Substituted pyrrolopyridine JAK inhibitors and methods of making and using same

Abstract

The present invention relates to substituted pyrrolopyridine JAK inhibitors, methods of making and methods of using the same. The invention also relates to novel pyrrolopyridine compounds and compositions and their use as medicaments for the treatment of disease. Also provided are methods of inhibiting JAK1 and JAK3 kinase activity in a human or animal subject to treat diseases such as pruritus, alopecia, androgen-derived alopecia, alopecia areata, vitiligo, and psoriasis.

Description

[0001] This application is a divisional application of the PCT international application PCT / US2018 / 059071 filed on November 2, 2018, which entered the Chinese national phase on June 19, 2020, and the Chinese patent application number is 201880082616.4, and the invention name is "Substituted pyrrolopyridine JAK inhibitors and methods for their preparation and use".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 581,428, filed on November 3, 2017, and U.S. Provisional Application No. 62 / 670,448, filed on May 11, 2018. The disclosures of both applications are incorporated herein by reference. The disclosures of the applications are incorporated herein by reference. Technical Field

[0004] The present application relates to substituted pyrrolopyridine JAK inhibitors and methods of making and using the same.

[0005] Embodiments herein are directed to compounds having structures of Formula (I) to Formula (IV), or derivatives thereof, wherein the R groups, ring labels, and n values ​​are defined herein:

[0006]

[0007] Disclosed herein are novel pyrrolopyridine compounds and compositions and their use as drugs for treating diseases. Also provided are methods for inhibiting JAK1 and JAK3 kinase activity in human subjects or animal subjects for treating JAK1 and / or JAK3 mediated diseases. Background Art

[0008] Janus Kinase (JAK) is a subgroup of non-receptor tyrosine kinases, which are essential for transducing signals derived from type I cytokine receptors and type II cytokine receptors, and its enzymatic activity is essential for the biological activity of cytokines. The JAK kinase family consists of four family members: JAK1, JAK2, JAK3 and Tyk2, and these kinases are important for the regulation of cytokine signaling in the immune system and in other tissues more widely. The kinase activity of JAK is directed to JAK itself, the intracellular part of cytokine receptors and several other substrates (including members of the STAT transcription factor family). STAT (STAT1 to STAT6) has a specific and unique effect on gene transcription in various types of cells (including immune cells), and is critical in processes such as cell proliferation and differentiation. Because these kinases have a wide range of effects in immunity and inflammation, many small molecule drugs have been developed to intervene in diseases in which JAK kinase signaling causes disease. These drugs were initially developed for systemic administration to prevent organ transplant rejection. Later, they have been developed as potential therapies for hematological malignancies, and autoimmune and inflammatory diseases (for example, including rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, atopic dermatitis, alopecia and vitiligo). Recently, due to the hematological toxicity, immunosuppressive toxicity and metabolic toxicity associated with systemic inhibition of JAK kinases, local delivery of these inhibitors as topical agents has been described. These include alopecia areata, atopic dermatitis, vitiligo, psoriasis, inflammatory bowel disease, and dry eyes, among others. Compounds that are expected to have excellent oral and topical bioavailability and are useful for systemic autoimmune diseases are described herein, as well as compounds that are designed to have limited stability and thereby limit systemic exposure, and are therefore most suitable for limited (e.g., topical) drug delivery.

[0009] It has been shown that the signal transduction of the cytokine receptor activated by cytokines occurs through the JAK kinase associated with the receptor cytoplasmic domain. Receptor stimulation causes the activation of JAK and the subsequent phosphorylation of the cytoplasmic domain of the related receptor chain. This produces the SH2 binding domain, which is used to recruit the potential cytoplasmic transcription factor known as STAT (signal transducer and transcription activator). When combined with the phosphorylated cytokine receptor, STAT itself is phosphorylated on tyrosine residues, which causes the formation of homodimers and heterodimers mediated by SH2 domains and translocation to the nucleus. Once the nucleus is reached, these proteins induce the transcription of genes related to the activation of the original cytokine receptor. This event (STAT protein phosphorylation within a few minutes, and STAT-induced gene transcription within a few hours) is sequentially suitable for characterizing the cell efficacy of the compound and informing both structure-activity relationships. Summary of the invention

[0010] Before describing the compositions and methods of the present invention, it should be understood that the present invention is not limited to the specific processes, preparations, compositions, or methods described, because these can change. It should also be understood that the terms used in the specification are only for the purpose of describing a specific type or embodiment, rather than being intended to limit the scope of the embodiments herein, and the scope of the embodiments herein will be limited only by the appended claims. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments of the embodiments herein, preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference as a whole. Any content herein should not be interpreted as admitting that the embodiments herein are not entitled to be disclosed earlier than such disclosure by means of prior inventions.

[0011] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula (I) is provided:

[0012]

[0013] in:

[0014] R 1 Selected from -CO 2 R 5 , -C 1 ~C 5 Alkyl-CO 2 R 5 , -C 3 ~C 6Cycloalkyl-CO 2 R 5 、-NHCO 2 R 5 、-N(C 1 ~C 5 Alkyl)-CO 2 R 5 、-O-CO 2 R 5 , or -C 1 ~C 5 Alkyl-O-CO 2 R 5 ;

[0015] R 2 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0016] n is 0, 1, or 2;

[0017] Ring A is substituted at one or more carbon atoms with one, two, or three R 3 Substituents, where each R 3 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0018] Two R on the same carbon atom or different carbon atoms of ring A 3 The group can be optionally linked to form a spirocyclic ring system or a bicyclic ring system with Ring A;

[0019] R 4 Selected from -C(O)-R 6 、-CH 2 R6 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 ,

[0020] -C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 7 R 8 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0021] R 5 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0022] R 6 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 7 R 8 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0023] R 7 and R 8 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group can be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0024] R 7 and R 8 They can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0025] In some embodiments, R 1 Yes-CO 2 R 5 In some embodiments, R 1 Yes-C 1 ~C 5 Alkyl-CO 2 R 5 In some embodiments, R 1 Yes-C 3 ~C 6 Cycloalkyl-CO 2 R 5 In some embodiments, R 1 Yes - NHCO 2 R 5 In some embodiments, R 1 Yes-N(C 1 ~C 5 Alkyl)-CO 2 R 5 In some embodiments, R 1 Yes-O-CO 2 R 5 In some embodiments, R 1 Yes-C 1 ~C 5 Alkyl-O-CO 2 R 5 .

[0026] In one aspect, a compound of formula (II), or a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula (II) is provided:

[0027]

[0028] in:

[0029] R 10 Selected from -CO 2 R 50 , -C 1 ~C 5 Alkyl-CO 2 R50 , -C 3 ~C 6 Cycloalkyl-CO 2 R 50 、-NHCO 2 R 50 、-N(C 1 ~C 5 Alkyl)-CO 2 R 50 、-O-CO 2 R 50 , or -C 1 ~C 5 Alkyl-O-CO 2 R 50 :

[0030] R 20 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0031] n is 0 or 1;

[0032] Ring I is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 70 C(O)-CH=CH 2 、-NR 70 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 70 C(O)-CH=CHCH 3 , or -NR 70 C(O)-CH=CHCH 2 NR 80 R 90, wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0033] Two R on the same carbon atom of ring I 30 Two or three R on different carbon atoms 30 The group can be optionally linked to form a spirocyclic, bicyclic or tricyclic ring system with Ring I, such as adamantyl;

[0034] R 40 Selected from H, -OH, -C(O)-R 60 、-OR 60 、-OC(O)-R 60 、-NR7 0 -C(O)-R 60 , -C 1 ~C 4 Alkyl-C(O)-R 60 、-SO 2 -R 60 、-SO 2 -NR 80 R 90 , -C 1 ~C 4 Alkyl-SO 2 -R 60 , or -C 1 ~C 4 Alkyl-SO 2 NR 80 R 90 ;

[0035] R 50 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0036] R 60 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0037] R 70 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0038] R 80 and R 90 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group can be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0039] R 80 and R 90 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine;

[0040] Wherein the compound of formula (II) is not:

[0041]

[0042] 4-(((1R, 2s, 3S, 5s, 7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0043]

[0044] 4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0045]

[0046] 4-(Cyclopentylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0047]

[0048] 4-(Cycloheptylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0049]

[0050] 4-(((1s,2R)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0051]

[0052] 4-(((1R, 2S)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0053]

[0054] 4-((3-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0055]

[0056] 4-((4-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0057]

[0058] 4-((2,2-dimethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester, or

[0059]

[0060] Ethyl 4-(((1S,2R)-2-ethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0061] In some embodiments, R 10 Yes-CO 2 R 50 ; R 20 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 The alkyl group is substituted with one or more groups.

[0062] In some embodiments, R 10 Yes-C 1 ~C5 Alkyl-CO 2 R 50 In some embodiments, R 10 Yes-C 3 ~C 6 Cycloalkyl-CO 2 R 5 In some embodiments, R 10 Yes - NHCO 2 R 50 In some embodiments, R 10 Yes-N(C 1 ~C 5 Alkyl)-CO 2 R 50 In some embodiments, R 10 Yes-O-CO 2 R 50 In some embodiments, R 10 Yes-C 1 ~C 5 Alkyl-O-CO 2 R 50 .

[0063] In one aspect, a compound of formula (III), or a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula (III) is provided:

[0064]

[0065] in:

[0066] R 1000 Selected from -CO 2 R 5000 , -C 1 ~C 5 Alkyl-CO 2 R 5000 , -C 3 ~C 6 Cycloalkyl-CO 2 R 5000 、-NHCO 2 R 5000 、-N(C 1 ~C 5 Alkyl)-CO 2 R 5000 、-O-CO 2 R 5000 , or -C 1 ~C 5 Alkyl-O-CO 2 R 5000 ;

[0067] R2000 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0068] n is 0, 1, or 2;

[0069] Ring Q is replaced at one or more carbon atoms by one, two, or three R 3 Substituents, where each R 3000 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0070] Two R on the same carbon atom or different carbon atoms of ring Q 3000 The group can be optionally linked to form a spirocyclic ring system or a bicyclic ring system with ring Q;

[0071] R 4000 Selected from -C(O)-R 6000 、-CH 2 R 6000 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 7 R 8 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0072] R 5000 Selected from H, -C 1 ~C 5 Alkyl, and -C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen elements, -OH, -C 3 ~C 5 Cycloalkyl, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0073] R 6000 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 7000 R 8000 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0074] R 7000 and R 8000 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group can be optionally selected from halogen, -OH, -CN, or -C 3 ~C 5 One or more radicals of the cycloalkyl group are substituted;

[0075] R 7000 and R 8000 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0076] In one aspect, a compound of formula (IV), or a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula (IV) is provided:

[0077]

[0078] in:

[0079] R 10000 Selected from -CO 2 R 50000 , -C 1 ~C 5 Alkyl-CO 2 R 50000 , -C 3 ~C 6 Cycloalkyl-CO 2 R 50000 、-NHCO 2 R 50000 、-N(C 1 ~C 5 Alkyl)-CO 2 R 50000 、-O-CO 2 R 50000 , or -C 1 ~C 5 Alkyl-O-CO 2 R 50000 ;

[0080] R 20000 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0081] n is 0 or 1;

[0082] Ring S is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30000 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5Alkyl, -NR 70000 C(O)-CH=CH 2 、-NR7 0000 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 70000 C(O)-CH=CHCH 3 , or -NR 70000 C(O)-CH=CHCH 2 NR 80000 R 90000 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -CN, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0083] Two R on the same carbon atom of ring S 30000 Two or three R on different carbon atoms 30 The group can be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring S, such as adamantyl;

[0084] R 40000 Selected from H, -OH, -C(O)-R 60000 、-OR 60000 、-OC(O)-R 60000 、-NR 70000 -C(O)-R 60000 , -C 1 ~C 4 Alkyl-C(O)-R 60000 、-SO 2 -R 60000 、-SO 2 -NR 80000 R 90000 , -C 1 ~C 4 Alkyl-SO 2 -R 60000 , or -C 1 ~C 4 Alkyl-SO 2 NR 80000 R 90000 ;

[0085] R 50000 Selected from H, -C 1 ~C 5 Alkyl, and -C 3 ~C 6Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen elements, -OH, -C 3 ~C 5 Cycloalkyl, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0086] R 60000 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0087] R 70000 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 6 Cycloalkyl;

[0088] R 80000 and R 90000 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 6 Cycloalkyl, wherein the alkyl group can be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0089] R 80000 and R 90000 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0090] Wherein the compound of formula (IV) is not

[0091]

[0092] 4-(((1R, 2s, 3S, 5s, 7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0093]

[0094] 4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0095]

[0096] 4-(Cyclopentylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0097]

[0098] 4-(Cycloheptylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0099]

[0100] 4-(((1S,2R)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0101]

[0102] 4-(((1R,2S)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0103]

[0104] 4-((3-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0105]

[0106] 4-((4-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester,

[0107]

[0108] 4-((2,2-dimethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester, or

[0109]

[0110] Ethyl 4-(((1S,2R)-2-ethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0111] In some embodiments, the compound is selected from the group consisting of:

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

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

[0136]

[0137]

[0138] In some embodiments, the compound is selected from the group consisting of:

[0139]

[0140]

[0141]

[0142] In one aspect, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound disclosed in the present invention, a pharmaceutically acceptable salt of the compound, a derivative of the compound, or a combination thereof; and a pharmaceutically acceptable carrier.

[0143] In one aspect, a method of treating a JAK1 and / or JAK3-mediated disease in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound, a derivative of the compound, or a combination thereof disclosed herein.

[0144] In some embodiments, the methods further comprise administering an additional therapeutic agent.

[0145] In some embodiments, the JAK1 and / or JAK3 mediated disease is selected from the group consisting of: an autoimmune disorder or autoimmune response, a generalized activation of an immune response, a bacterial infection, a viral infection, inflammation, a chronic and / or acute inflammatory disorder or condition, and / or an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasm, a cardiovascular disorder, a cerebrovascular disorder, a skin disorder, pruritus, a hair loss disorder, a cancer or malignancy, an autoimmune connective tissue disease, an autoimmune condition; Still's disease, adult-onset Still's disease, Th17-related inflammation, polychondritis (e.g., relapsing polychondritis); myositis, polymyositis, Autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, arthritis associated with inflammatory bowel disease, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathies (ankylosing spondylitis), gout, scleroderma (systemic sclerosis, juvenile sclerosis), Reiter syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus (SLE) ( Lupus erythematosus, systemic lupus erythematosus in children, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / discoid lupus, chilblain lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesitis, carditis, myocarditis, angiogenesis disorders, myelodysplastic syndrome, atherosclerosis, restenosis (atherosclerotic coronary artery restenosis), acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, transplant artery disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndrome, vasculitis syndrome includes Takayasu arteritis, Wei's disease Gastrointestinal disorders, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, inflammatory bowel syndrome / spontive colon, celiac disease; acute pancreatitis and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, or cirrhosis due to fatty liver disease (e.g., alcoholic and nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis;Kidney disease, immune-mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive kidney disease, diabetic kidney disease / diabetic nephropathy, renal fibrosis, renal ischemia / reperfusion injury, HIV-related nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; pneumonitis bronchiolitis, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease; eye disorders, including, for example, eye inflammation, uveitis, dry eyes / keratoconjunctivitis sicca, scleritis, episcleritis , keratitis / keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy (diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), myelodysplastic syndrome, idiopathic thrombocytopenic purpura; bone resorption disorders; neurodegenerative disorders, neurological disorders / neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease Donald's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Langer-Evans myasthenic syndrome (LEMS), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury; damage to the nervous system, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke / neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric illness; paresthesia pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia), nerve irritation, peripheral neuropathy;Pruritus / itch (atopic pruritus, dry pruritus, itch associated with psoriasis / psoriatic pruritus / psoriatic pruritus), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic pruritus, biliary pruritus, hepatobiliary pruritus, renal pruritus / renal pruritus, uremic pruritus, cholestasis, intrahepatic cholestasis of pregnancy, pruritus associated with chronic simple lichen, lymphoma-associated pruritus, leukemia-associated pruritus, nodular pruritus, atopic dermatitis-associated pruritus, atopic pruritus / atopic pruritus, bullous pruritus, brachioradialis pruritus, neurogenic pruritus, neuropathic pruritus, paresthesia dorsalis, HIV-associated pruritic papules, psychogenic pruritus, swimmer's itch, pruritus or uremic pruritus, urticarial pruritus;Skin Diseases (e.g.), Skin Diseases Drug Reactions / Drug Rash, Xerosis / Dry Skin, Rash, Skin Sensitization, Skin Irritation, Sunburn, Shaving, Body Lice, Head Lice / Penicillosis, Pubic Lice, Cutaneous Larva Migrans, Scabies, Parasitic Infestations, Insect Infestations, Urticaria / Hives, Urticaria Papularis, Insect Bites, Insect Stings, Dandruff, Foreign Objects or Devices on the Skin, Fungal Infections, Herpes, Varicella / Chickenpox, Eosinophilic Folliculitis, Pregnancy Dermatosis / Pruritic Urticarial Papules and Plaques of Pregnancy (PUPP), Inflammatory Dermatosis, Neutrophilic Dermatosis, Histiocytoid Neutrophilic Dermatosis, Intestinal Bypass Syndrome Dermatosis, Psoriasis / Psoriasis Vulgaris, Lichen Planus, Lichen Sclerosus Atrophicus, Acne (Acne Vulgaris, Acne vulgaris, inflammatory acne, nodulocystic acne, acne scar, acne keloidal on the neck), atopy (allergic contact sensitization, allergic dermatitis), dermatitis (atopic dermatitis / eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis), acute febrile neutrophilic dermatosis (Sweet syndrome), chronic atypical neutrophilic and lipodystrophy dermatosis and hyperthermia syndrome (CANDLE syndrome), suppurative hidradenitis, urticaria, gangrenosum pyoderma, alopecia (eyebrow loss, nasal hair loss, scarring alopecia (central centrifugal scarring alopecia), non-scarring alopecia (alopecia areata (AA) (plaque AA, alopecia totalis (AT), alopecia universalis (AU), herpes zoster alopecia areata, horseshoe-shaped alopecia areata), androgen-derived / androgenic alopecia (AGA) / male and female AGA), telogen effluvium, tinea capitis, hypotrichosis (simple hereditary hypotrichosis), lichen planus pilaris (frontal fibrosing alopecia), palmoplantar keratoderma punctatus, erythema erythematosus (EED), neutrophilic exocrine hidradenitis, palisade neutrophilic granulomatous dermatitis, neutrophilic urticaria skin disease, vitiligo, vitiligo includes segmental vitiligo (single segmental vitiligo, two segmental vitiligo, multi-segmental vitiligo), non-segmental vitiligo (acral vitiligo, facial vitiligo, or acrofacial vitiligo, central facial vitiligo, mucosal vitiligo, paper-like vitiligo, tricolor vitiligo , marginal inflammatory vitiligo, tetrachromatic vitiligo, blue vitiligo, Kebner phenomenon, vitiligo vulgaris, generalized vitiligo, universal vitiligo), mixed vitiligo / non-segmental vitiligo with segmental vitiligo, localized vitiligo, isolated mucosal vitiligo, or vitiligo with or without white hair (body hair involvement); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), pemphigoid gestationis, xeroderma pigmentosum; fibrotic and scarring disorders: fibromas, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low-grade scarring such as scleroderma, increased fibrosis, keloids, postoperative scars;Wound healing, surgical scarring, radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), central nervous system scarring, digestive or gastrointestinal fibrosis, renal fibrosis, liver fibrosis or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cold pyrine-associated periodic syndrome (MERS) -Wei syndrome, familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal-onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue damage, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid resistance, glucose intolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immunosenescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune testicular inflammation, Goodpasture's disease, Sjögren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune hepatitis and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-related autoimmune disease, drug-induced autoimmunity, HIV-related autoimmune syndrome, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergic and allergic reactions, including hypersensitivity reactions, such as type I hypersensitivity reactions (e.g., including anaphylaxis), type II hypersensitivity reactions (e.g., (e.g., Goodpasture's disease, autoimmune hemolytic anemia), type III hypersensitivity disorders (e.g., Arthus reaction, serum sickness), and type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome);Rejection: Graft-versus-host reaction / graft-versus-host disease, allogeneic transplant rejection (e.g., acute allogeneic transplant rejection or chronic allogeneic transplant rejection), early transplant rejection; Malignancies, cancers, lymphomas, leukemias, multiple myeloma, solid tumors, teratomas, metastatic disorders and bone disorders, internal cancers, bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, stomach cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer (liver cancer), pancreatic cancer, nerve cancer, brain cancer ( For example, gliomas, glioblastoma multiforme, astrocytomas, neuroblastomas, and schwannomas), head and neck cancer, pharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer (kidney cancer), breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, eye cancer (ocular malignancies), and skin cancer (melanoma, keratoacanthoma); as well as fibrotic cancers, fibromas, fibroadenomas, fibrosarcomas, myeloproliferative disorders, neoplasms (hematopoietic neoplasms, spinal cord neoplasms, lymphoid neoplasms ( Myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemia (acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphoma Tumors (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides)), lymphomas (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased accumulation of exogenous opioids or synthetic opioids, paresthesia back pain, obsessive-compulsive disorder, homesickness associated with obsessive-compulsive disorder, and combinations thereof. ;

[0146] In some embodiments, the additional therapeutic agent is selected from the group consisting of: a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressant, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating an immunodeficiency disorder, and combinations thereof.

[0147] definition

[0148] It must also be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a JAK inhibitor" is a reference to one or more JAK inhibitors known to those skilled in the art and equivalents thereof, etc.

[0149] As used herein, the term "about" is intended to qualify the numerical value it modifies, thereby representing such a value as a variable within a range of error. When no specific range of error (such as the standard deviation of the mean value given in a chart or data table) is listed, the term "about" should be understood as the mean value of the numerical value of the number used with it plus or minus 10%. Therefore, about 50% means within the range of 45%-55%.

[0150] In embodiments or claims where the term "comprising" is used as a transitional phrase, such embodiments are also contemplated as replacing the term "comprising" with the terms "consisting of" or "consisting essentially of.

[0151] As used herein, the terms "consists of" or "consisting of" mean that a composition, formulation or method comprises only those elements, steps, or ingredients specifically recited in a particular claimed embodiment or claim.

[0152] As used herein, the term "consisting essentially of" or "consists essentially of" means that the composition, formulation, or method contains only the elements, steps, or ingredients specifically listed in the particular claimed embodiment or claim, and may optionally contain additional elements, steps, or ingredients that do not substantially affect the basic and novel characteristics of the particular embodiment or claim. For example, one or more of the only active ingredients in a formulation or method for treating a particular condition (e.g., nutrient depletion) are one or more therapeutic agents specifically listed in the particular embodiment or claim.

[0153] As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as being different from another embodiment. For example, an embodiment in which two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH 2 The embodiment wherein the same group is NH is mutually exclusive with the embodiment wherein the same group is NH.

[0154] As used herein, the term "derivative thereof" refers to a salt thereof, a pharmaceutically acceptable salt thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0155] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a base or acid that is acceptable for administration to a patient. The term "pharmaceutically acceptable salt" encompasses salts that are commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases as well as from pharmaceutically acceptable inorganic or organic acids.

[0156] When a numerical range is disclosed and the notation "from n1 ... to n2" or "between n1 ... and n2" (where n1 and n2 are numbers) is used, then unless otherwise specified, the notation is intended to include the numbers themselves and the range between them. The range can be integer or continuous between the end values ​​(including the end values). For example, the range "from 2 to 6 carbon atoms" is intended to include two, three, four, five, and six carbon atoms, because carbon atoms appear in integer units. In contrast, for example, the range "from 1 μM (micromolar) to 3 μM" is intended to include 1 μM, 3 μM, and any significant numbers therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0157] The term "acyl," as used herein, alone or in combination, refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety wherein the atom to which the carbonyl is attached is carbon. An "acetyl" group refers to -C(O)CH 3 Group. An "alkylcarbonyl" group or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

[0158] As used herein, individually or in combination, the term "alkenyl" refers to a straight or branched hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl will include from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system connected at two or more positions, such as vinylene (-CH=CH-). Examples of suitable alkenyl groups include vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, etc. Unless otherwise specified, the term "alkenyl" may include an "alkenylene" group.

[0159] As used herein, alone or in combination, the term "alkoxy" refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0160] As used herein, alone or in combination, the term "alkyl" refers to a straight or branched chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl will include from 1 to 10 carbon atoms. In other embodiments, the alkyl will include from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein.

[0161] Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, etc. As used herein, the term "alkylene" alone or in combination refers to a saturated aliphatic group derived from a straight or branched saturated hydrocarbon attached at two or more positions, such as a methylene (-CH 2 -). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[0162] As used herein, alone or in combination, the term "alkylamino" refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be monoalkylated or dialkylated groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, etc.

[0163]

[0046] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group wherein one carbon atom of the carbon-carbon double bond belongs to the portion to which the alkenyl group is attached.

[0164] As used herein, alone or in combination, the term "alkylthio" refers to an alkylthioether (RS-) group, wherein the term alkyl is as defined above, and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfinyl, ethanesulfinyl, and the like.

[0165] As used herein, alone or in combination, the term "alkynyl" refers to a straight or branched hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkynyl includes from 2 to 6 carbon atoms. In other embodiments, the alkynyl includes from 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond connected at two positions, such as ethynylene (-C≡C-).

[0166] Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.

[0167] As used herein, alone or in combination, the terms "amido" and "carbamoyl" refer to an amino group attached to the parent molecular moiety through a carbonyl group as described below, or vice versa. As used herein, alone or in combination, the term "C-amido" refers to a -C(O)N(RR') group, wherein R and R' are as defined herein or as defined by a specific list of "R" groups as specified. As used herein, alone or in combination, the term "N-amido" refers to a RC(O)NH(R')- group, wherein R and R' are as defined herein or as defined by a specific list of "R" groups as specified. As used herein, alone or in combination, the term "acylamino" encompasses an acyl group attached to the parent moiety through an amino group. Examples of "acylamino" groups are acetamido (CH 3 C(O)NH-).

[0168] As used herein, alone or in combination, the term "amino" refers to -NRR', wherein R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may itself be optionally substituted. In addition, R and R' may combine to form heterocycloalkyl, any of which may be optionally substituted.

[0169] As used herein, alone or in combination, the term "aryl" means a carbocyclic aromatic system containing one, two or three rings, wherein such polycyclic ring systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0170]

[0063] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0171]

[0063] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0172]

[0043] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[0173]

[0063] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0174] The term "arylalkanoyl" or "aralkanoyl" or "aroyl" as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid (e.g., benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyroyl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like).

[0175] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxygen group.

[0176] As used herein, the terms "benzo" and "benz", alone or in combination, refer to a divalent radical C derived from benzene. 6 H 4 =. Examples include benzothiophene and benzimidazole.

[0177] The term "carbamate," as used herein, alone or in combination, refers to an ester of a carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety from either the nitrogen terminus or the acid terminus, and which may be optionally substituted as defined herein.

[0178] The term "O-carbamyl," as used herein, alone or in combination, refers to a -OC(O)NRR' group, with R and R' as defined herein.

[0179] The term "N-carbamyl," as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.

[0180] As used herein, the term "carbonyl" when used alone encompasses the formyl group [-C(O)H] and when used in combination, the term "carbonyl" is a -C(O)- group.

[0181] As used herein, the term "carboxyl" or "carboxy" refers to -C(O)OH or the corresponding "carboxylate" anion (e.g., in carboxylates). An "O-carboxyl" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxyl" group refers to a -C(O)OR group, where R is as defined herein.

[0182] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, and tautomers of the described structure. The term "compound" also includes all isotopes incorporated into any position in the described structure in any enriched form (e.g., tritium, deuterium).

[0183] The term "cyano," as used herein, alone or in combination, refers to -CN.

[0184] As used herein individually or in combination, the term "cycloalkyl" or alternatively "carbocycle" refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, wherein each ring portion contains from 3 to 12 carbon atom ring members, and can be alternatively a benzo-fused ring system optionally substituted as defined herein. In certain embodiments, the cycloalkyl will include from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, etc. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems, such as decalin, octahydronaphthalene, and polycyclic (polycentric) saturated or partially unsaturated types. The latter type of isomers are typically exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0185]

[0063] The term "ester," as used herein, alone or in combination, refers to a carboxyl group bridging two moieties linked at carbon atoms.

[0186]

[0063] The term "ether," as used herein, alone or in combination, refers to an oxy group that bridges two moieties connected at carbon atoms.

[0187]

[0043] The term "halogen" or "halogen element" as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0188] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0189] As used herein individually or in combination, the term "haloalkyl" refers to an alkyl group with the meaning as defined above, in which one or more hydrogens are replaced by halogen elements. Specifically comprising monohaloalkyl groups, dihaloalkyl groups and polyhaloalkyl groups. For example, monohaloalkyl groups can have iodine atoms, bromine atoms, chlorine atoms or fluorine atoms in the group. Dihaloalkyl groups and polyhaloalkyl groups can have a combination of two or more identical halogen atoms or different halogen groups. The example of a haloalkyl group includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group connected at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethylene (-CHCl-), etc.

[0190] As used herein individually or in combination, the term "halocycloalkyl" refers to a cycloalkyl group with the meaning as defined above, in which one or more hydrogens are replaced by halogen elements. Specifically comprising a monohalocycloalkyl group, a dihalocycloalkyl group and a polyhalocycloalkyl group. For example, a monohaloalkyl group can have an iodine atom, a bromine atom, a chlorine atom or a fluorine atom in the group. A dihaloalkyl group and a polyhaloalkyl group can have a combination of two or more identical halogen atoms or different halogen groups. The example of a haloalkyl group comprises fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, chlorocyclobutyl and chlorocyclopentyl.

[0191] As used herein, alone or in combination, the term "heteroalkyl" refers to a stable straight or branched chain, or a combination thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of a specified number of carbon atoms and one to three heteroatoms selected from N, O, and S, and wherein the N and S atoms may be optionally oxidized, and the N heteroatom may be optionally quaternized. One or more heteroatoms may be located at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive (e.g., -CH 2 -NH-OCH 3 ).

[0192] As used herein, alone or in combination, the term "heteroaryl" refers to a 5- to 15-membered unsaturated heteromonocyclic ring, or a fused monocyclic ring system, a bicyclic ring system, or a tricyclic ring system, wherein at least one of the fused rings is aromatic, containing at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl will include from 1 to 4 heteroatoms as ring members. In other embodiments, the heteroaryl will include from 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will include from 5 to 7 atoms. The term also includes fused polycyclic groups, wherein the heterocycle is fused to an aryl ring, wherein the heteroaryl ring is fused to other heteroaryl rings, wherein the heteroaryl ring is fused to a heterocycloalkyl ring, or wherein the heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazole, The invention also includes but is not limited to benzophenone, benzothiophene ...

[0193] As used herein individually or in combination, the term "heterocycloalkyl" and interchangeable "heterocycle" each refer to a saturated, partially unsaturated, or completely unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each of the heteroatoms can be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, heterocycloalkyl will include from 1 to 4 heteroatoms as ring members. In other embodiments, the heterocycloalkyl will include from 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will include from 3 to 8 ring members in each ring. In other embodiments, the heterocycloalkyl will include from 3 to 7 ring members in each ring. In yet other embodiments, the heterocycloalkyl will include from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides having a tertiary nitrogen ring member, and carbocyclic fused ring systems and benzofused ring systems; in addition, both terms also include systems in which a heterocycle is fused to an aryl group as defined herein or to an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolanyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Unless explicitly prohibited, heterocyclic groups may be optionally substituted.

[0194] The term "hydrazino," as used herein, alone or in combination, refers to two amino groups connected by a single bond (ie, -NN-).

[0195] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[0196] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0197] The term "imino," as used herein, alone or in combination, refers to =N-.

[0198] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =NO-.

[0199] The phrase "in the backbone" refers to the longest continuous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compound having any of the formulae disclosed herein.

[0200] The term "isocyanato" refers to an -NCO group.

[0201] The term "isothiocyanato" refers to a -NCS group.

[0202] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur.

[0203] As used herein, alone or in combination, unless otherwise specifically defined, the term "lower" means a group containing from 1 to 6 carbon atoms (including 6 carbon atoms) (i.e., C 1 ~C 6 alkyl).

[0204] The term "lower aryl" as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as specified.

[0205] As used herein, the term "lower heteroaryl" alone or in combination means: 1) a monocyclic heteroaryl comprising five or six ring members, wherein between one and four of the ring members may be heteroatoms selected from N, O, and S; or 2) a bicyclic heteroaryl wherein each of the fused rings comprises five or six ring members, wherein between the ring members there are one to four heteroatoms selected from N, O, and S.

[0206] As used herein, alone or in combination, the term "lower cycloalkyl" means a monocyclic cycloalkyl group (i.e., C 3 ~C 6 The lower cycloalkyl group may be unsaturated. Examples of the lower cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0207] As used herein, the term "lower heterocycloalkyl" alone or in combination means a monocyclic heterocycloalkyl group having between three and six ring members, one and four of which may be heteroatoms selected from N, O, and S (i.e., C 3 ~C 6 Examples of lower heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl groups may be unsaturated.

[0208] The term "lower amino" as used herein, alone or in combination, refers to -NRR', wherein R and R' are independently selected from hydrogen and lower alkyl, either of which may be optionally substituted.

[0209] The term "thiol," as used herein, alone or in combination, refers to an RS- group, with R as defined herein.

[0210] As used herein, alone or in combination, the term "nitro" refers to -NO2 .

[0211] As used herein, "N-oxides" are formed from tertiary basic amines or imines present in the molecule using a convenient oxidizing agent.

[0212]

[0063] The term "oxy" or "oxa," as used herein, alone or in combination, refers to -O-.

[0213] The term "oxo," as used herein, alone or in combination, refers to =0.

[0214] The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms are replaced by halogen atoms.

[0215] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms are replaced with halogen atoms.

[0216] As used herein, alone or in combination, the term "substantially free" refers to a compound that is free of all other compounds within the detection limit as measured by any means, including nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GC / MS), or liquid chromatography / mass spectrometry (LC / MS).

[0217] As used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic" refer to -SO 3 H group, and use it in salt form as the anion of the sulfonic acid.

[0218] The term "sulfanyl," as used herein, alone or in combination, refers to -S-.

[0219] The term "sulfinyl," as used herein, alone or in combination, refers to -S(O)-.

[0220] As used herein, the term "sulfonyl" alone or in combination refers to -S(O) 2 -.

[0221] The term "N-sulfonamido" refers to RS(=O) 2 An NR'-group, wherein R and R' are as defined herein.

[0222] The term "S-sulfonamido" refers to -S(=O) 2 NRR' group, wherein R and R' are as defined herein.

[0223] As used herein, alone or in combination, the terms "thia" and "thio" refer to an -S- group or an ether in which the oxygen is replaced by sulfur. The oxidized derivatives of the thio group (ie, sulfinyl and sulfonyl) are included in the definition of thia and thio.

[0224] The term "thiol" as used herein, alone or in combination, refers to a -SH group.

[0225] As used herein, the term "thiocarbonyl" when used alone encompasses the thioformyl group -C(S)H and when used in combination, the term "thiocarbonyl" is a -C(S)- group.

[0226] The term "N-thiocarbamyl" refers to a ROC(S)NR'- group, where R and R' are as defined herein.

[0227] The term "O-thiocarbamyl" refers to a -OC(S)NRR' group, where R and R' are as defined herein.

[0228] The term "thiocyanato" refers to a -CNS group.

[0229] The term "trihalomethanesulfonamide" refers to X 3 CS(O) 2 An NR- group, wherein X is a halogen element, and R is as defined herein.

[0230] The term "trihalomethanesulfinyl" refers to 3 CS(O) 2 - group, wherein X is a halogen element.

[0231] The term "trihalomethoxy" refers to 3 CO- group, wherein X is a halogen element.

[0232] As used herein, alone or in combination, the term "trisubstituted silyl" refers to a silicone group which is substituted at its three free valencies with groups as listed herein under the definition of amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0233] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is the element connected to the parent moiety. For example, the composite group alkylamido represents an alkyl group connected to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group connected to the parent molecule via an alkyl group.

[0234] When a group is defined as "null", it means that the group does not exist.

[0235] The term "optionally substituted" means that the preceding group may or may not be substituted. When substituted, the substituents of the "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or groups specifically specified (alone or in combination): lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxylate, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amide, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonic acid, sulfonic acid, trisubstituted silyl, N- 4 ... 3 ,SH,SCH 3 、C(O)CH 3 , CO 2 CH 3 , CO 2 H, pyridyl, thiophene, furyl, low-level carbamate, and low-level urea. Where structurally feasible, two substituents can be linked together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, such as methylenedioxy or ethylenedioxy. The optionally substituted group can be unsubstituted (e.g., -CH 2 CH 3 ), is completely replaced (e.g., -CF 2 CF 3 ), is substituted by a single moiety (e.g., -CH 2 CH 2 F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ). Where substituents are listed without being characterized as substituted, both substituted and unsubstituted forms are included. Where a substituent is characterized as "substituted", the substituted form is specifically intended. In addition, different sets of optional substituents for a particular moiety may be defined as desired; in these cases, the optional substitution will generally be defined immediately following the phrase as "optionally substituted with".

[0236] Unless otherwise defined, the term R or the term R' refers to a portion selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl (any of which can be optionally substituted) when it appears alone and without a numerical designation. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether or not the R group has a numerical designation, it should be understood that each R group (including R, R' and Rn (where n = (1, 2, 3, ... n)), each substituent and each term are independent of each other in terms of selection from the group. If any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) appears more than once in a formula or family structure, its definition at each occurrence is independent of the definition at each other occurrence. Those skilled in the art will also recognize that certain groups can be connected to the parent molecule or can occupy a position in the chain of an element from either end as written. For example, an asymmetric group (such as -C (O) N (R) -) can be connected to the parent part at carbon or nitrogen.

[0237] Stereoisomeric source centers are present in some compounds disclosed herein. According to the configuration of the substituents around the stereoisomerization center, these centers are designated by the symbol "R" or "S". It should be understood that the present invention includes all stereochemical isomeric forms (including diastereomeric forms, enantiomeric forms, atropisomer forms, racemic forms and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof). The individual stereoisomers of the compound can be prepared synthetically from commercially available starting materials containing fixed stereoisomerization centers, or by preparing a racemic mixture of the product followed by enantiomeric separation (such as conversion into a mixture of diastereoisomers, followed by separation or recrystallization, chromatography techniques, direct separation of enantiomers on a chiral chromatographic column), or any other suitable method known in the art. The starting compound of a specific stereochemical configuration is commercially available, or can be manufactured and split by techniques known in the art. In addition, the compounds disclosed herein can exist as geometric isomers. The present invention includes all cis isomers, trans isomers, isomers, retro isomers, cis (E) isomers, and hetero (Z) isomers, and appropriate mixtures thereof. In addition, compounds may exist as tautomers; the present invention provides all tautomeric isomers. In addition, the compounds disclosed herein may exist in a non-solvated form, as well as in a solvated form with a pharmaceutically acceptable solvent (such as water, ethanol, etc.). Generally, the solvated form is considered to be equivalent to the non-solvated form.

[0238] When atoms connected by a bond are considered to be part of a larger substructure, the term "bond" refers to a covalent bond between two atoms, or two moieties. Unless otherwise specified, a bond can be a single bond, a double bond, or a triple bond. A dotted line between two atoms in a molecular diagram indicates that an additional bond may or may not be present at that position.

[0239] As used herein, the term "disease" is intended to be generally synonymous with and used interchangeably with the terms "disorder," "symptom," and "condition" (in the medical context), as all reflect an abnormal condition of the human or animal body, or one of its parts, which impairs normal function, is usually manifested by distinctive signs and symptoms, and causes the human or animal to have a reduced lifespan or quality of life.

[0240] The term "combination therapy" means the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in the present disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single topical composition having a fixed ratio of active ingredients, or in multiple separate topical compositions of each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the conditions or disorders described herein.

[0241] A "JAK1 and / or JAK3 inhibitor" is used herein to refer to an inhibitor that exhibits an IC against JAK1 and / or JAK3 activity of no more than about 100 μM and more typically no more than about 50 μM. 50 In some embodiments, the compound will exhibit an IC for JAK1 and / or JAK3 activity of about 1 μM to about 50 μM. 50 IC 50 The concentration of the inhibitor that reduces the activity of an enzyme (e.g., JAK1 and / or JAK3) to half-maximal levels. It has been found that certain compounds disclosed herein exhibit inhibition of JAK1 and / or JAK3. In some embodiments, the compound will exhibit an IC of no more than about 300 nM for JAK1 and / or JAK3 activity. 50 In some embodiments, the compound will exhibit an IC of no more than about 1 nM for JAK1 and / or JAK3 activity. 50 In certain embodiments, the compound will exhibit an IC of no more than about 50 μM for JAK1 and / or JAK3 activity. 50 In further embodiments, the compound will exhibit an IC of no more than about 10 μM for JAK1 and / or JAK3 activity. 50In yet further embodiments, the compound will exhibit an IC of no more than about 5 μM for JAK1 and / or JAK3 activity 50 In yet further embodiments, the compound will exhibit an IC of no more than about 1 μM for JAK1 and / or JAK3 activity 50 (as measured in the JAK1 and / or JAK3 assays described herein).

[0242] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used for the treatment of a disease or disorder, or the effect of a clinical endpoint.

[0243] As used herein, the term "therapeutic agent" means an agent used to treat, combat, ameliorate, prevent or improve an undesirable condition or disease in a patient.In part, embodiments of the present invention are directed to the treatment of JAK1 and / or JAK3 mediated diseases.

[0244] The term "therapeutically acceptable" refers to those compounds or derivatives thereof that are suitable for contact with the tissues of patients without excessive toxicity, irritation and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0245] As used herein, reference to "treatment" of a patient is intended to include prevention. Treatment may also be preemptive in nature, that is, it may include the prevention of a disease. The prevention of a disease may involve being completely free from the disease (e.g., as in the case of preventing a pathogen infection), or may involve the prevention of disease progression. For example, the prevention of a disease may not mean the complete elimination of any effect associated with the disease at any level, but may mean preventing the symptoms of the disease to a clinically significant or detectable level. The prevention of a disease may also mean preventing the disease from progressing to a late stage of the disease.

[0246] When used in conjunction with a treatment, "administering" means administering a therapeutic agent directly into or onto a target tissue, or administering a therapeutic agent to a patient, whereby the therapeutic agent positively affects the tissue to which it is targeted. Therefore, as used herein, when used in conjunction with the compounds of the embodiments herein, the term "administering" may include (but is not limited to): providing a compound into or onto a target tissue; providing a compound systemically to a patient, such as by intravenous injection, whereby the therapeutic agent reaches the target tissue; providing a compound in a form encoding its sequence to the target tissue (e.g., by so-called gene therapy techniques). "Administering" a composition may be achieved by injection, topically, orally, or by any of these methods in combination with other known techniques.

[0247] The term "patient" is generally synonymous with the term "subject" and includes all mammals (including humans). Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0248] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). The prodrug of the compound described herein is a structurally modified form of a compound that is easily subjected to chemical changes under physiological conditions and provides a compound. In addition, the prodrug can be converted into a compound by a chemical method or a biochemical method in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound. Prodrugs are generally useful because in some cases, prodrugs can be easier to apply than compounds or parent drugs. For example, prodrugs can be bioavailable by oral administration, while parent drugs are not. Compared with parent drugs, prodrugs can also have improved solubility in pharmaceutical compositions. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.

[0249] As used herein, the term "therapeutically acceptable salt" means a salt or zwitterionic form of a compound disclosed herein, which is water-soluble or oil-soluble or dispersible and as defined herein for therapeutically acceptable. Salt can be prepared during the final separation and purification of the compound, or prepared individually by reacting the appropriate compound of the free alkali form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzenesulfonate) (benzenesulfonate (besylate)), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, enanthate, caproate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethylsulfonate (esylate), lactate, maleic acid The compounds disclosed herein can be quaternized with the following: methyl, ethyl, propyl and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl and diamyl sulfides; decyl, lauryl, myristyl and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (such as oxalic acid, maleic acid, succinic acid, and citric acid). Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth ion. Thus, the present invention contemplates sodium salts, potassium salts, magnesium salts, and calcium salts of the compounds disclosed herein, and the like.

[0250] Novel compounds and pharmaceutical compositions, some of which have been found to inhibit JAK1 and / or JAK3 kinases, have been discovered, as well as methods of synthesizing and using the compounds (including but not limited to, methods for treating JAK1 and / or JAK3 mediated diseases in patients by topical administration of the compounds).

[0251] The compounds of the present invention may be selective in JAK1 and / or JAK3 isoforms in various ways. For example, the compounds described herein may have selectivity for JAK1 and / or JAK3 over other isoforms (such as JAK2 and Tyk-2), may be pan-inhibitors of all isoforms, or may be selective for only one isoform. In certain embodiments, the compounds of the present invention have selectivity for JAK1 and / or JAK3 over other isoforms. In some embodiments, the compounds disclosed herein have selectivity for JAK1 and / or JAK3 over JAK2 and Tyk-2. Enzyme assays, cell assays, or both may be used to determine selectivity. In some embodiments, the compounds disclosed herein have selectivity for JAK1 and / or JAK3 receptors over JAK2 receptors by at least about 10×. In some embodiments, the compounds disclosed herein have selectivity for JAK1 and / or JAK3 receptors over Tyk-2 receptors by at least about 10×. Specific implementation plan

[0252] Compound

[0253] Embodiments herein are directed to compounds and pharmaceutical compositions, some of which have been found to inhibit JAK1 and / or JAK3 kinases, and methods of synthesizing and using the compounds.Some embodiments comprise methods for treating a disease in a patient by topically administering a compound of the embodiments herein.

[0254] Certain compounds disclosed herein may have useful JAK1 and / or JAK3 inhibitory activity and may be used to treat or prevent diseases or conditions in which JAK1 and / or JAK3 play an active role. Therefore, embodiments are also directed to pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, as well as methods for making and using compounds and compositions. Certain embodiments are directed to methods for inhibiting JAK1 and / or JAK3. Other embodiments are directed to methods for treating JAK1 and / or JAK3-mediated disorders in patients in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein in the manufacture of drugs for treating diseases or conditions improved by the inhibition of JAK1 and / or JAK3.

[0255] Embodiments are also provided wherein any embodiment herein can be combined with any one or more of the other embodiments unless otherwise specified and provided that the combinations are not mutually exclusive.

[0256] Also provided are compounds selected from the examples disclosed herein. The compounds of the embodiments herein may also refer to salts thereof, esters thereof, free acid forms thereof, free base forms thereof, solvates thereof, deuterated derivatives thereof, hydrates thereof, N-oxides thereof, clathrates thereof, prodrugs thereof, polymorphs thereof, stereoisomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, mixtures of stereoisomers thereof, tautomers thereof, mixtures of tautomers thereof, or the aforementioned combinations of compounds of the embodiments herein.

[0257] Compounds described herein may contain stereoisomerism source centers, and may have chirality, thereby existing as enantiomers. In the case where the compound according to the embodiments herein has two or more stereoisomerism source centers, it may additionally exist as diastereomers. Embodiments herein include all possible stereoisomers as substantially pure enantiomers, its racemic mixture and mixtures of diastereomers through resolution. In some embodiments, the formula shown does not have a determined stereochemistry at certain positions. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. The diastereomer pairs of stereoisomers can be separated from a suitable solvent by, for example, fractional crystallization, and the enantiomer pairs thus obtained can be separated into individual stereoisomers by conventional means (for example, by using optically active acids or optically active bases as resolving agents or on chiral HPLC columns). In addition, any enantiomer or diastereomer of a compound of formula may be obtained by stereospecific synthesis or stereoselective synthesis using optically pure or enantiomerically enriched starting materials or reagents of known configuration. The scope of the embodiments described and claimed herein encompasses the racemic form of the compound as well as individual enantiomers, diastereomers, and stereoisomerically enriched mixtures.

[0258] Conventional techniques for the preparation / separation of individual enantiomers include stereoselective synthesis from suitable enantiomerically enriched or optically pure precursors or separation of racemates using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., alcohol, or an acid or base (such as tartaric acid or 1-phenylethylamine) (when the compound contains an acidic or basic moiety). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted into corresponding one or more pure enantiomers by means well known to those skilled in the art. The chiral compounds of the embodiments herein (and chiral precursors thereof) can be obtained in enantiomerically enriched form on an asymmetric resin using chromatography (typically HPLC) wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane), containing from 0 to 50% (typically from 2 to 20%) isopropanol and from 0 to 5% alkylamine (typically 0.1% diethylamine). Concentration of the eluent provides an enriched mixture. Stereoisomers can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).

[0259] Atropisomers are stereoisomers arising from hindered rotation about a single bond, where the steric strain barrier to rotation is high enough to allow separation of the conformers. Oki (Oki, M; Topics in Stereochemistry 1983, 1) defines atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature. The scope of the embodiments described and claimed herein encompasses the racemic forms of the compounds as well as individual atropisomers (atropisomers that are "substantially free" of their corresponding atropisomers) and stereoisomerically enriched mixtures (i.e., mixtures of atropisomers).

[0260] Separation of atropisomers may be performed by chiral resolution methods such as selective crystallization. In atropisomer-enantioselective synthesis or atropisomer-selective synthesis, one atropisomer is formed at the expense of another atropisomer. When the isomerization reaction favors one atropisomer over the other atropisomer, atropisomer-selective synthesis may be performed by using a chiral auxiliary such as a Corey-Bakshi-Shibata (CBS) catalyst (an asymmetric catalyst derived from proline) in the total synthesis of knipholone or by methods based on thermodynamic equilibrium.

[0261] Suitable pharmaceutically acceptable acid addition salts of the compounds of the embodiments herein may be prepared from inorganic or organic acids. All of these salts may be prepared from the corresponding compounds of the embodiments herein by conventional means, for example, by treating the compounds with an appropriate acid or base.

[0262] Pharmaceutically acceptable acids include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid and pyrophosphoric acid) and organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, enbolic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, malonic acid, galactic acid, galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, ascorbic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), naphthalene disulfonic acid (napadisilic acid) acid) (1,5-naphthalenedisulfonic acid, etc.).

[0263] Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including alkylamines, arylalkylamines, heterocyclic amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0264] Other preferred salts according to embodiments of the present invention are quaternary ammonium compounds, wherein the equivalent of the anion (X-) is related to the positive charge of the N atom. X- can be an anion of various inorganic acids (such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate), or an anion of an organic acid (such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate). X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X- is chloride, bromide, trifluoroacetate or methanesulfonate.

[0265] As used herein, N-oxides are formed from tertiary basic amines or imines present in the molecule using a convenient oxidizing agent.

[0266] The compound of the present embodiment can exist in an unsolvated form and a solvated form. The term solvate is used herein to describe a molecular complex including a compound of the present embodiment and a certain amount of one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the term hydrate is used. Examples of solvate forms include, but are not limited to, compounds of the present embodiment associated with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a mixture thereof. It is particularly contemplated that in the present embodiment, a solvent molecule can be associated with a molecule of the compound of the present embodiment, such as a hydrate.

[0267] In addition, it is specifically contemplated that, in embodiments herein, more than one solvent molecule may be associated with one molecule of a compound of embodiments herein, such as a dihydrate. In addition, it is specifically contemplated that, in embodiments herein, less than one solvent molecule may be associated with one molecule of a compound of embodiments herein, such as a hemihydrate. In addition, solvates of embodiments herein are contemplated as solvates of compounds of embodiments herein that retain the biological effectiveness of the non-solvated form of the compound.

[0268] The embodiments herein also include isotopically labeled compounds of the embodiments herein, wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the embodiments herein include isotopes of hydrogen (e.g. 2 H and 3 H), carbon isotopes (such as 11 C. 13 C and 14 C), isotopes of chlorine (such as 31Cl), isotopes of fluorine (such as 18 F), isotopes of iodine (such as 123 I and 125 I), nitrogen isotopes (such as 13 N and 15 N), oxygen isotopes (such as 15 O. 17 O and 18 O), phosphorus isotopes (such as 32 P), and sulfur isotopes (such as 35 S). Certain isotopically labeled compounds of the embodiments herein (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are easily incorporated and readily available for detection, which is particularly useful for this purpose. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. 11 C. 18 F. 15 O and 13 N) substitutions may be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0269] Isotopically-labeled compounds of the embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0270] Preferred isotopically labeled compounds include deuterated derivatives of the compounds of the embodiments herein. As used herein, the term deuterated derivatives includes compounds of the embodiments herein in which at least one hydrogen atom at a specific position is replaced by deuterium. Deuterium (D or 2 H) is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mol %.

[0271] A hydrogen-deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. The exchange (incorporation) reaction may be complete or partial.

[0272] Typically, deuterated derivatives of the compounds of the embodiments herein have an isotopic enrichment factor (the ratio between the isotopic abundance and the natural abundance of that isotope, i.e., the percentage of deuterium incorporated in place of hydrogen at a given position in a molecule) of at least 3500 (52.5% deuterium incorporation) for each deuterium present at a site on the compound designated as a potential deuteration site.

[0273] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It should be understood that the isotopic enrichment factor of each deuterium present at a site designated as a deuterated site is independent of the other deuterated sites.

[0274] The isotopic enrichment factor can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0275] Prodrugs of compounds described herein are also within the scope of embodiments herein. Therefore, some derivatives of compounds of embodiments herein (the derivatives themselves may have little pharmacological activity or no pharmacological activity) can be converted into compounds of embodiments herein with desired activity, for example, by hydrolytic cleavage when applied to or on the body. Such derivatives are referred to as 'prodrugs'. Further information on the application of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

[0276] Prodrugs according to the embodiments herein can be prepared, for example, by replacing appropriate functional groups present in the compounds of the embodiments herein with certain moieties known to those skilled in the art as 'pro-moieties', as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[0277] Where the compounds of the embodiments herein are solids, it will be appreciated by those skilled in the art that the compounds and salts of the invention may exist in different crystalline or polymorphic forms or in an amorphous form, all of which are intended to be within the scope of the embodiments herein.

[0278] The compounds disclosed herein may exist as, and therefore encompass, all stereoisomers, conformers, and mixtures thereof in all ratios, as well as isotopic forms (such as deuterated compounds).

[0279] The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts (including acid addition salts). Suitable salts include salts formed with organic or inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may have utility in the preparation and purification of the compounds in question. Base addition salts may also be formed and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0280] Base addition salts can be prepared during the final separation and purification of the compound by reacting the carboxyl group with a suitable base (such as hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary amine, secondary amine, or tertiary amine. The cation of the therapeutically acceptable salt includes lithium, sodium, potassium, calcium, magnesium, and aluminum, and nontoxic quaternary amine cations (such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, and N, N'-dibenzylethylenediamine). Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0281] In certain embodiments, the compound has structural formula (I):

[0282]

[0283] in:

[0284] R 1 Selected from -CO 2 R 5 , -C 1~C 5 Alkyl-CO 2 R 5 , -C 3 ~C 6 Cycloalkyl-CO 2 R 5 、-NHCO 2 R 5 、-N(C 1 ~C 5 Alkyl)-CO 2 R 5 、-O-CO 2 R 5 , or -C 1 ~C 5 Alkyl-O-CO 2 R 5 ;

[0285] R 2 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0286] n is 0, 1, or 2;

[0287] Ring A is substituted at one or more carbon atoms with one, two or three R 3 Substituents, where each R 3 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0288] Two R on the same carbon atom or different carbon atoms of ring A 3 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring A;

[0289] R 4 Selected from -C(O)-R 6 、-CH 2 R 6 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 ,

[0290] -C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 7 R 8 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0291] R 5 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0292] R 6 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 7 R 8 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0293] R 7 and R8 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0294] R 7 and R 8 They can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0295] In certain embodiments, the compound has structural formula (Ia):

[0296]

[0297] in:

[0298] R 21 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0299] n is 0, 1, or 2;

[0300] Ring B is substituted at one or more carbon atoms with one, two or three R 31 Substituents, where each R 31 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0301] Two R on the same carbon atom or different carbon atoms of ring B 31 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring B;

[0302] R 41 Selected from -C(O)-R 61 、-CH 2 R 61 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 71 R 81 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0303] R 51 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0304] R 61 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 71 R 81 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0305] R 71 and R 81 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0306] R 71 and R 81 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0307] In certain embodiments, the compound has structural formula (Ib):

[0308]

[0309] in:

[0310] R 22 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0311] n is 0, 1, or 2;

[0312] Ring C is substituted at one or more carbon atoms with one, two or three R 32 Substituents, where each R 32 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C5 Alkyl groups are substituted with one or more groups;

[0313] Two R on the same carbon atom or different carbon atoms of ring C 32 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring C;

[0314] R 42 Selected from -C(O)-R 62 、-CH 2 R 62 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 72 R 82 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0315] R 52 Selected from -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0316] R 62 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 73 R 83 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0317] R 72 and R 82 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0318] R 72 and R 82 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0319] In certain embodiments, the compound has structural formula (Ic):

[0320]

[0321] in:

[0322] R 23 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0323] n is 0, 1, or 2;

[0324] Ring D is substituted at one or more carbon atoms with one, two or three R 33 Substituents, where each R 33 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0325] Two R on the same carbon atom or different carbon atoms of ring D 33 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring D;

[0326] R 43 Selected from -C(O)-R 63 、-CH 2 R 63 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 73 R 83 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0327] R 53 Selected from -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0328] R 63 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 73 R 83 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0329] R 73 and R 83 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0330] R 73 and R 83 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0331] In certain embodiments, the compound has structural formula (Id):

[0332]

[0333] in:

[0334] R 24 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0335] n is 0, 1, or 2;

[0336] Ring E is substituted at one or more carbon atoms with one, two or three R 34 Substituents, where each R 34 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0337] Two R on the same carbon atom or different carbon atoms of ring E 34 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring E;

[0338] R 44 Selected from -C(O)-R 64 、-CH 2 R 64 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 74 R 84 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0339] R 54 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0340] R 64 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 74 R 84, -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0341] R 74 and R 84 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0342] R 74 and R 84 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0343] In certain embodiments, the compound has structural formula (Ie):

[0344]

[0345] in:

[0346] R 25 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0347] n is 0, 1, or 2;

[0348] Ring F is substituted at one or more carbon atoms with one, two, or three R 35 Substituents, where each R 35 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0349] Two R on the same carbon atom or different carbon atoms of ring F 35 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring F;

[0350] R 45 Selected from -C(O)-R 65 、-CH 2 R 65 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 75 R 85 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0351] R 55 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0352] R 65 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C6 Cycloalkyl, -NR 75 R 85 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0353] R 75 and R 85 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0354] R 75 and R 85 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0355] In certain embodiments, the compound has the structural formula (If):

[0356]

[0357] in:

[0358] R 26 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0359] n is 0, 1, or 2;

[0360] Ring G is substituted at one or more carbon atoms with one, two, or three R 36 Substituents, where each R 36The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0361] Two R on the same carbon atom or different carbon atoms of ring G 36 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring G;

[0362] R 46 Selected from -C(O)-R 66 、-CH 2 R 66 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 76 R 86 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0363] R 56 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0364] R 66 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 76 R 86 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0365] R 76 and R 86 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0366] R 76 and R 86 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0367] In certain embodiments, the compound has structural formula (Ig):

[0368]

[0369] in:

[0370] R 27 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0371] n is 0, 1, or 2;

[0372] Ring H is replaced at one or more carbon atoms by one, two, or three R 37 Substituents, where each R 37 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0373] Two R on the same carbon atom or different carbon atoms of ring H 37 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring H;

[0374] R 47 Selected from -C(O)-R 67 、-CH 2 R 67 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 77 R 87 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0375] R 57 Selected from -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0376] R 67 Selected from -C 1~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 77 R 87 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0377] R 77 and R 87 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0378] R 77 and R 87 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0379] In certain embodiments, the compound has structural formula (II):

[0380]

[0381] in:

[0382] R 10 Selected from -CO 2 R 50 , -C 1 ~C 5 Alkyl-CO 2 R 50 , -C 3 ~C 6 Cycloalkyl-CO 2 R 50 、-NHCO 2 R 50 、-N(C 1 ~C 5 Alkyl)-CO2 R 50 、-O-CO 2 R 50 , or -C 1 ~C 5 Alkyl-O-CO 2 R 50 ;

[0383] R 20 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0384] n is 0 or 1;

[0385] Ring I is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 70 C(O)-CH=CH 2 、-NR 70 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 70 C(O)-CH=CHCH 3 , or -NR 70 C(O)-CH=CHCH 2 NR 80 R 90 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0386] Two R on the same carbon atom of ring I30 Two or three R on different carbon atoms 30 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with Ring I, such as adamantyl;

[0387] R 40 Selected from H, -OH, -C(O)-R 60 、-OR 60 、-OC(O)-R 60 、-NR 70 -C(O)-R 60 , -C 1 ~C 4 Alkyl-C(O)-R 60 、-SO 2 -R 601 、-SO 2 -NR 80 R 90 , -C 1 ~C 4 Alkyl-SO 2 -R 60 , or -C 1 ~C 4 Alkyl-SO 2 NR 80 R 90 ;

[0388] R 50 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0389] R 60 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0390] R 70 Selected from H, -C 1~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0391] R 80 and R 90 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0392] R 80 and R 90 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0393] In certain embodiments, the compound has structural formula (IIa):

[0394]

[0395] in:

[0396] R 201 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0397] n is 0 or 1;

[0398] Ring J is replaced at one or more carbon atoms by one, two, or three R 301 Substituents, where each R 301 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 701 C(O)-CH=CH 2、-NR 701 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 701 C(O)-CH=CHCH 3 , or -NR 701 C(O)-CH=CHCH 2 NR 801 R 901 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0399] Two R on the same carbon atom of ring J 301 Two or three R on different carbon atoms 301 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring J, such as adamantyl;

[0400] R 401 Selected from H, -OH, -C(O)-R 601 、-OR 601 、-OC(O)-R 601 、-NR 701 -C(O)-R 601 , -C 1 ~C 4 Alkyl-C(O)-R 601 、-SO 2 -R 601 、-SO 2 -NR 801 R 901 , -C 1 ~C 4 Alkyl-SO 2 -R 601 , or -C 1 ~C 4 Alkyl-SO 2 NR 801 R 901 ;

[0401] R 501 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C5 Alkyl groups are substituted with one or more groups;

[0402] R 601 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0403] R 701 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0404] R 810 and R 901 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; or

[0405] R 801 and R 901 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0406] In certain embodiments, the compound has structural formula (IIb):

[0407]

[0408] in:

[0409] R 202 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0410] n is 0 or 1;

[0411] Ring K is substituted at one or more carbon atoms with one, two, or three R 302 Substituents, where each R 302 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 702 C(O)-CH=CH 2 、-NR 702 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 702 C(O)-CH=CHCH 3 , or -NR 702 C(O)-CH=CHCH 2 NR 802 R 902 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0412] Two R on the same carbon atom of ring K 302 Two or three R on different carbon atoms 302 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring K, such as adamantyl;

[0413] R 402 Selected from H, -OH, -C(O)-R 602 、-OR 602 、-OC(O)-R 602 、-NR 702 -C(O)-R 602 , -C 1 ~C 4 Alkyl-C(O)-R 602 、-SO 2 -R 602、-SO 2 -NR 802 R 902 , -C 1 ~C 4 Alkyl-SO 2 -R 602 , or -C 1 ~C 4 Alkyl-SO 2 NR 802 R 902 ;

[0414] R 502 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0415] R 602 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0416] R 702 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0417] R 802 and R 902 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0418] R 802 and R902 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0419] In certain embodiments, the compound has structural formula (IIc):

[0420]

[0421] in:

[0422] R 203 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0423] n is 0 or 1;

[0424] Ring L is substituted at one or more carbon atoms with one, two, or three R 303 Substituents, where each R 303 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 703 C(O)-CH=CH 2 、-NR 703 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 703 C(O)-CH=CHCH 3 , or -NR 703 C(O)-CH=CHCH 2 NR 803 R 903 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0425] Two R on the same carbon atom of ring I 303 Two or three R on different carbon atoms 303 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring L, such as adamantyl;

[0426] R 403 Selected from H, -OH, -C(O)-R 603 、-OR 603 、-OC(O)-R 603 、-NR 703 -C(O)-R 603 , -C 1 ~C 4 Alkyl-C(O)-R 603 、-SO 2 -R 603 、-SO 2 -NR 803 R 903 , -C 1 ~C 4 Alkyl-SO 2 -R 603 , or -C 1 ~C 4 Alkyl-SO 2 NR 803 R 903 ;

[0427] R 503 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0428] R 603 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0429] R 703 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0430] R 803 and R 903 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0431] R 803 and R 903 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0432] In certain embodiments, the compound has structural formula (IId):

[0433]

[0434] in:

[0435] R 204 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0436] n is 0 or 1;

[0437] Ring M is substituted at one or more carbon atoms with one, two, or three R 304 Substituents, where each R 304 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5Alkyl, -NR 704 C(O)-CH=CH 2 、-NR 704 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 704 C(O)-CH=CHCH 3 , or -NR 704 C(O)-CH=CHCH 2 NR 804 R 904 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0438] Two R on the same carbon atom of ring M 304 Two or three R on different carbon atoms 304 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring M, such as adamantyl;

[0439] R 404 Selected from H, -OH, -C(O)-R 604 、-OR 604 、-OC(O)-R 604 、-NR 704 -C(O)-R 604 , -C 1 ~C 4 Alkyl-C(O)-R 604 、-SO 2 -R 604 、-SO 2 -NR 804 R 904 , -C 1 ~C 4 Alkyl-SO 2 -R 604 , or -C 1 ~C 4 Alkyl-SO 2 NR 804 R 904 ;

[0440] R 504 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0441] R 604 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0442] R 704 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0443] R 804 and R 904 Independently selected from H, -C 1 ~C 5 Alkyl, or -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0444] R 804 and R 904 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0445] In certain embodiments, the compound has structural formula (IIe):

[0446]

[0447] in:

[0448] R 205 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0449] n is 0 or 1;

[0450] Ring N is substituted at one or more carbon atoms with one, two, or three R 305 Substituents, where each R 305 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 705 C(O)-CH=CH 2 、-NR 705 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 705 C(O)-CH=CHCH 3 , or -NR 705 C(O)-CH=CHCH 2 NR 805 R 905 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0451] Two R on the same carbon atom of ring N 305 Two or three R on different carbon atoms 305 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with the ring N, such as adamantyl;

[0452] R 405 Selected from H, -OH, -C(O)-R 605 、-OR 605 、-OC(O)-R 605 、-NR 70 -C(O)-R 605 , -C 1 ~C 4 Alkyl-C(O)-R605 、-SO 2 -R 605 、-SO 2 -NR 805 R 905 , -C 1 ~C 4 Alkyl-SO 2 -R 605 , or -C 1 ~C 4 Alkyl-SO 2 NR 805 R 905 ;

[0453] R 505 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0454] R 605 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0455] R 705 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0456] R 805 and R 905 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0457] R 805 and R 905 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0458] In certain embodiments, the compound has the structural formula (IIf):

[0459]

[0460] in:

[0461] R 206 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0462] n is 0 or 1;

[0463] Ring O is replaced at one or more carbon atoms by one, two, or three R 306 Substituents, where each R 306 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 706 C(O)-CH=CH 2 、-NR 706 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 706 C(O)-CH=CHCH 3 , or -NR 706 C(O)-CH=CHCH 2 NR 806 R 906 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC1 ~C 5 Alkyl groups are substituted with one or more groups;

[0464] Two R on the same carbon atom of ring O 306 Two or three R on different carbon atoms 306 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring O, such as adamantyl;

[0465] R 406 Selected from H, -OH, -C(O)-R 606 、-OR 606 、-OC(O)-R 606 、-NR 706 -C(O)-R 606 , -C 1 ~C 4 Alkyl-C(O)-R 606 、-SO 2 -R 606 、-SO 2 -NR 806 R 906 , -C 1 ~C 4 Alkyl-SO 2 -R 606 , or -C 1 ~C 4 Alkyl-SO 2 NR 806 R 906 ;

[0466] R 506 Selected from -C 1 ~C 5 Alkyl, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0467] R 606 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C5 Alkyl groups are substituted with one or more groups;

[0468] R 706 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0469] R 806 and R 906 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0470] R 806 and R 906 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0471] In certain embodiments, the compound has structural formula (IIg):

[0472]

[0473] in:

[0474] R 207 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0475] n is 0 or 1;

[0476] Ring P is substituted at one or more carbon atoms with one, two, or three R 307 Substituents, where each R 307 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 707 C(O)-CH=CH 2 、-NR 707 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 707 C(O)-CH=CHCH 3 , or -NR 707 C(O)-CH=CHCH 2 NR 807 R 907 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0477] Two R on the same carbon atom of ring P 307 Two or three R on different carbon atoms 307 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring P, such as adamantyl;

[0478] R 407 Selected from H, -OH, -C(O)-R 607 、-OR 607 、-OC(O)-R 607 、-NR 707 -C(O)-R 607 , -C 1 ~C 4 Alkyl-C(O)-R 607 、-SO 2 -R 607 、-SO 2 -NR 807 R 907 , -C 1 ~C 4 Alkyl-SO 2 -R 607 , or -C 1 ~C 4 Alkyl-SO 2 NR 807 R 907 ;

[0479] R 507 Selected from -C 1 ~C 5 Alkyl, or -C3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0480] R 607 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 5 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0481] R 707 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 5 Cycloalkyl;

[0482] R 807 and R 907 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0483] R 807 and R 907 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0484] In certain embodiments, the compound has structural formula (III):

[0485]

[0486] in:

[0487] R 1000 Selected from -CO 2 R 5000 , -C 1 ~C 5Alkyl-CO 2 R 5000 , -C 3 ~C 6 Cycloalkyl-CO 2 R 5000 、-NHCO 2 R 5000 、-N(C 1 ~C 5 Alkyl)-CO 2 R 5000 、-O-CO 2 R 5000 , or -C 1 ~C 5 Alkyl-O-CO 2 R 5000 ;

[0488] R 2000 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0489] n is 0, 1, or 2;

[0490] Ring Q is replaced at one or more carbon atoms by one, two, or three R 3 Substituents, where each R 3000 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, or -OC 1 ~C 5 Alkyl, wherein each alkyl group or cycloalkyl group is optionally selected from halogen, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0491] Two R on the same carbon atom or different carbon atoms of ring Q 3000 The group may be optionally linked to form a spirocyclic or bicyclic ring system with ring Q;

[0492] R 4000 Selected from -C(O)-R 6000 、-CH 2 R 6000 、-C(O)-CH=CH 2 、-C(O)-C(CH 2 OCH 3 )=CH 2 、-C(O)-CH=CHCH 3 、-C(O)-CH=CHCH 2 NR 7 R 8 、-C(O)-C 1 ~C 5 Alkyl, or -C(O)-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally substituted with one or more groups selected from -OH, halogen, alkyne, or -CN;

[0493] R 5000 Selected from H, -C 1 ~C 5 Alkyl, and -C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, -C 3 ~C 5 Cycloalkyl, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0494] R 6000 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl, -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, -NR 7000 R 8000 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally selected from halogen elements, -CN, alkyne, -OH, trifluoromethyl, -OC 1 ~C 5 Alkyl, or -OC 3 ~C 6 One or more radicals of the cycloalkyl group are substituted;

[0495] R 7000 and R8000 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 5 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN;

[0496] R 7000 and R 8000 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0497] In certain embodiments of the present invention, the compound has structural formula (IV):

[0498]

[0499] in:

[0500] R 10000 Selected from -CO 2 R 50000 , -C 1 ~C 5 Alkyl-CO 2 R 50000 , -C 3 ~C 6 Cycloalkyl-CO 2 R 50000 、-NHCO 2 R 50000 、-N(C 1 ~C 5 Alkyl)-CO 2 R 50000 、-O-CO 2 R 50000 , or -C 1 ~C 5 Alkyl-O-CO 2 R 50000 ;

[0501] R 20000 Selected from H, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, or -C 1 ~C 2 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group is optionally selected from halogen elements, -OH, or -OC 1~C 5 Alkyl groups are substituted with one or more groups;

[0502] n is 0 or 1;

[0503] Ring S is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30000 The groups are independently selected from H, halogen elements, -C 1 ~C 4 Alkyl, -C 3 ~C 6 Cycloalkyl, -OH, -OC 1 ~C 5 Alkyl, -NR 70000 C(O)-CH=CH 2 、-NR 70000 C(O)-C(CH 2 OCH 3 )=CH 2 、-NR 70000 C(O)-CH=CHCH 3 , or -NR 70000 C(O)-CH=CHCH 2 NR 80000 R 90000 , wherein each alkyl group or cycloalkyl group is optionally selected from halogen elements, -CN, -OH, -C 1 ~C 5 Alkyl alkoxy, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0504] Two R on the same carbon atom of ring S 30000 Two or three R on different carbon atoms 30 The group may be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring S, such as adamantyl;

[0505] R 40000 Selected from H, -OH, -C(O)-R 60000 、-OR 60000 、-OC(O)-R 60000 、-NR 70000 -C(O)-R 60000 , -C 1 ~C 4 Alkyl-C(O)-R 60000 、-SO 2 -R 60000 、-SO 2 -NR 80000 R90000 , -C 1 ~C 4 Alkyl-SO 2 -R 60000 , or -C 1 ~C 4 Alkyl-SO 2 NR 80000 R 90000 ;

[0506] R 50000 Selected from H, -C 1 ~C 5 Alkyl, and -C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen elements, -OH, -C 3 ~C 6 Cycloalkyl, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0507] R 60000 Selected from -C 1 ~C 5 Alkyl, -C 3 ~C 6 Cycloalkyl or -C 1 ~C 5 Alkyl-C 3 ~C 6 Cycloalkyl, wherein the alkyl group or the cycloalkyl group may be optionally selected from halogen, -CN, alkyne, -OH, or -OC 1 ~C 5 Alkyl groups are substituted with one or more groups;

[0508] R 70000 Selected from H, -C 1 ~C 5 Alkyl or -C 3 ~C 6 Cycloalkyl;

[0509] R 80000 and R 90000 Independently selected from H, -C 1 ~C 5 Alkyl, -C 1 ~C 5 Alkoxy, or -C 3 ~C 6 Cycloalkyl, wherein the alkyl group may be optionally substituted with one or more groups selected from halogen, -OH, or -CN; and

[0510] R 80000 and R90000 They may optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

[0511] In certain embodiments, the compound of formula (II), formula (IIa), or formula (IV) is not the following:

[0512]

[0513] 4-(((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0514]

[0515] Ethyl 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0516]

[0517] Ethyl 4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0518]

[0519] Ethyl 4-(cycloheptylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0520]

[0521] 4-(((1S,2R)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0522]

[0523] 4-(((1R,2S)-2-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0524]

[0525] Ethyl 4-((3-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0526]

[0527] Ethyl 4-((4-methylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0528]

[0529] Ethyl 4-((2,2-dimethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0530]

[0531] Ethyl 4-(((1S,2R)-2-ethylcyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0532] The present invention is further illustrated by the following examples of compounds of formula (I).

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547] The present invention is further illustrated by the following examples of compounds of formula (II).

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557] The present invention is further illustrated by the following examples of compounds of formula (III).

[0558]

[0559]

[0560] The present invention is further illustrated by the following examples of compounds of formula (IV).

[0561]

[0562]

[0563]

[0564]

[0565] Pharmaceutical composition

[0566] Some embodiments herein are directed to pharmaceutical compositions comprising a compound of the embodiments herein and a pharmaceutically acceptable carrier or diluent.

[0567] Also provided are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0568] Although the compounds described herein may be administered in the form of raw materials, it is also possible to present them as pharmaceutical preparations. Therefore, pharmaceutical preparations are provided herein, and pharmaceutical preparations include one or more of some compounds disclosed herein, or derivatives thereof, and one or more pharmaceutically acceptable carriers thereof and optional one or more other therapeutic components. One or more carriers must be "acceptable" in the sense that they are compatible with the other ingredients of the preparation and harmless to the recipient thereof. Suitable preparations depend on the selected route of administration. Any of the known techniques, carriers, and excipients can be used as suitable and understood in the art. Pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by conventional mixing processes, dissolution processes, granulation processes, dragee manufacturing processes, grinding processes, emulsification processes, encapsulation processes, entrapping processes, or compression processes.

[0569] In some embodiments, pharmaceutical compositions for use in accordance with the embodiments herein may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.

[0570] Although the most suitable approach may depend on, for example, the patient's condition and disorder, the preparation includes those suitable for oral administration, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary) administration, intraperitoneal administration, intrathecal administration, intradural administration, transmucosal administration, transdermal administration, rectal administration, intranasal administration, topical (including, for example, skin, cheek, sublingual and intraocular) administration, intravitreal administration or intravaginal administration. The preparation may include those preparations suitable for injection by reservoir or administration by implantation. The preparation may include those preparations suitable for administration by suction (such as, for example, gas, steam or powder). The preparation may include those preparations suitable for administration in aerosol form, for example, via a nebulizer, humidifier, inhaler and vaporizer. The preparation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field. Typically, these methods include the step of combining the compound disclosed herein or its derivative ("active ingredient") with a carrier constituting one or more auxiliary components. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0571] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0572] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets can be made by pressing or molding with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient (such as powder or granules) in a free-flowing form in a suitable machine (optionally mixed with a binder, an inert diluent, or a lubricant, a surfactant or a dispersant). Die-printed tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored optionally, and can be formulated to provide a slow release or controlled release of the active ingredient therein. All preparations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain active ingredients mixed with fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optional stabilizers. In soft capsules, the active compound can be dissolved in or suspended in a suitable liquid (such as fatty oil, liquid paraffin or liquid polyethylene glycol). In addition, a stabilizing agent can be added. The dragee core is provided with a suitable coating. For this reason, concentrated sugar solution can be used, and concentrated sugar solution can contain gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol, and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture alternatively. Coloring agent or pigment can be added to tablet or dragee coating to identify or characterize the different combinations of active compound dosage.

[0573] The compound can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). The preparation for injection can be present in a unit dosage form, for example, in an ampoule or a multi-dose container with an added preservative. The composition can take such a form (such as a suspension, solution or emulsion in an oily or aqueous vehicle) and can contain a formulation agent (such as a suspending agent, a stabilizer and / or a dispersant). The preparation can be present in a unit dose container or a multi-dose container (e.g., a sealed ampoule and a vial) and can be stored in a powder form or stored under freeze drying (lyophilization) conditions that only require the addition of a sterile liquid carrier (e.g., saline or sterile pyrogen-free water) before use. Extemporaneous injections and suspensions can be prepared from sterile powders, granules and tablets of the aforementioned types.

[0574] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound (which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions (which may contain suspending agents and thickening agents). Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil), or synthetic fatty acid esters (such as ethyl oleate or triglycerides), or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension (such as sodium carboxymethylcellulose, sorbitol, or dextran). Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

[0575] In addition to the preparations described previously, the compound can also be formulated into a depot preparation. Such a long-acting preparation can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or be formulated into a slightly soluble derivative (e.g., formulated into a slightly soluble salt).

[0576] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may include the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0577] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0578] Certain compounds disclosed herein can be administered topically (i.e., by non-systemic administration). This includes applying compounds disclosed herein externally to the epidermis or buccal cavity, and dropping such compounds into the ears, eyes, and nose. In contrast, systemic administration refers to oral administration, intravenous administration, intraperitoneal administration, and intramuscular administration.

[0579] In some embodiments, the compounds disclosed herein can be administered ophthalmically. In some embodiments, the compounds disclosed herein can be administered in the form of an ophthalmic composition. The compounds of the embodiments herein can be administered in the form of, for example, a liquid preparation (including an eye lotion, spray or eye drops for topical administration). In some embodiments, the compounds disclosed herein can be administered (for example, applied to the eyelid) in the form of a semisolid preparation (such as a cream, lotion, gel, ointment or paste). In some embodiments, the compounds disclosed herein can be administered (for example, applied to the eye surface) in the form of a solid dosage form (such as a powder) to produce improved release. In some embodiments, the compounds of the embodiments herein are administered by a device for surgical implantation, a parenteral product (for example, an intracorneal product or an intravitreal product), a liquid for flushing, etc. In some embodiments, the composition including the compounds disclosed herein is sterile and does not contain particulate matter. In some embodiments, the compounds disclosed herein can be administered by intraocular injection, intraorbital injection or intravitreal injection. In some embodiments, intraocular injection can be for the anterior chamber of the eye, the posterior chamber of the eye, or a combination thereof. For example, the compounds disclosed herein can be administered to the posterior intraorbital region of the eye.

[0580] In some embodiments, preparations suitable for topical administration include liquid preparations or semi-liquid preparations suitable for penetration through the skin to reach the site of inflammation (such as solutions, powders, liquid emulsions, liquid suspensions, semisolids, ointments, pastes, creams, gels, jelly, foams, liniments, lotions, and drops suitable for administration to the eyes, ears, or noses). The active ingredient for topical administration may account for, for example, from 0.001% w / w to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient may account for up to 10% w / w. In other embodiments, it may account for less than 5% w / w. In certain embodiments, the active ingredient may account for from 2% w / w to 5% w / w. In other embodiments, it may account for from 0.1% w / w to 1% w / w of the preparation.

[0581] Gels for topical or transdermal administration may generally include a mixture of a volatile solvent, a nonvolatile solvent, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include a low (C 1 ~C 6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In other embodiments, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer and also has a cooling effect on the skin when evaporating. The non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The non-volatile solvent slows down the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. As with the volatile solvent, the amount of this non-volatile solvent component is determined by the drug compound or drug used. When there is too little non-volatile solvent in the system, the drug compound may crystallize due to the evaporation of the volatile solvent, and an excess may cause a lack of bioavailability due to poor release of the drug from the solvent mixture. The buffer component of the buffered solvent system can be selected from any buffer commonly used in the art; in certain embodiments, water is used. The common ratio of the ingredients is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. There are several optional ingredients that can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents may include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers as well as cosmetic agents.

[0582] Lotions include those suitable for application to the skin or eyes. Eye lotions may include sterile aqueous solutions optionally containing bactericides, and may be prepared by methods similar to those for preparing drops. Lotions or liniments for application to the skin may also include agents (such as alcohol or acetone) that accelerate drying and cool the skin, and / or humectants (such as glycerol) or oils (such as castor oil or peanut oil).

[0583] Cream, ointment or paste is a semi-solid preparation of an active ingredient for external use. It can be made by mixing finely ground or powdered active ingredients (alone or in a solution or suspension in an aqueous or non-aqueous fluid) with an oily or non-oily matrix by means of a suitable machine. The matrix can include hydrocarbons, such as hard paraffin, soft paraffin or liquid paraffin, glycerol, beeswax, metal soaps; mucilage; oils of natural origin, such as almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or its derivatives or fatty acids (such as stearic acid or oleic acid) and alcohols (such as propylene glycol) or macrogranular gels. The preparation can incorporate any suitable surfactant, such as anionic surfactants, cationic surfactants or nonionic surfactants (such as sorbitan esters or their polyethylene oxide derivatives). Suspending agents (such as natural gums), cellulose derivatives or inorganic materials (such as siliceous silica), and other ingredients (such as lanolin) can also be included.

[0584] Drops can include aseptic aqueous or oily solutions or suspensions, and can be prepared by dissolving active ingredients in a suitable aqueous solution of bactericides and / or fungicides and / or any other suitable preservatives (and comprising surfactants in certain embodiments). Then, the resulting solution can be clarified by filtration, transferred to a suitable container sealed afterwards, and sterilized by autoclaving or keeping at 98°C-100°C for half an hour. Alternatively, the solution can be sterilized by being suitable for being included in the drops with a fungicide, which is phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol and propylene glycol.

[0585] Formulations for topical administration in the mouth, for example buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.

[0586] For administration by inhalation, the compound can be conveniently delivered from an insufflator, atomizer pressurized packaging or other convenient means of delivering an aerosol spray. The pressurized packaging can include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention can take the form of a dry powder composition (e.g., a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch)). The powder composition can be present in, for example, a capsule, a cartridge, a gelatin package or a blister package in a unit dosage form, from which the powder can be administered by means of an insufflator or insufflator.

[0587] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0588] It should be understood that in addition to the ingredients particularly mentioned above the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0589] The compound can be administered at a dosage of from 0.1 mg / kg to 500 mg / kg per day. The dosage range for adults is generally from 5 mg / day to 2 g / day. The tablet or other presentation provided in discrete units can conveniently contain one or more compounds in such a dosage or as a multiple effective amount of an equal dose, for example, a unit containing 5 mg to 500 mg (usually about 10 mg to 200 mg).

[0590] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0591] When used as a medicine, the compound can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner known to the pharmaceutical field, and can be administered by a variety of routes depending on whether local treatment or systemic treatment and the area to be treated are desired. The administration of the disclosed compound or composition can be oral administration, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary) administration, pulmonary (for example, by inhalation or insufflation of powders or aerosols (including by a nebulizer); intratracheal or intranasal) administration, intraperitoneal administration, transmucosal administration, transdermal administration, rectal administration, local (including skin, cheek, sublingual and intraocular) administration or intravaginal administration. Parenteral administration includes intravenous administration, intraarterial administration, subcutaneous administration, intraperitoneal administration, intramuscular administration or injection administration or infusion administration; or intracranial (for example, intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single dose, or can be performed, for example, by a continuous infusion pump. The pharmaceutical composition for topical application can include foams, transdermal patches, ointments, lotions, creams, gels, solutions, liquid emulsions, liquid suspensions, semisolids, pastes, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous powders or oily bases, thickeners, etc. may be necessary or desirable. Coated condoms, gloves, etc. may also be useful. In some embodiments, the compound may be contained in such a preparation together with a pharmaceutically acceptable diluent, filler, disintegrant, binder, lubricant, surfactant, hydrophobic carrier, water-soluble carrier, emulsifier, buffer, wetting agent, humectant, solubilizer, preservative, etc. Technicians may refer to various pharmaceutical references as guidance. For example, one may refer to Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13th Edition, McGraw Hill, New York (2018).

[0592] In some embodiments, a method of treating a disease mediated by JAK1 and / or JAK3 by administering a pharmaceutical composition of an embodiment disclosed herein. In some embodiments, the compound is a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount disclosed herein.

[0593] Some embodiments disclosed herein also encompass pharmaceutical compositions containing, as active ingredients, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients).

[0594] In some embodiments, the method of making a pharmaceutical composition includes mixing the active ingredient with an excipient, diluting the active ingredient with an excipient, or enclosing the active ingredient in a carrier, such as in the form of a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it can be a solid material, a semisolid material, or a liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0595] Some examples of suitable excipients include the following: lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose containing a deep eutectic solvent, a deep eutectic ionic liquid, or an ionic liquid. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. By adopting procedures known in the art, the composition can be formulated to provide rapid release, sustained release or delayed release of the active ingredient after administration to the patient.

[0596] The compositions can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0597] The active compound can be effective over a wide dosage range and can generally be administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will generally be determined by a physician based on relevant circumstances (including the condition to be treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

[0598] In some embodiments, a pharmaceutical composition may include about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the content of one or more compounds is about 0.01% to about 50%, about 0.01% to about 45%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about 45%, about 0.05 ...10%, about 0.01% to about 10%, about 0.0 .05% to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, From about 0.5% to about 30%, from about 0.5% to about 20%, from about 0.5% to about 10%, from about 0.5% to about 5%, from about 1% to about 50%, from about 1% to about 45%, from about 1% to about 40%, from about 1% to about 35%, from about 1% to about 30%, from about 1% to about 25%, from about 1% to about 20%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 45%, from about 5 % to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, or a value within one of these ranges. Specific examples can include about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90% or the range between any two of these values. The aforementioned all represent the weight percentage of the composition. In some embodiments, the composition is suitable for topical application. In some embodiments, the composition is suitable for oral administration, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary) administration, intraperitoneal administration, intrathecal administration, intradural administration, transmucosal administration, transdermal administration, rectal administration, intranasal administration, local (including, for example, skin, buccal, sublingual and intraocular) administration, intravitreal administration or intravaginal administration.

[0599] In some embodiments, the compound is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount can be from about 1 mg to about 1000 mg, from about 1 mg to about 900 mg, from about 1 mg to about 800 mg, from about 1 mg to about 700 mg, from about 1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 400 mg, from about 1 mg to about 300 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 1000 mg. g, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 100 mg to about 300 mg, about 50 mg to about 300 mg, from about 100 mg to about 300 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg to about 120 mg, or a range between any two of these values. Specific examples include, for example, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400 mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, or any value between the ranges disclosed above.

[0600] In some embodiments, the therapeutically effective amount can vary according to, for example, the specific application for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound in the pharmaceutical composition can vary according to many factors (including dosage, chemical properties (e.g., hydrophobicity), and route of administration). For example, the compound can be provided in a physiological buffered aqueous solution containing about 0.1% w / v to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges of the compound are from about 1 μg / kg body weight per day to about 1g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight per day to about 100 mg / kg body weight per day. The dosage may depend on variables, such as the type and degree of progression of the disease or disorder, the overall health of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be inferred from a dose response curve derived from an in vitro or animal model test system.

[0601] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration (e.g., prevention or treatment), the state of the patient, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0602] In order to prepare solid compositions (such as tablets), the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a uniform mixture of the compounds of the present invention. When these preformulation compositions are referred to as uniform, the active ingredient is generally evenly dispersed throughout the composition so that the composition can be easily and evenly divided into therapeutically effective unit dosage forms (such as tablets, pills and capsules). The solid preformulation is then divided into unit dosage forms of the above type containing, for example, from about 0.1 mg to about 1000 mg of the active ingredient.

[0603] Tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that gives the advantage of prolonged action. For example, tablets or pills can include an inner dosage component and an outer dosage component, the latter being the form of a wrapper on the former. These two components can be separated by an enteric layer, which is used to resist disintegration in the stomach, and allows the inner component to enter the duodenum intact or to be delayed for release. Various materials can be used for such enteric layers or coatings, and such materials comprise a mixture of many polymeric acids and polymeric acids and materials (such as shellac, cetyl alcohol and cellulose acetate).

[0604] Liquid forms for oral administration or by injection into which the compounds and compositions of the invention may be incorporated include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0605] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid compositions or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory routes to produce local or systemic effects. The composition can be atomized by using an inert gas. The atomized solution can be breathed directly from the atomizing device, or the atomizing device can be connected to a face mask tent or an intermittent positive pressure breathing machine. Solution compositions, suspension compositions, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0606] In some embodiments, the composition used to the patient can be in the form of the above-mentioned pharmaceutical composition. In some embodiments, these compositions can be sterilized by conventional sterilization techniques, or can be aseptically filtered. Aqueous solutions can be packaged to be used as is or lyophilized (lyophilized preparations are combined with sterile aqueous carriers before use). In some embodiments, the pH of the compound preparation is about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5 or about 5.5 to about 7.5. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers will cause the formation of pharmaceutical salts.

[0607] How to use

[0608] The present invention relates to methods of modulating JAK1 and / or JAK3 mediated function in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein.

[0609] The present invention also relates to a method of inhibiting at least one JAK1 and / or JAK3 function, the method comprising the step of contacting JAK1 and / or JAK3 with a compound described herein. Cell phenotype, cell proliferation, activity of JAK1 and / or JAK3, changes in biochemical output produced by active JAK1 and / or JAK3, expression of JAK1 and / or JAK3, or binding of JAK1 and / or JAK3 to a natural binding partner can be monitored. Such methods can be treatment modalities for disease, biological assays, cell assays, biochemical assays, etc.

[0610] Also provided herein is a method for treating a JAK1 and / or JAK3-mediated disease, the method comprising administering a therapeutically effective amount of a compound disclosed herein, a derivative of a compound disclosed herein, or a combination thereof to a patient in need thereof. In certain embodiments, a therapeutically effective amount of a compound disclosed herein, a derivative of a compound disclosed herein, or a combination thereof may be in the form of a pharmaceutical composition. In an embodiment, the pharmaceutical composition may include a pharmaceutically acceptable excipient.

[0611] In an embodiment, the disease or disorder associated with JAK1 kinase and / or JAK3 kinase treated by the compounds of the invention comprises an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasia, or a cardiovascular disorder or a cerebrovascular disorder. Thus, in some embodiments, the invention provides a method for treating a JAK1 and / or JAK3 mediated disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a provided compound or composition thereof. Such JAK1 and / or JAK3 mediated diseases or disorders include, but are not limited to, those described herein.

[0612] In some embodiments, the JAK1 and / or JAK3 mediated disease or disorder is selected from a skin disorder, pruritus, a hair loss disorder, cancer, a neoplasm, Alzheimer's disease, an inflammatory condition, a connective tissue disease, and an autoimmune condition.

[0613] In certain embodiments, the JAK1 and / or JAK3 mediated disease or disorder is a neoplasm, a malignancy, a myeloproliferative disorder, a hematopoietic neoplasm, a spinal cord neoplasm, a lymphoid neoplasm (including myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia, acute and chronic leukemias, lymphoma, cutaneous lymphoma (including mycosis fungoides), other myeloid malignancies, and myelodysplastic syndrome).

[0614] In certain embodiments, the JAK1 and / or JAK3 mediated disease is selected from the group consisting of: an autoimmune disorder or autoimmune response, a generalized activation of an immune response, a bacterial infection, a viral infection, inflammation, a chronic and / or acute inflammatory disorder or condition, and / or an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasm, or a cardiovascular disorder or a cerebrovascular disorder, a skin disorder, pruritus, a hair loss disorder, a cancer or a malignancy, an autoimmune connective tissue disease, and an autoimmune condition; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (e.g., relapsing polychondritis); myositis, polymyositis myositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, arthritis associated with inflammatory bowel disease, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathies (ankylosing spondylitis), gout, scleroderma (systemic sclerosis, juvenile sclerosis), Reiter syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus (SLE) (lupus erythematosus, systemic lupus erythematosus in children, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / discoid lupus, pernio lupus erythematosus)), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesitis, carditis, myocarditis, angiogenic disorders, myelodysplastic syndrome, atherosclerosis, restenosis (atherosclerotic coronary restenosis), acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, transplant artery disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndromes including large vessel arteritis , Wegener's granulomatosis, Behçet's disease), STING-associated vasculopathy of infancy (SAVI); gastrointestinal disorders, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, inflammatory bowel syndrome / spontive colon, celiac disease; acute pancreatitis and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, or cirrhosis due to fatty liver disease (e.g., alcoholic and nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis;Kidney Disease: Immune-mediated glomerulonephropathy, Autoimmune nephropathy, Membranous glomerulopathy, Chronic progressive kidney disease, Diabetic kidney disease / diabetic nephropathy, Renal fibrosis, Renal ischemia / reperfusion injury, HIV-related nephropathy, Uretero-obstructive nephropathy, Glomerulosclerosis, Proteinuria, Nephrotic syndrome, Polycystic kidney disease, Autosomal dominant polycystic kidney disease, Kidney disease is immune-mediated nephropathy, Autoimmune nephropathy, Chronic progressive kidney disease, Diabetic nephropathy, Renal fibrosis, Ischemia / reperfusion injury-related nephropathy, HIV-related nephropathy, Uretero-obstructive nephropathy, Glomerulonephritis, Chronic kidney disease (e.g., diabetic nephropathy) disease), hypertension-induced nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; lung inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced Lung injury; Meniere's disease; ocular disorders, including, for example, ocular inflammation, uveitis, dry eyes / keratoconjunctivitis sicca, scleritis, episcleritis, keratitis / keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy (diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), myelodysplastic syndrome, idiopathic thrombocytopenic purpura; bone resorption diseases; neurodegenerative disorders, neuro Menstrual disorders / neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Langer-Evans myasthenic syndrome (LEMS), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury; damage to the nervous system, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke / neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders; paresthesia pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia), nerve irritation, peripheral neuropathy;Pruritus / itch (atopic pruritus, dry pruritus, itch associated with psoriasis / psoriatic pruritus / psoriatic pruritus), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic pruritus, biliary pruritus, hepatobiliary pruritus, renal pruritus / renal pruritus, uremic pruritus, cholestasis, intrahepatic cholestasis of pregnancy, pruritus associated with chronic simple lichen, lymphoma-associated pruritus, leukemia-associated pruritus, nodular pruritus, atopic dermatitis-associated pruritus, atopic pruritus / atopic pruritus, bullous pruritus, brachioradialis pruritus, neurogenic pruritus, neuropathic pruritus, paresthesia dorsalis, HIV-associated pruritic papules, psychogenic pruritus, swimmer's itch, pruritus or uremic pruritus, urticarial pruritus;Skin Diseases (e.g.), Skin Diseases Drug Reactions / Drug Rash, Xerosis / Dry Skin, Rash, Skin Sensitization, Skin Irritation, Sunburn, Shaving, Body Lice, Head Lice / Penicillosis, Pubic Lice, Cutaneous Larva Migrans, Scabies, Parasitic Infestation, Insect Infestation, Urticarial / Hives, Papular Urticaria, Insect Bites, Insect Stings, Dandruff, Foreign Objects or Devices on Skin, Fungal Infection, Herpes, Varicella / Chickenpox pox), eosinophilic folliculitis, pregnancy skin diseases / pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory skin diseases, neutrophilic skin diseases, histiocytic neutrophilic skin diseases, intestinal bypass syndrome skin diseases, psoriasis / psoriasis vulgaris, lichen planus, lichen sclerosus atrophicus, acne (acne vulgaris, acne comedonalis, inflammatory acne, nodulocystic acne, acne keloidalis, acne nuchal), atopy (allergic contact sensitization, allergic dermatitis), dermatitis (atopic dermatitis / eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis), acute Febrile neutrophilic dermatosis (Sweet syndrome), chronic atypical neutrophilic and lipodystrophy dermatosis and hyperthermia syndrome (CANDLE syndrome), suppurative hidradenitis, urticaria, gangrenosum pyoderma, hair loss (eyebrow loss, nasal hair loss, scarring alopecia (central centrifugal scarring alopecia), non-scarring alopecia (alopecia areata (AA) (plaque AA, alopecia totalis (AT), alopecia universalis (AU), snake-like alopecia, horseshoe-shaped alopecia)), androgen / androgenic alopecia (AGA) / male and female AGA), telogen effluvium, tinea capitis, hypotrichosis (simple hereditary hypotrichosis), Lichen planus pilaris (frontal fibrosing alopecia), punctate palmoplantar keratoderma, erythema erythematosus (EED), neutrophilic exocrine hidradenitis, palisade neutrophilic granulomatous dermatitis, neutrophilic urticaria dermatosis, vitiligo, including segmental vitiligo (monosegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo), non-segmental vitiligo (acral vitiligo, facial vitiligo, or acrofacial vitiligo, central facial vitiligo, mucosal vitiligo, shredded paper vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo, Kebne phenomenon, common vitiligo vitiligo, generalized vitiligo, universal vitiligo), mixed vitiligo / non-segmental vitiligo with segmental vitiligo, localized vitiligo, isolated mucosal vitiligo, or vitiligo with or without white hair (body hair involvement); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), pemphigoid gestationis, xeroderma pigmentosum; fibrotic and scarring disorders: fibromas, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low-grade scarring such as scleroderma, increased fibrosis, keloids, postoperative scars;Wound healing, surgical scarring, radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), central nervous system scarring, digestive or gastrointestinal fibrosis, renal fibrosis, liver fibrosis or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cold pyrine-associated periodic syndromes (Merck-Weiss syndrome, familial Familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue damage, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid resistance, glucose intolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immunosenescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjögren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematological manifestations of autoimmune diseases (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune hepatitis and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-related autoimmune diseases, drug-induced autoimmunity, HIV-related autoimmune syndrome, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergic reactions and allergic reactions, including hypersensitivity reactions, such as type I hypersensitivity reactions (e.g., including anaphylaxis), II Type I hypersensitivity reactions (e.g., Goodpasture's disease, autoimmune hemolytic anemia), Type III hypersensitivity disorders (e.g., Arthus reaction, serum sickness), and Type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome);Rejection: Graft-versus-host reaction / graft-versus-host disease, allogeneic transplant rejection (e.g., acute allogeneic transplant rejection or chronic allogeneic transplant rejection), early transplant rejection; Malignancies, cancers, lymphomas, leukemias, multiple myeloma, solid tumors, teratomas, metastatic disorders and bone disorders, internal cancers, bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, stomach cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer (liver cancer), pancreatic cancer, nerve cancer, brain cancer ( For example, gliomas, glioblastoma multiforme, astrocytomas, neuroblastomas, and schwannomas), head and neck cancer, pharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer (kidney cancer), breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, eye cancer (ocular malignancies), and skin cancer (melanoma, keratoacanthoma); as well as fibrotic cancers, fibromas, fibroadenomas, fibrosarcomas, myeloproliferative disorders, neoplasms (hematopoietic neoplasms, spinal cord neoplasms, lymphoid neoplasms ( Myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemia (acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphoma Tumors (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides)), lymphomas (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased accumulation of exogenous opioids or synthetic opioids, paresthesia back pain, obsessive-compulsive disorder, homesickness associated with obsessive-compulsive disorder, and combinations thereof. ;

[0615] In some embodiments, additional exemplary disorders include, but are not limited to, complications from organ transplantation (including xenotransplantation), such as graft-versus-host reaction (e.g., graft-versus-host disease), allogeneic transplant rejection (e.g., acute allogeneic transplant rejection or chronic allogeneic transplant rejection), early transplantation, diabetes, myeloproliferative disorders, rejection (e.g., acute allogeneic transplant rejection); bone resorption diseases, asthma (e.g., bronchial asthma), atopy, autoimmune thyroid disorders, chronic atypical neutrophilic lipodystrophy and hyperthermia syndrome (CANDLE syndrome), SAVI (STING-associated vasculopathy of infancy), ulcerative colitis, inflammatory bowel disease, Crohn's disease, celiac disease, ulcerative colitis , Behcet's disease, myasthenia gravis, nephropathy, and myocarditis, secondary hematologic manifestations of autoimmune disease (e.g., anemia), autoimmune hemolytic syndrome, autoimmune hepatitis and inflammatory hepatitis, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-related autoimmune disease, drug-induced autoimmunity, HIV-related autoimmune syndrome; acute and chronic infections, sepsis syndromes (e.g., sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome); hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue damage, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia).

[0616] In an embodiment, the vitiligo is segmental vitiligo (including single segmental vitiligo, double segmental vitiligo or multi-segmental vitiligo), non-segmental vitiligo (including acrofacial vitiligo, facial vitiligo, or acrofacial vitiligo, central facial vitiligo, mucosal vitiligo, broken paper vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, four-color vitiligo, blue vitiligo, Kebner phenomenon, common vitiligo, generalized vitiligo, universal vitiligo), mixed vitiligo (non-segmental vitiligo with segmental vitiligo), localized vitiligo, isolated mucosal vitiligo, or vitiligo with or without white hair (body hair involvement), or any type of vitiligo shown in Table 1 below:

[0617] Table 1

[0618]

[0619] In embodiments, the skin disorder is atopic dermatitis, psoriasis, psoriasis vulgaris, skin sensitization, skin irritation, rash, contact dermatitis, allergic contact sensitization, allergic dermatitis, inflammatory skin disease, or neutrophilic skin disease.

[0620] As used herein, "itch" and "itch" are interchangeable. In some embodiments, itch comprises chronic idiopathic pruritus, as well as itch components of other itch disorders. In some embodiments, itch may be a symptom of a disease or condition selected from the group consisting of: allergy, arthropod bites, athlete's foot, atopic dermatitis (AD), atopic pruritus, atopic dermatitis-associated pruritus, autoimmune response, autoimmune connective tissue disease, bacterial infection, biliary pruritus, generalized activation of immune response, body lice, bullous disease, brachioradialis pruritus, brain tumor, chronic idiopathic pruritus, contact dermatitis, cholestasis, cutaneous larva migrans, cutaneous T-cell lymphoma, nervous system damage dermatomyositis, dandruff, delusional parasitosis, dermatomyositis, skin diseases of pregnancy, diabetes, drug eruptions, dysregulation of neuronal processes and sensory perceptions, eczema, eosinophilic folliculitis, foreign bodies or devices on the skin, fungal infections, pemphigoid gestationis, head lice, herpes, hidradenitis suppurativa, urticaria, Hodgkin's disease, hyperparathyroidism, idiopathic chronic pruritus, inflammation, insect infestations, insect bites, insect stings, intrahepatic cholestasis of pregnancy, iron deficiency anemia, increased accumulation of exogenous opioids or synthetic opioids , internal cancer, jaundice, lichen planus, lichen sclerosus atrophicus, lupus erythematosus, lymphoma, lymphoma-associated pruritus, leukemia-associated pruritus, malignant tumors, mastocytosis, menopause, multiple sclerosis, neoplasms, nerve irritation, neurogenic pruritus, neuropathic pruritus, paresthesia back pain, paresthesia back pain, obsessive-compulsive disorder, parasitic infestation, papular urticaria, pediculosis, peripheral neuropathy, photodermatitis, polycythemia vera, mental illness, psychogenic pruritus, HIV-associated pruritus papules, pruritic urticarial papules and plaques of pregnancy (PUPPP), psoriasis, psoriasis-associated itch, psoriatic itch, pubic lice, palmoplantar keratoderma punctata, renal pruritus, rheumatoid arthritis, scabies, scarring, shaving, seborrheic dermatitis, stasis dermatitis, sunburn, swimmer's itch, systemic immunosenescence, tactile hallucinations, Th17-related inflammation, thyroid disease, uremia, pruritus or uremic itch, urticaria, urticarial pruritus, chickenpox, viral infections, wound or scab healing, and xerosis.

[0621] In an embodiment, the hair loss disorder is selected from alopecia, alopecia areata, alopecia areata in patches, alopecia totalis, alopecia universalis, alopecia serpiginosa, alopecia horseshoe, androgenic alopecia (male and female pattern hair loss), telogen effluvium, tinea capitis, hypotrichosis, hypotrichosis simplex, cicatricial alopecia, lichen planus pilaris, central centrifugal cicatricial alopecia, or frontal fibrosing alopecia.

[0622] In an embodiment, the connective tissue disease is selected from SLE (systemic lupus erythematosus), cutaneous lupus (e.g., SCLE, discoid lupus), pernio lupus erythematosus, myositis, polymyositis, dermatomyositis, scleroderma, Sjogren's syndrome, polychondritis (relapsing polychondritis), vasculitis, or large vessel vasculitis.

[0623] In an embodiment, the kidney disease is selected from immune-mediated kidney disease, autoimmune kidney disease, chronic progressive kidney disease, diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-related kidney disease, HIV-related kidney disease, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, or diabetic kidney disease.

[0624] In embodiments, the cancer is a solid tumor.

[0625] In embodiments, the cancer is prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease, or pancreatic cancer.

[0626] In embodiments, the cancer is lymphoma, leukemia, or multiple myeloma.

[0627] In embodiments, the myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

[0628] In embodiments, the myeloproliferative disorder is myelofibrosis.

[0629] In embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF).

[0630] In embodiments, the bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormone imbalance, bone resorption associated with hormone therapy, bone resorption associated with an autoimmune disease, or bone resorption associated with cancer.

[0631] In some embodiments, the disease or disorder mediated by JAK1 and / or JAK3 is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, central nervous system scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, digestive or gastrointestinal tract fibrosis, renal fibrosis, liver fibrosis or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cirrhosis ( For example, primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic steatosis and nonalcoholic steatosis), radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrotic cancer, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0632] In some embodiments, the disease or disorder mediated by JAK1 and / or JAK3 is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome. In some embodiments, the disease or disorder mediated by JAK1 and / or JAK3 is a neoplasia. Exemplary neoplasias include cancer. In some embodiments, exemplary neoplasias include angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, or promyelocytic leukemia), lymphoma (e.g., B cell lymphoma, T cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma and skin cancer.

[0633] In some embodiments, the disorders mediated by JAK1 and / or JAK3 are cardiovascular disorders and cerebrovascular disorders. Exemplary cardiovascular disorders include atherosclerosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

[0634] Also provided herein are compounds disclosed herein for use as medicaments.

[0635] Also provided herein are compounds disclosed herein for use as medicaments for treating JAK1 and / or JAK3 mediated diseases.

[0636] Also provided are compounds disclosed herein for use as medicaments.

[0637] Also provided are the uses of the compounds disclosed herein as medicaments for treating JAK1 and / or JAK3 mediated diseases.

[0638] Also provided are compounds disclosed herein for use in the manufacture of a medicament for treating a JAK1 and / or JAK3 mediated disease.

[0639] Also provided are uses of the compounds disclosed herein for treating JAK1 and / or JAK3 mediated diseases.

[0640] Also provided herein are methods of inhibiting JAK1 and / or JAK3 comprising administering a compound disclosed herein or a derivative of a compound disclosed herein.

[0641] Also provided herein are methods for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a salt of a compound disclosed herein, wherein the effect is selected from cognitive enhancement.

[0642] In certain embodiments, the JAK1 and / or JAK3 mediated disease is selected from pruritus, alopecia, alopecia areata, vitiligo, male pattern androgenic alopecia, female pattern androgenic alopecia, atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis.

[0643] Compounds can be administered in various ways, for example, orally, parenterally (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneally, intrathecally, intradurally, transmucosally, transdermally, rectly, intranasally, topically (including, for example, skin, cheek, sublingual, and intraocular), intravitreal, or intravaginally. The specific dosage level for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated. In addition, the route of administration can vary depending on the condition and its severity.

[0644] Thus, in another aspect, certain embodiments provide methods for treating a JAK1 and / or JAK3-mediated disorder in a human or animal subject in need of such treatment, the method comprising administering to the subject an amount of a compound disclosed herein effective to reduce or prevent the disorder in the subject in combination with at least one additional agent known in the art for treating the disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for treating a JAK1 and / or JAK3-mediated disorder.

[0645] In certain embodiments, topically or orally administered JAK1 and / or JAK3 inhibitors / antagonists described herein can be used alone for the treatment of alopecia areata (e.g., alopecia areata in patches, alopecia totalis, alopecia universalis) or in combination with topical or intralesional corticosteroids, topical minoxidil, oral finasteride, oral dutasteride, contact sensitization therapy (such as with dibutyl squarate, dinitrochlorobenzene, diphenylcyclopropenone), topical or oral methoxalen and ultraviolet A (PUVA), topical anthralin, hair transplantation, or other therapies known to have a beneficial effect on the condition.

[0646] In certain embodiments, topically or orally administered JAK1 and / or JAK3 inhibitors / antagonists described herein may be used alone or in combination with topical minoxidil, oral finasteride (in men), oral dutasteride (in men), topical anti-androgens, hair transplantation, or other therapies known to have a beneficial effect on the condition for the treatment of male pattern baldness or female pattern baldness (androgenetic alopecia).

[0647] In certain embodiments, the compounds can be used alone for vitiligo (e.g., localized vitiligo, focal vitiligo, vitiligo), generalized vitiligo, segmental vitiligo, acrofacial vitiligo, facial vitiligo, acrofacial vitiligo, mucosal vitiligo, shredded paper vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo, Kebner's phenomenon, vitiligo vulgaris, mixed acrofacial and vulgaris, or universal vitiligo, or in combination with topical corticosteroids, topical tacrolimus, topical pimecrolimus, phototherapy (e.g., ultraviolet therapy with UVB, narrow-band UVB, oral or topical psoralen plus ultraviolet A (PUVA), calcipotriene or other topical vitamin D analogs, excimer laser phototherapy), systemic immunosuppressants, surgical treatments (e.g., skin micrografts, transplantation of autologous epidermal suspensions, concealing agents (e.g., with cosmetics or dihydroxyacetone), or other treatments known to have a beneficial effect on the condition for vitiligo (e.g., localized vitiligo ... vitiligo), focal vitiligo, generalized vitiligo, segmental vitiligo, acrofacial vitiligo, facial vitiligo, acrofacial vitiligo, mucosal vitiligo, shredded paper vitiligo, tricolor vitiligo, marginal inflammatory vitiligo, tetracolor vitiligo, blue vitiligo, Cabner phenomenon, vitiligo vulgaris, mixed acrofacial and vulgaris, or universal vitiligo).

[0648] Specific JAK1 and / or JAK3 mediated diseases to be treated by the compounds, compositions and methods disclosed herein include skin disorders, pruritus, cancer, Alzheimer's disease, inflammatory conditions, and autoimmune conditions.

[0649] In embodiments, the skin disorder is pruritus, atopic dermatitis, psoriasis, acne vulgaris, acne comedonalis, inflammatory acne, nodulocystic acne, acne keloids, hidradenitis suppurativa, pyoderma gangrenosum, skin sensitization, skin irritation, rash, contact dermatitis, or allergic contact sensitization.

[0650] In embodiments, the bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormone imbalance, bone resorption associated with hormone therapy, bone resorption associated with an autoimmune disease, or bone resorption associated with cancer.

[0651] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0652] Combination therapy

[0653] The compounds and pharmaceutical compositions of the present disclosure can be used to prevent or treat JAK-mediated disorders by sequential administration or co-administration with additional pharmaceutical agents.

[0654] In some cases, it may be appropriate to administer at least one of the compounds described herein or a derivative of the compound in combination with another pharmaceutical agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with an initial pharmaceutical agent. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may only have minimal therapeutic benefit, but when combined with another pharmaceutical agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein together with another pharmaceutical agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in a treatment for diabetes involving the administration of one of the compounds described herein, an increased therapeutic benefit may also be generated by providing the patient with another pharmaceutical agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be only the sum of the two pharmaceutical agents, or the patient may experience a synergistic benefit.

[0655] Specific non-limiting examples of possible combination therapies include the use of a compound of the embodiments herein with a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating an immunodeficiency disorder.

[0656] Specific non-limiting examples of possible combination therapies for inflammation include the use of certain compounds of the present disclosure with: (1) corticosteroids, including but not limited to cortisone, dexamethasone, and methylprednisolone; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON); TM ), Flurbiprofen (ANSAID TM ), ketoprofen, oxaprozin (DAYPRO TM )、Diclofenac Sodium (VOLTAREN TM)、Diclofenac Potassium (CATAFLAM TM ), etodolac (LODINE TM ), indomethacin TM ), TORADOL TM ), sulindac (CLINORIL TM ), TOLECTIN TM )、Meclofenamic acid (MECLOMEN TM ), mefenamic acid (PONSTEL TM ), nabumetone (RELAFEN TM ) and piroxicam (FELDENE TM ); (3) immunosuppressants, including but not limited to methotrexate (RHEUMATREX TM ), leflunomide (ARAVA TM ), azathioprine (IMURAN TM ), cyclosporine (NEORAL TM 、SANDIMMUNE TM ), tacrolimus and cyclophosphamide (CYTOXAN TM ); (4) CD20 blockers, including but not limited to rituximab (RITUXAN TM ); (5) tumor necrosis factor (TNF) blockers, including but not limited to etanercept (ENBREL TM ), infliximab (REMICADE TM ) and adalimumab (HUMIRA TM ); (6) interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET TM ); (7) interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA TM ); (8) interleukin-17 inhibitors, including but not limited to AIN457; (9) Janus kinase inhibitors, including but not limited to tasocitinib; and (10) SYK inhibitors, including but not limited to fostamatinib.

[0657] Specific non-limiting examples of possible combination therapies for the treatment of cancer include the use of certain compounds of the present disclosure with: (1) alkylating agents, including but not limited to cisplatin (PLATIN TM ), carboplatin (PARAPLATIN TM ), oxaliplatin (ELOXATIN TM ), ZANOSARTM ), busulfan (MYLERAN TM ) and cyclophosphamide (ENDOXAN); (2) antimetabolites, including but not limited to mercaptopurine (PURINETHOL TM ), thioguanine, pentostatin (NIPENT TM ), cytosine arabinoside (ARA-C TM ), gemcitabine (GEMZAR TM ), fluorouracil (CARAC TM ), folinic acid (FUSILEV TM ) and methotrexate (RHEUMATREX TM ); (3) plant alkaloids and terpenoids, including but not limited to vincristine (ONCOVIN TM ), vinblastine and taxol (TAXOL TM ); (4) topoisomerase inhibitors, including but not limited to irinotecan (CAMPTOSAR TM ), Topotecan (HYCAMTIN TM ) and etoposide (EPOSIN TM ); (5) cytotoxic antibiotics, including but not limited to actinomycin D (COSMEGEN TM ), ADRIAMYCIN TM ), bleomycin (BLENOXANE TM ) and mitomycin (MITOSOL TM ); (6) angiogenesis inhibitors, including but not limited to sunitinib (SUTENT TM ) and bevacizumab (AVASTIN TM ); (7) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC TM ), erlotinib (TARCEVA TM ), lapatinib (TYKERB TM ) and axitinib (INLYTA TM ); and (8) immune checkpoint inhibitors, including but not limited to atezolizumab (TECENTRIQ TM ), avelumab (BAVENCIO TM )、durvalumab (IMFINZI TM ), ipilimumab (YERVOY TM ), pembrolizumab (KEYTRUDA TM), nivolumab (OPDIVO TM ), and tremelimumab.

[0658] In some embodiments, the compounds disclosed in the embodiments herein may also be co-administered (simultaneously or sequentially) with a variety of other pharmaceutical agents or treatments, e.g., pharmaceutical agents or treatments that are administered systemically (e.g., orally or parenterally). Examples of such systemic treatments include topical or systemic corticosteroids (e.g., prednisone), antibiotics (e.g., erythromycin, tetracycline, and dicloxacillin), antifungal agents (e.g., those sold under the trade name Diflucan TM ketoconazole and fluconazole), antivirals (such as those sold under the brand name Valtrex TM Valacyclovir, acyclovir, and Famvir sold under the brand name TM famciclovir, sold under the brand name Cytoxan TM Cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, biologics (such as Rituxan TM Rituximab is sold under the brand name Enbrel TM Etanercept is sold under the brand name Humira TM Adalimumab is sold under the brand name Remicade TM Infliximab is sold under the brand name Stelara TM Ustekinumab, sold under the brand name Amevive TM alefacept, which is sold on the market, and / or thyroid hormone replacement.

[0659] In some embodiments, other therapies that can be used in combination with the compounds disclosed herein include, for example, mercaptopurine, topical or systemic corticosteroids (such as prednisone, methylprednisolone and prednisolone), alkylating agents (such as cyclophosphamide), calcineurin inhibitors (such as cyclosporine, sirolimus and tacrolimus), inhibitors of inosine monophosphate dehydrogenase (IMPDH) (such as mycophenolate mofetil, mycophenolate mofetil, azathioprine), various antibodies (e.g., anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), and radiation. These various agents can be used according to their standard doses or commonly used doses (as specified in the prescribing information accompanying the commercially available drug form (see also the prescribing information in The Physician's Desk Reference (2006 edition)). In some embodiments, the standard doses of these agents can be reduced when used in combination with the compounds of the embodiments herein. Without limiting the scope of the present disclosure, it is believed that such a combination can produce a synergistic result with better efficacy, less toxicity, longer duration of action, or faster response to therapy. In some embodiments, the combination therapy of the embodiments herein can be administered in the form of a subtherapeutic amount of a compound of the embodiments herein, or an additional pharmaceutical agent, or both a compound of the embodiments herein and an additional pharmaceutical agent. Azathioprine is currently available under the brand name Azasan TM Available from Salix Pharmaceuticals, Inc.; mercaptopurine is currently available under the brand name Purinethol TM Available from Gate Pharmaceuticals, Inc.; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available under the brand name Rapamune TM Available from Wyeth-Ayerst; tacrolimus is currently available under the brand name Prograf TM Obtained from Fujisawa; cyclosporine is currently available under the brand name Sandimmune TM Acquired from Novartis and under the brand name Gengraf TM Obtained from Abbott; IMPDH inhibitors (such as mycophenolate mofetil and mycophenolic acid) are currently available under the brand name Cellcept TM Obtained from Roche and under the brand name Myfortic TM Obtained from Novartis; azathioprine is currently available under the brand name Imuran TMobtained from Glaxo Smith Kline; and the antibody is currently available under the brand name Orthoclone TM Obtained from Ortho Biotech under the brand name Simulect TM (basiliximab) from Novartis and under the brand name Zenapax TM (daclizumab) was obtained from Roche.

[0660] In some embodiments, the compound of the embodiments herein is administered in combination, concomitantly or adjunctively with the above pharmaceutical agents or therapies and / or with pharmaceutical agents or therapies for other diseases. For example, the compound of the embodiments herein can be combined with thyroid hormone replacement therapy or with anti-inflammatory therapy or immunomodulatory therapy.

[0661] In some embodiments, the combination therapy of the embodiments herein may be administered in the form of a subtherapeutic amount of a compound of the embodiments herein, or an additional pharmaceutical agent, or both a compound of the embodiments herein and an additional pharmaceutical agent.

[0662] In any case, multiple drug agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, multiple drug agents can be provided in a single unified form or in multiple forms (as a single pill or as two separate pills, for example only). One of the drug agents can be administered in multiple doses, or two drug agents can be administered in multiple doses. If not administered simultaneously, the time between multiple doses can be any duration from a few minutes to eight weeks, or at any interval suitable for maintaining the desired therapeutic efficacy. In some embodiments, the time between multiple doses can be one minute, one hour, six hours, one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks or eight weeks.

[0663] One or more additional pharmaceutical agents (such as, for example, anti-inflammatory agents, steroids, immunosuppressants, and one or more other ITK kinase inhibitors and / or other kinase inhibitors (such as JAK3 kinase inhibitors, JAK1 kinase inhibitors, JAK1 / 2 kinase inhibitors, or JAK2 kinase inhibitors (such as, for example, those described in WO 99 / 65909, WO 00 / 00202 and / or WO / 2004 / 099205)) or other agents) can be used in combination with the compounds of the invention for treating JAK1 and / or JAK3-associated diseases, disorders or conditions.

[0664] In certain embodiments, the additional pharmaceutical agent is selected from a taxane, an inhibitor of bcr-abl, an inhibitor of EGFR, a DNA damaging agent, an antimetabolite, paclitaxel, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, cisplatin, oxaliplatin, carboplatin, anthracyclines, AraC, 5-FU, camptothecin, doxorubicin, idarubicin, paclitaxel, docetaxel, vincristine, a MEK inhibitor, U0126, a KSP inhibitor, vorinostat, pembrolizumab, nivolumab, atezolizumab, avelumab, tesimumab, and durvalumab.

[0665] In some embodiments, the composition further comprises an additional pharmaceutical agent selected from a chemotherapeutic or antiproliferative agent, an antiviral agent, an antibiotic, an antihistamine, a lubricant, systemic phototherapy, psoralen photochemotherapy, laser therapy, hormone replacement therapy, an anti-inflammatory agent, an immunomodulator or immunosuppressant, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder.

[0666] In some embodiments, one or more compounds of the embodiments herein can be used in combination with one or more other therapeutic agents used in the treatment of JAK-mediated disorders, and compared with the response to other therapeutic agents alone, the treatment response can be improved without exacerbating its toxic effects. In some embodiments, the compounds of the embodiments herein can be used in combination with one or more other ITK inhibitors, and / or JAK1 and / or JAK3 inhibitors, and / or JAK2 inhibitors, and / or TYK2 inhibitors for the treatment of JAK-mediated disorders. An additive effect or synergistic effect is the desired result of such a combination. Additional agents can be combined with the compounds of the present invention in a single dosage form or a continuous dosage form, or the agents can be administered simultaneously or sequentially as a separate dosage form. In some embodiments, one or more additional agents can be administered to a patient in combination with at least one JAK1 and / or JAK3 inhibitor / antagonist described herein, wherein the additional agents are administered intermittently (rather than continuously).

[0667] General synthetic methods for preparing compounds

[0668] The compounds of the present invention can be prepared using the methods described in the general synthetic schemes and experimental procedures described in detail below. The general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using conventional methods known in the art. Representative procedures for preparing the compounds of the present invention are outlined in Schemes 1-5 below. Additional schemes for analogs are provided in the examples. Solvents and reagents for synthesizing preparations not described below can be purchased at Sigma-Aldrich or Fisher Scientific. Additional schemes for synthesizing specific analogs are also provided in the Examples section.

[0669] Scheme 1 depicts a compound of formula (I) (wherein R 1 , R 2 , R 3 , and R 4 As defined above, n is 0, 1 or 2, and X is a halogen element). 1 is an indole protecting group, such as benzenesulfonyl, toluenesulfonyl, mesitylenesulfonyl, tert-butyl carbamate (Boc), allyl, benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), or p-methoxybenzyl. PG 2 It is a secondary amine protecting group, such as tert-butyl carbamate (Boc), benzyl carbamate (Cbz), benzyl (Bn), p-methoxybenzyl (PMB), or N-acetyl (Ac). Compound CI is formed by coupling DI with EI. Removal of the amine protecting group PG 2 The operation of BI produces compound BI. BI and HOR 4 or halogen-R 4 The coupling of the compounds yields compound AI. Finally, the indole protecting group PG 1 Alternatively, the two protecting groups of CI can be removed and the intermediate product can be reacted with a compound of formula HOR 4 The compound of is coupled to produce compound I.

[0670] Scheme 1: General synthesis of pyrrolopyridine analogs of formula (I).

[0671]

[0672] Scheme 2 illustrates compounds of formula I (in R 1 Yes-CO 2 R 5The general synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (CAS#885500-55-0) can be protected with SEM-Cl under standard reaction conditions using a base (such as sodium hydride) in a solvent (such as DMF or THF) and then adding SEM-Cl. The synthesis of diamine 3 (CAS#1251908-18-5) has been described previously (Shirakami et al., WO 2010119875), and it can be converted to intermediate 3a by reducing the Boc protecting group with lithium aluminum hydride in a solvent (such as THF). Alternatively, diamine 3 (CAS#1251908-18-5) can be deprotected using TFA in dichloromethane to produce 3b. Secondary or primary amines 3a or 3b can be used to replace the chloride of 2 via a nucleophilic aromatic substitution reaction by heating in a solvent (such as NMP). The resulting benzyl protected amine 4a or 4b can be deprotected with palladium on carbon in a solvent such as methanol. Once deprotected, amine 5a or 5b can be coupled with a variety of carboxylic acids under standard amide coupling procedures; the reaction with acid 6 using propylphosphonic tricyclic anhydride and triethylamine in dichloromethane is exemplified. Final deprotection using tetrabutylammonium fluoride in THF can yield the final compounds 8a (ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate) or 8b (ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate). Other amines besides 3a and 3b can be used. For example, (R)-1-benzylpiperidin-3-amine can be used and the corresponding analogue lacking the methyl group on the piperidine can be synthesized.

[0673] Scheme 2. Synthesis of 5-ester pyrrolopyridines.

[0674]

[0675] Analogs with a linker between the carbonyl group of the ester and the pyrrolopyridine core can be obtained by the method described in Scheme 3. Commercially available 4-chloro-1-[tri(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (9) can be selectively lithiated at the 5-position using s-BuLi (Heinrich et al., J. Med. Chem. 2013) and can be reacted with I 2Reaction to produce 4-chloro-5-iodo-1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine (10). Alternatively, the lithiated intermediate can be directly reacted with an electrophilic reagent such as ethyl 2-bromoacetate to produce intermediate 12. Other electrophilic reagents such as allyl bromide can be used with esters formed in subsequent steps by known methods. Compound 10 can be transformed in a variety of ways by palladium-catalyzed cross-coupling to produce analogs of interest. Illustrated here is a reaction with ethyl acrylate (Heck reaction) followed by reduction of the double bond to produce intermediate 11. Intermediates 11 and 12 can be converted into JAK inhibitors using protected diamines such as (3R, 4R)-1-benzyl-N, 4-dimethylpiperidin-3-amine or (3R, 4R)-1-benzyl-4-methylpiperidin-3-amine by the methods described in Scheme 2.

[0676] Scheme 3. Preparation of 5-alkyl ester pyrrolopyridines.

[0677]

[0678] Scheme 4 depicts the general synthesis of compounds of formula (II). 10 , R 20 , R 30 and R 40 As defined above, n is 0 or 1, and X is a halogen element. 10 is an indole protecting group, such as benzenesulfonyl, toluenesulfonyl, mesitylenesulfonyl, tert-butyl carbamate (Boc), allyl, benzyl, triisopropylsilyl (TIPS), 2-(trimethylsilyl)ethoxymethyl (SEM), or p-methoxybenzyl. 2 R 20 Compound FII is formed by reductive amination of compound GII with formula EII. Compound DII is formed by coupling FII with a compound of formula EII. Compound CII is formed by removal of the ketal group from the compound of DII. Compound BII is formed by reduction of the ketone from the compound of formula CII using sodium borohydride. Compound BII is formed by reacting the compound of formula BII with a compound of formula HOR under standard acylation or alkylation conditions. 40 Finally, the indole protecting group PG 10 Removal of produces a compound of formula (II). In some cases, BII is deprotected to provide a compound wherein R 40 II for OH.

[0679] Scheme 4: General synthesis of formula (II).

[0680]

[0681] Compounds of formula II can be produced by the method described in Scheme 5, which illustrates the synthesis of methyl 4-((4-(2-cyanoacetoxy)-2-methylcyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. Commercially available 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (13) can be converted to N,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (15) by reductive amination using sodium cyanoborohydride. Nucleophilic aromatic substitution of aromatic chlorides such as 16 with 15 under thermal conditions in water or NMP provides the ketal protected intermediate 17. Deprotection followed by reduction can produce the alcohol 19. Ester formation and deprotection produce the final analog 22.

[0682] Scheme 5. Synthesis of 5-ester pyrrolopyridines.

[0683]

[0684] Although the present invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail may be made without departing from the spirit and scope of the present invention. All published patents and publications mentioned in this application are hereby incorporated herein by reference in their entirety.

[0685] Exemplary synthetic methods for certain compounds detailed in the Examples section are further illustrated by the following:

[0686] Synthesis of Example 1: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0687]

[0688] Scheme 6. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0689]

[0690] Preparation of (3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine

[0691]

[0692] To a solution of ((3R, 4R)-1-benzyl-4-methylpiperidin-3-yl)carbamic acid tert-butyl ester (1 g, 3.28 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (4.9 mL, 4.9 mmol, 1 M in THF), and the mixture was heated to 60 ° C for 5 hours. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to provide (3R, 4R)-1-benzyl-N, 4-dimethylpiperidin-3-amine (0.6 g, crude): MS (ES) m / z 219 (M+H).

[0693] Step 1: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0694]

[0695] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.17g, 0.75mmol) in diphenyl ether (0.1mL) was added (3R, 4R)-1-benzyl-N, 4-dimethylpiperidin-3-amine (0.18g, 0.83mmol). The mixture was subjected to microwave radiation for 0.5 hour at 190 ° C. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to afford ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.035 g, 12% yield) as a viscous liquid: MS (ES) m / z 407.2 (M+H).

[0696] Step 2: Preparation of ethyl 4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0697]

[0698] To a solution of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.09 g, 0.2 mmol) in tetrahydrofuran (1 mL) was added palladium on carbon (0.25 g, 50% wet w / w), and the mixture was stirred at room temperature for 30 hours under a hydrogen atmosphere. The reactants were partitioned between 50% methanol / ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo to afford 4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (crude 0.07 g, 100% yield): MS (ES) m / z 317.2 (M+H).

[0699] Step 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0700]

[0701] To a solution of 4-(methyl((3R, 4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.07g, 0.22mmol) in dichloromethane (2mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.068g, 0.4mmol), 1-hydroxybenzotriazole (0.05g, 0.44mmol), N,N-diisopropylethylamine (0.05g, 0.4mmol) and cyanoacetic acid (0.028g, 0.33mmol), and the mixture was stirred at ambient temperature for 12 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (6% methanol / dichloromethane) to provide ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.013 g, 5% yield): 1 H NMR (400 MHz, DMSO-d 6, at 90℃) δ11.58(s,1H),8.32(s,1H),7.33(s,1H),6.54(br s,1H)4.28-4.29(m,2H)3.81-3.94(m,4H),3.37-3.49(m,3H),2.94(s,3H),2.16(m,1H ), 1.61 (m, 2H), 1.30-1.33 (t, J = 12Hz, 3H), 0.94-0.96 (m, 3H); MS (ES) m / z384.2 (M+H).

[0702] Synthesis of Example 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0703]

[0704] Scheme 7. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0705]

[0706] Preparation of (3R,4R)-1-Benzyl-4-methylpiperidin-3-amine

[0707]

[0708] A solution of ((3R, 4R)-1-benzyl-4-methylpiperidin-3-yl)t-butyl carbamate (2g, 6.57mmol) in dioxane (10mL, 4M) in HCl was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and neutralized with triethylamine (7mL). The residue was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to provide (3R, 4R)-1-benzyl-4-methylpiperidin-3-amine (1.3g, crude product): MS (ES) m / z 205.1 (M+H).

[0709] Step 1: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0710]

[0711] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (9g, 40.17mmol) in N-methyl-2-pyrrolidone (100mL) in a sealed tube, (3R, 4R)-1-benzyl-4-methylpiperidin-3-amine (9.8g, 48.2mmol) and triethylamine (4.5mL) were added, and the mixture was heated to 170°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to afford ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 64% yield) as a semisolid: MS (ES) m / z 393.4 (M+H).

[0712] Step 2: Preparation of ethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0713]

[0714] To a solution of 4-(((3R, 4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (10 g, 25.5 mmol) in tetrahydrofuran (120 mL) was added palladium / carbon (30 g, 50% wet w / w), and the mixture was stirred at ambient temperature for 30 hours using a Parr-vibrator (70 psi) under a hydrogen atmosphere. The reaction mixture was distributed between 50% methanol / ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated to provide 4-(((3R, 4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (4.7 g, 95% yield): MS (ES) m / z 303.1 (M+H).

[0715] Step 3: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0716]

[0717] To a solution of ethyl 4-(((3R, 4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (4.7 g, 15.8 mmol) in dichloromethane (50 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.9 g, 31.6 mmol), 1-hydroxybenzotriazole (4.2 g, 31.7 mmol), N,N-diisopropylethylamine (12.2 mL, 31.6 mmol) and cyanoacetic acid (2.7 g, 31.7 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified by using flash chromatography (6% methanol / dichloromethane) to provide ethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.8 g, 66% yield): 1 H NMR (400 MHz, DMSO-d 6 , at 90℃) δ11.49(s,1H),8.79-8.81(m,1H),8.56(s,1H),7.16(s,1H)6.64(s,1H)4.27-4 .36(m,4H),3.91(m,1H),3.70(m,1H),3.42(m,1H),3.15(m,1H),2.88(m,1H),2.14(br s, 2H), 1.64 (m, 1H), 1.30-1.33 (t, J = 8.75Hz, 3H), 0.95 (bs, 3H); MS (ES) m / z 370.3 (M+H).

[0718] Synthesis of Example 21: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0719]

[0720] Scheme 8. Preparation of 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0721]

[0722] Step 1: Preparation of 2-methoxyethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0723]

[0724] To the solution of 4- chloro- 1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (4.0g, 17.80mmol) in methoxyethanol (40mL) add cesium carbonate (29.0g, 89.0mmol), and the mixture is stirred at ambient temperature for 16 hours. The reaction is quenched with water, and extracted with ethyl acetate. The organic layer is washed with water, brine, and dried over anhydrous sodium sulfate. The solution is filtered, and concentrated in a vacuum. The crude material is purified using flash chromatography (40% ethyl acetate / hexane) to provide 4- chloro- 1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid 2- methoxyethyl ester (2.6g, 57% yield) as a white solid: MS (ES) m / z255 (M+H).

[0725] Step 2: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0726]

[0727] A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2-methoxyethyl ester (0.6 g, 2.35 mmol), (3R, 4R)-1-benzyl-4-methylpiperidin-3-amine (0.48 g, 2.35 mmol) and triethylamine (0.1 mL) in N-methyl-2-pyrrolidone (10 mL) was heated to 140 ° C for 12 hours. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (45% ethyl acetate / hexanes) to afford 2-methoxyethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.35 g, 35% yield) as an off-white solid: MS (ES) m / z 423 (M+H).

[0728] Step 3: Preparation of 2-methoxyethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0729]

[0730] Palladium / carbon (0.3 g, 50% wet w / w) was added to a solution of 4-(((3R, 4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2-methoxyethyl ester (0.35 g, 0.82 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at ambient temperature for 48 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo to provide 4-(((3R, 4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2-methoxyethyl ester (crude 0.16 g, 58% yield): MS (ES) m / z 333 (M+H).

[0731] Step 4: Preparation of 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0732]

[0733] 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14g, 0.96mmol), 1-hydroxybenzotriazole (0.13g, 0.96mmol), N,N-diisopropylethylamine (0.25mL, 1.44mmol) and cyanoacetic acid (0.08g, 0.96mmol) were added to a solution of 4-(((3R, 4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 2-methoxyethyl ester (0.16g, 0.48mmol) in N,N-dimethylformamide (10mL), and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was distributed between ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (5% methanol / dichloromethane) to provide 2-methoxyethyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.03 g, 16% yield): 1 H NMR (400 MHz, DMSO-d 6, at 80℃) δ11.52(s,1H),8.74(s,1H),8.57(s,1H),7.16(s,1H)6.65(s,1H)4.34-4.36(m,3H),4.24(m,1 H),3.91(m,2H),3.65-3.67(m,3H),3.32(s,3H),3.14(m,1H),2.15(m,1H),1.56-1.65(m,3H),0.95(br s,3H); MS(ES)m / z 400(M+H).

[0734] Synthesis of Example 24: Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0735]

[0736] Scheme 9. Preparation of ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0737]

[0738] A solution of ethyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 0.311 mmol), acrylonitrile (0.035 g, 0.66 mmol) and triethylamine (0.13 mL, 0.99 mmol) in ethanol (10 mL) was heated at 70 °C for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the crude material was purified using flash chromatography (50% ethyl acetate / hexanes) to provide ethyl 4-(((3R,4R)-1-(2-cyanoethyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.07 g, 63% yield): 1 H NMR (400 MHz, DMSO-d 6)δ11.61(br s,1H),9.08(d,J=9.2Hz,1H),8.52(s,1H),7.13(s,1H),6.62(s,1H),4.37(br s,1H),4.24-4.25(m,2H),2.79(d,J=8.8Hz,2H),2.43-2.60(m,4H),2.02(br s,1H),1.87(br s,1H),1.70-1.55(br s, 2H), 1.22-1.31 (m, 4H), 0.85 (d, J = 6.0Hz, 3H); MS (ES) m / z 356.2 (M+H).

[0739] Synthesis of Example 34: Preparation of (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0740]

[0741] Scheme 10. Preparation of (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0742]

[0743] Step-1: Preparation of (R)-ethyl 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0744]

[0745] 4- chloro-1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (0.5g, 2.23mmol), (R) -3- aminopiperidine -1- carboxylic acid tert-butyl ester (0.53g, 2.67mmol) and triethylamine (0.3mL) in N- methyl -2- pyrrolidone (10mL) solution was subjected to microwave radiation for 2 hours at 180 ° C. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The crude material was purified by using flash chromatography (50% ethyl acetate / hexane) to provide (R) -4- ((1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (0.6g, 35% yield) as an off-white solid: MS (ES) m / z: 389.2 (M+H).

[0746] Step 2: Preparation of (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester hydrochloride

[0747]

[0748] To a solution of (R)-ethyl 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.6 g, 1.17 mmol) in dichloromethane (15 mL) at 0° C. was added HCl in dioxane (2.0 mL, 4 M), and the mixture was stirred at ambient temperature for 6 hours. The solution was concentrated in vacuo to provide (R)-ethyl 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate hydrochloride (0.3 g, crude) as an off-white solid: MS (ES) m / z: 289.2 (M+H).

[0749] Step 3: Preparation of (R)-4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0750]

[0751] To a solution of (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester hydrochloride (0.13 g, 0.45 mmol) in tetrahydrofuran:water (1:1, 2 mL:2 mL) at 0 ° C, N-diisopropylethylamine (0.2 mL, 0.92 mmol) was added, followed by acryloyl chloride (0.01 mL, 0.092 mmol). The mixture was stirred for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified by using flash chromatography (ethyl acetate / hexanes) to provide (R)-ethyl 4-((1-acryloylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate as an off-white solid (0.035 g, 22% yield): 1 H NMR (400 MHz, DMSO-d 6)δ11.68(br s,1H),8.85(br s,1H),8.53(s,1H),7.19(s,1H),6.75-6.82(m,1H),6.50-6.59(m,1H),6.0 1-6.21(m,1H),5.32-5.66(m,1H),4.24(q,J=7.2Hz,2H),4.11(m,1H),3.72 -3.84(m,1H)3.57(m,1H),2.06(m,1H),1.70(m,2H),1.58(m,1H),1.31(t,J =6.8Hz,3H),1.22-1.25(m,1H),0.82-1.09(m,1H); MS(ES)m / z:343.2(M+H).

[0752] Synthesis of Example 68A and Example 68B: Preparation of Enantiomers 68A and 68B of (trans)-4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0753]

[0754] Scheme 11: Preparation of enantiomers of ethyl (trans)-4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0755]

[0756] Chiral Separation of (trans)-(racemic)-3-((tert-Butyloxycarbonyl)amino)cyclopentyl 4-nitrobenzoate

[0757] The enantiomers of (trans)-(rac)-3-((tert-butoxycarbonyl)amino)cyclopentyl 4-nitrobenzoate were separated by chiral chromatography.

[0758] Analysis conditions:

[0759] Column: CHIRALPAK IA (250mm×4.6mm×5ìm)

[0760] Mobile phase: n-hexane:ethanol with 0.1% DEA (50:50)

[0761] Flow rate: 1.0mL / min

[0762] Enantiomer 1: retention time 4.161 min

[0763] Enantiomer 2: retention time 5.296 min.

[0764] Step 1: Preparation of tert-butyl (trans)-(3-hydroxycyclopentyl)carbamate

[0765]

[0766] To one of the enantiomers of (trans)-3-((tert-butoxycarbonyl) amino) cyclopentyl 4-nitrobenzoate (1.2g, 3.42mmol) in methanol (30mL) solution of potassium carbonate (0.71g, 5.14mmol), and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated in a vacuum, the residue was dissolved in water, and extracted with ethyl acetate. The organic layer was washed with water, salt water, and dried over anhydrous sodium sulfate. The solution was filtered, and concentrated in a vacuum. Purification of crude material by flash chromatography (30% ethyl acetate / hexane) to provide tert-butyl (3-hydroxycyclopentyl) carbamate (0.42g, 60.95% yield) as off-white solid: 1 H NMR (400 MHz, DMSO-d 6 )δ6.72(br s,1H),4.37(d,J=3.6Hz,1H),4.09-4.10(m,1H),3.89-3.91(m,1H),1.75-1.91 (m,2H),1.66-1.70(m,1H),1.44-1.51(m,1H),1.35(s,9H),1.19-1.31(m,2H).

[0767] Step 2: Preparation of (trans)-3-(methylamino)cyclopentan-1-ol

[0768]

[0769] To one of the enantiomers of (trans)-(3-hydroxycyclopentyl) tert-butyl carbamate (0.15g, 0.74mmol) in tetrahydrofuran (5mL) at 0°C, lithium aluminum hydride (2.23mL, 2.23mmol, 1.0M solution in tetrahydrofuran) is added dropwise, and the mixture is heated at 70°C for 4 hours. After cooling, the reaction mixture is quenched with aqueous sodium hydroxide solution and ethyl acetate, and the suspension is filtered through diatomaceous earth. The organic layer is separated, washed with water, and dried over anhydrous sodium sulfate. The filtrate is concentrated in vacuo to provide 3-(methylamino) cyclopentane-1-ol (0.1g, 80% yield) as a yellow oil: MS (ES) m / z 116 (M+H).

[0770] Step 3: Preparation of ethyl (trans)-4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0771]

[0772] By 4- chloro- 1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (0.15g, 0.66mmol) and 3- (methylamino) cyclopentane -1- alcohol one of the enantiomers (0.092g, 0.8mmol) in dimethyl sulfoxide (3mL) solution was heated under microwave radiation for 2 hours. After being cooled to ambient temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water, salt water, and dried over anhydrous sodium sulfate. The solution was filtered, and concentrated in a vacuum. Purification of crude material by flash chromatography (9% methanol / dichloromethane), to obtain 4- ((3- hydroxycyclopentyl) (methyl) amino) -1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (0.015g, 7.42% yield) as brown solid.

[0773] Example 68A: (trans)-4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester, Enantiomer 1

[0774]

[0775] 1 H NMR (400 MHz, DMSO-d 6 )δ11.59(s,1H),8.20(m,1H),7.24-7.26(m,1H),6.57-6.58(m,1H),4.66-4.80(m,1H),4.57(m,1H),4.06-4.27 (m,3H),2.82(s,3H),1.78-1.96(m,3H),1.60-1.76(m,2H),1.48-1.50(m,1H),1.30(t,J=8.8Hz,3H);MS(ES)m / z 304(M+H).

[0776] Example 68B: (trans)-4-((3-hydroxycyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester, Enantiomer 2

[0777]

[0778] 1 H NMR (400 MHz, DMSO-d 6)δ11.59(br s,1H),8.20(m,1H),7.24-7.26(m,1H),6.57-6.58(m,1H),4.66-4.74(m,1H),4.54-4.55(m,1H),4.20-4 .27(m,3H),2.78(s,3H),1.80-1.94(m,3H),1.71-1.78(m,2H),1.48-1.51(m,1H),1.31(t,J=8.8Hz,3H).

[0779] Synthesis of Example 69: Isolation of the trans enantiomer of 2-((trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0780]

[0781] Trans-enantiomer-2

[0782] 1 H NMR (400 MHz, DMSO-d 6 )δ11.64(s,1H),8.24(s,1H),7.26-7.28(m,1H),6.55-6.56(m,1H),5.21-5.22(m,1H),4.57-4.61(m,1H),4.26(q,J=6.8Hz 2H),3.94(s,2H),2.84(s,3H),2.11-2.20(m,2H),1.92-2.0(m,3H),1.83-1.86(m,1H),1.29(t,J=7.6Hz,3H). Retention time: 21.666min.

[0783] Synthesis of Example 70: Isolation of the trans enantiomer of 1((trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0784]

[0785] Trans-enantiomer-1

[0786] 1 H NMR (400 MHz, DMSO-d 6)δ11.64(s,1H),8.24(s,1H),7.26-7.28(m,1H),6.55-6.56(m,1H),5.21-5.22(m,1H),4.57-4.61(m,1H),4.25(q,J=6.8Hz,2H),3.94(s,2H),2.82(s,3H),2.10-2.11(m,2H),1.85-1.96(m,3H),1.68-1.70(m,1H),1.27(t,J=7.2Hz,3H); retention time:19.434min.

[0787] Synthesis of Examples 72-75: Preparation of Enantiomers of (trans)-4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic Acid Ethyl Ester (72 and 75) and (trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic Acid Ethyl Ester (73 and 74)

[0788]

[0789] Scheme 13. Preparation of enantiomers of ethyl (trans)-4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate and ethyl (trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0790]

[0791] Step-1: Preparation of (trans)-(racemic)-3-aminocyclopentan-1-ol hydrochloride

[0792]

[0793] Trans racemic

[0794] To a solution of tert-butyl (trans)-(rac)-(3-hydroxycyclopentyl)carbamate (0.27 g, 1.34 mmol) in dichloromethane (5 mL) at 0° C. was added HCl in dioxane (4 M, 5 mL), and the solution was warmed to ambient temperature and stirred for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was washed with diethyl ether to provide 3-aminocyclopentane-1-ol hydrochloride (0.18 g, 96% yield) as a yellow oil: MS (ES) m / z 102 (M+H).

[0795] Step-2: Preparation of ethyl (trans)-4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0796]

[0797] Trans racemic

[0798] By (trans)-(racemic)-4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.05g, 0.22mmol), 3-aminocyclopentane-1-ol hydrochloride (0.036g, 0.26mmol) and triethylamine (0.15mL, 1.11mmol) in dimethyl sulfoxide (3mL) solution at 150 DEG C under microwave radiation for 1 hour.After cooling to ambient temperature, the reaction mixture is quenched with water, and extracted with ethyl acetate.The organic layer is washed with water, brine, and dried over anhydrous sodium sulfate.The solution is filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (9% methanol / dichloromethane) to afford ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.01 g, 17% yield) as an off-white solid: MS (ES) m / z 290 (M+H).

[0799] Step 3: Preparation of (trans)-(racemic)-4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0800]

[0801] To (trans)-(racemic)-4-((3-hydroxycyclopentyl) amino)-1H-pyrrolo-[2,3-b] pyridine-5-carboxylic acid ethyl ester (0.14g, 0.48mmol) in dichloromethane (10mL) solution add 2-cyanoacetic acid (0.062g, 0.72mmol), 4-dimethylaminopyridine (0.06g, 0.48mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.14g, 0.72mmol), and the mixture is stirred at ambient temperature for 16 hours. The reaction mixture is quenched with water, and extracted with dichloromethane. The organic layer is washed with water, salt water, and dried over anhydrous sodium sulfate. The solution is filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (5% methanol / dichloromethane) to afford ethyl 4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.035 g, 20% yield) as an off-white solid: MS (ES) m / z 357 (M+H).

[0802] Synthesis of Example 72: Isolation of the trans enantiomer of 2-((trans)-4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0803]

[0804] Opposing enantiomer-2

[0805] 1 H NMR (400 MHz, DMSO-d 6 )δ11.66(br s,1H),8.82(d,J=7.6Hz,1H),8.52(s,1H),7.17-7.18(m,1H),6.67(s,1H),4.61-4.63(m,2H),4.21-4.26(m,3H),1.98-2.37(m,3H),1.68-1.69(m,1H),1.53(m,2H),1.29(t,J=7.2Hz,3H). Retention time:7.625min.

[0806] Analysis conditions:

[0807] Column: CHIRALPAK IA (250mm×4.6mm×5ìm)

[0808] Mobile phase: Methanol with 0.1% DEA (50:50)

[0809] Flow rate: 0.5mL / min.

[0810] Synthesis of Example 73: Isolation of the trans enantiomer of 1-((trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0811]

[0812] Trans-enantiomer-1

[0813] 1 H NMR (400 MHz, DMSO-d 6)δ11.67(s,1H),8.81(d,J=3.8Hz,1H),8.53(s,1H),7.17(s,1H),6.65(s,1H),5.30(br,1H),4.63-4.66(m,1H),4.25(q,J=6.8Hz,2H),3.99(s,2H),2.05-2.31(m,3H),1.93-2.0(m,1H),1.79-1.81(m,1H),1.60-1.67(m,1H),1.30(t,J=6.8Hz,3H). Retention time:9.484min.

[0814] Analysis conditions:

[0815] Column: CHIRALPAK IA (250mm×4.6mm×5ìm)

[0816] Mobile phase: Methanol with 0.1% DEA (50:50)

[0817] Flow rate: 0.5mL / min.

[0818] Synthesis of Example 74: Isolation of the trans enantiomer of 2-((trans)-4-((3-(2-cyanoacetoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0819]

[0820] Trans-enantiomer-2

[0821] 1 H NMR (400 MHz, DMSO-d 6 )δ11.70(br s,1H),8.84(d,J=7.2Hz,1H),8.53(s,1H),7.18(s,1H),6.65(s,1H),5.25(br s,1H),4.63-4.67(m,1H),4.24(q,J=7.2Hz,2H),3.99(s,2H),2.14-2.31(m,3H),1.93-2.00(m,1H),1.80(m,1H),1.63-1.65(m,1H),1.33(t,J=7.2Hz,3H). Retention time: 4.846min.

[0822] Analysis conditions:

[0823] Column: CHIRALPAK IA (250mm×4.6mm×5ìm)

[0824] Mobile phase: Methanol with 0.1% DEA (50:50)

[0825] Flow rate: 0.5mL / min.

[0826] Synthesis of Example 75: Isolation of the trans enantiomer of 1-((trans)-4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester)

[0827]

[0828] Opposite enantiomer-1

[0829] 1 H NMR (400 MHz, DMSO-d 6 )δ11.65(s,1H),8.80(d,J=7.6Hz 1H),8.51(s,1H),7.17(s,1H),6.66(s,1H),4.59-4.66(m,2H),4.21-4.26(m,3H),2.23-2.31(m,1H),2.05-2.10(m,1H),1.93-2.04(m,1H),1.64-1.69(m,1H),1.46-1.58(m,2H),1.27(t,J=7.6Hz,3H). Retention time: 7.540min.

[0830] Analysis conditions:

[0831] Column: CHIRALPAK IA (250mm×4.6mm×5ìm)

[0832] Mobile phase: Methanol with 0.1% DEA (50:50)

[0833] Flow rate: 0.5mL / min.

[0834] Synthesis of Example 92: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0835]

[0836] Scheme 14. Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0837]

[0838] Preparation of ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride

[0839]

[0840] To a stirred solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1 g, 17.47 mmol) in dioxane (5 mL) at 0° C. was added 1,4-dioxane hydrochloride (10 mL) and the solution was stirred for 2 hours. The reaction was concentrated in vacuo to afford crude ((1r,4r)-4-aminocyclohexyl)methanol hydrochloride (0.6 g crude) as a semisolid.

[0841] Step 1: Preparation of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0842]

[0843] To the stirred solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (3g, 13.39mmol) in N-methylpyrrolidine (10mL) was added triethylamine (0.3mL) and ((1r, 4r)-4-aminocyclohexyl) methanol hydrochloride (2.59g, 19.9mmol). The solution was heated at 160 ° C for 2 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with salt water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by using flash chromatography (55% ethyl acetate / hexanes) to afford ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 71% yield) as a brown solid: MS (ES) m / z 318.1 (M+H).

[0844] Step 2: Preparation of ethyl 1-p-toluenesulfonyl-4-(((1r,4r)-4-((p-toluenesulfonyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0845]

[0846] To a solution of 4-(((1r, 4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.5 g, 4.73 mmol) in dichloromethane (20 mL) at 0°C, triethylamine (1.2 mL, 12.08 mmol), 4-dimethylaminopyridine (0.28 g, 2.36 mmol) and 4-toluenesulfonyl chloride (2.7 g, 14.19 mmol) were added. The mixture was stirred at room temperature for 12 hours, the reaction was quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by using flash chromatography (55% ethyl acetate / hexanes) to afford ethyl 1-p-toluenesulfonyl-4-(((1r,4r)-4-((p-toluenesulfonyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.6 g, 55% yield) as an off-white solid: MS (ES) m / z 626.1 (M+H).

[0847] Step-3: Preparation of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0848]

[0849] To a solution of 1-toluenesulfonyl-4-(((1r,4r)-4-((toluenesulfonyloxy)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.6 g, 2.56 mmol) in dimethyl sulfoxide (5 mL) was added potassium thioacetate (0.33 g, 2.89 mmol), and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with ice water. The obtained solid was filtered, washed with water, and dried to provide 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.6 g, 74%) as a white solid: MS (ES) m / z 530.1 (M+H).

[0850] Step 4: Preparation of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid

[0851]

[0852] A solution of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.3 g, 0.56 mmol) in hydrogen peroxide (0.15 mL) at 0° C. was treated with formic acid (0.8 mL) and the solution was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with ice water, and the obtained solid was filtered, washed with water, and dried to provide ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.21 g, 66% yield) as a white solid: MS (ES) m / z 535.1 (M+H).

[0853] Step 5: Preparation of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0854]

[0855] To a stirred solution of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.21 g, 0.39 mmol) in N,N-dimethylformamide (0.1 mL) at 0° C., thionyl chloride (2.0 mL) was added and the solution was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo to provide ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.35 g crude) as a light yellow solid.

[0856] Step 6: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0857]

[0858] Methylamine (15mL, 2.0M in tetrahydrofuran) was added to a solution of 4-(((1r, 4r)-4-((chlorosulfonyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.21g, 0.37mmol) in tetrahydrofuran (10mL), and the solution was stirred at room temperature for 12 hours in a sealed tube. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (40% ethyl acetate / hexanes) to afford ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.07 g, 70% yield) as a brown solid: MS (ES) m / z 548.1 (M+H).

[0859] Step 7: Preparation of ethyl 4-(((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0860]

[0861] To a solution of 4-(((1r, 4r)-4-((N- methylsulfamoyl) methyl) cyclohexyl) amino)-1-tosyl-1H- pyrrolo[2,3-b] pyridine-5-carboxylic acid ethyl ester (0.14g, 0.25mmol) in tetrahydrofuran (1mL) potassium tert-butoxide (0.07g, 0.63mmol) was added, and the solution was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (40% ethyl acetate / hexane), to provide 4-(((1r, 4r)-4-((N- methylsulfamoyl) methyl) cyclohexyl) amino)-1H- pyrrolo[2,3-b] pyridine-5-carboxylic acid ethyl ester (0.07g, 37% yield) as an off-white solid: 1 H NMR (400 MHz, DMSO-d 6)δ11.63(br s,1H),8.71-8.73(m,1H),8.51(s,1H),7.16(s,1H),6.85(s,1H),6.51(s,1H),4.22-4.24(m,2H),3.87(br s,1H),2.92-2.93(m,2H),2.55(m,3H),2.11(m,2H),1.97(m,2H),1.84(m,2H),1.29-1.30(m,6H); MS(ES)m / z 382.1(M+H).

[0862] Synthesis of Example 94: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0863]

[0864] Scheme 15: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0865]

[0866] Preparation of ((1r,4r)-4-(methylamino)cyclohexyl)methanol

[0867]

[0868] To a stirred solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (4 g, 17.47 mmol) in tetrahydrofuran (75 mL) at 0°C was slowly added lithium aluminum hydride (26 mL, 26.2 mmol, 1 M in tetrahydrofuran), and the mixture was slowly heated at 60°C for 12 hours. The reaction mixture was cooled to room temperature and quenched with ethyl acetate and filtered through celite. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide ((1r,4r)-4-(methylamino)cyclohexyl)methanol (3 g crude) as a yellow solid: MS (ES) m / z 144.1 (M+H).

[0869] Step 1: Preparation of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0870]

[0871] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (3g, 13.39mmol) in diphenyl ether (10mL), ((1r, 4r)-4-(methylamino)cyclohexyl)methanol (3.4g, 24.10mmol) was added, and the solution was subjected to microwave radiation for 2 hours at 180°C. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by using flash chromatography (55% ethyl acetate / hexane) to provide 4-(((1r, 4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (1g, 27% yield) as a brown solid: MS (ES) m / z 332.2 (M+H).

[0872] Step 2: Preparation of ethyl 4-(methyl((1r,4r)-4-((p-toluenesulfonyloxy)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0873]

[0874] To a stirred solution of ethyl 4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.0 g, 3.02 mmol) in dichloromethane (20 mL) at 0°C was added triethylamine (1.2 mL, 12.08 mmol) followed by 4-dimethylaminopyridine (0.18 g, 1.51 mmol) and 4-toluenesulfonyl chloride (1.7 g, 9.06 mmol). The mixture was stirred at N 2 Atmosphere, stirred at room temperature for 12 hours.Reaction mixture was quenched with water, and extracted with dichloromethane.The organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuum.By using flash chromatography (20% ethyl acetate / hexane) purification of crude material, 4-(methyl ((1r, 4r)-4-((tosyloxy) methyl) cyclohexyl) amino)-1-tosyl-1H-pyrrolo-[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.4g, 73% yield) was provided as off-white solid: MS (ES) m / z 640.2 (M+H).

[0875] Step 3: Preparation of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0876]

[0877] To a stirred solution of ethyl 4-(methyl((1r,4r)-4-((p-toluenesulfonyloxy)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.4 g, 2.18 mmol) in dimethyl sulfoxide (30 mL) was added potassium thioacetate (0.28 g, 2.47 mmol), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was quenched with ice water, and the obtained solid was filtered, washed with water, and dried to provide ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.0 g, 84% yield) as a brown solid: MS (ES) m / z 544.2 (M+H).

[0878] Step 4: Preparation of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonic acid

[0879]

[0880] A stirred solution of ethyl 4-(((1r,4r)-4-((acetylthio)methyl)cyclohexyl)(methyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.1 g, 2.02 mmol) in hydrogen peroxide (1 mL) at 0°C was treated with formic acid (9 mL) and the solution was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with ice water and the obtained solid was filtered, washed with water, and dried to afford ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonic acid (0.55 g, 50% yield) as an off-white solid: 1 HNMR (400 MHz, DMSO-d 6 )δ8.21(s,1H),7.9(d,J=7.6Hz,2H),7.7(d,J=5.2Hz,1H),7.39(d,J=8Hz,2H),6.67(d,J=3.2Hz,1H),4.25-4.18(q,2H),3.64- 3.60(m,2H),2.75(s,3H),2.37-02.32(m,5H),2.06-2.03(m,2H),1.75-1.70(m,5H),1.29(t,J=6.8Hz,3H),1.06-0.96(m,2H).

[0881] Step 5: Preparation of ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0882]

[0883] To a solution of ((1r,4r)-4-((5-(ethoxycarbonyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)cyclohexyl)methanesulfonic acid (0.5 g, 0.9 mmol) in N,N-dimethylformamide (0.5 mL) at 0° C. was added thionyl chloride (5 mL), and the solution was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to afford ethyl 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.35 g crude) as a colorless liquid: MS (ES) m / z 568.2 (M+H).

[0884] Step 6: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0885]

[0886] To a stirred solution of 4-(((1r,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)(methyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.35 g, 0.61 mmol) in tetrahydrofuran (10 mL) was added methylamine (15 mL, 2.0 M in tetrahydrofuran), and the solution was stirred at room temperature for 12 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by using flash chromatography (40% ethyl acetate / hexanes) to provide ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.300 g, 87%) as a yellow solid: MS (ES) m / z 563.2 (M+H).

[0887] Step 7: Preparation of ethyl 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0888]

[0889] To a stirred solution of 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.3g, 0.53mmol) in tetrahydrofuran (8mL) was added potassium tert-butoxide (0.15g, 1.33mmol), and the solution was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by using flash chromatography (45% ethyl acetate / hexane) to provide 4-(methyl((1r,4r)-4-((N-methylsulfamoyl)methyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.08g, 37% yield) as an off-white solid: 1 H NMR (400 MHz, DMSO-d 6 ): δ11.64(s,1H),8.18(s,1H),7.25(s,1H),6.85(d,J=4.8Hz,1H),6.40(s,1H),4.25-4.20(q,2H),3.81(bs,1H),2.90(d,J=5.6Hz, 2H),2.80(s,3H),2.55(d,J=4.8Hz,3H),2.05-2.02(m,2H),1.81-1.76(m,5H),1.29(t,J=6.8Hz,3H),1.21-1.19(m,2H); MS(ES)m / z 409.0[M+H].

[0890] Synthesis of Example 113: Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0891]

[0892] Scheme 16. Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0893]

[0894] Step 1: Preparation of 3-aminocyclopentan-1-ol trifluoroacetate

[0895]

[0896] To a solution of tert-butyl (3-hydroxycyclopentyl)carbamate (1.0 g, 5.47 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at ambient temperature for 5 hours and then concentrated to dryness in vacuo to provide 3-aminocyclopentane-1-ol trifluoroacetate (1.17 g, crude).

[0897] Step 2: Preparation of ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0898]

[0899] The stirred solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.27 g, 5.44 mmol), 3-aminocyclopentane-1-ol trifluoroacetate (1.17 g, 5.44 mmol), triethylamine (2.27 g, 16.3 mmol) in N-methyl-2-pyrrolidone (10 mL) was heated at 160 ° C for 12 hours in a sealed tube. After cooling to ambient temperature, the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using flash chromatography (10% methanol / dichloromethane) to afford ethyl 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.82 g, 50% yield) as a colorless gum: MS (ES) m / z 290.1 ​​(M+H).

[0900] Step 3: Preparation of ethyl 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0901]

[0902] 4-((3-hydroxycyclopentyl)amino)-1H-pyrrolo-[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.74g, 2.56mmol) is added to a suspension of potassium carbonate (0.86g, 6.25mmol) in ethanol (10mL), and the mixture is stirred at ambient temperature for 0.5 hour. Then, acrylonitrile (1.35g, 25.6mmol) is added, and the mixture is stirred for 15 hours. The solvent is concentrated in a vacuum, and the residue is distributed between ethyl acetate and water. The organic layer is washed with water, brine, and dried over anhydrous magnesium sulfate. The solution is filtered, and concentrated in a vacuum. The crude material is purified by reverse phase preparative HPLC (0.1% ammonia in water: acetonitrile), to provide 4-((3-(2-cyanoethoxy)cyclopentyl)amino)-1H-pyrrolo-[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.05g, 6% yield): 1 H NMR (400 MHz, DMSO-d 6 )δ11.61(br s,1H),8.95(d,J=7.6Hz,1H),8.50(s,1H),7.14(s,1H),6.58(s,1H),4.59-4.5(m,1H),4.25(q,J=7.2Hz,2H),4.02-4.10(m,1H),3.56-.351 (m,2H),2.73(t,J=6.4Hz,2H),2.26-2.19(m,1H),2.15-2.07(m,1H),1.90-1.82(m,2H),1.73-1.69(m,2H),1.29(t,J=6.2Hz,3H); MS(ES)m / z 343.1(M+H).

[0903] Preparative HPLC analysis conditions

[0904] Column: Inertsil ODS 3V (250mm×4.6mm×5mic)

[0905] Mobile phase (A): 0.1% ammonia in water

[0906] Mobile phase (B): ACN

[0907] Flow rate: 1.0mL / min

[0908] Retention time: 12.61min.

[0909] Synthesis of Example 117: Preparation of (R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0910]

[0911] Scheme 17. Preparation of (R)-ethyl 4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0912]

[0913] Step 1: Preparation of (R)-4-((1-benzylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0914]

[0915] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (5 g, 22.3 mmol) in N-methyl-2-pyrrolidone (35 mL) was added (R)-1-benzylpiperidin-3-amine (8.48 g, 44.6 mmol) and triethylamine (1 mL) in a sealed tube. The mixture was heated to 170 ° C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water to precipitate a solid, which was filtered, washed with water, dried, and concentrated in vacuo to provide (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (8 g, 95% yield) as a brown solid: MS (ES) m / z 379.1 (M+H).

[0916] Step 2: Preparation of (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

[0917]

[0918] To a solution of (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.25 g, 0.66 mmol) in methanol (5 mL) was added 10% palladium / carbon (0.3 g, 50% wet w / w), and the mixture was stirred at ambient temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was partitioned between 50% methanol / ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated in vacuo to provide (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.1 g, 90% yield) as an off-white solid: MS (ES) m / z 289.3 (M+H).

[0919] Step 3: Preparation of (R)-ethyl 4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0920]

[0921] To (R) -4- (piperidin-3-ylamino) -1H- pyrrolo [2,3-b] pyridine -5- carboxylic acid ethyl ester (9g, 31.3mmol) in dichloromethane (50mL) solution add N- (3- dimethylaminopropyl) -N '- ethylcarbodiimide hydrochloride (9.7g, 62.5mmol), 1- hydroxybenzotriazole (8.43g, 62.5mmol), N, N- diisopropylethylamine (11.3mL, 62.5mmol) and cyanoacetic acid (0.76g, 9.0mmol), and the mixture is stirred at ambient temperature for 18 hours. The reaction mixture is quenched with water, and extracted with dichloromethane. The organic layer is washed with water, salt water, and dried over anhydrous sodium sulfate. The solution is filtered, and concentrated in vacuo. The crude material was purified by using flash chromatography (5% methanol / dichloromethane) to provide (R)-ethyl 4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (7.5 g, 68% yield): 1 HNMR (400 MHz, DMSO-d 6 )δ11.68(br s,1H),8.86-8.79(m,1H),8.54(s,1H),7.20(s,1H),6.67(s,1H),4.17-4.4 4(m,3H),3.70-4.05(m,4H),3.45-3.48(m,1H),3.11-3.24(m,1H),2.06(br s, 1H), 1.57-1.72 (m, 3H), 1.28-1.32 (t, J = 7.2Hz, 3H); MS (ES) m / z 356.1 (M+H).

[0922] Synthesis of Example 118: Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0923]

[0924] Scheme 18. Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

[0925]

[0926] Step 1: Preparation of 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[0927]

[0928] To a solution of 4-(((3R, 4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo-[2,3-b]pyridine-5-carboxylic acid ethyl ester (0.1 g, 0.25 mmol) in methanol (10 mL) was added lithium hydroxide (0.017 g, 0.75 mmol), and the mixture was heated to 600 ° C for 10 hours. After cooling to ambient temperature, the reaction mixture was concentrated to dryness in a vacuum. The residue was dissolved in water, and acidified with 2N hydrochloric acid, and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to provide 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.085 g, 91% yield): MS (ES) m / z 365.2 (M+H).

[0929] Step 2: Preparation of ethyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0930]

[0931] To a solution of 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.08 g, 0.22 mmol) in methanol (10 mL) was added sulfuric acid (1.0 mL), and the solution was heated to 80 ° C for 48 hours. After cooling to ambient temperature, the reaction was quenched with a saturated bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to provide methyl 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, crude): MS (ES) m / z 379.1 (M+H).

[0932] Step 3: Preparation of methyl 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

[0933]

[0934] To a solution of 4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (0.1 g, 0.34 mmol) in tetrahydrofuran (5 mL) was added palladium / carbon (0.5 g, 50% wet w / w), and the mixture was stirred at ambient temperature for 12 hours under a hydrogen atmosphere. The resulting solution was partitioned between 50% methanol / ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated in vacuo to provide 4-(((3R,4R)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (0.09 g, 93% yield): MS (ES) m / z 289.2 (M+H).

[0935] Step 4: Preparation of methyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (I): in: R1 is selected from -CO2R5, -C1~C5 alkyl-CO2R5, -C3~C6 cycloalkyl-CO2R5, -NHCO2R5, -N(C1~C5 alkyl)-CO2R5, -O-CO2R5, or -C1~C5 alkyl-O-CO2R5; R2 is selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally substituted with one or more groups selected from halogen elements, -OH, or -O-C1-C5 alkyl; n is 0, 1, or 2; Ring A is substituted at one or more carbons with one, two, or three R3 substituents, wherein each R3 group is independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, wherein each alkyl group or cycloalkyl group is optionally substituted with one or more groups selected from halogen, -OH, -C1-C5 alkylalkoxy, or -O-C1-C5 alkyl; The two R3 groups on the same carbon atom or different carbon atoms of the ring A can be optionally connected to form a spirocyclic ring system or a bicyclic ring system with the ring A; R4 is selected from -C(O)-R6, -CH2R6, -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR7R8, -C(O)-C1~C5 alkyl, or -C(O)-C3~C6 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from -OH, halogen elements, alkynes, or -CN; R5 is selected from -C1-C5 alkyl, or -C3-C6 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1-C5 alkyl; R6 is selected from -C1~C5 alkyl, -C3~C6 cycloalkyl, -C1~C5 alkyl-C3~C6 cycloalkyl, -NR7R8, -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group can be optionally substituted by one or more groups selected from halogen elements, -CN, alkynes, -OH, trifluoromethyl, -O-C1~C5 alkyl, or -O-C3~C6 cycloalkyl; R7 and R8 are independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, wherein the alkyl group can be optionally substituted with one or more groups selected from halogen elements, -OH, or -CN; and R7 and R8 can optionally be linked to form a ring to form a heterocyclic ring such as piperidine, pyrrolidine, or linked to another heteroatom to form a ring such as morpholine.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -CO2R5.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -C1~C5 alkyl-CO2R5.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -C3~C6 cycloalkyl-CO2R5.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -NHCO2R5.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -N(C1-C5 alkyl)-CO2R5.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -O-CO2R5.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R1 is -C1~C5 alkyl-O-CO2R5.

9. A compound of formula (II), or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (II): in: R 10 Selected from -CO2R 50 、-C1~C5 alkyl-CO2R 50 、-C3~C6 cycloalkyl-CO2R 50 、-NHCO2R 50 、-N(C1~C5 alkyl)-CO2R 50 、-O-CO2R 50 , or -C1~C5 alkyl-O-CO2R 50 ; R 20 Selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1-C5 alkyl; n is 0 or 1; Ring I is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30 The groups are independently selected from H, halogen elements, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 70 C(O)-CH=CH2、-NR 70 C(O)-C(CH2OCH3)=CH2、-NR 70 C(O)-CH=CHCH3, or -NR 70 C(O)-CH=CHCH2NR 80 R 90 , wherein each alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -OH, -C1~C5 alkylalkoxy, or -O-C1~C5 alkyl; Two R on the same carbon atom of ring I 30 Two or three R on different carbon atoms 30 The group can be optionally linked to form a spirocyclic, bicyclic or tricyclic ring system with Ring I, such as adamantyl; R 40 Selected from H, -OH, -C(O)-R 60 、-OR 60 、-OC(O)-R 60 、-NR 70 -C(O)-R 60 、-C1~C4 alkyl-C(O)-R 60 、-SO2-R 60 、-SO2-NR 80 R 90 、-C1~C4 alkyl-SO2-R 60 , or -C1~C4 alkyl-SO2NR 80 R 90 ; R 50 Selected from -C1~C5 alkyl, or -C3~C5 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1~C5 alkyl; R 60 Selected from -C1~C5 alkyl, -C3~C6 cycloalkyl or -C1~C5 alkyl-C3~C5 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -CN, alkyne, -OH, or -O-C1~C5 alkyl; R 70 Selected from H, -C1~C5 alkyl or -C3~C5 cycloalkyl; R 80 and R 90 independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, -C3-C6 cycloalkyl, wherein the alkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, or -CN; and R 80 and R 90 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine; Wherein the compound of formula (II) is not:

10. The compound according to claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 Yes-CO2R 50 ; R 20 Selected from H, -C1~C4 alkyl, -C3~C6 cycloalkyl, or -C1~C2 alkyl-C3~C6 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1~C5 alkyl.

11. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 Yes -C1~C5 alkyl -CO2R 50 .

12. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 It is -C3~C6 cycloalkyl-CO2R5.

13. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 Yes-NHCO2R 50 .

14. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 It is -N(C1~C5 alkyl)-CO2R 50 .

15. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 Yes-O-CO2R 50 .

16. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, wherein: R 10 Yes -C1~C5 alkyl-O-CO2R 50 .

17. A compound of formula (III), or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (III): in: R 1000 Selected from -CO2R 5000 、-C1~C5 alkyl-CO2R 5000 、-C3~C6 cycloalkyl-CO2R 5000 、-NHCO2R 5000 、-N(C1~C5 alkyl)-CO2R 5000 、-O-CO2R 5000 , or -C1~C5 alkyl-O-CO2R 5000 ; R 2000 Selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1-C5 alkyl; n is 0, 1, or 2; Ring Q is substituted at one or more carbons with one, two, or three R3 substituents, wherein each R 3000 The groups are independently selected from H, halogen, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, or -O-C1-C5 alkyl, wherein each alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen, -OH, -C1-C5 alkyl alkoxy, or -O-C1-C5 alkyl; The two R on the same carbon atom or different carbon atoms of the ring Q 3000 The group can be optionally linked to form a spirocyclic ring system or a bicyclic ring system with ring Q; R 4000 Selected from -C(O)-R 6000 、-CH2R 6000 , -C(O)-CH=CH2, -C(O)-C(CH2OCH3)=CH2, -C(O)-CH=CHCH3, -C(O)-CH=CHCH2NR7R8, -C(O)-C1~C5 alkyl, or -C(O)-C3~C6 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from -OH, halogen elements, alkynes, or -CN; R 5000 Selected from H, -C1~C5 alkyl, and -C3~C6 cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, -C3~C5 cycloalkyl, or -O-C1~C5 alkyl; R 6000 Selected from -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C5 alkyl-C3-C6 cycloalkyl, -NR 7000 R 8000 , -O-aryl, -O-heteroaryl, aryl, or heteroaryl, wherein the alkyl group, cycloalkyl group, aryl group, or heteroaryl group can be optionally substituted by one or more groups selected from halogen elements, -CN, alkynes, -OH, trifluoromethyl, -O-C1~C5 alkyl, or -O-C3~C6 cycloalkyl; R 7000 and R 8000 Independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C5 cycloalkyl, wherein the alkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, -CN, or -C3-C5 cycloalkyl; R 7000 and R 8000 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine.

18. A compound of formula (IV), or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (IV): in: R 10000 Selected from -CO2R 50000 、-C1~C5 alkyl-CO2R 50000 、-C3~C6 cycloalkyl-CO2R 50000 、-NHCO2R 50000 、-N(C1~C5 alkyl)-CO2R 50000 、-O-CO2R 50000 , or -C1~C5 alkyl-O-CO2R 50000 ; R 20000 Selected from H, -C1-C4 alkyl, -C3-C6 cycloalkyl, or -C1-C2 alkyl-C3-C6 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -OH, or -O-C1-C5 alkyl; n is 0 or 1; Ring S is substituted at one or more carbon atoms with one, two, or three R 30 Substituents, where each R 30000 The groups are independently selected from H, halogen elements, -C1-C4 alkyl, -C3-C6 cycloalkyl, -OH, -O-C1-C5 alkyl, -NR 70000 C(O)-CH=CH2、-NR 70000 C(O)-C(CH2OCH3)=CH2、-NR 70000 C(O)-CH=CHCH3, or -NR 70000 C(O)-CH=CHCH2NR 80000 R 90000 , wherein each alkyl group or cycloalkyl group is optionally substituted by one or more groups selected from halogen elements, -CN, -OH, -C1~C5 alkylalkoxy, or -O-C1~C5 alkyl; Two R on the same carbon atom of ring S 30000 Two or three R on different carbon atoms 30 The group can be optionally linked to form a spirocyclic ring system, a bicyclic ring system, or a tricyclic ring system with ring S, such as adamantyl; R 40000 Selected from H, -OH, -C(O)-R 60000 、-OR 60000 、-OC(O)-R 60000 、-NR 70000 -C(O)-R 60000 、-C1~C4 alkyl-C(O)-R 60000 、-SO2-R 60000 、-SO2-NR 80000 R 90000 、-C1~C4 alkyl-SO2-R 60000 , or -C1~C4 alkyl-SO2NR 80000 R 90000 ; R 50000 Selected from H, -C1~C5 alkyl, and -C3~C6 cycloalkyl, wherein the alkyl group or the cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -OH, -C3~C5 cycloalkyl, or -O-C1~C5 alkyl; R 60000 Selected from -C1~C5 alkyl, -C3~C6 cycloalkyl or -C1~C5 alkyl-C3~C6 cycloalkyl, wherein the alkyl group or cycloalkyl group can be optionally substituted by one or more groups selected from halogen elements, -CN, alkyne, -OH, or -O-C1~C5 alkyl; R 70000 Selected from H, -C1-C5 alkyl or -C3-C6 cycloalkyl; R 80000 and R 90000 independently selected from H, -C1-C5 alkyl, -C1-C5 alkoxy, or -C3-C6 cycloalkyl, wherein the alkyl group can be optionally substituted with one or more groups selected from halogen elements, -OH, or -CN; and R 80000 and R 90000 Can optionally be linked into rings to form heterocycles such as piperidine, pyrrolidine, or linked to additional heteroatoms to form rings such as morpholine. wherein the compound of formula (IV) is not 19. The compound of claim 1, wherein the compound is selected from the group consisting of:

20. The compound of claim 9, wherein the compound is selected from the group consisting of:

21. The compound of claim 17, wherein the compound is selected from the group consisting of:

22. The compound of claim 18, wherein the compound is selected from the group consisting of:

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 22, a pharmaceutically acceptable salt of the compound, a derivative of the compound, or a combination thereof; and a pharmaceutically acceptable carrier.

24. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 22, a derivative of the compound, or a combination thereof in the manufacture of a medicament for treating a JAK1 and / or JAK3-mediated disease in a subject in need thereof.

25. The use of claim 24, wherein the treatment further comprises administering an additional therapeutic agent.

26. The use of claim 24, wherein the JAK1 and / or JAK3 mediated disease is selected from the group consisting of: autoimmune disorders or autoimmune responses, generalized activation of immune responses, bacterial infections, viral infections, inflammation, chronic and / or acute inflammatory disorders or conditions, and / or autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, cardiovascular disorders, cerebrovascular disorders, skin disorders, pruritus, hair loss disorders, cancer or malignancy, autoimmune connective tissue diseases, autoimmune conditions; Still's disease, adult-onset Still's disease, Th17-related inflammation, polychondritis (e.g., relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; Myasthenia gravis; Arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, arthritis associated with inflammatory bowel disease, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis / spondyloarthritis / spondyloarthropathies (ankylosing spondylitis), gout, scleroderma (systemic sclerosis, juvenile sclerosis), Reiter syndrome / reactive arthritis, Lyme disease, lupus / systemic lupus erythematosus (SLE) (lupus erythematosus, juvenile SLE, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus / discoid lupus, chilblain lupus erythematosus)), Polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesitis, carditis, myocarditis, angiogenic disorders, myelodysplastic syndrome, atherosclerosis, restenosis (atherosclerotic coronary artery restenosis), acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, transplant artery disease; vasculitis (large vessel vasculitis, small vessel vasculitis, giant cell arteritis, polyarteritis nodosa, vasculitis syndrome, the vasculitis syndrome includes Takayasu arteritis, Wegener's granulomatosis, Behcet's disease), stimulator of interferon genes (STING)-associated vasculopathy of infancy (SAVI); gastrointestinal disorders, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis acute pancreatitis and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (e.g., primary biliary cirrhosis, or cirrhosis due to fatty liver disease (e.g., alcoholic and nonalcoholic steatosis)); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; kidney disease, immune-mediated glomerulonephropathy, autoimmune kidney disease, membranous glomerulopathy, chronic progressive kidney disease, diabetic kidney disease / diabetic nephropathy, renal fibrosis, renal ischemia / reperfusion injury, HIV-related nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, Nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; lung inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease;Ocular disorders, including, for example, ocular inflammation, uveitis, dry eyes / keratoconjunctivitis sicca, scleritis, episcleritis, keratitis / keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy (diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration); mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mastocytosis (SM CD), myelodysplastic syndrome, idiopathic thrombocytopenic purpura; bone resorption diseases; neurodegenerative disorders, neurological disorders / neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Langer-Evans myasthenic syndrome (LEMS), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury; nervous system damage, delusional parasitosis, neuronal Dysregulation of processes and sensory perception, stroke / neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disorders; paresthesia pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia), nerve irritation, peripheral neuropathy; pruritus / itch (atopic pruritus, dry pruritus, itch associated with psoriasis / psoriatic itch / psoriatic itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary related Sexual pruritus, kidney-related pruritus / renal pruritus, uremic pruritus, cholestasis, intrahepatic cholestasis of pregnancy, pruritus associated with chronic simple lichen, lymphoma-related pruritus, leukemia-related pruritus, nodular pruritus, atopic dermatitis-related pruritus, atopic pruritus / atopic pruritus, bullous pruritus, brachioradialis pruritus, neurogenic pruritus, neuropathic pruritus, paresthesia back pain, HIV-related pruritic papules, psychogenic pruritus, swimmer's itch, pruritus or uremic pruritus, urticarial pruritus;Skin Diseases (e.g.), Skin Diseases Drug Reactions / Drug Rash, Xerosis / Dry Skin, Rash, Skin Sensitization, Skin Irritation, Sunburn, Shaving, Body Lice, Head Lice / Penicillosis, Pubic Lice, Cutaneous Larva Migrans, Scabies, Parasitic Infestations, Insect Infestations, Urticaria / Hives, Urticaria Papularis, Insect Bites, Insect Stings, Dandruff, Foreign Objects or Devices on the Skin, Fungal Infections, Herpes, Varicella / Chickenpox, Eosinophilic Folliculitis, Pregnancy Dermatosis / Pruritic Urticarial Papules and Plaques of Pregnancy (PUPP), Inflammatory Dermatosis, Neutrophilic Dermatosis, Histiocytic Neutrophilic Dermatosis, Intestinal Bypass Syndrome Dermatosis, Psoriasis / Psoriasis Vulgaris, Lichen Planus, Lichen Sclerosus Atrophicus, Acne (Acne Vulgaris, Pityriasis ... Acne thornis, inflammatory acne, nodulocystic acne, acne scar, keloid acne on the neck), atopy (allergic contact sensitization, allergic dermatitis), dermatitis (atopic dermatitis / eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis), acute febrile neutrophilic dermatosis (Sweet syndrome), chronic atypical neutrophilic and lipodystrophy dermatosis and hyperthermia syndrome (CANDLE syndrome), suppurative hidradenitis, urticaria, gangrenosum pyoderma, hair loss (eyebrow loss, nasal hair loss, scarring alopecia (central centrifugal scarring alopecia), non-scarring alopecia (alopecia areata (AA) (plaque AA, alopecia totalis (AT), alopecia universalis (AU), serpentine Alopecia areata, horseshoe-shaped alopecia areata), androgen-derived / androgenic alopecia (AGA) / male and female type AGA), telogen effluvium, tinea capitis, hypotrichosis (simple hereditary hypotrichosis), lichen planus pilaris (frontal fibrosing alopecia), palmoplantar keratoderma punctatus, erythema erythematosus (EED), neutrophilic exocrine hidradenitis, palisade neutrophilic granulomatous dermatitis, neutrophilic urticaria skin disease, vitiligo, the vitiligo includes segmental vitiligo (single segmental vitiligo, two segmental vitiligo, multi-segmental vitiligo), non-segmental vitiligo (acral vitiligo, facial vitiligo, or acrofacial vitiligo, central facial vitiligo, mucosal vitiligo, paper-like vitiligo, tricolor vitiligo , marginal inflammatory vitiligo, tetrachromatic vitiligo, blue vitiligo, Kebner phenomenon, vitiligo vulgaris, generalized vitiligo, universal vitiligo), mixed vitiligo / non-segmental vitiligo with segmental vitiligo, localized vitiligo, isolated mucosal vitiligo, or vitiligo with or without white hair (body hair involvement); bullous diseases, immune bullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), pemphigoid gestationis, xeroderma pigmentosum; fibrotic and scarring disorders: fibromas, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low-grade scarring such as scleroderma, increased fibrosis, keloids, postoperative scars;Wound healing, surgical scarring, radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), central nervous system scarring, digestive or gastrointestinal fibrosis, renal fibrosis, liver fibrosis or bile duct fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis / Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, cold pyrine-associated periodic syndrome (MERS) -Wei syndrome, familial cold autoinflammatory syndrome / familial cold urticaria / TNF receptor-associated periodic syndrome, neonatal-onset multisystem inflammatory disease), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue damage, hyperthermia syndrome; diabetes (type I diabetes, type II diabetes) / diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid resistance, glucose intolerance, metabolic syndrome, thyroid disease, hypophysitis; systemic immunosenescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis , Goodpasture's disease, Sjögren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematological manifestations of autoimmune diseases (e.g., anemia), autoimmune hemolytic syndrome (autoimmune hemolytic anemia), autoimmune hepatitis and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant-related autoimmune diseases, drug-induced autoimmunity, HIV-related autoimmune syndrome, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergic reactions and allergic reactions, including hypersensitivity reactions, such as type I hypersensitivity reactions (e.g., including anaphylaxis), type II hypersensitivity reactions ( e.g., Goodpasture's disease, autoimmune hemolytic anemia), type III hypersensitivity disorders (e.g., Arthus reaction, serum sickness), and type IV hypersensitivity reactions (e.g., contact dermatitis, allograft rejection); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome); acute and chronic infections, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, Gram-positive sepsis, fungal sepsis, toxic shock syndrome);Rejection: Graft-versus-host reaction / graft-versus-host disease, allogeneic transplant rejection (e.g., acute allogeneic transplant rejection or chronic allogeneic transplant rejection), early transplant rejection; Malignancies, cancers, lymphomas, leukemias, multiple myeloma, solid tumors, teratomas, metastatic disorders and bone disorders, internal cancers, bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, stomach cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer (liver cancer), pancreatic cancer, nerve cancer, brain cancer ( For example, gliomas, glioblastoma multiforme, astrocytomas, neuroblastomas, and schwannomas), head and neck cancer, pharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer (kidney cancer), breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, eye cancer (ocular malignancies), and skin cancer (melanoma, keratoacanthoma); as well as fibrotic cancers, fibromas, fibroadenomas, fibrosarcomas, myeloproliferative disorders, neoplasms (hematopoietic neoplasms, spinal cord neoplasms, lymphoid neoplasms ( Myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemia (acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphoma Tumors (Hodgkin's disease, cutaneous lymphoma (cutaneous T-cell lymphoma, mycosis fungoides)), lymphomas (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, follicular thyroid carcinoma; increased accumulation of exogenous opioids or synthetic opioids, paresthesia back pain, obsessive-compulsive disorder, homesickness associated with obsessive-compulsive disorder, and combinations thereof. ; 27. The use of claim 25, wherein the additional therapeutic agent is selected from the group consisting of chemotherapeutic agents, antiproliferative agents, anti-inflammatory agents, immunomodulators, immunosuppressants, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, agents for treating immunodeficiency disorders, and combinations thereof.

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