituents, e.g., pyridine N-oxide. The heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0038] "Heteroaryl" also includes ring groups in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment to the parent molecular structure is on the aryl or heteroaryl ring, or a heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment to the parent molecular 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 point of attachment to the parent molecular structure can be on either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring group having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring group, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-8 membered aromatic ring group having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring group, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-6 membered aromatic ring group having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring group, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0039] Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, and the like. ranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[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, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl quinazolinyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5] These include thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated specifically herein, heteroaryl moieties are independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, 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, phosphophate, 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(NRa )N(R a )2, -N(R a )S(O) t N(R a )2 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2[where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0040] As used herein, the term "administer" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracerebral, intranasal, or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, into a subject. The route of administration suitable for a particular patient will depend on the characteristics and severity of the disease or condition being treated or the characteristics of the treatment being used, as well as the characteristics of the active compound.

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

[0042] By "co-administered" it is meant that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutics.

[0043] The compounds of the present invention can be administered alone or co-administered to patients. Co-administration is intended to include simultaneous or sequential administration of the compounds separately or in combination (one or more compounds or drugs). Thus, the formulations can also be combined with other active substances (e.g., to reduce metabolic degradation) if desired.

[0044] The composition of the present invention can be delivered by topical route, transdermal, and formulated as applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, and aerosol. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by patients. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, gels, for example, water or water / propylene glycol solutions.

[0045] The compositions of the present invention may further include components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and fine drug carrier materials. These components are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patent documents are incorporated by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered by intradermal injection of drug-containing microspheres for delayed subcutaneous release (see Rao, 1995 J. Biomater Sci. Polym. Ed. 7:623-645); as biodegradable and injectable gel formulations (see, e.g., Gao 1995 Pharm. Res. 12:857-863); or as microspheres for oral administration (see, e.g., Eyles 1997 J. Pharm. Pharmacol. 49:669-674).

[0046] As used herein, the terms "disease," "condition," and "disorder" are used interchangeably herein and refer to a condition of a patient or subject that is treated or can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0047] As used herein, the term "effective amount" of an active agent refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound 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, the terms "inhibition", "inhibit", and "inhibiting", etc., with respect to the interaction of a biological target (e.g., JAK) with an inhibitor, refer to negatively affecting (e.g., decreasing) the activity or function of a protein, compared to the activity or function of the protein in the absence of the inhibitor. In an embodiment, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein, compared to the concentration or level of the concentration or level in the absence of the inhibitor. In an embodiment, inhibition refers to a decrease in the activity of a particular protein target. Inhibition includes at least partially, partially, or fully preventing, decreasing, preventing, or delaying the activity, or inactivating, desensitizing, or downregulating the signaling or enzymatic activity or amount of the protein. In an embodiment, inhibition refers to a decrease in the activity of a target protein resulting from a direct interaction (e.g., an inhibitor binding to a target protein). In an embodiment, inhibition refers to a decrease in the activity of a target protein from an indirect interaction (e.g., an inhibitor binding 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" refer to material that is substantially or essentially free from components that normally accompany it in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high performance liquid chromatography.

[0050] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0051] In some embodiments, the pharma- ceutically acceptable form is a pharma- ceutically acceptable salt. As used herein, the term "pharma- ceutically acceptable salt" refers to a salt that is within the scope of sound medical judgment, suitable for use in contact with a subject without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharma- ceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange methods. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. , 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, valerate, and the like.In certain embodiments, organic acids from which salts can 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 situ during the isolation and purification of the disclosed compounds, or separately by reacting the free base or free acid of the parent compound with an appropriate base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-alkane salts. + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which are formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc.), 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 some embodiments, the pharma- ceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be of the disclosed compound or a pharma- ceutically acceptable salt thereof. When 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. It is understood that the term "compound" as used herein includes compounds and solvates of the compounds, as well as mixtures thereof.

[0054] In some embodiments, the pharma- ceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to produce a pharma- ceutically acceptable form of the disclosed compound or the compound. A prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in blood). In some cases, a prodrug has improved physiological and / or delivery properties than the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by allowing for enhanced absorption into the blood after oral administration) or enhance delivery to a biological structure of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced aqueous solubility or active transport across intestinal membranes compared to the parent compound.

[0055] The prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., 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 entireties.

[0056] Prodrug forms often offer advantages of solubility, tissue compatibility, or sustained release in 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 the parent acid with a suitable alcohol, amides prepared by reacting the parent acid compound with an amine, and base groups reacted to form acylated base derivatives. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. Thus, one skilled in the art will appreciate that certain disclosed compounds having free amino, amido, 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 above substituents disclosed herein.

[0057] Exemplary advantages of a prodrug include, but are not limited to, its physiological properties, such as increased aqueous solubility for parenteral administration at physiological pH, enhanced absorption from the gastrointestinal tract, or enhanced drug stability for long-term storage, as compared to the parent compound.

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

[0059] As used herein, the term "subject" refers to any animal (e.g., mammal), including, but not limited to, humans, non-human primates, rodents, etc. (recipients of a particular treatment). The subjects to which administration is contemplated include, but are 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 geriatrics)), and / or other non-human animals, e.g., non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice), etc. In some embodiments, the non-human animals are mammals. The non-human animals may be male or female at any stage of development. The non-human animals may be genetically modified animals. Typically, the terms "subject" and "patient" are used interchangeably herein with respect to human subjects.

[0060] As used herein, the term "treatment" of a disease or disorder or "treating" a disease or disorder refers to a method of alleviating, delaying, or alleviating a pre- or post-onset condition. Treatment can be directed to one or more effects or symptoms of a disease and / or its underlying pathology. Treatment can be any alleviation, including but not limited to, complete disappearance of a disease or symptoms of a disease. Thus, treating or treatment refers to any indication of success in treating or alleviating an injury, disease, lesion, or condition, including any objective or subjective parameter, such as alleviation; mitigation; reducing symptoms or making the injury, lesion, or condition tolerable to the patient; slowing the rate of degeneration or decline; not attenuating the end point of degeneration; improving the physical or mental health of the patient. Treatment or alleviation of symptoms can be based on objective or subjective parameters, such as the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation. The degree of such reduction or alleviation, as compared to comparable untreated controls, can be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as measured by any standard technique.

[0061] The method of treatment includes administering to a subject a therapeutically effective amount of a compound described herein. The administration step may be a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It is also understood that the effective dose of the agent used in the treatment may increase or decrease over the course of a particular treatment regimen. Dose changes can be determined and clarified by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the composition is administered to the subject in an amount and for a period sufficient to treat the patient.

[0062] Detailed Description of the Invention The present invention is based on the unexpected discovery of a new class of selective and potent JAK1 therapeutics that can be orally and / or locally utilized.The present invention also provides pharmaceutical compositions of these compounds and their preparation and use methods.The JAK1 inhibitors disclosed herein have shown exceptional potency and selectivity profiles.

[0063] More specifically, the novel JAK1 inhibitors disclosed herein enjoy improved potency as 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 as indicated by their superior specificity (e.g., IC50 values ​​for JAK2 >20xJAK1).

[0064] In one aspect, the present invention generally provides a compound of structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 with; Each R 3are 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, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R x and R y each of which may be 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., CHO-alkyl); Each of R' and R'' is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0065] In certain embodiments of Formula (I), R 4 is H, and the compound has structural formula (II): [ka] (II) As shown in the figure.

[0066] In certain embodiments of Formula (II), n is 1 and the compound has structural formula (III): [ka] (III) As shown in the figure.

[0067] In certain embodiments of Formula (I), R 1 is H, and the compound has structural formula (IV): [ka] (IV) As shown in the figure.

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

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

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

[0071] In one embodiment, R 3 is H.

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

[0073] In further exemplary embodiments of Formula (V), R 3 is H, and the compound has structural formula (VI): [ka] (VI) As shown in the figure. R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 and R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y each may be 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., CHO-alkyl), and R x and R ymay be taken together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring. Each of R' and R'' is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl. R' and R'' may be taken together to 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) ring optionally formed together with may have a hetero 3- to 7-membered (e.g., 3- or 4-membered) ring having 0-3 carbon atoms substituted by one or more heteroatoms selected from N, O, S and P.

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

[0076] In one embodiment, R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where NR'C(=O)R x is replaced by.

[0077] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where NR'C(=O)OR x is replaced by.

[0078] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where NR'C(=O)NRx R y is replaced by.

[0079] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, and C(=O)NR x R y is replaced by.

[0080] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where NR'SO2R x is replaced by.

[0081] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, wherein NR'SO2NR x R y is replaced by.

[0082] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where CR'R''SO2R x is replaced by.

[0083] In one embodiment, R 2 is C3-C 10 (e.g., C3-C6)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, wherein CR'R''SO2NR x R y is replaced by.

[0084] In certain embodiments, R2 is the following moiety: [ka] [In the formula, each R L are independently (CH2) m and m is independently 0, 1, 2, or 3, and when m is 0, each bridge is absent; with the proviso that at least one of the m's is not 0. Includes.

[0085] In certain embodiments, m is not 0 (ie, each m is independently 1, 2, or 3).

[0086] In certain embodiments, no more than one m is 0 (i.e., no more than one R L is non-existent).

[0087] In certain embodiments, each m is independently 1, 2, or 3.

[0088] In certain embodiments, all m are the same integer selected from 1, 2, and 3.

[0089] In certain embodiments, all m are not the same integer selected from 1, 2, and 3.

[0090] In certain embodiments, each m is 1 (ie, forming a [1.1.1]-bicyclic moiety).

[0091] In certain embodiments, each m is 2 (ie, forming a [2,2,2]-bicyclic moiety).

[0092] In certain embodiments, R2 is [ka] [In the formula, R 5 is R x or NR x R y Where R x and R yEach of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R x and R y each may be 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., CHO-alkyl); with the proviso that R 5 But R x and R x But not H (i.e., R 5 is not H)] Each of R' and R'' is independently selected from hydrogen and C1-C6 unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3-7 membered (e.g., 3 or 4 membered) ring.

[0093] In one embodiment, R 5 is R x It is.

[0094] In one embodiment, R 5 is C1-C6 alkyl (e.g., C1-C3 alkyl) optionally substituted with one or more halogen (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxy, CN, or amino groups.

[0095] In one embodiment, R 5 is C1-C6 alkyl (e.g., C1-C3 alkyl).

[0096] In one embodiment, R 5 is halogen (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxy, or C1-C6 alkyl (e.g., C1-C3 alkyl) substituted with CN.

[0097] In one embodiment, R 5 is C1-C6 alkyl (e.g., C1-C3 alkyl) substituted with CN.

[0098] In one embodiment, R x is a straight or branched C1-C6 alkyl.

[0099] In one embodiment, R x is a straight or branched C2-C4 alkyl.

[0100] In one embodiment, R x is n-propyl or isopropyl.

[0101] In one embodiment, R 5 is NR x R y It is.

[0102] In one embodiment, R x and R y One of them is H.

[0103] In one embodiment, R 5 is NR x R y Where R x and R y Each of is independently selected from hydrogen and C1-C6 (eg, C1-C3) unsubstituted and substituted alkyl.

[0104] In one embodiment, R 5 is NR x R y Where R x and R y is NRx R y may be combined with the N in to form a 3- to 7-membered (e.g., 3-, 4-, or 5-membered) heterocyclic group 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., CHO-alkyl).

[0105] In certain embodiments, the heterocyclic group is a 4-membered heterocyclic group.

[0106] In one embodiment, R 5 is NR x R y Where R x and R y each is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted alkyl.

[0107] In one embodiment, R 5 is NR x R y Where R x and R y taken together form a 3- or 4-membered cycloalkyl ring substituted with CN.

[0108] In certain embodiments, each R L is CH2.

[0109] In certain embodiments, each R L is (CH2)2.

[0110] In another aspect, the present invention generally provides a compound of structural formula (VII): [ka] (VII) [In the formula, R 1is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R 3 are 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, halogen (e.g., F, Cl), CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R 5 is R x or NR x R y Where R x and R y Each of is independently 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., C-C heteroaryl), R x and R y may be taken together to form a 3- to 7-membered (e.g., 3 or 4-membered) ring and may be 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., CHO-alkyl); with the proviso that R 5 R x If R x is not H (i.e., R 5 is not H); Each R L are independently (CH2) m wherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge 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 be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0111] In some embodiments of (VII), no more than one m is 0 (i.e., no more than one R L is non-existent).

[0112] In some embodiments of (VII), m is not 0 (ie, each m is independently 1, 2, or 3).

[0113] In some embodiments of (VII), all m are the same integer selected from 1, 2, and 3.

[0114] In some embodiments of (VII), all m are not the same integer selected from 1, 2, and 3.

[0115] In certain embodiments of (VII), each m is 1 (ie, forming a [1.1.1]-bicyclic moiety).

[0116] In certain embodiments of (VII), each m is 2 (ie, forming a [2,2,2]-bicyclic moiety).

[0117] In some embodiments of (VII), R 4 is H.

[0118] In some embodiments of (VII), R 1 is H.

[0119] In some embodiments of (VII), R 1 is methyl.

[0120] In some embodiments of (VII), n is 1.

[0121] In some embodiments of (VII), R 4 is H, n is 1, and the compound has structural formula (VIII): [ka] (VIII) As shown in the figure.

[0122] In some embodiments of (VIII), R 1 is methyl, R 3 is H.

[0123] In some embodiments of (VIII), R 1 and R 3 are both H and have structural formula (IX): [ka] (IX) As shown in the figure.

[0124] In some embodiments of (VIII), each R L is CH2, and the compound has structural formula (X): [ka] (X) As shown in the figure.

[0125] In some embodiments of (X), R 5 is R x It is.

[0126] In some embodiments of (X), R x is a straight or branched C1-C6 (e.g., C1-C3) alkyl optionally substituted with one or more halogen (e.g., F, Cl), C1-C6 (e.g., C1-C3) alkoxy, CN, or amino groups.

[0127] In some embodiments of (X), R x is a straight or branched C2-C4 alkyl.

[0128] In some embodiments of (X), R x is n-propyl or isopropyl.

[0129] In some embodiments of (X), R 5 is NR x R y It is.

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

[0131] In one embodiment, R x and R y is NR x R y together with the N in form a 3-5 membered (e.g., 3, 4, or 5 membered) heterocyclic group 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., CHO-alkyl).

[0132] In certain embodiments, the heterocyclic group is a 4-membered heterocyclic group.

[0133] A non-limiting list of exemplary compounds of the present invention is set forth in Table 1. Table 1. Exemplary Compounds [ka] [ka]

[0134] In certain embodiments, the compound has the structural formula of Compound 1. In certain embodiments, the compound has the structural formula of Compound 4. In certain embodiments, the compound has the structural formula of Compound 5. In certain embodiments, the compound has the structural formula of Compound 6. In certain embodiments, the compound has the structural formula of Compound 21. In certain embodiments, the compound has the structural formula of Compound 23. In certain embodiments, the compound has the structural formula of Compound 31. In certain embodiments, the compound has the structural formula of Compound 32. In certain embodiments, the compound has the structural formula of Compound 45. In certain embodiments, the compound has the structural formula of Compound 46. In certain embodiments, the compound has the structural formula of Compound 48. Table 1A. Exemplary Compounds [Table 1] [Table 2]

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

[0136] In yet another aspect, the present invention generally relates to pharmaceutical compositions comprising a compound according to the invention described herein and a pharma- ceutical acceptable excipient, carrier, or diluent, which are effective in treating or ameliorating one or more diseases or disorders in a mammal, including a human.

[0137] In yet another aspect, the present invention generally provides a compound of structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 with; Each R 3 are 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, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R xand R y each of which may be 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., CHO-alkyl); Each of R' and R'' is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0138] In yet another aspect, the present invention generally provides a compound of 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 are 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, halogen (e.g., F, Cl), CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R 5 is R x or NR x R y Where R x and R yEach of is independently 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., C-C heteroaryl), and R x and R y may be taken together to form a 3- to 7-membered (e.g., 3 or 4-membered) ring and may be 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., CHO-alkyl); with the proviso that R 5 R x If R x is not H (i.e., R 5 is not H); Each R L are independently (CH2) m wherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge 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 be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutically acceptable excipient, carrier, or diluent.

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

[0140] In certain embodiments, the pharmaceutical compositions of the present invention are suitable for topical administration.

[0141] In certain embodiments, the pharmaceutical compositions disclosed herein are effective in treating or ameliorating one or more of an inflammatory disease, an immune-mediated disease, and cancer, or a related disease or disorder.

[0142] In certain embodiments, the pharmaceutical compositions disclosed herein are effective in treating or ameliorating one or more of an autoimmune disease, or a related disease or disorder.

[0143] In certain embodiments 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), Sjogren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barré syndrome, glaucoma ... The disease is selected from Barre syndrome, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular disease (e.g., autoimmune deafness, systemic vasculitis, and atherosclerosis), skin disease (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, 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, transplant rejection (allograft rejection), graft versus host disease (GVDH), or a disease or disorder related thereto.

[0144] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

[0145] In some embodiments, the unit dosage form is in the form of a solid dosage form, such as a capsule, tablet, pill, powder, or granules. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a capsule.

[0146] In certain embodiments, the unit dosage form is a liquid formulation, for example, in the form of an emulsion, solution, suspension, syrup, or elixir.

[0147] In yet another aspect, the invention generally relates to a method for treating or ameliorating a disease or disorder, the method comprising administering to a mammal, including a human, a compound having structural formula (I): [ka] (I) [In the formula, R 1 is selected from hydrogen, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R 2 is C3-C 10 (e.g., C-C)cycloalkyl, bicycloalkyl, spirocyclic or bridged cycloalkyl, where 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 with; Each R 3 are 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, halogen, CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl, OR', and NHR'; R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring, and R x and R y each of which may be 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., CHO-alkyl); Each of R' and R'' is independently selected from hydrogen and C1-C6 (e.g., C1-C3) unsubstituted and substituted alkyl, and R' and R'' may be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof to a subject in need thereof.

[0148] In yet another aspect, the invention generally relates to a method for treating or ameliorating a disease or disorder, the method comprising administering to a mammal, including a human, a compound having 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 are 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'; R 5 is R x or NR x R y Where R x and R y Each of is independently 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., C-C heteroaryl), and R x and R y may be taken together to form a 3- to 7-membered (e.g., 3 or 4-membered) ring and may be 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., CHO-alkyl); with the proviso that R 5 R x If R x is not H (i.e., R 5 is not H); Each R Lare independently (CH2) m wherein m is independently 0, 1, 2, or 3, and when m is 0, each bridge 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 be joined together to form a 3- to 7-membered (e.g., 3- or 4-membered) ring; and n is 1 or 2] or a pharma- ceutically acceptable form or isotopic derivative thereof and a pharma- ceutical composition comprising a pharma- ceutical acceptable excipient, carrier, or diluent to a subject in need thereof.

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

[0150] In certain embodiments, the methods of the invention are useful in treating or ameliorating an autoimmune disease.

[0151] In certain embodiments, the disease or disorder is selected from the group consisting of 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-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjogren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barre syndrome, and rheumatoid arthritis. syndrome, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular disease (e.g., autoimmune deafness, systemic vasculitis, and atherosclerosis), skin disease (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, 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, transplant rejection (allograft rejection), graft versus host disease (GVDH), or a disease or disorder related thereto.

[0152] In certain embodiments, the methods of the present invention are useful for treating or ameliorating an inflammatory disease, or a related disease or disorder.

[0153] In certain embodiments, the methods of the invention are useful for treating or ameliorating an autoimmune disease, or a related disease or disorder.

[0154] In certain embodiments, the methods of the invention are useful for treating or ameliorating an immune-mediated disease or related disease or disorder.

[0155] In certain embodiments, the methods of the present invention are useful in treating or ameliorating cancer, or a related disease or disorder.

[0156] In certain embodiments, the methods of the invention are effective in treating or alleviating one or more of rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, DES, vitiligo, alopecia areata, and alopecia totalis.

[0157] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharma- ceutically acceptable excipient, carrier, or diluent in the manufacture of a medicament for the treatment of a disease or disorder.

[0158] In certain embodiments of such uses, said disease or disorder is one or more of an inflammatory disease, an immune-mediated disease, and cancer.

[0159] In certain embodiments of such uses, said disease or disorder is an autoimmune disease.

[0160] In certain embodiments of such uses, 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), Sjogren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barré syndrome, and others). Reay'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, plaque psoriasis, 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, transplant rejection (allograft rejection), graft versus host disease (GVDH), or a disease or disorder related thereto.

[0161] In certain embodiments of such uses, 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 alopecia totalis.

[0162] In certain embodiments of said use, said medicament is for oral administration.

[0163] In one embodiment of said use, said medicament is for topical administration.

[0164] The term "inflammatory disease" refers to a disease or condition characterized by an abnormality of inflammation, e.g., an increased level of inflammation compared to a control, such as a healthy, disease-free human. 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-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, and autoimmune thyroiditis. , Behcet'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. Such diseases are frequently closely associated with other diseases, disorders, and illnesses. For example, a non-limiting list of inflammation-related diseases, disorders, and illnesses that may be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when inflammatory cytokines impede 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, infectious diseases, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis. Some of the above diseases, disorders, and conditions for which the compounds of the present disclosure may be particularly effective (e.g., due to limitations of current treatments) are described in more detail below.

[0165] The term "autoimmune disease" refers to a disease or condition in which a subject's immune system displays an abnormal immune response to a substance that would not normally provoke 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, Aicardi-Goutière 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, autoimmune cochlear dysplasia, and autoimmune rheumatoid arthritis. Disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Balo's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic atypical neutrophilic dermatosis syndrome with lipodystrophy and fever (CANDLE), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Schulman's disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Trauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, 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), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome , fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, graft-versus-host disease (GVDH), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosing disease, inflammatory bowel disease (IBD), immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis,Juvenile diabetes mellitus (type 1 diabetes), juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, childhood autoimmune streptococcal neuropsychiatric disorder, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg disease, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy , perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), polyglandular autoimmune syndrome types 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, plaque psoriasis, 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's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity & testicular autoimmunity), stiff man syndrome, STING-associated vasculitis in infancy (SAVI), subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transplant rejection (allograft rejection), transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous disease, vitiligo, or Wegener's granulomatosis.

[0166] The term "immune-mediated disease" refers to chronic inflammatory diseases perpetuated by antibody and cell-mediated 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 diseases (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjogren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, and other conditions. These include, for example, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune deafness, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, 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, transplant rejection (allograft rejection), and graft versus host disease (GVDH).

[0167] The term "cancer" as used herein refers to all types of cancer, neoplasms or malignant tumors found in mammals (e.g., humans), including blood cancer leukemia, as well as lymphoma, T-ALL, solid cancers such as carcinomas and sarcomas. Exemplary cancers include blood cancer, brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and head cancer. Exemplary cancers include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Further examples include myeloproliferative neoplasms, thyroid cancer, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's 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, uterine cancer, adrenal cortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0168] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, "isotopically labeled compounds" or "isotopic derivatives" refer to compounds of the present disclosure (including pharmaceutical salts and prodrugs thereof, including those described herein) in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O.31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0169] By isotopically labelling the compounds of the present disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can provide certain therapeutic benefits resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. Isotopically labeled compounds of the present disclosure, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any method known in the art.

[0170] In addition, the normally abundant hydrogen ( 1 Substitution of H for heavier isotopes (e.g., deuterium) can provide certain therapeutic advantages, for example resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. The advantages are also usually abundant 12 C 13 C. (see WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0171] All stereoisomers (e.g., cis and trans isomers) and optical isomers (e.g., R and S enantiomers) of the disclosed compounds, as well as racemic, diastereomeric and other mixtures of such isomers, are within the scope of the disclosure.

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

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

[0174] A general description of the formulation and / or manufacture of pharmaceutical compositions or medicaments can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. 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 art of pharmacy.In general, such preparation methods include the steps of combining the compounds described herein ("active ingredients") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dose unit.

[0176] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dose of active ingredient administered to a subject, and / or is a convenient division of such dose, for example, a half or a third of such dose.

[0177] Solid formulations for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, the compounds described herein or their derivatives are administered in a solid dosage form with at least one inert common excipient (or carrier), such as sodium citrate or calcium hydrogen phosphate, or (i) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, such as carboxymethylcellulose, alignate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, such as glycerol, (iv) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicic acids, and sodium carbonate, (v) solution retarders, such as paraffin, and (vi) absorption enhancers. Accelerator), such as quaternary ammonium compounds, (Vii) wetting agents, such as cetyl alcohol and glycerol monostearate, (Viii) adsorbents, such as kaolin and bentonite, and (IX) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the preparation may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid preparations, such as tablets, dragees, capsules, pills, and granules, may be prepared with coatings and shells, such as enteric coatings and other agents known in the art.

[0178] Liquid preparations for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.In addition to active compounds, the liquid preparations may contain inert 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, particularly 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 of these substances.In addition to such inert diluents, the compositions may also contain additional agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, or aromatics.

[0179] The relative amounts of any of the active ingredient, pharma- ceutically acceptable excipients and / or additional ingredients in a pharmaceutical composition of the present disclosure may vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. As an example, the composition may contain 0.1 (w / w)% to 100 (w / w)% active ingredient.

[0180] The exact amount of compound required to achieve an effective dose varies from subject to subject, depending on, for example, the type, age, and general condition of the subject, the severity of side effects or disease, the specificity of the particular compound, the mode of administration, etc. The desired dose can be delivered three times a day, twice a day, once a day, every 2 days, every 3 days, every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the desired dose can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0181] In certain embodiments, an effective amount of a compound for administration once or more per day to a 70 kg adult human may include about 0.001 mg to about 3,000 mg (e.g., about 0.001 mg to about 2,000 mg, about 0.001 mg to about 1,000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, about 0.001 mg to about 10 mg, about 0.01 mg to about 1,000 mg, about 0.1 mg to about 1,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1,000 mg, about 100 mg to about 1,000 mg, about 1 mg to about 500 mg, about 5 mg to about 250 mg) of the compound per unit formulation.

[0182] In certain embodiments, the compounds described herein are administered at a dose of about 0.001 mg / Kg to about 1,000 mg / Kg (e.g., about 0.01 mg / Kg to about 1,000 mg / Kg, about 0.1 mg / Kg to about 1,000 mg / Kg, about 1 mg / Kg to about 1,000 mg / Kg, about 0.001 mg / Kg to about 1 The compound may be administered at a dosage level sufficient to deliver about 100 mg / Kg, about 0.001 mg / Kg to about 10 mg / Kg, about 0.001 mg / Kg to about 1 mg / Kg, about 0.1 mg / Kg to about 40 mg / Kg, about 0.5 mg / Kg to about 30 mg / Kg, about 0.01 mg / Kg to about 10 mg / Kg, about 0.1 mg / Kg to about 10 mg / Kg, or about 1 mg / Kg to about 25 mg / Kg).

[0183] In some embodiments, the dosing regimen continues for days, weeks, months, or years.

[0184] It is understood that the dosage ranges described herein provide guidance for the administration of pharmaceutical compositions to adults.For example, the amount to be administered to children or young people can be determined by medical practitioners or those 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 compound or pharmaceutical composition described herein can be administered in combination with one or more additional therapeutically active agents.In some embodiments, the compound or pharmaceutical composition provided herein is administered in combination with one or more additional therapeutically active agents that improve its bioavailability in the body, reduce and / or regulate its metabolism, inhibit its excretion, and / or regulate its distribution.It is also understood that the treatments used can achieve the desired effect on the same disease and / or achieve different effects.

[0186] Said compound or pharmaceutical composition can be administered simultaneously, before or after one or more additional therapeutically active agents. Generally, each agent is administered at a dose and / or time schedule determined for that agent. It is further understood that the additional therapeutically active agents used in this combination can be administered together in a single composition or administered separately in different compositions. The specific combination to be used in the dosage regimen will take into consideration the compatibility of the compound and the additional therapeutically active agent provided and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents used in combination will be used at a level that does not exceed the level at which they are used individually. In some embodiments, the level used in combination is lower than the level used individually.

[0187] Exemplary additional therapeutically 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-bound 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 can be used for the disclosed methods and compositions, can be used in combination with the disclosed methods and compositions, can be used in the manufacture of the disclosed methods and compositions, or are products of the disclosed methods and compositions. Although specific references to each of the various individual and total combinations and permutations of each of these compounds may not be expressly disclosed, it is understood that when combinations, subsets, interactions, groups, etc. of these substances are disclosed, each is expressly contemplated and described herein. For example, when a method is disclosed and described, and a number of modifications that can be made to a number of molecules contained in the method are described, each and every combination and permutation of the method and possible modifications is expressly contemplated unless otherwise indicated to the contrary. Likewise, any subset or combination of these is also expressly contemplated and described. This concept applies to all aspects of the present disclosure, including but not limited to steps in methods using the disclosed compounds or compositions. Thus, where there are various additional steps that may be performed, it is understood that each of these additional steps may be performed with any specific method step or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered as disclosed.

[0189] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention includes within its scope all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are intended to be included in the present invention.

[0190] Isomeric mixtures containing any of a variety of isomeric ratios may be used according to the present invention. For example, when only two isomers are combined, mixtures containing isomeric 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 appreciate that similar ratios are encompassed for more complex isomeric mixtures.

[0191] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereoisomeric mixture separated, and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino group) or an acidic functional group (e.g., carboxyl group), a diastereomeric salt can be formed with a suitable optically active acid or base, and the diastereomers can then be resolved by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

[0192] The following examples are illustrative of the practice of the 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 Ethyl acetate: EtOAc Triethylamine: TEA Sodium hydroxide: NaOH Nitrogen: N2 Diphenylphosphoryl 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] Representative Prep-HPLC Method: (Flow rates and gradients may vary) An exemplary method for Prep-HPLC is provided below. Method A: NH4HCO3: (Column: XBrige Prep C18 5μm OBD 19 * 150mm, PN186002979; Mobile phase: 20%-60% CH3CN (0.1% NH4HCO3) in water, Flow rate: 15mL / min). Method B: (Column: XBridge Prep C18 5μm OBD 19 * 150 mm, PN186002979; Mobile phase: 15%-40% CH3CN (0.1% formic acid) in water, flow rate: 15 mL / min)

[0195] Representative HPLC analysis methods Method 1: The analysis was carried out using an Agilent 1260 series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%-95% acetonitrile in water (containing 0.02% NH4OAc) at a flow rate of 1.5 mL / min for a run time of 6.5 min. XBridge C18 column (5 μm, 4.6 * 50 mm; 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 5% to 95% acetonitrile in water (containing 0.1% trifluoroacetic acid) with a flow rate of 1.5 mL / min and a run time of 6.5 min. XBridge C18 column (5 μm, 4.6 * 50 mm; PN186003113) was used at a temperature of 40°C.

[0197] Method 3: The analysis was carried out using an Agilent 1260 series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%-95% acetonitrile in water (containing 0.02% NHOAc) at a flow rate of 2 mL / min for a run time of 6.5 min. Diamonsil Plus C18 column (5 μm, 4.6 * 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. After stirring at room temperature for 1 h, the mixture was concentrated to 100 mL of solvent and cooled with ice water. The solid formed was filtered and dried to give the title product as a white solid (52 g, 86% yield). 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 in portions at 0° C., followed by slow addition of trifluoroacetic anhydride (3.14 mL, 22.2 mmol). Stirred at room temperature for 16 hours, and added additional amounts of tetrabutylammonium nitrate (0.58 g, 4.23 mmol) and trifluoroacetic anhydride (0.8 mL, 5.7 mmol) at 0° C. Warmed to room temperature, 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×2), and then concentrated to dryness. The residue was triturated in MeOH to give the title product as a white solid (3.15 g, 55% yield). LC-MS (Method 2): 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]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-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 h. Upon cooling, the solid formed was collected by filtration and dried to give the title product as a brown solid (612 mg, 86% yield). 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]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1e) Compound 1d (600 mg, 1.22 mmol) was dissolved in MeOH (6 mL) followed by the addition of Pd / C (48 mg, 10% wt) in one portion. The mixture was hydrogenated (1 atm) at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (PE:EtOAc=1:1) to give the title product as a white solid (258 mg, 46% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentane-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 h. After cooling, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc=1:1) to give the title product as a brown solid (191 mg, 73% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (1g) To a solution of compound 1f (191 mg, 0.40 mmol) in DCM (2 mL) was added TFA (1 mL). After stirring at room temperature for 16 h, the mixture was concentrated to dryness to give the crude title product as a brown solid (170 mg, 100% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1h) To a mixture of compound 1g (153 mg, 0.36 mmol) in tert-butanol (7.2 mL) was added DPPA (130 mg, 0.47 mmol) and TEA (73 mg, 0.72 mmol) under N2. The mixture was stirred at room temperature for 30 min, then heated to 90 °C and stirred for an additional 16 h. Upon cooling, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 50:1) to give the title product as a brown solid (160 mg, 89% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1i) To a solution of compound 1h (160mg, 0.32mmol) in MeOH (3mL) and water (3mL), NaOH (300mg, 7.5mmol) was added. After stirring at room temperature for 4 hours, the mixture was concentrated. The residue was diluted with water (20mL) and extracted with EtOAc (30mL*2). The combined organic layer was concentrated to dryness, and the residue was purified by chromatography on silica gel (eluent: DCM:MeOH=20:1) to give the title product as a white solid (60mg, 55% yield). 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-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-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) was added TFA (0.5 mL). After stirring at room temperature for 1 h, the mixture was concentrated to dryness to give the crude title product as a brown solid (100 mg, 100% yield). LC-MS (Method 2): R = 0.309 min, m / z (M+H) + = 240.0

[0207] Step 10. N-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (1) To a solution of compound 1j (40 mg, 0.16 mmol) and TEA (51 mg, 50 mmol) in DMF (1 mL) was added propane-1-sulfonyl chloride (28 mg, 0.5 mmol) at 0° C. After stirring at room temperature for 3 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layers were combined and concentrated to dryness. The residue was purified by Prep-HPLC (Method A) to give the title product as a white solid (10 mg, 18% yield). 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]pyridin-4-yl)amino)cyclobutyl)carbamate (2a) Compound 2a (380 mg) was synthesized in a yield of 89% by using compound 1c (300 mg, 0.85 mmol) and tert-butyl (cis-3-aminocyclobutyl)carbamate (191 mg, 1.02 mmol) as starting materials in 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]pyridin-4-yl)amino)cyclobutyl)carbamate (2b) Compound 2b (300 mg) was synthesized in 84% yield by 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]pyridin-1(6H)-yl)cyclobutyl)carbamate (2c) Compound 2c (260 mg) was synthesized in a yield of 85% by using compound 2b (300 mg, 0.64 mmol) and triethoxymethane (236 mg, 1.59 mmol) as starting materials in 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]pyridin-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): R = 1.47 min, m / z (M+H) + = 328.1.

[0212] Step 5. cis-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-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 and 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]pyridin-1(6H)-yl)cyclobutyl)propane-1-sulfonamide (2) Example 2 (28.8 mg) was synthesized in 25% yield by using the same preparation method as in the final step of Example 1 starting from compound 2e (160 mg, crude, 0.35 mmol) and propane-1-sulfonyl chloride (60 mg, 0.42 mmol). LC-MS (Method 1): 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]pyridin-4-yl)amino)cyclobutyl)carbamate (3a) Compound 3a (0.64 g) was synthesized in a yield of 89% by using compound 1c (500 mg, 1.42 mmol) and tert-butyl (trans-3-aminocyclobutyl)carbamate (318 mg, 1.71 mmol) as starting materials in 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]pyridin-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]pyridin-1(6H)-yl)cyclobutyl)carbamate (3c) Compound 3c (160 mg) was synthesized in a yield of 35% by using compound 3b (0.45 g, 0.95 mmol) and triethoxymethane (432 mg, 2.91 mmol) as starting materials in 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]pyridin-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 and 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]pyridin-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]pyridin-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 using the same preparation method as the final step of Example 2. LC-MS (Method 1): 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-sulfonamide (4) Example 4 (22.6 mg) was synthesized in 28% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (45 mg, 0.25 mmol). LC-MS (Method 1): 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]pyridin-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 by using the same preparation method as in the final step of Example 1 starting from compound 1j (43 mg, 0.18 mmol) and 2-methylpropane-1-sulfonyl chloride (34 mg, 0.22 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-2-methoxyethanesulfonamide (6) Example 6 (21.1 mg) was synthesized in 31% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (45 mg, 0.19 mmol) and 2-methoxyethanesulfonyl chloride (36 mg, 0.23 mmol). LC-MS (Method 1): 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclopropanesulfonamide (7) Example 7 (15.5 mg) was synthesized in 25% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (43 mg, 0.18 mmol) and cyclopropanesulfonyl chloride (30 mg, 0.21 mmol). LC-MS (Method 1): 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methylbutanamide (8) Example 8 (17.3 mg) was synthesized in 26% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 3-methylbutanoyl chloride (38 mg, 0.31 mmol). LC-MS (Method 1): 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)butyramide (9) Example 9 (12.4 mg) was synthesized in 14% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and butyryl chloride (53 mg, 0.32 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (10) Example 10 (2.3 mg) was synthesized in 3% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and isobutyl carbonochloridate (31 mg, 0.230 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-amine (11a) To a solution of compound 1j (200 mg, 0.84 mmol) in DMF (2 mL) was added NaH (100 mg, 2.56 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h. TIPSCl (240 mg, 1.28 mmol) was added to the reaction mixture at 0° C. After stirring for 4 h, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL). The organic layer was separated, concentrated, and the residue was purified by Prep-HPLC (Method A) to give the title product as a colorless oil (150 mg, 45% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (11b) To a solution of compound 11a (150 mg, 0.39 mmol), 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 give the title compound (150 mg, 83% yield) 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]pyridin-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) was added TBAF (0.49 mL, 0.49 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to give the title product as a white solid (33 mg, 34% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclopropanecarboxamide (12) Example 12 (6 mg) was synthesized in 9% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and cyclopropanecarbonyl chloride (33 mg, 0.31 mmol). 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]pyridin-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) was added DMF (1 drop) and oxalyl chloride (508 mg, 4.0 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give 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) was added 2-cyclopropylacetyl chloride (37.2 mg, 0.315 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was purified by Prep-HPLC (Method B) to give the title compound (30 mg, 44% yield) 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propanamide (14) Example 14 (8.8 mg) was synthesized in 13% yield by using the same preparation method as in Example 13 starting from compound 1j (50 mg, 0.21 mmol) and 3-cyanopropanoic acid (69 mg, 0.69 mmol). 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]pyridin-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 using 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]pyridin-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-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)cyclobutanecarboxamide (17) Example 17 (3.7 mg) was synthesized in 4% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 3,3-difluorocyclobutanecarbonyl chloride (49 mg, 0.32 mmol). 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]pyridin-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]pyridin-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, followed by dropwise addition of a solution of bis(trichloromethyl)carbonate (124 mg, 0.42 mmol) in THF (1 mL) at the same temperature. The reaction was warmed to room temperature and stirred for 30 min. Then 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. After stirring at room temperature for 1 h, the mixture was diluted with DCM (10 mL) and washed with brine (5 mL). The organic layer was separated and concentrated to give a residue that was purified by Prep-HPLC (Method A) to give 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]pyridin-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), followed by dropwise addition of a solution of SO2Cl2 (122 mg, 0.91 mmol) in 6.0 mL of DCM at -78 °C. The mixture was stirred at -78 °C for 30 min and warmed to room temperature. Aqueous HCl (1N, 10 mL) and brine (10 mL) were added to the solution. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give a brown oil. This was then dissolved in DCM (0.5 mL). The resulting solution was added 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) at room temperature. The reaction was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to dryness to give a residue that was purified by Prep-HPLC (Method A) to give 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methoxyazetidine-1-sulfonamide (21) Example 21 (13 mg) was synthesized in a yield of 16% by using compound 1j (50 mg, 0.21 mmol) and compound 21a (150 mg, 1.21 mmol) as starting materials and 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]pyridin-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-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-sulfonamide (23) Example 23 (8.0 mg) was synthesized in a 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]pyridin-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) was added a solution of dimethylsulfamoyl chloride (36 mg, 0.25 mmol) in 0.5 mL of THF dropwise at 0° C. The mixture was stirred at 25° C. for 14 h. The mixture was diluted with H2O (15 mL) and extracted with DCM (20 mL*2). The organic layers were combined and concentrated, and the residue was purified by Prep-HPLC (Method A) to give the title product as a white solid (15 mg, 17% yield). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-N'-methyl-N'-ethyl-1-sulfonamide (25) To a mixture 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 a solution of ethyl(methyl)sulfamoyl chloride (46.0 mg, 0.29 mmol) in 0.5 mL of ACN at 0° C. The mixture was stirred at 30° C. for 14 h. The mixture was diluted with H2O (20 mL) and extracted with DCM (40 mL*2). The combined organic layers were concentrated to dryness, and the residue was purified by Prep-HPLC (Method A) to give 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-methoxypropane-1-sulfonamide (26) Example 26 (15 mg) was synthesized in 12% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (80 mg, 0.33 mmol) and 3-methoxypropane-1-sulfonyl chloride (58 mg, 0.33 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)ethanesulfonamide (27) Example 27 (11 mg) was synthesized in 16% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and ethanesulfonyl chloride (35 mg, 0.27 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide (28) Example 28 (12.4 mg) was synthesized in 14% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 4-chlorobenzene-1-sulfonyl chloride (58 mg, 0.27 mmol). 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]pyridin-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 by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (49 mg, 0.27 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-2-sulfonamide (30) Example 30 (3.4 mg) was synthesized in 5% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and propane-2-sulfonyl chloride (39 mg, 0.27 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)butane-1-sulfonamide (31) Example 31 (10 mg) was synthesized in 13% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and butane-1-sulfonyl chloride (66 mg, 0.42 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (32) Example 32 (4.7 mg) was synthesized in 6% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and 3,3,3-trifluoropropane-1-sulfonyl chloride (62 mg, 0.32 mmol). The final compound was purified by Prep-HPLC (Method B) to give 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (33) Example 33 (4.5 mg) was synthesized in 6% yield by using the same preparation method as in the final step of Example 1 starting from compound 1j (50 mg, 0.21 mmol) and cyanomethanesulfonyl chloride (45 mg, 0.32 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-propylurea (34) To a well-stirred solution of compound 1j (50 mg, 0.21 mmol), THF (0.6 mL), and DMSO (0.2 mL) was added 1-isocyanatopropane (36 mg, 0.42 mmol). The mixture was stirred at 30° C. for 3 h. The mixture was concentrated to dryness to give a residue that was purified by Prep-HPLC (Method A) to give 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)urea (35) Example 35 (29.6 mg) was synthesized in 44% yield by using the same preparation method as in Example 34, starting from compound 1j (50 mg, 0.21 mmol) and isocyanatocyclopropane (35 mg, 0.42 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)-3-isobutylurea (36) Example 36 (17.4 mg) was synthesized in 25% yield by using the same preparation method as in Example 34 starting from compound 1j (50 mg, 0.21 mmol) and 1-isocyanato-2-methylpropane (41 mg, 0.42 mmol). 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-carboxamide (37) To a well-stirred solution of compound 1j (50 mg, 0.21 mmol), TEA (74 mg, 0.73 mmol), DCM (1.0 mL), and DMSO (0.5 mL) was added CDI (68 mg, 0.42 mmol) in one portion. The mixture was stirred at room temperature for 2 h. 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 at room temperature overnight. The mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to give the title product as a white solid (1.1.1 mg, 15% yield). 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]pyridin-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]pyridin-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-carbonitrile 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]pyridin-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]pyridin-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 by using the same preparation method as in Example 37 starting from compound 1j (60 mg, 0.25 mmol) and 2,2,2-trifluoroethanamine (87 mg, 0.88 mmol). 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]pyridin-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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)urea (43) Example 43 (12.8 mg) was synthesized in 18% yield by using the same preparation method as in Example 37 starting from compound 1j (50 mg, 0.21 mmol) and 3-aminopropanenitrile (51 mg, 0.73 mmol). 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 was added TFA (2.5 mL) at 0° C. The solution was stirred at 0° C.-5° C. for 1.5 h. The solution was concentrated to give 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]pyridin-4-yl)amino)cyclobutanecarboxylate (44c) Compound 44c (760 mg) was synthesized in a yield of 78% by 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 in 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]pyridin-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]pyridin-1(6H)-yl)cyclobutanecarboxylate (44e) Compound 44e (550 mg) was synthesized in a yield of 84% by using compound 44d (640 mg, 1.54 mmol) and triethoxymethane (571 mg, 3.86 mmol) as starting materials in 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]pyridin-1(6H)-yl)cyclobutyl)methanol (44f) To a solution of compound 44e (550 mg, 1.30 mmol) in 5 mL of dry THF was added LiAlH4 (73.9 mg, 1.94 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 h. Cooled to 0° C., the reaction mixture was quenched with 0.1 mL of water, 0.2 mL of 10% NaOH solution, followed by 0.3 mL of water. The mixture was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude title product as a white solid (450 mg, 88% yield). 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]pyridin-1(6H)-yl)cyclobutyl)methyl methanesulfonate (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. After stirring at room temperature for 1 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The organic layer was separated, washed with brine (40 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness to give 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]pyridin-1(6H)-yl)cyclobutyl)methyl)ethanethioate (44h) Compound 44g (535 mg, 1.13 mmol) and potassium thioacetate (386 mg, 3.38 mmol) were mixed in DMF (16 mL) and then heated at 50° C. for 5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The organic layer was separated and concentrated. The residue was purified by reverse phase chromatography (ACN in water (5-95%)) to give the crude title compound (338 mg, 66% yield) 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]pyridin-1(6H)-yl)cyclobutyl)methanesulfonic acid (44i) Aqueous hydrogen peroxide (0.55 mL, 30%) was added dropwise to a stirred suspension of compound 44h (330 mg, 0.73 mmol) in formic acid (4 mL). The resulting mixture was stirred at room temperature for 1 h, and then the reaction mixture was concentrated to give 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]pyridin-1(6H)-yl)cyclobutyl)methanesulfonyl chloride (44j) To a mixture of compound 44i (330 mg, 0.73 mmol) in DCM (50 mL) and DMF (1.0 mL) was added thionyl chloride (930 mg, 7.82 mmol). The reaction mixture was then heated at 50° C. for 3 h. The mixture was concentrated to give 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]pyridin-1(6H)-yl)cyclobutyl)methanesulfonamide (44k) Compound 44j (200 mg, 0.42 mmol) was added to a solution of CH3NH2·HCl (34 mg, 0.50 mmol), TEA (127 mg, 1.25 mmol) and DCM (2 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL). The separated organic layer was washed with water (30 mL*2) and concentrated to give the crude title product as a white solid (25 mg, 13% yield). 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]pyridin-1(6H)-yl)cyclobutyl)-N-methylmethanesulfonamide (44) Compound 44k (22 mg, 0.05 mmol) and LiOH·HO (10 mg, 0.05 mmol) were dissolved in a mixture of i-PrOH and HO (2.5 mL, V:V=4:1). The solution was stirred at 60° C. for 24 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The separated organic layer was concentrated and the residue was purified by Prep-HPLC (Method A) to give the title compound (3.7 mg, 25% yield) 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]pyridin-1(6H)-yl)cyclobutyl)methyl)sulfonyl)azetidine-3-carbonitrile (45a) Compound 45a (80 mg) was synthesized in 64% yield by using compound 44j (120 mg, 0.25 mmol) and azetidine-3-carbonitrile hydrochloride (32 mg, 0.26 mmol) as starting materials and a preparation method similar to that of 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-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclobutyl)methyl)sulfonyl)azetidine-3-carbonitrile (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 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (Method A) to give 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) To 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 added TsCl (889 mg, 9.83 mmol) at 0° C. and warmed to room temperature. After stirring at room temperature overnight, the mixture was diluted with 20 mL of DCM, washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated to give the crude title compound (1.89 g crude, 79% yield) as a yellow oil.

[0277] Step 2. Benzyl ((3,3-difluorocyclobutyl)methyl)sulfane (46c) To a mixture of compound 46b (100 mg, 0.36 mmol) and benzyl carbamimidothioate hydrochloride (88 mg, 0.43 mmol) in DMF (0.5 mL) was added NaOH (36 mg, 0.90 mmol) in H2O (0.5 mL). The mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=80:1) to give 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (46) To a mixture of compound 46c (82 mg, 0.36 mmol), DCM (1.5 mL), and H2O (0.4 mL) was added SO2Cl2 (418 mg, 3.09 mmol) at -5°C. The mixture was stirred at 0°C for 30 min. Then, ice water (15 mL) was added, and the mixture was extracted with DCM (20 mL*2). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (0.5 mL), and the solution was added 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) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (20 mL*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 give 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-(propylsulfonamido)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) was added propane-1-sulfonyl chloride (1.0 g, 7.56 mmol) at 0° C. After stirring at room temperature for 3 h, the mixture was diluted with water (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, and filtered. The filtrate was concentrated to give the title compound (1.45 g, 97% yield) 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 EtOAc (20 mL) was added HCl (g) in EtOAc (2 M, 20 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give the title compound (1.2 g, crude, 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]pyridin-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 using a preparation method similar to that 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]pyridin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (47e) To a solution of compound 47d (2.4 g, 4.62 mmol), NH4Cl (1.2 g, 23.1 mmol), MeOH (900 mL), and H2O (300 mL) was added Fe powder (905 mg, 16.2 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the title compound (2.2 g, 95.6%, crude) 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-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 min. 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 h. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL*2). The organic layers were combined and concentrated, and the residue was purified by prep-TLC (DCM:MeOH=10:1) to give the desired compound (55 mg, 50% yield) 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (47) To a solution of compound 47f (55 mg, 0.10 mmol) in a mixture of MeOH and HO (5.5 mL, V:V=1:5), NaOH (12 mg, 0.30 mmol) was added in one portion. After stirring at 30° C. for 25 h, the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL*2). The separated aqueous layer was concentrated to dryness, and the residue was purified by Prep-HPLC (Method A) to give the title compound (10 mg, 16% yield) 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (48a) Compound 48a (89 mg) was synthesized in 57% yield by using compound 47e (150 mg, 0.31 mmol) and 1.1.1-triethoxyethane (124 mg, 0.76 mmol) as starting materials in 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]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (48) To a solution of compound 48a (85 mg, 0.17 mmol) in MeOH and HO (3.3 mL, V:V=1:10), NaOH (20 mg, 0.50 mmol) was added in one portion. After stirring at 30° C. for 20 h, the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL*2). The separated aqueous layer was concentrated to dryness, and the residue was purified by Prep-HPLC (Method A) to give 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 (15g) was synthesized in a 92% yield by using compound 49a (10 g, 65 mmol) and TsCl (14.8 g, 78 mmol) as starting materials in 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]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-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 h under microwave irradiation. Upon cooling, the mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL×2). The combined organic layer was concentrated to dryness, and the residue was purified by chromatography on silica gel (eluent: PE:EtOAc=3:1) to give the title product as a white solid (400 mg, 92% yield). 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]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (49d) To a solution of compound 49c (430 mg, 0.95 mmol) in dry THF (6 mL) was added LiHMDS (2.8 mL, 2.8 mmol, 1M in THF) at -50°C. After stirring at 0°C for 30 min, CHI (268 mg, 1.89 mmol) was added to the solution. The mixture was stirred at 40°C for 1.5 h. After cooling, the reaction mixture was quenched with saturated NHCl (20 mL) and water (20 mL). The mixture was extracted with EtOAc (30 mLX2). The organic layers were combined and concentrated to dryness, and the residue was purified by chromatography on silica gel (eluent: PE:EtOAc=1:1) to give the title product as a white solid (125 mg, 28% yield). 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]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentane-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 and 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]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (49f) Compound 49f (120 mg) was synthesized in 66% yield by using compound 49e (154 mg, 0.37 mmol) as the starting material and 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]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (49g) Compound 49g (40 mg) was synthesized in 49% yield using compound 49f (120 mg, 0.25 mmol) as the starting material and 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]pyrimidin-4-yl)bicyclo[1.1.1]pentane-1,3-diamine 2,2,2-trifluoroacetate (49h) Compound 49h (55 mg, crude) was synthesized in 100% yield using compound 49g (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]pyrimidin-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 using 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]pyrimidin-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 h. The mixture was then filtered. The filter cake was washed with i-PrOH and dried to give the title product as a white solid (580 mg, 88% yield). LC-MS (Method 2): t R = 1.79 min, m / z (M+H) + =506.2.

[0296] Step 2. cis-N 1 -Methyl-N 1 -(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclobutane-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 h. The mixture was concentrated to dryness to give the crude title product as a brown solid (170 mg, crude, 65% yield). 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]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide (50c) A mixture of 50b (170 mg, crude, 0.46 mmol) and DIPEA (614 mg, 4.76 mmol) in DCM (8 mL) at 0° C. gave 3-cyanoazetidine-1-sulfonyl chloride (163 mg, 1.14 mmol). After stirring at room temperature for 3 h, the mixture was diluted with water (70 mL) and extracted with DCM (50 mL). The separated organic layer was concentrated to dryness to give 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]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide (50) Compound 50c (215 mg, 0.45 mmol) was dissolved in i-PrOH and HO (5.8 mL, V:V=25:4), followed by the addition of LiOH·HO (95 mg, 2.25 mmol) in one portion. The mixture was stirred at 60° C. for 13 h, diluted with water (30 mL), and then extracted with EtOAc (50 mL). The separated organic layer was concentrated to dryness. The residue was purified by Prep-HPLC (Method A) to give the title product as a white solid (50.0 mg, 35% yield). 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 assays JAK activity was examined in reaction buffer (50 mM HEPES, 0.01% Brij35, 10 mM MgCl2, 2 mM DTT) by microfluidic assay. Phosphorylation of FAM-labeled peptide substrate was monitored with a Caliper EZ Reader II (Perkin Elmer). Measurement conditions for each batch of enzyme (Carna Biosciences) were optimized to obtain 10% conversion of the peptide substrate.

[0300] Test compounds were dissolved in DMSO to a stock concentration of 10 mM. Compounds, 3-fold serially diluted with a maximum concentration of 5 μM, were pre-incubated with JAK1, JAK2 or TYK2 for 10 minutes at ambient temperature. The final DMSO concentration of the assay mixture was 1%. Kinase reactions were initiated at 28° C. by sequential addition of FAM-labeled peptide substrate (final concentration 3 μM) and ATP (Km concentration or 1 mM). The reactions were stopped by adding 50 mM EDTA.

[0301] Test plate wells containing no enzyme were defined as 100% inhibition, and wells containing no compound but an equal amount of DMSO were defined as no inhibition. Percent inhibition was calculated according to 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 means the conversion rate in positive wells where no compound was added. Conversion rate 最小 means the conversion in wells where no enzyme was added. Conversion rate サンプル means the conversion rate of the test compound.

[0302] Dose response (percent inhibition) curves were plotted and IC50 values ​​were determined using GraphPad software. The IC50 values ​​of 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] Antiproliferation assay The dimerization domain of Tel protein fused to the JAK kinase domain was permanently introduced into BaF3 cells, whose cell proliferation depends on JAK activity in the absence of IL-3 induction, and these generated BaF3-Tel-JAK cells were used to monitor the JAK inhibitory activity of compounds in the cells.

[0304] BaF3-Tel-JAK cells were cultured in RPMI-1640 (Corning) containing 10% fetal bovine serum. Cells were seeded at 2000 / well in white flat-bottom 96-well plates. Wells containing medium alone served as background controls. After 24 hours of growth, cells were treated with compounds. The test compounds were dissolved in DMSO to a stock concentration of 10 mM. Compounds were added to each well in 3-fold serial dilutions at nine concentrations with a maximum concentration of 10 μM. The final DMSO concentration was 0.2%. The cells were allowed to continue growing for 72 hours after compound treatment at 37°C with 5% CO2. Viability was measured by cellular ATP assay using Cell-Titer Glo luciferase reagent (Promega). Luminescence values ​​were recorded by a multi-label reader Envision (PerkinElmer). Values ​​were converted to percent inhibition using the following formula: Inhibition% = (reading 最大 -Readings サンプル ) / (Reading value 最大 -Readings 最小 )*100 Wells containing no compound but an equal amount of DMSO were used to measure the readings. 最大 It stipulated that: Wells containing only DMSO, similar to the medium, were used to measure the readings. 最小 It stipulated that:

[0305] Dose response (percent inhibition) curves were plotted and GI50 values ​​(concentration producing 50% growth inhibition) were determined using GraphPad software. The GI50 of the test compounds is shown in Table 3. Table 3 [Table 12]

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

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

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

[0309] In determining the in vitro elimination constant (ke) of the control compound, the peak area ratio of the analyte / internal standard was calculated according to the following formula: [Table 13] Convert to percent remaining (%) using

[0310] Microsomal CLint was calculated using the formula: CLint(mic)=0.693 / T1 / 2 / mg microsomal protein (per mL). Exemplary results are summarized in Table 4. Table 4 [Table 14]

[0311] Pharmacokinetic study in rats: The pharmacokinetic profile of the test substance was evaluated using fasted Sprague-Dawley rats. Typically, rats were dosed at 1 mg / kg and 2 mg / kg by intravenous injection and oral gavage, respectively. After dosing, blood samples were collected at each time point. For the IV injection group, the time points were set at 5, 15, 30 minutes, followed by 1, 2, 4, 8, and 24 hours after dosing. For the oral gavage group, the time points were set at 15, 30 minutes, followed by 1, 2, 4, 8, and 24 hours after dosing. Blood was collected into 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 analyzed by LC / MS / MS for quantification.

[0312] PK parameter values, including but not 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. Exemplary results are summarized in Table 5. Table 5 [Table 15]

[0313] Conclusion: Examples 1 and 4 show excellent pharmacokinetic profiles in rats. Applicant's disclosure is described herein in preferred embodiments with reference to figures in which like numerals represent the same or similar features. References throughout this specification to "one embodiment," "an embodiment," or similar terms mean that a particular feature, structure, or property described with respect to an embodiment is included in at least one embodiment of the invention. Thus, references herein to the terms "in one embodiment," "in an embodiment," and similar terms refer to the same embodiment, although not necessarily all of them.

[0314] The features, structures, or properties described in the applicant's disclosure may be combined in any suitable manner in one or more embodiments. In this specification, many specific details are described to provide an understanding of the embodiments of the present invention. However, those skilled in the art will understand that the applicant's compositions and / or methods may be practiced without one or more of the specific details, or with other methods, configurations, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring aspects of the present disclosure.

[0315] In this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0316] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.Methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, but preferred methods and materials are described herein.The methods described herein can be carried out in any order that is logically possible, in addition to the specific order disclosed.

[0317] Incorporation by Reference References are made to and cited in other documents, such as patents, patent applications, patent publications, journals, books, articles, web contents, etc. All such documents are incorporated herein by reference in their entirety for all purposes. Any material or portion thereof that is said to be incorporated herein by reference but that conflicts with existing definitions, descriptions, or other disclosed material that is expressly set forth herein is incorporated only to the extent that there is no conflict between the incorporated material and the material of this disclosure. In case of conflict, the conflict should be resolved by giving priority to the present disclosure as the preferred disclosure.

[0318] Equivalent The representative examples are intended to aid in illustrating the invention and are not intended, and should not be construed, as limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the entire contents of this specification, including the examples and references to the scientific and patent literature contained herein. The examples contain important additional information, exemplification, and guidance that can be applied to the practice of the invention in its various embodiments and equivalents thereof.

Claims

1. Structural formula (VII): 【Chemistry 1】 (VII) [In the formula, R １ is hydrogen, C １ -C ６ selected from unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; Each R ３ are independently hydrogen, C １ -C ６ selected from unsubstituted or substituted alkyl, OR', COOR', and CONR'R''; R ４ is hydrogen, halogen, CN, C １ -C ６ is a group selected from unsubstituted or substituted alkyl, OR′, and NHR′; R ５ is R ｘ Or N.R. ｘ R ｙ Wherein R ｘ and R ｙ is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and R ｘ and R ｙ may be joined together to form a 3- to 7-membered ring, and R ｘ and R ｙ each may be optionally substituted with one or more of halogen, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl; with the proviso that R ５ R ｘ If R ｘ is not H; Each R Ｌ (CH ２ ) ｍ and m is 1; Each R′ and R″ is independently selected from hydrogen and C １ -C ６ is selected from unsubstituted and substituted alkyl, and R′ and R″ may be taken together to form a 3- to 7-membered ring; and n is 1 or 2. or a pharma- ceutically acceptable salt or isotopic derivative thereof.

2. R ４ The compound of claim 1 , wherein

3. R １ The compound according to claim 1 or 2, wherein is H.

4. R １ The compound according to claim 1 or 2, wherein is methyl.

5. n is 1, and the compound has structural formula (VIII): 【Chemistry 2】 (VIII) The compound according to claim 2, wherein

6. R ３ The compound of claim 4 , wherein is H.

7. In structural formula (VIII), R １ and R ３ and 【Chemistry 3】 (X) The compound according to claim 5, wherein

8. R ５ But, R ｘ The compound according to any one of claims 1 to 7,

9. R ｘ is a linear or branched chain C １ -C ６ The compound of claim 8 which is alkyl.

10. R ｘ is a linear or branched chain C ２ -C ４ The compound of claim 8 which is alkyl.

11. R ｘ The compound of claim 8, wherein is n-propyl or isopropyl.

12. R ５ But, N.R. ｘ R ｙ The compound according to any one of claims 1 to 7,

13. R ｘ and R ｙ The compound of claim 12, wherein one of is H.

14. R ｘ and R ｙ But, N.R. ｘ R ｙ The compound according to claim 12, wherein, together with the N in the formula (I), the compound (II) forms a 3-5 membered heterocyclic ring optionally substituted with one or more of halogen, CN, OR', NR'R'', alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, and alkoxyalkyl.

15. The compound of claim 14 , wherein the heterocyclic group is a four-membered heterocyclic group.

16. Below formula: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 A compound selected from the group consisting of compounds represented by the formula:

17. Below formula: 【Chemistry 8】 17. The compound of claim 16, selected from the group consisting of compounds represented by:

18. Below formula: 【Chemistry 9】 The compound according to claim 16, wherein

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharma- ceutically acceptable excipient, carrier, or diluent.

20. The compound has the following formula: 【Chemistry 10】 20. The pharmaceutical composition of claim 19,

21. 21. Use of the pharmaceutical composition of claim 19 or 20 in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, and cancer.

22. The compound has the following formula: 【Chemistry 11】 22. The use according to claim 21 ,

23. 23. The use according to claim 21 or 22, wherein the disease or disorder is an autoimmune disease.

24. 23. The use according to claim 21 or 22, wherein the disease or disorder is selected from asthma, allergies, arthritis, juvenile arthritis, inflammatory bowel disease, endocrine disorders, neurodegenerative diseases, autism spectrum disorders, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjogren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barre syndrome, 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, pemphigus, transplant rejection (allograft rejection), graft versus host disease (GVDH), or related diseases or disorders thereof.

25. 23. The use according to claim 21 or 22, wherein 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, alopecia totalis.

26. 23. The use according to claim 21 or 22, wherein the disease or disorder is selected from hidradenitis suppurativa, giant cell arteritis, Takayasu's arteritis, polymyalgia rheumatica, dermatomyositis, psoriatic arthritis, type 1 diabetes, Graves' disease, multiple sclerosis (MS), autoimmune hearing loss, systemic vasculitis, atherosclerosis, acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, and alopecia.

27. 20. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of a disease or disorder, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, and cancer.

28. 28. The use of claim 27, wherein the therapeutic agent is for oral administration.

29. 28. The use of claim 27, wherein the therapeutic agent is for topical administration.

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