TW202021977A - Prodrugs of jak inhibitor containing glucosidic acid derivatives, their preparation method and application thereof - Google Patents

Abstract

The invention relates to prodrugs of JAK inhibitor containing Glucosidic acid derivatives, their preparation method and application thereof. The present invention provides compounds of general formula (I) and their pharmaceutical compositions as the prodrugs of JAK inhibitor, methods for treating inflammatory diseases and cancer diseases using the compounds, and the methods for preparing the compounds and the intermediates thereof. The definitions of substituents in the general formula (I) are the same as those in the specification.

Description

Prodrug containing glucuronide derivative JAK inhibitor and preparation method and application thereof

The invention belongs to the field of drug synthesis, and specifically relates to a prodrug containing a glucuronide derivative JAK inhibitor, and a preparation method and application thereof.

Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3 and TYK2. Each subtype mediates different types of cytokine signaling pathways. JAK-1, JAK-2 and TYK-2 are found in all tissues and cells of the human body. Expression, JAK-3 is mainly expressed in hematopoietic tissue cells. The common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK. When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and the receptor is phosphorylated. The phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, so that STAT is Recruited to the receptor and phosphorylated by JAKs, then phosphotyrosine mediates STAT two By polymerization, the activated STAT dimer transfers to the nucleus and activates the transcription of its target genes, thereby regulating the growth, activation, differentiation and other functions of a variety of cells.

JAK/STAT signal pathway mediates the signal transduction of most cytokines in cells, and plays a key role in the biological processes of immune regulation and immune cell proliferation. The JAK/STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. It is related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease. (Ulcerative colitis and Crohn’s disease) are closely related; at the same time, the JAK/STAT signaling pathway is closely related to tumorous diseases such as myelofibrosis, polycythemia vera and essential thrombocythemia, and mutations in the JAK molecule itself It can also lead to neoplastic diseases such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC).

Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis and Crohn's disease. At present, the main drugs for the treatment of inflammatory bowel disease are aminosalicylic acid preparations, glucocorticoids, immunosuppressants, antibiotics and so on. The main principle of UC treatment is to regulate the immune response and inhibit inflammation. At present, in clinical practice, sulfasalazine is mainly used to treat mild to moderate UC. The currently commonly used drugs for moderate to severe UC include glucocorticoids, but because the risks outweigh the benefits, they will not be used as long-term treatments. Monoclonal antibodies have problems with drugs, which are expensive, the production of drug antibodies affects the safety and effectiveness of drugs, and the way of intravenous administration is not convenient. There are still far unmet medical needs in this field. Many patients receiving treatment have not yet been relieved, and up to 80% of Crohn's disease patients and 30% of UC patients will eventually need surgery.

Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of adult patients with moderately to severely active UC. It has significant inhibitory activity against JAK1, 2, and 3 subtypes, and its JAK2/JAK3 selectivity Only 20 times. The activity of JAK1 and JAK2 increases tofacitinib However, it also brings more serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage and cholesterol increase. Tofacitinib (Tofacitinib) is listed on the back of many black boxes: serious infection (tuberculosis, bacteria, fungi, virus) and malignant tumors (lymphoma, etc.). As JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of the above-mentioned adverse reactions are considered to be related to the insufficient selectivity of Tofacitinib to JAK-3, which is caused by the non-selective inhibition of the drug. The JAK inhibitors currently on the market and under research mainly compete for the binding of the kinase domain and ADP, so there is a general problem of low selectivity, even for selective inhibitors of a certain subtype of JAK. Target-related side effects.

Due to the good efficacy of JAK inhibitors and the serious side effects associated with multiple targets, the development of a safer JAK inhibitor drug has become an urgent problem to be solved. Since inflammatory bowel disease occurs on the surface of the intestinal lumen of the gastrointestinal tract, it does not require drugs to enter the blood system to function. Therefore, the development of a method to reduce the systemic exposure of drugs in the blood circulation and increase the local exposure of drugs in the inflammation Medicine becomes a good strategy to improve safety. International application WO2017091544(A1) reported that Theravance company obtained its prodrug related compounds by modifying tofacitinib. This class of compounds showed good tissue distribution selectivity, reflecting the feasibility of this strategy, and Significant clinical application value.

其中：M、M₁或M₂為O、S或NH；L為鍵、-C(=O)-或-C(=O)NR₂(CH₂)_xNR₃C(=O)-；G為JAK抑制劑，選自托法替尼(Tofacitinib)、魯索替尼(Ruxolitinib)、巴瑞替尼(Baricitinib)、匹伏替尼(Peficitinib)、帕克替尼(Pacritinib)、得格替尼(Delgocitinib)、Pf-04965842、烏帕替尼(Upadacitinib)、菲格替尼(Filgotinib)、伊他替尼(Itacitinib)、菲得替尼(Fedratinib)、達沙替尼(Decernotinib)、SHR-0302、得格替尼(Delgocitinib)、ASN-002、塞度替尼(Cerdulatinib)、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、氘修飾魯索替尼類似物(Deuterium-modified ruxolitinib analog)、ATI-501、R-348、R-348、NS-018、SHR0302、杰克替尼鹽酸鹽(Jaktinib hydrochloride)、杰克替尼鹽酸鹽(Jaktinib hydrochloride)或KL-130008；R為-CH₂OH或-COOPg；R₁選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氘、烷基、鹵烷基、鹵素、胺基、側氧基、硫基、硝 基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代；R₂和R₃各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、巰基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基；Pg為氫或羧基保護基，當Pg為羧基保護基時，選自-DMB、-Bn、-Allyl、-PfP、-Me、-PMB、-EM或t-Boc；Pg₁、Pg₂和Pg₃為氫或羥基保護基，當Pg₁、Pg₂和Pg₃為羥基保護基時，各自獨立的選自-CH₃、-C(CH₃)₃、-CPh₃、-CH₂Ph、-CH₂OCH₃、-Si(CH₃)₃、-THP、-SiMe₂(t-Bu)、-Ac或-COPh；n為0、1、2、3或4；且x為0、1、2或3。 The object of the present invention is to provide a compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:

Wherein: M, M ₁ or M ₂ is O, S or NH; L is a bond, -C(=O)- or -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-; G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, and Degerti Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR -0302, Delgocitinib, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, deuterium modified Lu Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride hydrochloride) or KL-130008; R is -CH ₂ OH or -COOPg; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine , Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl The oxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, thio, One or more substituents in nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution; R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, mercapto, nitro, hydroxyl, cyanide Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Pg is a hydrogen or carboxy protecting group, when Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl, -PfP, -Me, -PMB, -EM or t-Boc; Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups, when Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independently selected From -CH ₃ , -C(CH ₃ ) ₃ , -CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si(CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh; n is 0, 1, 2, 3 or 4; And x is 0, 1, 2, or 3.

其中：M為O、S或NH；L為鍵、-C(=O)-或-C(=O)NR₂(CH₂)_xNR₃C(=O)-； G為JAK抑制劑，選自托法替尼(Tofacitinib)、魯索替尼(Ruxolitinib)、巴瑞替尼(Baricitinib)、匹伏替尼(Peficitinib)、帕克替尼(Pacritinib)、得格替尼(Delgocitinib)、Pf-04965842、烏帕替尼(Upadacitinib)、菲格替尼(Filgotinib)、伊他替尼(Itacitinib)、菲得替尼(Fedratinib)、達沙替尼(Decernotinib)、SHR-0302、得格替尼(Delgocitinib)、ASN-002、塞度替尼(Cerdulatinib)、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、氘修飾魯索替尼類似物(Deuterium-modified ruxolitinib analog)、ATI-501、R-348、R-348、NS-018、SHR0302、杰克替尼鹽酸鹽(Jaktinib hydrochloride)、杰克替尼鹽酸鹽(Jaktinib hydrochloride)或KL-130008；較佳SHR-0302；R為-CH₂OH或-COOPg R₁選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氘、烷基、鹵烷基、鹵素、胺基、側氧基、硫基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代；R₂和R₃各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、巰基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基；Pg為氫或羧基保護基，當Pg為羧基保護基時，選自-DMB(2,4-二甲氧基苄基)、-Bn(苄基)、-Allyl(烯丙基)、-PfP(五氟苯基)、-Me(甲基)、-PMB(對甲基苄基)、-EME(甲氧乙氧甲基)或t-Boc(第三丁氧羰基)；Pg₁、Pg₂和Pg₃為氫或羥基保護基，當Pg₁、Pg₂和Pg₃為羥基保護基時，各自獨立的選自-CH₃(甲基)、-C(CH₃)₃(第三丁基)、-CPh₃(三苯基)、-CH₂Ph(苄醚基)、 -CH₂OCH₃(甲氧基甲基)、-Si(CH₃)₃(三甲基矽基)、-THP(四氫呋喃基)、-SiMe₂(t-Bu)(第三丁基二甲矽基)、-Ac(乙醯基)或-COPh(苯甲醯基)；n為0、1、2、3或4的整數；且x為0、1、2或3的整數；當M為O，Pg₁、Pg₂和Pg₃為氫，R為-COOPg，Pg為氫，R₁選自氫、胺 基、硝基、鹵素、甲基或甲氧基，R₁位於的

鄰位，L為-C(=O)NR₂(CH₂)_xNR₃C(=O)-，R₂和R₃同時選自甲基，且x為1時，G不為托法替尼(Tofacitinib)；當M為O，Pg₁、Pg₂和Pg₃為氫，R為-COOPg，Pg為氫，R₁為硝基，R₁ 位於的

鄰位，L為-C(=O)NR₂(CH₂)_xNR₃C(=O)-，R₂和R₃同時選自甲基，且x為1時，G不為魯索替尼(Ruxolitinib)或巴瑞替尼(Baricitinib)。 The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:

Among them: M is O, S or NH; L is a bond, -C(=O)- or -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-; G is a JAK inhibitor, Selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf -04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Degetinib Delgocitinib, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified Ruxolinib analogues ( Deuterium-modified ruxolitinib analog), ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride (Jaktinib hydrochloride) or KL-130008 ; Preferably SHR-0302; R is -CH ₂ OH or -COOPg R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy Group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium, alkyl group, haloalkyl group, halogen, amine group, pendant oxy group, thio group, nitro group Substituted by one or more substituents in the group, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl ; R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, mercapto, nitro, hydroxyl, cyano , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Pg is a hydrogen or carboxy protecting group, when Pg is a carboxy protecting group, it is selected from -DMB(2,4-Dimethoxy Benzyl), -Bn (benzyl), -Allyl (allyl), -PfP (pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME (form Oxyethoxymethyl) or t-Boc (third butoxycarbonyl); Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protected When Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, they are each independently selected from -CH ₃ (methyl), -C(CH ₃ ) ₃ (tertiary butyl), -CPh ₃ (triphenyl Group), -CH ₂ Ph (benzyl ether group), -CH ₂ OCH ₃ (methoxymethyl), -Si(CH ₃ ) ₃ (trimethylsilyl), -THP (tetrahydrofuranyl), -SiMe ₂ (t-Bu) (tertiary butyldimethylsilyl), -Ac (acetyl) or -COPh (benzyl); n is an integer of 0, 1, 2, 3 or 4; and x Is an integer of 0, ₁ , 2 or 3; when M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, and R _{1 is} selected from hydrogen, amino, nitro, halogen, Methyl or methoxy, where R ₁ is located

Ortho position, L is -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-, R ₂ and R _{3 are} both selected from methyl, and when x is 1, G is not tofat Ni (Tofacitinib); when M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R ₁ is nitro, and R ₁ is located at

Ortho position, L is -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-, R ₂ and R _{3 are} both selected from methyl, and when x is 1, G is not Ruxote Ni (Ruxolitinib) or Baricitinib (Baricitinib).

The present invention also relates to a preferred solution. The compound represented by the general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (II) :

Wherein: M, G, R~R ₃ , Pg ₁ to Pg ₃ , n and x are as described in general formula (I).

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (IIA) :

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (III) :

Wherein: M, G, R, R ₁ , Pg ₁ to Pg ₃ and n are as described in general formula (I).

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (IV) :

Wherein: G, R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x are as described in general formula (I).

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomers or pharmaceutically acceptable salts thereof is characterized in that it is further represented by general formula (V) :

Wherein: M, G, R, R ₁ and Pg ₁ to Pg _{3 are} as described in general formula (I).

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (VI) :

Wherein: R, R ₁ to R ₃ , Pg ₁ to Pg ₃ and x are as described in general formula (I).

The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (VII) :

Wherein: R ₁ to R ₃ and x are as described in general formula (I).

其中：R為-CH₂OH或-COOH；G選自托法替尼(Tofacitinib)或SHR-0302；R₁選自氫、鹵素、氰基、硝基、胺基、C_1-6烷基、C_1-6鹵烷基、C_1-6烷氧基或C_1-6鹵烷氧基，較佳氫、鹵素、氰基、硝基、胺基、C_1-3烷基、C_1-3鹵烷基、C_1-3烷氧基或C_1-3鹵烷氧基；更佳氫、氟、氯、氰基、硝基、胺基、甲基、甲氧基或三氟甲基；x選自0、1、2或3的整數，較佳1；且，當x為1，G為托法替尼(Tofacitinib)且R₁選自硝基時，R為-CH₂OH。 The present invention also relates to a preferred solution. The compound represented by general formula (IA) or (I), its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (VIII) :

Wherein: R is -CH ₂ OH or -COOH; G is selected from Tofacitinib or SHR-0302; R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, preferably hydrogen, halogen, cyano, nitro, amino, C _1-3 alkyl, C _{1 -3} haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy; more preferably hydrogen, fluorine, chlorine, cyano, nitro, amino, methyl, methoxy or trifluoromethyl Group; x is selected from an integer of 0, 1, 2 or 3, preferably 1; and, when x is 1, G is Tofacitinib and R _{1 is} selected from a nitro group, R is -CH ₂ OH .

其中：R₁~R₃和x如通式(I)所述。 The present invention also relates to a preferred solution. The compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are characterized in that they are further represented by general formula (IX):

Wherein: R ₁ to R ₃ and x are as described in general formula (I).

其中：M₁為O、S或NH；L₁為鍵、-C(=O)-或-C(=O)NR₂(CH₂)_xNR₃C(=O)-；G₁為JAK抑制劑，選自托法替尼(Tofacitinib)、魯索替尼(Ruxolitinib)、巴瑞替尼(Baricitinib)、匹伏替尼(Peficitinib)、帕克替尼(Pacritinib)、得格替尼(Delgocitinib)、Pf-04965842、烏帕替尼(Upadacitinib)、菲格替尼(Filgotinib)、伊他替尼(Itacitinib)、菲得替尼(Fedratinib)、達沙替尼(Decernotinib)、SHR-0302、得格 替尼(Delgocitinib)、ASN-002、塞度替尼(Cerdulatinib)、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、氘修飾魯索替尼類似物(Deuterium-modified ruxolitinib analog)、ATI-501、R-348、R-348、NS-018、SHR0302、杰克替尼鹽酸鹽(Jaktinib hydrochloride)、杰克替尼鹽酸鹽(Jaktinib hydrochloride)或KL-130008；R’為-CH₂OH或-COOPg；R₁’選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氘、烷基、鹵烷基、鹵素、胺基、側氧基、硫基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代；R₂和R₃各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、巰基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基；Pg’為氫或羧基保護基，當Pg為羧基保護基時，選自-DMB(2,4-二甲氧基苄基)、-Bn(苄基)、-Allyl(烯丙基)、-PfP(五氟苯基)、-Me(甲基)、-PMB(對甲基苄基)、-EME(甲氧乙氧甲基)或t-Boc(第三丁氧羰基)；Pg₁’、Pg₂’和Pg₃’為氫或羥基保護基，當Pg₁、Pg₂和Pg₃為羥基保護基時，各自獨立的選自-CH₃(甲基)、-C(CH₃)₃(第三丁基)、-CPh₃(三苯基)、-CH₂Ph(苄醚基)、-CH₂OCH₃(甲氧基甲基)、-Si(CH₃)₃(三甲基矽基)、-THP(四氫呋喃基)、-SiMe₂(t-Bu)(第三丁基二甲矽基)、-Ac(乙醯基)或-COPh(苯甲醯基)；n1為0、1、2、3或4的整數；且x為0、1、2或3的整數。 The present invention also relates to a compound represented by general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof:

Among them: M ₁ is O, S or NH; L ₁ is a bond, -C(=O)- or -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-; G ₁ is JAK Inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib ), Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Delgocitinib, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified Ruxolinib Analog (Deuterium-modified ruxolitinib analog), ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride (Jaktinib hydrochloride), Jaktinib hydrochloride (Jaktinib hydrochloride) or KL-130008; R'is -CH ₂ OH or -COOPg; R ₁ 'is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy Group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium, alkyl group, haloalkyl group, halogen, amine group, pendant oxy group, thio group, nitro group Substituted by one or more substituents in the group, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl ; R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, mercapto, nitro, hydroxyl, cyano , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Pg' is a hydrogen or carboxy protecting group, when Pg is a carboxy protecting group, it is selected from -DMB(2,4-dimethyl Oxybenzyl), -Bn (benzyl), -Allyl (allyl), -PfP (pentafluorophenyl), -Me (methyl), -PMB (p-methylbenzyl), -EME ( Methoxyethoxymethyl) or t-Boc (third butoxycarbonyl); Pg ₁ ', Pg ₂ 'and Pg ₃ ' are hydrogen or hydroxyl When Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, they are each independently selected from -CH ₃ (methyl), -C(CH ₃ ) ₃ (tertiary butyl), -CPh ₃ ( Triphenyl), -CH ₂ Ph (benzyl ether group), -CH ₂ OCH ₃ (methoxymethyl), -Si(CH ₃ ) ₃ (trimethylsilyl), -THP (tetrahydrofuranyl), -SiMe ₂ (t-Bu) (tertiary butyl dimethylsilyl), -Ac (acetyl) or -COPh (benzyl); n1 is an integer of 0, 1, 2, 3 or 4; And x is an integer of 0, 1, 2 or 3.

The present invention also relates to a preferred solution. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the G is selected from the following JAK inhibitors:

，托法替尼(Tofacitinib)為

Among them, SHR0302 is

, Tofacitinib is

The present invention also relates to a preferred solution, any one of the compound, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R _{1 is} selected from hydrogen, halogen, cyano, nitro, amine Group, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy; R ₂ and R ₃ are each independently selected from C _1-6 alkyl Or C _1-6 haloalkyl.

The present invention also relates to a method for preparing the compound represented by the general formula (VII) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:

General formula (VII-1) is deprotected to obtain the compound represented by general formula (VII) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: rings R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x is as described in general formula (I).

The present invention also relates to a method for preparing the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps:

The general formula (VI-1) reacts with the general formula (VII-2) to obtain the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: ring R ₁ ~R ₃ , R , Pg ₁ ~Pg ₃ and x are as described in general formula (I).

The present invention also relates to a method for preparing the compound represented by the general formula (VI-2) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:

SHR-0302 reacts with general formula (IX) to obtain the compound represented by general formula (VI-2) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: X is selected from halogen.

The present invention also relates to a method for preparing a compound represented by general formula (VII) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

The present invention also relates to a method for preparing the compound represented by general formula (IX) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

The present invention also relates to a pharmaceutical composition, which comprises a compound of general formula (I) shown in any one of the therapeutically effective doses, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable Carrier, diluent or excipient.

The present invention also relates to the application of the compound of general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of JAK inhibitor drugs, the application comprising JAK inhibitor The agent contains a glucuronide prodrug, which releases JAK inhibitors, preferably JAK1, JAK2, and JAK3 inhibitors, by β -glucuronidase cleavage in the application.

The present invention also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of a drug containing a glucuronide derivative JAK inhibitor prodrug In the application.

The present invention also relates to the application of the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of drugs related to the treatment of inflammatory diseases and tumor diseases.

The present invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which include administering a therapeutically effective dose of a pharmaceutical composition to a patient.

The above-mentioned inflammatory diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the neoplastic diseases are selected from myelofibrosis, polycythemia vera Syndrome and essential thrombocythemia, myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC), among which gastrointestinal inflammatory diseases are chronic intestinal inflammatory diseases , And ulcerative colitis and Crohn's disease are further preferred.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons An alkyl group having 1 to 3 carbon atoms is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy or carboxylate, the The preferred invention is methyl, ethyl, isopropyl, tertiary butyl, haloalkyl, deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH ₂ -, "ethylene" means -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ -, etc. The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Cycloalkyl groups, cyclooctyl groups, etc.; polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, and more preferably ring Propyl.

也包含單螺環烷基與雜環烷基共用螺原子的螺環烷基，非限制性實例包括：

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members. It may contain one or more double bonds, but none of the rings have complete conjugation. Π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

It also contains a spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom, non-limiting examples include:

和

。 The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-member/5-member or 5-member/6-member bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

with

.

The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydro Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl , Piperazinyl and pyranyl. More preferably oxetanyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups by single bonds, or Any two or more atoms on the ring are further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 3 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 3 members/5 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 members/5 members, 4 members/5 members or 5 members/6 members Member bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

和

等。 The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

with

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazole Group, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, Thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkane Group, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , Carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), where the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , Mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl Or carboxylate group.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to -NH ₂ .

"Cyano" refers to -CN.

"Nitro" refers to -NO ₂ .

"Carboxy" refers to -C(O)OH.

"THF" means tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" means methanol.

"DCM" means dichloromethane.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" means diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" means acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

"Et ₂ O" means diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ "refers to tris(dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"N-BuLi" means n-butyl lithium.

"NaBH(OAc) ₃ "refers to sodium triacetoxyborohydride.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.

The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Stereoisomerism" includes geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

"As needed" or "as needed" means that the event or environment described later can but need not occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration of the biological body, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

[Example]

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The measurement of NMR was carried out by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methyl Silane (TMS).

The liquid mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

Example 1 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy Group) Tetrahydro-2H-pyran-2-carboxylic acid

The first step: (2S,3R,4S,5S,6S)-2-(4-methanyl-2-nitrophenoxy)-6-(carbomethoxy)tetrahydro-2H-pyran-3 Preparation of ,4,5-triyltriacetate

To (2R,3R,4S,5S,6S)-2-bromo-6-(carbomethoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (12.5g, 31.5mmol Add 4-hydroxy-3-nitrobenzene(form)aldehyde (5.16g, 30.9mmol), Ag ₂ O (9.30g, 40.1mmol) to the acetonitrile solution (200mL) in sequence, then stir at room temperature in the dark overnight. The insoluble matter was removed by filtration with Celite, the filtrate was concentrated, and column chromatography (EA:PE from 0 to 1:1) was used to obtain 11.8 g of the title compound as a pale yellow solid, with a yield of 79%.

¹ H NMR(400MHz,CDCl ₃ ): δ 2.05(s,3H), 2.08(s,3H), 2.14(s,3H), 3.71(s,3H), 4.32(d, J =8.0Hz,1H) ,5.28-5.45(m,4H),7.51(d, J =8.0Hz,1H), 8.10(d, J =8.0Hz,1H), 8.32(s,1H), 9.98(s,1H).

The second step: (2S, 3R, 4S, 5S, 6S)-2-(4-(hydroxymethyl)-2-nitrophenoxy)-6-(carbomethoxy)tetrahydro-2H-pyran -3,4,5-triyl triacetate preparation

At 0℃, to (2S,3R,4S,5S,6S)-2-(4-methanyl-2-nitrophenoxy)-6-(carbomethoxy)tetrahydro-2H-pyran- To a mixed solution of 3,4,5-triyltriacetate (11.7g, 24.2mmol) in DCM (110mL) and isopropanol (22mL), NaBH ₄ (550mg, 14.5mmol) was added in three batches, and then Continue stirring at this temperature for 90 minutes. Add ice water to separate the organic phase. The aqueous phase was extracted twice with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain the title compound 8.0 g, yield: 68%.

¹ H NMR (400MHz, CDCl ₃ ): δ 2.04 (s, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.75 (s, 3H), 4.20 (d, J = 8.0 Hz, 1H) ,4.72(s,2H),5.19-5.38(m,4H),7.37(d, J =8.0Hz,1H),7.75(dd, J =8.0,2.0Hz,1H),7.81(d, J =2.0 Hz, 1H).

The third step: (2S,3S,4S,5R,6S)-2-(methylamino)-6-(4-((((2-(methylamino)ethyl)aminomethyl)oxy (Phenyl)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate preparation

Under ice water bath, go to (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-2-nitrophenoxy)-6-(carbomethoxy)tetrahydro-2H-pyridine N,N'-carbonyldiimidazole ( CDI ) (1.08g, 6.70mmol) was added to the DCM solution (30mL) of pyran-3,4,5-triyltriacetate (2.5g, 5.15mmol), and then After stirring for 3 hours at room temperature, the reaction was completed as monitored by TLC.

In another round-bottom flask, add N ₁ , N ₂ -dimethylethane-1,2-diamine (1.58g, 18.0mmol), DCM (20mL), under ice-water bath, while stirring, slowly add dropwise Acetic acid (1.08g, 18.0mmol), then slowly added dropwise to the reaction solution of the intermediate in the previous step. After the addition is complete, stir at room temperature for 3 hours. Add ice water to separate the organic phase, dry the organic phase and place it in a refrigerator at 0-4°C for later use.

MS m/z(ESI): 600.2[M+H] ⁺ .

The fourth step: (2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy- 1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H- (Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy)-6- (Carbomethoxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate preparation

Under ice water bath, add (3aR,5s,6aS)-N-(3-methoxy-1,2,4 to the acetonitrile solution (7mL) of p-nitrophenyl chloroformate (190mg, 0.94mmol) -Thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2( 1H)-formamide (320mg, 0.772mmol), then slowly added DIPEA (0.181mL, 1.10mmol) dropwise, after the addition, slowly warmed to room temperature, and stirred at room temperature for 4 hours. Then after cooling with an ice water bath, slowly add dropwise (2S,3S,4S,5R,6S)-2-(methylamino)-6-(4-(((((2-(methylamino)ethyl) (Aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate in DCM (7.4mL, about 0.772mmol ). After the addition is complete, Slowly rise to room temperature and continue stirring at room temperature for 1 hour. It was quenched with acetic acid, water and DCM were added to separate the organic phase, the organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography was used to obtain 290 mg of the title compound. Yield: 36%.

MS m/z(ESI): 1040.3[M+H] ⁺ .

Step 5: (2S,3S,4S,5R,6S)-3,4,5-Trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2 -((3-Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino )-N-Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethano)oxy)methyl)-2- (Nitrophenoxy) tetrahydro-2H-pyran-2-carboxylic acid preparation

Under ice water bath, go to (2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H -Pyrrolo[2,3-d]pyrimidine-7-carboweed (amino)ethyl)(methyl)aminomethano)oxy)methyl)-2-nitrophenoxy)-6 -(Carbomethoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (50mg, 0.048mmol) in THF (2mL) was added dropwise LiOH aqueous solution (1M, 0.19mL), Then it was stirred at this temperature for 2 hours, acetic acid (0.2 mL) was added, and the mixture was concentrated to dryness under reduced pressure, and purified with a reverse preparation column to obtain 24 mg of the title compound. Yield: 56%.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.84 (m, 4H), 2.42-2.45 (m, 6H), 2.46-2.56 (m, 1H), 2.61-3.13 (m, 12H), 3.44-3.68 ( m,5H),3.76-3.94(m,4H),4.51-5.72(m,6H),6.67(s, 1H),6.96-7.03(m,1H),7.31-7.38(m,1H),7.56- 7.62(m,1H),7.81(s,1H),8.07-8.10(m,1H),11.55(s,1H); ¹³ C NMR(100MHz,DMSO- d ⁶ ) δ 31.88,34.49,52.67,55.48, 56.35,65.22,71.66,73.26,75.83,76.37,100.48,102.91,104.52,117.47,124.49,131.61,133.88,140.39,149.19,150.80,152.35,152.57,153.25,157.57,167.79,170.44,178.41 (representative 13C signal ); MS m/z(ESI): 900.3[M+H] ⁺ .

Example 2 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H -Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5- Trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3R,4S,5S,6S)-2-(4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy-1,2, 4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2 ,3-d)pyrimidine-7-carboweedamino)ethyl)(methyl)aminoformyl)oxy)methyl)-2-nitrophenoxy)-6-(carbomethoxy) ) Tetrahydro-2H-pyran-3,4,5-triyltriacetate (50mg, 0.048mmol), Pd(OH) ₂ /C (20 wt%, 10mg) are mixed in ethanol (2mL), In a hydrogen atmosphere, at room temperature and pressure, the mixture was stirred for 3 days, filtered through Celite to remove insoluble matter, and the filtrate was concentrated to dryness.

To the above residue, add MeOH (1mL), a mixed solvent of THF (1mL) and water (1mL) to dissolve, then add solid lithium hydroxide monohydrate (11mg, 0.27mmol), stir at room temperature for 1 hour, add It was quenched with acetic acid, concentrated to dryness under reduced pressure, and purified by reverse preparation column to obtain 13 mg of the title compound, yield: 31%.

MS m/z(ESI): 870.3[M+H] ⁺ .

Example 3 (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2- ((3-Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta(c)pyrrol-5-yl)(methyl)amino) -N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweed (amino)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy) Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2- ((3-Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta(c)pyrrol-5-yl)(methyl)amino) -N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweed (amino)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy) Refer to Example 1 for the preparation of tetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 981.3[M+H] ⁺ .

Example 4 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy)tetrahydro- 2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy)tetrahydro- Refer to Example 1 for the preparation of 2H-pyran-2-carboxylic acid.

MS m/z(ESI): 855.3[M+H] ⁺ .

Example 5 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- Methyl-7H-pyrrole And[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)-2-methylphenoxy)tetrahydro-2H -Pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoxy)methyl)-2-methylphenoxy For the preparation of tetrahydro-2H-pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI): 869.3[M+H] ⁺ .

Example 6 (2S,3S,4S,5R,6S)-6-(2-chloro-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy- 1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5-tri Hydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-chloro-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy- 1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5-tri Refer to Example 1 for the preparation of hydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 889.3[M+H] ⁺ .

Example 7 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-methoxy-4-((((2-(4-(((3aR,5s,6aS) -2-((3-Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbamido)ethyl)(methyl)aminomethano)oxy)methyl)benzene (Oxy)tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-methoxy-4-((((2-(4-(((3aR,5s,6aS) -2-((3-Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbamido)ethyl)(methyl)aminomethano)oxy)methyl)benzene The preparation of oxy)tetrahydro-2H-pyran-2-carboxylic acid refers to Example 1.

MS m/z(ESI): 885.3[M+H] ⁺ .

Example 8 (2S,3S,4S,5R,6S)-6-(2-Fluoro-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy- 1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5-tri Hydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-Fluoro-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy- 1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5-tri Refer to Example 1 for the preparation of hydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 873.3[M+H] ⁺ .

Example 9 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoyl)oxy)methyl)-2-(trifluoromethyl) (Yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoyl)oxy)methyl)-2-(trifluoromethyl) Refer to Example 1 for the preparation of (yl)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 923.3[M+H] ⁺ .

Example 10 (2S,3S,4S,5R,6S)-6-(2-cyano-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H -Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5- Trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-cyano-4-((((2-(4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H -Pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethano)oxy)methyl)phenoxy)-3,4,5- Refer to Example 1 for the preparation of trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 880.3[M+H] ⁺ .

Example 11 3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl (2-(4-(((3aR,5s,6aS)-2-((3-methoxy-1,2,4-thiadiazol-5-yl)aminomethyl) Octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido )Ethyl)(methyl)carbamate

3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl (2-(4-(((3aR,5s,6aS)-2-((3-methoxy-1,2,4-thiadiazol-5-yl)aminomethyl) Octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido Refer to Example 1 for the preparation of ethyl) (methyl) carbamate.

MS m/z(ESI): 886.3[M+H] ⁺ .

Example 12 (2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy Yl)tetrahydro-2H-thiopyran-2-carboxylic acid

(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(4-((((2-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- (Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy Refer to Example 1 for the preparation of tetrahydro-2H-thiopyran-2-carboxylic acid.

MS m/z(ESI): 916.3[M+H] ⁺ .

Example 13 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((3-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)propyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy Group) Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((3-(4-(((3aR,5s,6aS)-2-((3 -Methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-N- Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)propyl)(methyl)aminomethanoxy)methyl)-2-nitrophenoxy For the preparation of tetrahydro-2H-pyran-2-carboxylic acid, refer to Example 1.

MS m/z(ESI): 914.3[M+H] ⁺ .

Example 14 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methyl)oxy)methyl)-2-(difluoromethoxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methoxy)methyl)-2-(difluoromethoxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Reference Example 1.

MS m/z(ESI): 819.3[M+H] ⁺ .

Example 15 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methyl)oxy)methyl)-2-(trifluoromethoxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methoxy)methyl)-2-(trifluoromethoxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Reference Example 1.

MS m/z(ESI): 837.3[M+H] ⁺ .

Example 16 (2S,3S,4S,5R,6S)-6-(4-((((3-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)propyl)(methyl)amine (Methyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((3-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)propyl)(methyl)amine (Methoxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid is prepared according to Example 1.

MS m/z(ESI): 812.3[M+H] ⁺ .

Example 17 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(propyl)amine (Methyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(propyl)amine (Methoxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid is prepared according to Example 1.

MS m/z(ESI): 826.3[M+H] ⁺ .

Example 18 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-propyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-propyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methoxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid is prepared according to Example 1.

MS m/z(ESI): 826.3[M+H] ⁺ .

Example 19 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine (Methyl)thio)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methyl (Piperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)amine The preparation of (methyl)thio)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid refers to Example 1.

MS m/z(ESI): 814.3[M+H] ⁺ .

Example 20 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl Yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethyl (Ao)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl Yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethyl Refer to Example 2 for the preparation of ((oxy)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 762.3[M+H] ⁺ .

Example 21 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfon ((Azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl )(Methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfon ((Azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl ) The preparation of (methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid refers to Example 2.

MS m/z(ESI): 827.3[M+H] ⁺ .

Example 22 (2S,3S,4S,5R,6S)-6-(4-((((2-(5-aminomethyl-4-(((1R,2S,5S,7S)-5-hydroxyadamantane -2-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboamido)ethyl)(methyl)aminomethano)oxy )Methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(5-aminomethyl-4-(((1R,2S,5S,7S)-5-hydroxyadamantane -2-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboamido)ethyl)(methyl)aminomethano)oxy )Methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid is prepared according to Example 1.

MS m/z(ESI): 812.3[M+H] ⁺ .

Example 23 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(5-aminomethyl-4-(((1R,2S,5S,7S)- 5-Hydroxyadamantan-2-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboamido)ethyl)(methyl)amino (Formyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(5-aminomethyl-4-(((1R,2S,5S,7S)- 5-Hydroxyadamantan-2-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboamido)ethyl)(methyl)amino Refer to Example 2 for the preparation of (formyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 782.3[M+H] ⁺ .

Example 24 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-((3S,4R)-1-(2-cyanoacetyl)-3-methyl- 1,6-diazaspiro[3.4]octane-6-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)( (Methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-((3S,4R)-1-(2-cyanoacetyl)-3-methyl- 1,6-diazaspiro[3.4]octane-6-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl ((Methyl)aminomethyl)oxy)(methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Example 1.

MS m/z(ESI): 796.3[M+H] ⁺ .

Example 25 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-((3S,4R)-1-(2-cyanoacetyl)- 3-Methyl-1,6-diazaspiro[3.4]octane-6-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido )Ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-((3S,4R)-1-(2-cyanoacetyl)- 3-Methyl-1,6-diazaspiro[3.4]octane-6-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido )Ethyl)(Methyl)aminomethyl)oxy)Methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid preparation refer to Example 2 .

MS m/z(ESI): 766.3[M+H] ⁺ .

Example 26 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((methyl(2-(N-methyl-4-(methyl((1s,3s )-3-(Propylsulfonamido)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)aminomethan) (Oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((methyl(2-(N-methyl-4-(methyl((1s,3s )-3-(Propylsulfonamido)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)aminomethan) The preparation of oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylic acid refers to Example 1.

MS m/z(ESI): 809.3[M+H] ⁺ .

Example 27 (2S,3S,4S,5R,6S)-6-(2-amino-4-(((methyl(2-(N-methyl-4-(methyl((1s,3s)-3- (Propylsulfonamido)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)aminomethano)oxy)methyl (Yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-(((methyl(2-(N-methyl-4-(methyl((1s,3s)-3- (Propylsulfonamido)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboweedamido)ethyl)aminomethano)oxy)methyl (Phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid is prepared according to Example 2.

MS m/z(ESI): 779.3[M+H] ⁺ .

Example 28 (2S,3S,4S,5R,6S)-6-(4-((((2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoro (Ethyl)aminomethyl)pyrrolidin-3-yl)-N-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboweed (Amino) ethyl) (methyl) aminomethyl (oxy) methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxy acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(8-((3R,4S)-4-ethyl-1-((2,2,2-trifluoro (Ethyl)aminomethyl)pyrrolidin-3-yl)-N-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3-carboweed (Amino) ethyl) (methyl) aminomethyl (oxy) methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxy Refer to Example 1 for acid preparation.

MS m/z(ESI): 866.3[M+H] ⁺ .

Example 29 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(8-((3R,4S)-4-ethyl-1-((2,2 ,2-Trifluoroethyl)aminomethyl)pyrrolidin-3-yl)-N-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3 -Carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxy acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(8-((3R,4S)-4-ethyl-1-((2,2 ,2-Trifluoroethyl)aminomethyl)pyrrolidin-3-yl)-N-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-3 -Carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxy Refer to Example 2 for acid preparation.

MS m/z(ESI): 836.3[M+H] ⁺ .

Example 30 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(1-(3-(cyanomethyl)-1-(1-(3-fluoro-2 -(Trifluoromethyl)isonicotine)piperidin-4-yl)azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3 -d) pyrimidine-7-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxy Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(1-(3-(cyanomethyl)-1-(1-(3-fluoro-2 -(Trifluoromethyl)isonicotine)piperidin-4-yl)azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3 -d) pyrimidine-7-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxy Refer to Example 1 for the preparation of tetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 1039.3[M+H] ⁺ .

Example 31 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-(3-(cyanomethyl)-1-(1-( 3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrole And [2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy)-3,4,5-trihydroxy Tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(4-(1-(3-(cyanomethyl)-1-(1-( 3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidine-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrole And [2,3-d]pyrimidine-7-carboweedamido)ethyl)(methyl)aminomethanyl)oxy)methyl)phenoxy)-3,4,5-trihydroxy Refer to Example 2 for the preparation of tetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 1009.3[M+H] ⁺ .

Example 32 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((methyl(2-(N-methyl-3-(4-(((R) -2-Methyl-1-carbonyl-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)amino)pyrimidin-2-yl)-1H-pyrrolo[ 2,3-b)pyridine-1-carboweed (amino)ethyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2- carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((methyl(2-(N-methyl-3-(4-(((R) -2-Methyl-1-carbonyl-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)amino)pyrimidin-2-yl)-1H-pyrrolo[ 2,3-b)pyridine-1-carboweed (amino)ethyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2- Refer to Example 1 for the preparation of carboxylic acid.

MS m/z(ESI): 778.3[M+H] ⁺ .

Example 33 (2S,3S,4S,5R,6S)-6-(2-amino-4-(((methyl(2-(N-methyl-3-(4-(((R)-2-methyl -1-carbonyl-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)amino)pyrimidin-2-yl)-1H-pyrrolo[2,3- b) pyridine-1-carboweed (amino)ethyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2- carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-(((methyl(2-(N-methyl-3-(4-(((R)-2-methyl -1-carbonyl-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)amino)pyrimidin-2-yl)-1H-pyrrolo[2,3- b) pyridine-1-carboweed (amino)ethyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2- Refer to Example 2 for the preparation of carboxylic acid.

MS m/z(ESI): 848.3[M+H] ⁺ .

Example 34 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-propenyl-6-methylpiperidin-3-yl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethano)oxy)methyl)- 2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-propenyl-6-methylpiperidin-3-yl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethano)oxy)methyl)- Refer to Example 1 for the preparation of 2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 771.3[M+H] ⁺ .

Example 35 (2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-propenyl-6-methylpiperidin-3-yl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethano)oxy)methyl)- 2-aminophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(4-(((3R,6S)-1-propenyl-6-methylpiperidin-3-yl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)aminomethano)oxy)methyl)- Refer to Example 2 for the preparation of 2-aminophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 741.3[M+H] ⁺ .

Example 36 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(3-(2-((3-methoxy-1-methyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-methyl-7-((R)-2-(4-methylpiperazin-1-yl)propanamido )-1H-indole-1-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran -2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-((((2-(3-(2-((3-methoxy-1-methyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-methyl-7-((R)-2-(4-methylpiperazin-1-yl)propanamido )-1H-indole-1-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran Refer to Example 1 for the preparation of -2-carboxylic acid.

MS m/z(ESI): 975.4[M+H] ⁺ .

Example 37 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(3-(2-((3-methoxy-1-methyl-1H-pyridine (Azol-4-yl)amino)pyrimidin-4-yl)-N-methyl-7-((R)-2-(4-methylpiperazin-1-yl)propanamido)-1H- Indole-1-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran -2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(3-(2-((3-methoxy-1-methyl-1H-pyridine (Azol-4-yl)amino)pyrimidin-4-yl)-N-methyl-7-((R)-2-(4-methylpiperazin-1-yl)propanamido)-1H- Indole-1-carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran Refer to Example 2 for the preparation of -2-carboxylic acid.

MS m/z(ESI): 945.4[M+H] ⁺ .

Example 38 (2S,3S,4S,5R,6S)-6-(4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-Difluoro Propane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)-1-methyl-3-(1-methyl-1H- (Pyrazol-4-yl)ureido)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H -Pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-((((2-(3-(4-((1R,5S)-8-((S)-2,2-Difluoro Propane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)-1-methyl-3-(1-methyl-1H- (Pyrazol-4-yl)ureido)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H -The preparation of pyran-2-carboxylic acid refers to Example 1.

MS m/z(ESI): 875.3[M+H] ⁺ .

Example 39 (2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(3-(4-((1R,5S)-8-((S)-2, 2-Difluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)-1-methyl-3-(1- (Methyl-1H-pyrazol-4-yl)ureido)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H -Pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(2-amino-4-((((2-(3-(4-((1R,5S)-8-((S)-2, 2-Difluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)-1-methyl-3-(1- (Methyl-1H-pyrazol-4-yl)ureido)ethyl)(methyl)aminomethyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H -The preparation of pyran-2-carboxylic acid refers to Example 2.

MS m/z(ESI): 845.3[M+H] ⁺ .

Example 40 (2S,3S,4S,5R,6S)-6-(4-(((4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methylpiperidine-3 -Yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carbonyl)oxy)methyl)-2-nitrophenoxy)-3,4,5- Trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-6-(4-(((4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methylpiperidine-3 -Yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carbonyl)oxy)methyl)-2-nitrophenoxy)-3,4,5- Refer to Example 1 for the preparation of trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

MS m/z(ESI): 684.2[M+H] ⁺ .

Example 41 3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl 4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo [2,3-d]pyrimidine-7-carboxylate

3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl 4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo Refer to Example 1 for the preparation of [2,3-d]pyrimidine-7-carboxylate.

MS m/z(ESI): 670.2[M+H] ⁺ .

Example 42 3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl(2-(4-(((3R,4R)-1-(2-cyanoacetinyl)-4-methylpiperidin-3-yl)(methyl)amino)- N-Methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl)carbamate

The first step: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-methan-2-nitrophenoxy)tetrahydro-2H-pyridine Preparation of pyran-3,4,5-triyltriacetate

To (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyltriacetate (8.00g , 19.5mmol) of acetonitrile solution (140mL), add 4-hydroxy-3-nitrobenzene (form)aldehyde (3.19g, 19.1mmol), Ag ₂ O (5.75g), and then at room temperature, protected from light, Stir overnight. The insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure and the organic solvent was concentrated, and the title compound was separated by column chromatography to obtain 9.00 g of the title compound. Yield: 95%.

MS m/z(ESI): 498.1[M+H] ⁺ .

The second step: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(hydroxymethyl)-2-nitrophenoxy)tetrahydro-2H -Preparation of pyran-3,4,5-triyltriacetate

Under ice water bath, to (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-methan-2-nitrophenoxy)tetrahydro-2H- To a mixed solution of pyran-3,4,5-triyltriacetate (2.00g, 4.02mmol) in dichloromethane (20mL) and isopropanol (5mL), add NaBH ₄ (91.3mg, 2.41mmol) ), and then continue to stir in an ice-water bath for 2 hours. It was quenched by adding ice water, extracted twice with dichloromethane, combined the organic phases, washed with saturated brine, separated the organic phase and dried with anhydrous sodium sulfate, filtered, concentrated the organic solvent, and separated by column chromatography to obtain 1.30g of the title compound. Yield: 65%.

MS m/z(ESI): 500.1[M+H] ⁺ .

The third step: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(((methyl(2-(methylamino)ethyl)amine (Methyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate

To (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(hydroxymethyl)-2-nitrophenoxy)tetrahydro-2H-pyran CDI (269 mg, 1.66 mmol) was added to a dichloromethane solution (6 mL) of 3,4,5-triyltriacetate (637 mg, 1.28 mmol), and then stirred at room temperature for 2 hours.

In another round-bottomed flask, prepare the dichloromethane solution (4mL) of N1,N2-dimethylethane-1,2-diamine (0.490mL, 4.46mmol), in an ice water bath, while stirring, in turn Add glacial acetic acid (0.255 mL, 4.46 mmol) and the reaction solution in the above step dropwise to this solution. After the addition is complete, slowly warm to room temperature and stir at room temperature for 3 hours.

The reaction solution was diluted with dichloromethane, and then washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the title compound was separated by column chromatography to obtain 255 mg of the title compound. Yield: 33%.

MS m/z(ESI): 614.2[M+H] ⁺ .

The fourth step: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((((2-(4-(((3R,4R)-1 -(2-Cyanoacetoxy)-4-methylpiperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7- (Carbamido) ethyl) (methyl) aminomethyl) oxy) methyl)-2-nitrophenoxy) tetrahydro-2H-pyran-3,4,5-triyl Preparation of triacetate

Under an ice water bath, add DIPEA (0.089mL, 0.451mmol) to the acetonitrile solution (5mL) of tofacitinib (130mg, 0.416mmol), bis(p-nitrophenyl) carbonate (139mg, 0.458mmol), Then slowly rise to room temperature, and continue stirring at room temperature for 2 hours.

Then put the reaction solution in an ice-water bath, and add (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(((methyl(2-( (Methylamino)ethyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro A dichloromethane solution (2 mL) of -2H-pyran-3,4,5-triyltriacetate (255 mg, 0.416 mmol) was then stirred at room temperature for 2 hours.

Add glacial acetic acid (1mL) to quench, dilute the reaction solution with dichloromethane, and then wash the solution with saturated aqueous sodium bicarbonate solution and saturated brine successively. The organic phase is then dried over anhydrous sodium sulfate, and the organic solvent is concentrated under reduced pressure. Chromatographic separation gave 130 mg of the title compound, yield: 33%.

MS m/z(ESI): 952.4[M+H] ⁺ .

The fifth step: 3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2 -Yl)oxy)benzyl(2-(4-(((3R,4R)-1-(2-cyanoacetoxy)-4-methylpiperidin-3-yl)(methyl) (Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboamido)ethyl)(methyl) carbamate

Under ice water bath, go to (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((((2-(4-(((3R,4R)- 1-(2-Cyanoacetoxy)-4-methylpiperidin-3-yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7 -Carboweed (amino)ethyl)(methyl)aminomethyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-tri LiOH.H ₂ O (6.2 mg, 0.15 mmol) in aqueous solution (2 mL) was added dropwise to the tetrahydrofuran solution (5 mL) of triacetate (35 mg, 0.037 mmol). After the addition, the temperature was slowly raised to room temperature. Stir overnight at room temperature. Two drops of acetic acid were added to the reaction solution, the organic solvent was removed under reduced pressure, and extraction was performed twice with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and separated and purified with a reverse preparation column to obtain 9 mg of the title compound, yield: 31%.

¹ H NMR (400MHz, CD ₃ OD): δ 1.10 (d, J =8.4Hz, 3H), 1.71-2.03 (m, 3H), 2.47 (m, 2H), 2.85-3.56 (m, 20H), 3.63 -3.98 (m, 6H), 6.73 (s, 1H), 6.78 (s, 1H), 7.74 (m, 1H), 7.65 (m, 1H), 8.17 (m, 2H), 8.41 (br s, 1H) ; MS m/z(ESI): 784.2[M+H] ⁺ .

Example 43 (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-7H-pyrrolo[2 ,3-d)pyrimidine-7-carbonyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylic acid

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(4-(((4-(((3aR,5s,6aS)-2-((3-methoxy -1,2,4-thiadiazol-5-yl)aminomethan)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)amino)-7H-pyrrolo[2 The preparation of ,3-d]pyrimidine-7-carbonyl)oxy)methyl)-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylic acid refers to Example 1.

MS m/z(ESI): 786.2[M+H] ⁺ .

Example 44 3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl 4-(((3aR,5s,6aS)-2-((3-methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopentan Dieno[c]pyrrol-5-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate

3-nitro-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy Yl)benzyl 4-(((3aR,5s,6aS)-2-((3-methoxy-1,2,4-thiadiazol-5-yl)aminomethyl)octahydrocyclopentan Refer to Example 1 for the preparation of dieno[c]pyrrol-5-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate.

MS m/z(ESI): 772.2[M+H] ⁺ .

Biological test evaluation

The following further describes the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

Test Example 1. Determination of the inhibitory effect of the compound of the present invention on JAK kinase activity

Experimental purpose: The purpose of this test case is to test the activity of the compound to inhibit JAK kinase activity.

Experimental instrument: centrifuge (5702R) purchased from Eppendorf company; pipette purchased from Eppendorf or Rainin company; The microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.

Experimental method: In this experiment, the fluorescence resonance energy transfer (TR-FRET) method was used to test the inhibitory effect of the compound on JAK kinase activity, and the half inhibitory concentration IC _{50 of the} compound on JAK kinase activity was obtained.

The specific experimental operation is as follows: the kinase reaction is carried out in a white 384-well plate (PerkinElmer), each well is added with 1-5 μL of compounds of different concentrations diluted with DMSO and ddH ₂ O, and 1-5 μL of the corresponding solvent is added to the positive control well, and then each well Add 1-5μL of 0.1-20nM JAK kinase solution diluted with kinase buffer (HEPES 50-250mM, MgCl ₂ 5-20mM, etc.), add 1-5μL of kinase buffer to the negative control wells, and add 1~5μL containing peptide substrate Incubate the substrate mixture with ATP for 0.5 to 5 hours at room temperature, add 10 μL of EDTA and the detection solution containing labeled antibody, and incubate for 2 to 24 hours at room temperature. Use the BioTek Synergy H1 microplate reader to measure about 615 nm and The fluorescence signal value at 665nm is used to calculate the inhibition rate. According to the inhibition rate of different concentrations, the IC _{50 of the} compound was obtained by curve fitting.

Experimental data processing method: Calculate the percentage inhibition data of the wells treated with the compound based on the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100-[(test compound value-negative Control value)]/(positive control value-negative control value)×100}. Fitting using GraphPad prism and the corresponding concentrations of the different percent inhibition data to a 4 parameter nonlinear logic formula ₅₀ value _was calculated IC, obtained by the above embodiment of the present invention shown in the embodiments of the compounds exhibit JAK kinase activity assay in the following table 1 biological activity.

Test Example 2. Determination of the inhibitory effect of the compound of the present invention on the cell JAK1/TYK2-STAT signal pathway

Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound on the cell JAK1/TYK2-STAT signal pathway.

Experimental instrument: Microplate shaker (88880024) was purchased from Thermo Scientific ^TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American BioTek company, the model was SynergyH1 full function Microplate reader.

Experimental method: In this experiment, the U266 cell line was used to activate the JAK1/TYK2-STAT signal pathway by INF-stimulation, to detect the inhibitory activity of the compound on its downstream STAT3 phosphorylation, and obtain half of the compound's activity on the JAK1/TYK2-STAT signal pathway Inhibition concentration IC ₅₀ .

The specific experimental operation is as follows: Pour 3-12 μL of U266 cells in a 384-well detection plate, the number of cells in each well is 100-300K, add 2 μL of the compound solution in gradient dilution, and culture with shaking at 350 rpm for 2 hours at room temperature. After 2 hours, add 2μL of INF-α, the final concentration of INF-α is 1000U/mL, and shake at room temperature for 15min. Add 2-5μL (5X) LANCE Ultra Lysis Buffer 2 solution and shake at room temperature for 2h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubated overnight at room temperature. The microplate reader measures the 665nm fluorescence signal value of each well, and calculates the inhibition rate from the fluorescence signal value. According to the inhibition rate of different concentrations, the IC _{50 of the} compound is obtained by curve fitting.

Experimental data processing method: Calculate the percentage inhibition data of the wells treated with the compound based on the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate=100-[(test compound value-negative Control value)]/(positive control value-negative control value)×100}. Using GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value, the compound of this example has shown the following table 2 in the test of the inhibitory activity of the JAK1/TYK2-STAT signal pathway in U266 cells Biological activity:

Test Example 3. Stability of the compound of the present invention in β-glucuronidase solution

Experimental purpose: The purpose of this test case is to detect whether the compound is digested by β-glucuronidase and the time for complete digestion.

Experimental instrument: centrifuge (5702R) purchased from Eppendorf company, pipette purchased from Eppendorf or Rainin company, LC/MS/MS analytical instrument: AB Sciex API 4000.

experimental method:

A. Enzyme digestion reaction

The digestion reaction was carried out in a 96-well plate (Corning). Add 50μL of β-glucuronidase (sigma) solution to each well, this solution contains 10U of enzyme, then add 10nmol of compound to the corresponding wells and incubate for 0, 5, 10, 20, 30min, add 100μL at the corresponding time point The ACN terminates the reaction.

B. LC-MS analysis

Take 40 μL of the solution after the digestion is terminated in step A, add 160 μL of acetonitrile to precipitate, mix and centrifuge at 4000 rpm for 10 minutes. Then take 100 μL of the treated supernatant solution and perform LC/MS/MS analysis of the concentration of the test compound.

LC-MS/MS analysis conditions: liquid phase conditions: Shimadzu LC-20AD pump; mass spectrometry conditions: AB Sciex API 4000 mass spectrometer; chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm; mobile phase: A liquid is 0.1% formic acid Aqueous solution, B solution is acetonitrile, flow rate: 0.8 mL/min, extraction time: 0-4 minutes gradient extraction.

As shown in Table 3, the active metabolite (JAK inhibitor SHR0302) of the prodrug of the preferred embodiment of the present invention (Example 1) can be quickly cleaved by β-glucuronidase to release SHR0302. The mechanism of restriction is as shown above.

The sugar moiety in the structure of Example 42 is a glucose structure, which is different from the gluconic acid of the sugar moiety in the structure of Example 1. Therefore, under the same experimental conditions, β-glucuronidase cleaves Example 42 to release the active drug Tofacitinib. The rate is extremely slow and cannot be effectively released. However, Example 42 can be cleaved by β-D-glucosidase to quickly release the active drug Tofacitinib. The restriction mechanism is as follows:

Test Example 4. Pharmacokinetic analysis and determination of the compound of the present invention in mice

Experimental purpose: To perform pharmacokinetic testing and analysis of the preferred embodiment of the present invention in the blood and gastrointestinal tissues of mice

Experimental instrument: centrifuge (5702R) purchased from Eppendorf company, pipette purchased from Eppendorf or Rainin company, LC/MS/MS analytical instrument: AB Sciex API 4000.

Experimental animals: BALB/c mice were used, purchased from Shanghai Jiesjie Experimental Animal Co., Ltd.

Experimental method: Take BALB/c mice, 3 mice in each group, and administer the compound of the example by intragastric administration at a dose of 5 mg/10 ml/kg, 0.5, 1, 2, 4, 6, after administration. 8 and 24 hours venous blood collection and separation and collection of gastrointestinal tissues. The blood is placed in a K ₂ EDTA test tube, centrifuged at 1000-3000×g at room temperature for 5-20 minutes to separate the plasma, the gastrointestinal tissue is removed and rinsed with buffer solution, after adding homogenization buffer, the tissue is homogenized and then frozen or tested. After processing the plasma and tissue homogenate samples, the concentration of the test compound was analyzed by LC/MS/MS. The drug metabolism data obtained is shown in Table 4 below, where AUC _0-t is AUC _{0-8 hours} :

Experimental conclusion: The blood exposure of the active metabolite (Tofacitinib) of the preferred prodrug Example 42 of the present invention in mice is less than the blood exposure of a single gavage of Tofacitinib; The active metabolite (Tofacitinib) of Example 42 is exposed to greater intestinal tissues than a single gavage administration of Tofacitinib; the active metabolite of Example 1 SHR0302 The blood exposure is extremely low, while the intestinal tissue has a high exposure.

According to related literature reports, after intragastric administration of Example 42 in mice, it was cleaved with β-D-glucosidase to release the active drug Tofacitinib. Analysis of Prodrug Example 1 and Example 42 The molecular weight is larger than the corresponding active metabolite. If mice are intragastrically administered the prodrug of the same molar ratio and the corresponding active metabolite, the prodrug (Example 1 and Example 42) can achieve the active drug in the target organ (Ileum, colon) enrichment, and can greatly reduce the corresponding active metabolites (SHR0302 and Tofacitinib) exposure in the blood.

Claims (21)

A compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof,

Wherein: M, M ₁ or M ₂ is O, S or NH; L is a bond, -C(=O)- or -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-; G is a JAK inhibitor, selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, and Degerti Delgocitinib, Pf-04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Dasatinib, Decernotinib, SHR -0302, Delgocitinib, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, deuterium modified Lu Deuterium-modified ruxolitinib analog, ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride hydrochloride) or KL-130008; R is -CH ₂ OH or -COOPg; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine , Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, thio One or more substituents in, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted; R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, mercapto, nitro, hydroxyl, Cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Pg is a hydrogen or carboxy protecting group, when Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl , -PfP, -Me, -PMB, -EM or t-Boc; Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups, when Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independent Selected from -CH ₃ , -C(CH ₃ ) ₃ , -CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si(CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh; n is 0, 1, 2, 3 or 4 ; And x is 0, 1, 2 or 3. A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

Among them: M is O, S or NH; L is a bond, -C(=O)- or -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-; G is a JAK inhibitor, Selected from Tofacitinib, Ruxolitinib, Baricitinib, Peficitinib, Pacritinib, Delgocitinib, Pf -04965842, Upadacitinib, Filgotinib, Itacitinib, Fedratinib, Decernotinib, SHR-0302, Degetinib Delgocitinib, ASN-002, Cerdulatinib, BMS-986165, PF-06700841, INCB-52793, ATI-502, PF-06651600, AZD-4205, Deuterium-modified Ruxolinib analogues ( Deuterium-modified ruxolitinib analog), ATI-501, R-348, R-348, NS-018, SHR0302, Jaktinib hydrochloride, Jaktinib hydrochloride (Jaktinib hydrochloride) or KL-130008 ;Preferably SHR-0302; R is -CH ₂ OH or -COOPg; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino , Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, thio One or more substituents in, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted; R ₂ and R ₃ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, mercapto, nitro, hydroxyl, Cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Pg is a hydrogen or carboxy protecting group, when Pg is a carboxy protecting group, it is selected from -DMB, -Bn, -Allyl , -PfP, -Me, -PMB, -EM or t-Boc; Pg ₁ , Pg ₂ and Pg ₃ are hydrogen or hydroxyl protecting groups, when Pg ₁ , Pg ₂ and Pg ₃ are hydroxyl protecting groups, each is independent Selected from -CH ₃ , -C(CH ₃ ) ₃ ,- CPh ₃ , -CH ₂ Ph, -CH ₂ OCH ₃ , -Si(CH ₃ ) ₃ , -THP, -SiMe ₂ (t-Bu), -Ac or -COPh; n is 0, 1, 2, 3 or 4; and x is 0, 1, 2 or 3. The compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof as described in item 2 of the scope of patent application, characterized in that, when M is O, Pg ₁ , Pg ₂ and Pg ₃ Is hydrogen, R is -COOPg, Pg is hydrogen, R _{1 is} selected from hydrogen, amine, nitro, halogen, methyl or methoxy, R ₁ is located at

Ortho position, L is -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-, R ₂ and R ₃ are selected from methyl at the same time, and when x is 1, G is not a throwing method Tofacitinib; when M is O, Pg ₁ , Pg ₂ and Pg ₃ are hydrogen, R is -COOPg, Pg is hydrogen, R ₁ is nitro, and R ₁ is located at

Ortho position, L is -C(=O)NR ₂ (CH ₂ ) _x NR ₃ C(=O)-, R ₂ and R _{3 are} both selected from methyl, and when x is 1, G is not Ruxote Ni (Ruxolitinib) or Baricitinib (Baricitinib). The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 or 2 of the scope of the patent application, wherein it is further represented by the general formula (II):

Among them: M, G, R~R ₃ , Pg ₁ to Pg ₃ , n and x are as described in item 2 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 or 2 of the scope of patent application, wherein, further is represented by general formula (III):

Among them: M, G, R, R ₁ , Pg ₁ ~Pg ₃ and n are as described in item 2 of the scope of patent application. The compound described in item 1 or 2 of the scope of patent application, its stereoisomer or pharmaceutically acceptable salt thereof, wherein, further is represented by the general formula (IIA):

The compound described in item 1 or 2 of the scope of patent application, its stereoisomer or pharmaceutically acceptable salt thereof, wherein, further is represented by the general formula (IV):

Among them: G, R ₁ ~R ₃ , Pg, Pg ₁ ~Pg ₃ and x are as described in item 2 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 or 2 of the scope of patent application, wherein, further is represented by general formula (V):

Among them: G, R, R ₁ , Pg ₁ ~Pg _{3 are} as described in item 2 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 or 2 of the scope of the patent application, wherein it is further represented by the general formula (VI):

Among them: R, R ₁ ~R ₃ , Pg ₁ ~Pg ₃ and x are as described in item 2 of the scope of patent application. The compound described in item 1 or 2 of the scope of patent application, its stereoisomer or pharmaceutically acceptable salt thereof, wherein, further is represented by the general formula (VII):

Among them: R ₁ ~R ₃ and x are as described in item 2 of the scope of patent application. The compound described in item 1 or 2 of the scope of patent application, its stereoisomer or pharmaceutically acceptable salt thereof, wherein, further is represented by the general formula (VIII):

Wherein: R is -CH ₂ OH or -COOH; G is selected from Tofacitinib or SHR-0302; R _{1 is} selected from hydrogen, halogen, cyano, nitro, amino, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, preferably hydrogen, halogen, cyano, nitro, amino, C _1-3 alkyl, C _{1 -3} haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy; more preferably hydrogen, fluorine, chlorine, cyano, nitro, amino, methyl, methoxy or trifluoromethyl Group; x is selected from an integer of 0, 1, 2 or 3, preferably 1; and, when x is 1, G is Tofacitinib and R _{1 is} selected from a nitro group, R is -CH ₂ OH . The compound described in any one of items 1 to 8 and 11, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the G is selected from the following JAK inhibitors:

The compound according to any one of items 1 to 12 in the scope of the patent application, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from hydrogen, halogen, cyano, nitro, amine , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy; R ₂ and R ₃ are each independently selected from C _1-6 alkyl or C _1-6 haloalkyl. The compound described in any one of items 1 to 13 in the scope of the patent application, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the following compounds:

A method for preparing the compound represented by the general formula (VII) described in item 10 of the scope of patent application or its stereoisomer and pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

General formula (VII-1) is deprotected to obtain the compound represented by general formula (VII) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: rings R ₁ to R ₃ , Pg, Pg ₁ to Pg ₃ and x As stated in item 2 of the scope of patent application. A method for preparing the compound represented by the general formula (VI) described in item 9 of the scope of patent application or its stereoisomer and pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

The general formula (VI-1) reacts with the general formula (VII-2) to obtain the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: ring R ₁ ~R ₃ , R , Pg ₁ ~Pg ₃ and x are as described in item 2 of the scope of patent application. A method for preparing the compound represented by the general formula (VI-2) or its stereoisomers and pharmaceutically acceptable salts thereof described in item 16 of the scope of patent application, characterized in that it comprises the following steps:

SHR-0302 reacts with general formula (X) to obtain the compound represented by general formula (VI-2) or its stereoisomers and pharmaceutically acceptable salts thereof; wherein: X is selected from halogen. A pharmaceutical composition, which includes a therapeutically effective dose of the compound shown in any one of items 1 to 14 in the scope of patent application, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable Carrier, diluent or excipient. A compound according to any one of items 1 to 14 in the scope of patent application, its stereoisomer or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to item 18 in the scope of patent application, and its application In the preparation of JAK inhibitor drugs, the application includes a prodrug containing glucuronide in the JAK inhibitor, and the prodrug is cleaved by β -glucuronidase to release the JAK inhibitor, preferably JAK1, JAK2 , JAK3 and TYK2 inhibitors. The compound described in any one of items 1 to 14 in the scope of patent application, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in item 18 in the scope of patent application is used in the preparation of Glucuronide derivative JAK inhibitor prodrug application in medicine. A compound according to any one of items 1 to 14 in the scope of patent application, its stereoisomer or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to item 18 in the scope of patent application, and its application Preparation of drugs related to inflammatory diseases and tumor diseases, wherein the inflammatory diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease, and the tumor diseases are selected from myelofibrosis, polycythemia vera And primary thrombocythemia, myelogenous leukemia, acute lymphocytic leukemia, ductal carcinoma of the breast, and non-small cell lung cancer, among which gastrointestinal inflammatory diseases are chronic intestinal inflammatory diseases, and ulcerative colitis and gram Ron's disease.