CN113698403A - (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative and preparation method thereof - Google Patents

(1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative and preparation method thereof Download PDF

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CN113698403A
CN113698403A CN202010434406.6A CN202010434406A CN113698403A CN 113698403 A CN113698403 A CN 113698403A CN 202010434406 A CN202010434406 A CN 202010434406A CN 113698403 A CN113698403 A CN 113698403A
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azabicyclo
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CN113698403B (en
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沈宇
校登明
陈荣耀
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Nanjing Gentai Pharmaceutical Technology Co ltd
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Abstract

The invention belongs to the field of medicines, and discloses a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative and a preparation method thereof, wherein the preparation method comprises the following steps: (S1) carrying out nucleophilic aromatic substitution reaction on the compound I-1 and the compound I-2 to obtain a compound A-1; (S2) treating the compound A-1 with hydrochloric acid or trifluoroacetic acid for deprotection to obtain a compound A-2; (S3) subjecting the compound A-2 to a coupling reaction with an organic acid or an acid chloride, or a reaction with an amine and phosgene or a reaction with an amine and carbonyldiimidazole to obtain the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative. The (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative developed by the invention can avoid inhibiting JAK2, and selectively inhibit JAK1 or JAK1/Tyk2, and has important significance for treating autoimmune diseases.

Description

(1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative and preparation method thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative, and a preparation method and application thereof.
Background
The JAK-STAT signal pathway is a signal transduction pathway stimulated by cytokines and is involved in a plurality of important biological processes such as proliferation, differentiation, apoptosis, immunoregulation and the like of cells. Many cytokines and growth factors signal through the JAK-STAT signaling pathway, including interleukins 2-7(IL-2-7), GM-CSF (granulocyte/macrophage colony stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PDGF (platelet derived factor), and IFN (interferon), among others. The JAK protein family includes a total of 4 members: JAK1, JAK2, JAK3 and Tyk 2. Binding of cytokines to the receptor results in the formation of dimers or higher aggregates, allowing recruitment of a pair of JAK kinases to the intracellular domain of the receptor. When in proximity, JAK kinases are phosphorylated and phosphorylate tyrosine residues on the intracellular domain of cytokine receptors. These phosphorylated receptor residues serve as binding sites for Signal Transducer and Activator of Transcription (STAT), which upon binding to the receptor is activated by phosphorylation by JAK, initiating dimerization of STAT and translocation into the nucleus as a transcription factor for gene expression (Schwartz D.M., Kanno Y., et al., nat. Rev. drug Dis.2017; 16: 843-.
JAK1 is the most widespread subtype among these signal pairs, and inhibition of JAK1 inhibits JAK1/JAK3 dependent γ -common chain cytokines, JAK1/JAK2 dependent IFN γ and IL-6 and other gp130 cytokines, and JAK1/TYK2 dependent type I interferons and IL-10 family cytokines (O' Sullivan L.A., Liongue C., et al., mol. Immunol.2007; 44: 2497-2506). Recent findings indicate that inhibition of JAK1 is a major cause of in vivo efficacy of JAK inhibitors in immune inflammatory diseases (Haan c., Rolvering c., et al., chem.biol.2011; 18: 314-23).
TYK2 has an important role for the signaling of JAK1/TYK 2-dependent type I interferons and JAK2/TYK 2-dependent IL-12 and IL-23 (Dendrou C.A., cortex A., et al, Sci.Transl.Med.2016; 8:363ra 149). TYK2 signaling is involved in the pathophysiology of a variety of immune-mediated diseases, including psoriasis, lupus, and inflammatory bowel disease. Recently, a phase II clinical study of the selective TYK2 inhibitor of BMS, BMS-9861657, in the treatment of moderate to severe plaque psoriasis showed good efficacy and safety. In addition, the antibody, Ustekinumab, which inhibits the common P40 subunit of IL-12 and IL-23, has been approved for the treatment of PSO, PSA and CD and has shown efficacy in a secondary clinical SLE trial. IL-23 antagonists show efficacy in CD and PSO (Frieder J., Kivelevitch D., et al., Clin. Pharmacol. Ther.2018; 103: 88-101).
JAK2 uniquely forms homodimers and is important for Erythropoietin (EPO), Thrombopoietin (TPO) and IL-3 associated hematopoiesis through signal transduction (Neubauer H., et al., Cell, 1998; 93(3): 397-409; Parganas E., et al., Cell, 1998; 93(3): 385-95).
The clinical efficacy of JAK inhibitors in the treatment of autoimmune diseases, although becoming more pronounced with increasing doses, is limited by the side effects of red blood cell depletion due to JAK2 inhibition (genoves m.c., Smolen j.s., et al, Arthritis rhematotol.2016; 68: 2857-. Therefore, the development of selective JAK1 or JAK1/Tyk2 inhibitors that avoid inhibiting JAK2 would be of great interest for the treatment of autoimmune diseases.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the invention is to provide a novel (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative for JAK1/Tyk2 kinase inhibitor and pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof, which are not reported in the literature.
The invention also aims to provide a preparation method of the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative.
The technical problem to be solved by the present invention is finally to provide the use of the above (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivatives and pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, esters, optical isomers or prodrugs thereof and methods of using the compounds of the present invention for preventing or treating diseases associated with excessive Janus kinase activity in humans or mammals.
In order to solve the technical problems, the invention provides a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative shown as a formula I or pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer and prodrug thereof;
Figure BDA0002501678870000021
wherein the content of the first and second substances,
R1，R2each independently selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
Or, R1，R2N adjacent thereto may form a substituted or unsubstituted C3-7Heterocyclic amino radicals or C3-9A heteroaryl amino group;
wherein R is4Selected from hydrogen, deuterium, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, amino, substituted or unsubstituted C1-6Alkylamino, substituted or unsubstituted C1-6Haloalkylamino, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halocycloalkylamino, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkylamino, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoalkylamino, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C6-10Arylamino, substituted or unsubstituted C3-9Heteroaryl, or substituted or unsubstituted C3-9A heteroaromatic amino group;
R3a structural formula selected from the group consisting of formula II and formula III:
Figure BDA0002501678870000031
wherein X, Y, Z, Q and W are respectively and independently selected from N or CR6；
Wherein R is6Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group;
wherein R is5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group.
Preferably, said R is1，R2C substituted in (A)1-6Alkyl, substituted C1-6Haloalkyl, substituted C1-6Alkoxy, substituted C1-6Haloalkoxy, substituted C3-7Cycloalkyl, substituted C3-7Cycloalkoxy, substituted C3-7Halocycloalkyl, substituted C3-7Halogenated cycloalkoxy, substituted C3-7Heterocycloalkyl, substituted C3-7Heterocycloalkoxy, substituted C3-7Halogenated heterocycloalkyl, substituted C3-7Halogenoheterocycloalkoxy, substituted C6-10Aryl, substituted C3-9The substituent groups in the heteroaryl are respectively and independently selected from halogen, cyano, hydroxyl, amino, substituted or unsubstituted acylamino, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclic alkyl aminesRadical, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl
Preferably, said R is1，R2Each independently selected from hydrogen, deuterium, or one of the following structures:
Figure BDA0002501678870000041
preferably, said R is3In which X is N, Y is CH, Z is CH, Q is CH, W is N, i.e. R3Selected from one of the following structures:
Figure BDA0002501678870000042
preferably, said R is4C substituted in (A)1-6Alkyl, substituted C1-6Haloalkyl, substituted C1-6Alkoxy, substituted C1-6Haloalkoxy, substituted C1-6Alkylamino, substituted C1-6Haloalkylamino, substituted C3-7Cycloalkyl, substituted C3-7Cycloalkylamino, substituted C3-7Halocycloalkyl, substituted C3-7Halocycloalkylamino, substituted C3-7Heterocycloalkyl, substituted C3-7Heterocyclylamino, substituted C3-7Halogenated heterocycloalkyl, substituted C3-7Halogenoalkylamino, substituted C6-10Aryl, substituted C6-10Arylamino, substituted C3-9Heteroaryl, substituted C3-9The substituent groups in the heteroaralmino are respectively and independently selected from halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-4Alkenyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclylamino, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl groups.
Preferably, said R is5C substituted in (A)6-10Aryl, substituted C3-9The substituents in the heteroaryl group are independently selected from halogen, cyano, hydroxy, amino, -COOH, -COO (C)1-6Alkyl), -CONH2、-CONH(C1-6Alkyl), -CONH- (C)3-7Cycloalkyl), -CO- (C)3-7Cycloalkylamino), -CONH- (C)3-7Heterocycloalkyl), -CON (C)1-6Alkyl radical)2、-NHCO-(C1-6Alkyl), -NHCO- (C)3-7Cycloalkyl), -NHCO- (C)3-7Heterocycloalkyl), -NHCO- (C)6-10Aryl), -NHCO- (C)3-9Heteroaryl), substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclylamino, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl groups.
Further preferably, the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any one of the structures shown in formula A-3 or formula B-4:
Figure BDA0002501678870000051
wherein R is1Selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
R5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group; preferably, R5Selected from one of the following structures:
Figure BDA0002501678870000052
R6selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group.
Further preferably, the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any one of the structures shown in formula IV:
Figure BDA0002501678870000061
most preferably, the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any one of the structures shown in formula v:
Figure BDA0002501678870000062
a pharmaceutical composition containing the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof is also within the protection scope of the present invention.
A pharmaceutical formulation comprising a therapeutically effective amount of the above (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative, together with a pharmaceutically acceptable excipient is also within the scope of the invention.
Wherein the pharmaceutical formulation is formulated for a route of administration selected from oral, parenteral, oral, nasal, topical or rectal administration.
The use of a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative, or a pharmaceutical composition or formulation as described in any of the above, in the manufacture of a medicament for the prevention or treatment of a disease caused by excessive Janus kinase activation, i.e. a disease associated with excessive Janus kinase activity.
Wherein, the disease caused by the Janus kinase comprises autoimmune disease, inflammatory disease, allergic disease and cancer.
Wherein, the Janus kinase caused diseases include (but are not limited to) multiple sclerosis, lupus erythematosus, rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, psoriasis, asthma, vitiligo, psoriasis, alopecia, xerophthalmia, atopic dermatitis, autoimmune thyroid diseases, chronic or acute organ transplant rejection, ulcerative colitis, Crohn's disease, leukemia, multiple myeloma, pancreatic cancer, brain tumor, Alzheimer's disease and type I diabetes.
The invention includes the step of contacting the pharmaceutical formulation with a Janus kinase, said contacting step comprising an in vitro or in vivo assay.
The preparation method of the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative A-3 comprises the following steps: (S1) carrying out nucleophilic aromatic substitution (SNAr) reaction on the compounds I-1 and I-2 to obtain a compound A-1; (S2) treating the compound A-1 with hydrochloric acid or trifluoroacetic acid to remove Boc protection to obtain a compound A-2; (S3) subjecting compound a-2 to a coupling reaction with an organic acid or an acid chloride, or with an amine and phosgene solids, or with an amine and Carbonyldiimidazole (CDI) to give (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative a-3;
Figure BDA0002501678870000071
wherein R is1As previously described.
In the step (S1), the molar ratio of the intermediate I-1 to the intermediate I-2 is 1: 0.8-1.2, preferably 1: 1; the reaction is carried out at 70-80 ℃ for 3-6 h, and preferably at 75 ℃ for 5 h.
In the step (S2), the Boc removal with hydrochloric acid of the compound A-1 is carried out by adding HCl (4M dioxane solution) into methanol solution of the compound A-1 and reacting at room temperature for 2-4 h; wherein the concentration of the compound A-1 in the methanol solution of the compound A-1 is 0.07-0.09 mmol/mL, preferably 0.081 mmol/mL; the volume ratio of the methanol solution of the compound A-1 to the HCl is 8-12: 1, and preferably 10: 1.
In the step (S3), the reaction is preferably performed by coupling the compound a-2 with an acid chloride, or reacting with an amine and CDI to obtain a-3.
The coupling reaction of the compound A-2 and acyl chloride is to add acyl chloride into a dichloromethane solution of the A-2 and triethylamine at a low temperature (preferably 0 ℃), and stir at room temperature for 0.5-2 h. Wherein, the acyl chloride is any one of methane sulfonyl chloride, ethyl sulfonyl chloride, propyl sulfonyl chloride, butyl sulfonyl chloride and cyclopropyl sulfonyl; the molar ratio of the compound A-2 to acyl chloride is 0.9-1: 1, preferably 0.95: 1; the molar ratio of the compound A-2 to triethylamine is 1: 1.5-2.5, preferably 1: 2; the concentration of the compound A-2 is 0.01-0.02 mmol/mL, preferably 0.019 mmol/mL.
Wherein the reaction of the compound A-2, amine and CDI is to stir a tetrahydrofuran solution of the compound A-2 and CDI for 1.5-3 h (preferably 2h) at room temperature; and then adding amine, stirring and reacting at room temperature for 2-4 h (preferably 3 h). Wherein, the amine is preferably 2,2, 2-trifluoroethylamine; the molar ratio of the compound A-2 to the CDI is 0.8-1: 1, preferably 0.863: 1; the concentration of the compound A-2 is 0.01-0.02 mmol/mL, preferably 0.019 mmol/mL; the molar ratio of the compound A-2 to the amine is 0.8-1: 1, preferably 0.863: 1.
The preparation method 2 of the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4 comprises the following steps: (A1) carrying out nucleophilic aromatic substitution (SNAr) reaction on the compound I-3 and the compound I-1 to obtain a compound B-1; (A2) carrying out nucleophilic aromatic substitution (SNAr) reaction on the compound B-1 and organic amine, or coupling the compound B-1 and the organic amine under the catalysis of Pd to obtain a compound B-2; (A3) the compound B-2 is subjected to Boc removal protection by hydrochloric acid or trifluoroacetic acid to obtain a compound B-3; (A4) carrying out coupling reaction on the compound B-3 and organic acid or acyl chloride, or reacting with organic amine and solid phosgene, or reacting with amine and Carbonyl Diimidazole (CDI) to obtain a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4;
Figure BDA0002501678870000081
wherein R is1，R5，R6As previously described.
In the step (A1), the molar ratio of the compounds I-3 and I-1 is 1: 0.8-1.2, preferably 1: 1; the reaction is carried out at room temperature for 5-8 h, preferably 6 h.
In the step (A2), the molar ratio of the compound B-1 to the organic amine is 1: 0.8-1.2, preferably 1: 1; the reaction is carried out for 1-4 h at 130-160 ℃, preferably for 3h at 150 ℃.
In the step (A3), the removal of Boc protection by using the compound B-2 hydrochloric acid is carried out by adding HCl (4M dioxane solution) into a methanol solution of the compound B-2, and reacting at room temperature for 2-4 h; wherein the concentration of the compound B-2 in the methanol solution of the compound B-2 is 0.07-0.2 mmol/mL, preferably 0.1 mmol/mL; the volume ratio of the methanol solution of the compound B-2 to the HCl is 0.8-1.2: 1, preferably 1:1.
In the step (A4), the reaction is preferably carried out by coupling the compound B-3 with an organic acid or reacting with an amine and CDI to obtain B-4.
The coupling reaction of the compound B-3 and the organic acid is to stir a solution of the compound B-3, the organic acid, HATU and N, N-Diisopropylethylamine (DIEA) in N, N-dimethylformamide at room temperature for 1-3 h (preferably 2 h). Wherein the organic acid is any one of (1R, 2R) -2-cyanocyclopropane carboxylic acid, (R) -2, 2-difluorocyclopropane carboxylic acid, cyclopropane formic acid, 4,4, 4-trifluorobutyric acid and 2-cyanoacetic acid; the molar ratio of the compound B-3, the organic acid, HATU and DIEA is 1: 1-1.3: 1-1.3: 2-2.2; the concentration of the compound B-3 is 2-2.5 mmol/mL.
Wherein, the amine in the reaction of the compound B-3, amine and CDI is any one or a combination of more of 2-aminoacetonitrile hydrochloride, triethanolamine and 2,2, 2-trifluoroethyl-1-amine; the compound B-3 may be added with the amine and CDI for reaction, or the amine and CDI may be added first and then the compound B-3 may be added for reaction.
Wherein, the two are put together, namely, the compound B-3, the CDI and the amine (preferably triethanolamine and 2-aminoacetonitrile hydrochloride with the mol ratio of 1:1) are dissolved in tetrahydrofuran, and are stirred and reacted for 3-5 h at the temperature of 30-60 ℃; preferably stirring and reacting for 4 hours at 50 ℃; the molar ratio of compound B-3, CDI and amine was 1: 1.1-1.2: 4; the concentration of the compound B-3 is 0.04-0.06 mmol/mL, preferably 0.042 mmol/mL.
Wherein, firstly adding amine and CDI, and then adding the compound B-3 is to stir and react amine (preferably 2,2, 2-trifluoroethyl-1-amine) and a tetrahydrofuran solution of CDI at a low temperature (preferably 0 ℃) for 0.5 to 2 hours (preferably 1 hour); adding the compound B-3, and stirring at room temperature for 12-20 h; wherein the molar ratio of the amine to the CDI to the compound B-3 is 1:1: 0.8-0.9; the concentration of the amine is 0.02-0.04 mmol/mL, preferably 0.024 mmol/mL.
Another process for producing the above-mentioned (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4, comprises the steps of: (B1) carrying out nucleophilic aromatic substitution (SNAr) reaction on the compound I-3 and the compound I-1 to obtain a compound B-1; (B2) treating the compound B-1 with hydrochloric acid or trifluoroacetic acid to remove Boc protection and then converting the compound B-1 into a compound B-5; (B3) carrying out coupling reaction on the compound B-5 and organic acid or acyl chloride, or reacting with organic amine and solid phosgene, or reacting with amine and Carbonyl Diimidazole (CDI) to obtain a compound B-6; (B4) the compound B-6 and organic amine are coupled or SNAr reacted under the catalysis of Pd to obtain (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4;
Figure BDA0002501678870000091
wherein R is1，R5，R6As previously described.
In the step (B2), the Boc protection removal by using the compound B-1 hydrochloric acid is that HCl (4M dioxane solution) is added into a methanol solution of the compound B-1, and then the reaction is carried out for 2-4 h at room temperature; wherein the concentration of the compound B-1 in the methanol solution of the compound B-1 is 0.07-0.2 mmol/mL, preferably 0.1 mmol/mL; the volume ratio of the methanol solution of the compound B-1 to the HCl is 1.5-2.5: 1, preferably 2: 1.
In the step (B3), the reaction is preferably carried out by reacting the compound B-5 with an amine and Carbonyldiimidazole (CDI) to obtain a compound B-6; specifically, amine (preferably 2,2, 2-trifluoroethyl-1-amine) and a tetrahydrofuran solution of CDI are stirred and react for 0.5-2 h (preferably 1h) at a low temperature (preferably 0 ℃); adding the compound B-5, and stirring at room temperature for 12-20 h; wherein the molar ratio of the amine to the CDI to the compound B-3 is 1:1: 0.8-0.9; the concentration of the amine is 0.06-0.07 mmol/mL, preferably 0.069 mmol/mL.
In the step (B4), the compound B-6 and organic amine SNAr react to obtain the compound B-4, wherein the molar ratio of the compound B-6 to the organic amine is 3-4: 1, preferably 3.2: 1; the solvent is preferably isopropanol, and the concentration of the compound B-6 is 0.01-0.02 mmol/mL, preferably 0.0145 mmol/mL; the reaction is carried out at 120-150 ℃ for 1-3 h, preferably at 140 ℃ for 2 h.
In the step (B4), the compound B-6 and organic amine are coupled under the catalysis of Pd to obtain B-4, wherein the molar ratio of the compound B-6 to the organic amine is 1: 0.8-1, and preferably 1: 0.87; the mole ratio of the Pd catalyst to the compound B-6 is 1: 0.8-1.3, preferably 1: 1; the solvent is preferably dioxane, and the concentration of the compound B-6 is 0.01-0.02 mmol/mL, preferably 0.0145 mmol/mL; the reaction is carried out for 2-4 h at 90-110 ℃, preferably for 3h at 100 ℃.
There is no particular requirement for the rate of agitation in the present invention.
Each of the products of the reaction in compounds A-3 and B-4 described above may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials required for synthesis may be synthesized by themselves or purchased from commercial establishments, such as, but not limited to, Aldrich or Sigma. These materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described herein can be synthesized to give a single optical isomer or a mixture of optical isomers.
The letters in the present invention are indicated by the superscript number of the radical and the subscript number of the atom, for example: r1、R2、R3Represents 1 to 3R groups, C1-4The alkyl group represents an alkyl group having 1 to 4C atoms. The number of C atoms on the substituents is not counted in the main chain.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the invention develops the selective inhibition of JAK1 or JAK1/Tyk2 while avoiding the inhibition of JAK2, and the inhibitor has important significance for treating autoimmune diseases.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Example 1: synthesis of intermediate I-1
Synthetic route of intermediate I-1
Figure BDA0002501678870000111
(1)7(R) -amino-2- ((S) -1-phenylethyl) -2-aza-bicyclo [2,2,1] heptane 2
Figure BDA0002501678870000112
A solution of compound 1(1g, 3.57mmol) in a saturated solution of ammonia in methanol (10mL) was stirred at 80 ℃ for 2 hours. It was then concentrated to give crude 2(771mg, 99.5%) which was used in the next step without purification.
(2)2- ((S) -1-phenylethyl) -2-aza-bicyclo [2,2,1] heptane-7 (R) -carbamic acid tert-butyl ester 3
Figure BDA0002501678870000113
To a solution of Compound 2(500mg, 2.3mmol) in DCM (20mL) was added TEA (257mg, 2.53mmol) and Boc2O (555mg, 2.53mmol), and then stirred at room temperature for 4 hours. It was concentrated and purified by column chromatography, eluting with EA/PE ═ 1: 9 to give the desired compound 3(444mg, 61%).1HNMR(300MHz,DMSO)：δ＝7.15-7.30(m,5H)；6.71(s,1H)；4.00(m,1H)；3.50-3.60(m,2H)；3.05(m,1H)；2.85(m,1H)；2.05-2.15(m,2H)；1.60-1.80(m,2H)；1.38(s,9H)；1.31(m,1H),1.20-1.25(d,3H,J＝11.1Hz)。
(3) 2-azabicyclo [2,2,1] heptane-7 (R) -carbamic acid tert-butyl ester I-1
Figure BDA0002501678870000114
A mixed solution of Compound 3(443mg, 1.4mmol) and Pd/C (200mg) in MeOH (30mL) was H at room temperature2Stirring overnight under atmosphere (1atm), filtering and concentrating to give crude I-1(360mg, 99%) which was used in the next step without purification.1H NMR(500MHz,CDCl3)：δ＝4.54(s,br,1H)；3.80(s,1H)；3.34(s,1H)；3.10(d,1H,J＝9.75Hz)；2.66-2.67(d,1H,J＝9.65Hz)；2.30(s,1H)；1.70-1.90(m,4H)；1.50-1.60(m,1H)；1.38(s,9H)。
Example 2: synthesis of intermediate I-2
Figure BDA0002501678870000121
4-chloro-7- (benzenesulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine I-2
Figure BDA0002501678870000122
To a solution of compound 5(1g, 6.53mmol) in THF (20mL) at 0 deg.C was added NaH (391mg, 9.79mmol) portionwise, stirred for 20min, then PhSO was added2Cl (1.12g, 6.53mmol), stirred at room temperature for 2 h. Poured into water (20mL) and extracted with EA (2X20 mL). Separating the organic phase with anhydrous Na2SO4Drying, filtration and concentration, purification by column chromatography eluting with EA/PE-1/4 solvent gave compound I-2(1.3g, 68%).1H NMR(500MHz,CDCl3)：δ＝8.82(s,1H)；8.26-8.27(d,2H,J＝8.2Hz)；7.83-7.84(d,1H,J＝3.95Hz)；7.68-7.71(m,1H)；7.57-7.61(m,2H)；6.76-6.77(d,1H,J＝4.0Hz)。
Example 3: synthesis of Compound A-3
Synthetic route to compound A-3
Figure BDA0002501678870000123
(1)2- (7- (benzenesulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -ylcarbamic acid tert-butyl ester A-1
Figure BDA0002501678870000131
A mixture of compound I-2(304mg, 1.04mmol), compound I-1(220mg, 1.04mmol) and DIEA (268mg, 2.08mmol) in IPA (20mL) was heated to 75 deg.C and stirred for 5 hours. Poured into water (20mL) and extracted with EA (2X20 mL). Separating the organic phase fromAnhydrous Na2SO4Drying, filtration and concentration, purification by column chromatography eluting with EA/PE ═ 1/4 solvent afforded compound a-1(381mg, 81%). LC-MS M/z 470.0[ M +1]]+。
(2)7(R) -amino- (7- (benzenesulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptane A-2
Figure BDA0002501678870000132
To a solution of Compound A-1(381mg, 0.81mmol) in MeOH (10mL) was added 1mL of 4M HCl in dioxane. The mixture was stirred at room temperature for 2 hours. Poured into water (10mL) and treated with NaHCO3The pH was adjusted to 8 with aqueous solution and then extracted with EA (2X20 mL). Separating organic phase with anhydrous Na2SO4Drying, filtration and concentration, purification by column chromatography eluting with EA/PE-1/1 solvent afforded compound a-2(212mg, 72%).
(3-1) N- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) methanesulfonamide A-3-1
Figure BDA0002501678870000133
To a solution of compound A-2(35mg,0.095mmol) and Et3N (19mg, 0.19mmol) in DCM (5mL) was added methanesulfonyl chloride (11mg, 0.1mmol) at 0 deg.C, followed by stirring at room temperature for 1 hour. Poured into water (10mL) and extracted with DCM, the combined organic phases were separated and dried over anhydrous Na2SO4Dried, filtered and concentrated. The crude product was dissolved in THF (1mL)/H2To O (0.5mL), NaOH (6mg, 0.14mmol) was added and the mixture was heated to 60 ℃ and stirred for 3 hours. Poured into water (10mL) and extracted with DCM, the combined organic phases were separated and dried over anhydrous Na2SO4Dried, filtered and concentrated. Purification by column chromatography eluting with EA/PE 1:1 solvent gave compound a-3-1(10mg, 35%). LC-MS M/z 308.2[ M +1]]+。
(3-2) (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -yl) ethanesulfonamide A-3-2
Figure BDA0002501678870000141
Compound A-3-2(2mg, 7%) was synthesized using the same synthetic procedure as A-3-1, starting from A-2(35mg,0.095mmol) with ethylsulfonyl chloride (13mg, 0.1mmol) instead of methanesulfonyl chloride. LC-MS M/z 322.1[ M +1] +.
(3-3) N- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -yl) propane-1-sulfonamide A-3
Figure BDA0002501678870000142
Compound A-3-3(3mg, 10%) was synthesized using the same synthetic procedure as A-3-1, starting from A-2(35mg,0.095mmol) with propylsulfonyl chloride (14mg, 0.1mmol) instead of methanesulfonyl chloride. LC-MS M/z is 336.1[ M +1] +.
(3-4) N- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) butane-1-sulfonamide A-3-4
Figure BDA0002501678870000151
Compound A-3-4 was synthesized in the same manner as in A-3-1, from A-2(35mg,0.095mmol) using butylsulfonyl chloride (16mg, 0.1mmol) instead of methanesulfonyl chloride, to give compound A-3-4(2mg, 6%). LC-MS M/z 350.2[ M +1] +.
(3-5) N- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) cyclopropanesulfonamide A-3-5
Figure BDA0002501678870000152
Compound A-3-5(2mg, 6%) was synthesized using the same synthetic procedure as A-3-1, starting from A-2(35mg,0.095mmol) with cyclopropylsulfonyl chloride (16mg, 0.1mmol) instead of methanesulfonyl chloride. LC-MS M/z is 334.2[ M +1] +.
(3-6) Synthesis of Compound A-3-6
Figure BDA0002501678870000153
1- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -yl) -3- (2,2, 2-trifluoroethyl) urea A-3-6
A solution of Compound A-2(35mg,0.095mmol) and CDI (19mg, 0.11mmol) in THF (5mL) was stirred at room temperature for 2 hours. 2,2, 2-trifluoroethylamine (11mg, 0.11mmol) was added, stirring was further continued for 3 hours, poured into water (10mL) and extracted with DCM, the organic phase was separated, and Na anhydrous was used2SO4Dried, filtered and concentrated. The crude product was dissolved in THF (1mL)/H2To O (0.5mL), NaOH (6mg, 0.14mmol) was added and the mixture was heated to 60 ℃ and stirred for 3 hours. Poured into water (10mL) and extracted with DCM, the combined organic phases were separated and Na was used2SO4Dried, filtered and concentrated. Purification by column chromatography eluting with EA/PE 1:1 solvent gave compound a-3-6(3mg, 9%). LC-MS M/z 355.1[ M +1]]+。
Example 4: synthetic route of compound B-4-1-n
Figure BDA0002501678870000161
(1) (2-Chloropyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -carbamic acid tert-butyl ester B-1
Figure BDA0002501678870000162
A mixture of compound I-3-1(415mg, 2.8mmol), compound I-1(594mg, 2.8mmol) and TEA (1.13g, 11.2mmol) in DCM (20mL) was stirred at room temperature for 6 hours, concentrated and purified by column chromatography eluting with PE/EA ═ 1:1 solvent to give compound B-1-1(500mg, 55%).
(2) (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-azabicyclo [2,2,1] hept-7 (R) -carbamic acid tert-butyl ester B-2-1
Figure BDA0002501678870000171
A mixture of compound B-1-1(140mg, 0.43mmol), 1-methyl-1H-pyrazol-4-amine (42mg, 0.43mmol) and DIEA (0.1mL) in IPA (5mL) was heated to 150 ℃ and stirred for 3 hours. Cool to room temperature and evaporate the solvent to dryness, dilute the residue with DCM (50mL), wash with water and brine, dry and filter. Purification by column chromatography eluting with MeOH/DCM ═ 1:10 solvent afforded product B-2-1(115mg, 70%). MS M/z 386.1[ M +1] +.
(3)7(R) -amino- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-azabicyclo [2,2,1] heptane B-3-1
Figure BDA0002501678870000172
To a solution of compound B-2-1(115mg, 0.299mmol) in MeOH (3mL) was added 3mL HCl (4M in dioxane), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and dissolved in DCM (20mL), 3mL of TEA was added and filtered. The filtrate was concentrated and purified by column chromatography with MeOH/DCM ═ 1: solvent elution 8 gave product B-3-1 ═ 72mg, 85%. MS M/z 286.1[ M +1] +.
(4-1) (1R, 2R) -2-cyano-N- (2- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptane-7 (R) -yl) cyclopropanecarboxamide B-4-1
Figure BDA0002501678870000173
Compound B-3-1(21mg, 0.074mmol), (1R, 2R) -2-cyanocyclopropanecarboxylic acid (9mg, 0.08mmol), HATU (28mg, 0.074mmol) and DIEA (19mg, 0.148mmol) were stirred in DMF (1mL) at room temperature for 2 hours, poured into water (10mL) and extracted with ethyl acetate (2X10mL)Washing the organic substance with saturated NaCl aqueous solution, and passing through anhydrous Na2SO4Dried, filtered, concentrated, and purified by column chromatography with MeOH/DCM ═ 1: elution with 10 solvents gave compound B-4-1-1(6mg, 21%). LC-MS M/z 379.2[ M +1]]+。
(4-2) (1S) -2, 2-difluoro-N- (2- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptan-7 (R) -yl) cyclopropanecarboxamide B-4-1-2
Figure BDA0002501678870000181
Compound B-3-1(15mg, 0.053mmol), (R) -2, 2-difluorocyclopropanecarboxylic acid (7mg, 0.058mmol), HATU (22mg, 0.058mmol) and DIEA (15mg, 0.116mmol) were stirred in DMF (1mL) at room temperature for 2 hours, poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics washed with saturated aqueous NaCl solution, over anhydrous Na2SO4Dried, filtered, concentrated and purified by column chromatography, eluting with MeOH/DCM ═ 1: elution with 10 solvent gave compound B-4-1-2(5mg, 25%). LC-MS M/z 390.2[ M +1]]+。
(4-3) N- (2- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) cyclopropanecarboxamide B-4-1-3
Figure BDA0002501678870000182
A solution of compound B-3-1(23mg, 0.08mmol), cyclopropanecarboxylic acid (8.3mg, 0.097mmol), HATU (37mg, 0.097mmol) and DIEA (21mg, 0.16mmol) in DMF (1mL) was stirred at room temperature for 2 hours, poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics washed with saturated aqueous NaCl solution, over anhydrous Na2SO4Drying, filtration, concentration and purification by column chromatography eluting with MeOH/DCM ═ 1:10 solvent gave compound B-4-1-3(5mg, 18%). LC-MS M/z 354.1[ M +1]]+。
(4-4)4,4, 4-trifluoro-N- (2- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptan-7 (R) -yl) butanamide B-4-1-4
Figure BDA0002501678870000191
Compound B-3-1(15mg, 0.053mmol), 4,4, 4-trifluorobutanoic acid (8mg, 0.058mmol), HATU (22mg, 0.058mmol) and DIEA (15mg, 0.116mmol) in DMF solution (1mL) were stirred at room temperature for 2 hours, poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics washed with saturated aqueous NaCl solution, washed with anhydrous Na2SO4Drying, filtration, concentration and purification by column chromatography eluting with MeOH/DCM 1:10 solvent afforded compound B-4-1-4(6mg, 27%). LC-MS M/z 410.3[ M +1]]+。
(4-5) 2-cyano-N- (2- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) acetamide B-4-1-5
Figure BDA0002501678870000192
A solution of compound B-3-1(15mg, 0.053mmol), 2-cyanoacetic acid (7mg, 0.058mmol), HATU (22mg, 0.058mmol) and DIEA (15mg, 0.116mmol) in DCM (1mL) was stirred at room temperature for 2 hours, poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics washed with saturated aqueous NaCl solution, over anhydrous Na2SO4Drying, filtration, concentration and purification by column chromatography eluting with MeOH/DCM ═ 1:10 solvent gave compound B-4-1-5(8mg, 43%). LC-MS M/z 353.2[ M +1]]+。
(4-6) synthetic route of Compound B-4-1-6
Figure BDA0002501678870000201
1- (cyanomethyl) -3- (2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) urea B-4-1-6
Figure BDA0002501678870000202
A mixture of compound B-3-1(12mg, 0.042mmol), CDI (8mg, 0.05mmol), TEA (8.5mg, 0.084mmol) and 2-aminoacetonitrile hydrochloride (8mg, 0.084mmol) in THF (1mL) was stirred at 50 ℃ for 4 hours, concentrated and purified by column chromatography with MeOH/DCM ═ 1: solvent elution 10 gave product B-4-1-6(5mg, 32%). LC-MS M/z is 368.1[ M +1] +.
(4-7) synthetic route of Compound B-4-1-7
Figure BDA0002501678870000203
(2- (2- (1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -yl) -3- (2,2, 2-trifluoroethyl) urea B-4-1-7
Figure BDA0002501678870000211
A solution of 2,2, 2-trifluoroethyl-1-amine (7.2mg, 0.072mmol) and CDI (12mg, 0.072mmol) in THF (3mL) was stirred at 0 ℃ for 1h, then Compound B-3-1(17mg, 0.06mmol) was added and the mixture stirred at room temperature overnight. Poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics separated, dried, concentrated by filtration and purified by column chromatography with MeOH/DCM ═ 1: 20 to give product B-4-1-7(8mg, 28%). LC-MS M/z 411.1[ M +1] +.
Example 5: synthetic route of compound B-4-1-8/B-4-1-9
Figure BDA0002501678870000212
(1)7(R) -amino-N- (2-chloropyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptane B-5-1
Figure BDA0002501678870000213
To a solution of compound B-1-1(200mg, 0.62mmol) in DCM (6mL) was added 3mL HCl (4M in dioxane), the mixture was stirred at room temperature for 3 hours, the solvent was evaporated and the residue was dissolved in DCM (3mL), TEA (1mL) was added to adjust the pH to 8, filtered and the filtrate was concentrated and purified by column chromatography eluting with MeOH/DCM ═ 1:10 solvent to give product B-5-1(128mg, 93%).
(2)1- (2- (2-Chloropyrimidin-4-yl) -2-aza-bicyclo [2,2,1] hept-7 (R) -yl) -3- (2,2, 2-trifluoroethyl) urea B-6-1
Figure BDA0002501678870000221
A solution of 2,2, 2-trifluoroethylamine (68mg, 0.69mmol) and CDI (112mg, 0.69mmol) in THF (10mL) was stirred at 0 ℃ for 1h, then Compound B-5-1(128mg, 0.57mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water (10mL) and extracted with ethyl acetate (2X10mL), the organics were separated, dried, filtered and purified by column chromatography with MeOH/DCM ═ 1: solvent elution of 20 gave product B-6-1(149mg, 62%). LC-MS M/z 350.0[ M +1] +.
(3-1)1- (2- (2- (2- (4- (methylcarbamoyl) phenylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) -3- (2,2, 2-trifluoroethyl) urea B-4-1-8
Figure BDA0002501678870000222
A mixture of compound B-6-1(10mg, 0.029mmol) and 4-amino-N-methylbenzamide (435mg, 0.09mmol) in IPA (2mL) was stirred at 140 deg.C for 2 hours. After cooling, concentrate and purify by column chromatography with MeOH/DCM ═ 1: elution with 20 solvents gave compound B-4-1-8(4mg, 31%). LC-MS M/z 464.2[ M +1] +.
(3-2)1- (2- (2- (6- (6- (methylcarbamoyl) pyridin-3-ylamino) pyrimidin-4-yl) -2-aza-bicyclo [2,2,1] heptyl-7 (R) -yl) -3- (2,2, 2-trifluoroethyl) urea B-4-1-9
Figure BDA0002501678870000223
Compound B-6-1(10mg, 0.029mmol), 5-amino-N-methylpyridinemethylamide (5mg, 0.034mmol), Pd2dba3(2.6mg, 0.0029mmol), Xantphos (3.3mg, 0.0058mmol) and Cs2CO3A solution of (12mg, 0.038mmol) in dioxane (2mL) was stirred at 100 ℃ for 3h, concentrated under cooling, dissolved in DCM (20mL), concentrated by filtration, purified by column chromatography with MeOH/DCM ═ 1: elution with 10 solvent gave compound B-4-1-9(3mg, 22%). LC-MS M/z 465.1[ M +1]]+。
Example 6: in vitro inhibitory Activity against JAK1/JAK2/TYK2 (determination of IC50 value)
(1) Experimental methods
The substrate solution was prepared by adding the substrate poly (Glu, Tyr) sodium salt (Sigma Aldrich, St. Louis, Mo.) to a substrate reaction buffer (20mM Hepes, pH 7.5), 10mM MgCl2，1mM EGTA，0.02％Brij35，0.02mg/mL BSA，0.1mM Na3VO42mM DTT and 1% DMSO) (final substrate concentration in the reaction mixture is 0.2. mu.M). Test compounds (each compound in table 1) were formulated in stock solutions of 10mM concentration with 100% DMSO and 3-fold serial dilutions of 10 doses were performed in 384-well circulating olefin copolymer LDV microplates. JAK1/JAK2/TYK2 kinase (recombinant human full length protein, histidine tag, expressed in insect cells, Invitrogen, Carlsbad, CA) was added to the substrate solution and gently mixed (final concentration of JAK1/JAK2/TYK2 in the reaction was 8 nM). The test compounds in 100% DMSO were then added to the kinase reaction mixture by acoustic liquid transfer technique (Echo 550; nanoliter range) (labcell Inc, Sunnyvale, CA) and incubated for 20 minutes at room temperature. 33P-ATP (specific activity 10. mu. Ci/. mu.L) was added to the reaction mixture to initiate the reaction, followed by incubation at room temperature for 2 hours. A small portion of the reaction was spotted on P-81 ion exchange filter paper (Whatman). Unbound phosphate on the filter paper was washed off with 0.75% phosphate buffer (three times) and dried, and the residue on the filter paper was measuredIs not required. Kinase activity data is expressed as a percentage of the remaining kinase activity in the test sample reacted with the carrier (dimethyl sulfoxide) blank. IC50 values were calculated by curve fitting the obtained data using prism (graphpad software) software.
(2) Results of the experiment
Most of the compounds have stronger inhibition capability to JAK1 kinase activity (100 nM), more importantly, most of the compounds show weaker inhibition activity to JAK2, wherein the inhibition activities of the compounds A-3-6 to Jak1 and Jak2 are respectively 9.08nM and 457nM, and the compounds show higher selectivity compared with a reference substance PF-06700841(Jak2/Jak1: 50vs 4.5); compound B-4-1-8 has stronger inhibition (7.35 nM and 5.57nM respectively) on Jak1 and Tyk2, and has 162nM inhibition activity on Jak2, and the selectivity is better than that of reference PF-06700841(Jak2/Jak1:22vs 4.5; Jak2/Tyk 2: 29vs 3.3).
Table 1 results of inhibition of JAK1/JAK2/TYK2 kinase activity: a is less than or equal to 10 nM; b is more than 10nM and less than or equal to 100 nM; c is more than 100nM and less than or equal to 1 mu M; 1 μ M < D; NT-Not Tested;
Figure BDA0002501678870000241
the present invention provides the idea and method of (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivatives and the preparation method, and the method and the way to realize the technical scheme are many, the above mentioned is only the preferred embodiment of the present invention, it should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.

Claims (16)

1. (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivatives of formula I, or pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, esters, optical isomers, prodrugs thereof;
Figure FDA0002501678860000011
wherein the content of the first and second substances,
R1，R2each independently selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
Or, R1，R2Adjacent to it, N forms a substituted or unsubstituted C3-7Heterocyclic amino or substituted or unsubstituted C3-9A heteroaryl amino group;
wherein R is4Selected from hydrogen, deuterium, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, amino, substituted or unsubstituted C1-6Alkylamino, substituted or unsubstituted C1-6Haloalkylamino, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halocycloalkylamino, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkylamino, substituted or non-substitutedSubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoalkylamino, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C6-10Arylamino, substituted or unsubstituted C3-9Heteroaryl, or substituted or unsubstituted C3-9A heteroaromatic amino group;
R3a structural formula selected from the group consisting of formulas II and III:
Figure FDA0002501678860000012
wherein X, Y, Z, Q and W are respectively and independently selected from N or CR6；
Wherein R is6Selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group;
wherein R is5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group.
2. (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] according to claim 1]Heptane derivatives, characterized in that R is1，R2C substituted in (A)1-6Alkyl, substituted C1-6Haloalkyl, substituted C1-6Alkoxy, substituted C1-6Haloalkoxy, substituted C3-7Cycloalkyl, substituted C3-7Cycloalkoxy, substituted C3-7Halocycloalkyl, substituted C3-7Halogenated cycloalkoxy, substituted C3-7Heterocycloalkyl, substituted C3-7Heterocycloalkoxy, substituted C3-7Halogenated heterocycloalkyl, substituted C3-7Halogenoheterocycloalkoxy, substituted C6-10Aryl, substituted C3-9The substituent groups in the heteroaryl are respectively and independently selected from halogen, cyano, hydroxyl, amino, substituted or unsubstituted acylamino, substituted or unsubstituted aminoacyl, substituted or unsubstituted aminoOr unsubstituted C1-4Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclylamino, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl groups.
3. (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] according to claim 1]Heptane derivatives, characterized in that R is3In the structure (1), X is N, Y is CH, Z is CH, Q is CH, and W is N.
4. (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] according to claim 1]Heptane derivatives, characterized in that R is4C substituted in (A)1-6Alkyl, substituted C1-6Haloalkyl, substituted C1-6Alkoxy, substituted C1-6Haloalkoxy, substituted C1-6Alkylamino, substituted C1-6Haloalkylamino, substituted C3-7Cycloalkyl, substituted C3-7Cycloalkylamino, substituted C3-7Halocycloalkyl, substituted C3-7Halocycloalkylamino, substituted C3-7Heterocycloalkyl, substituted C3-7Heterocyclylamino, substituted C3-7Halogenated heterocycloalkyl, substituted C3-7Halogenoalkylamino, substituted C6-10Aryl, substituted C6-10Arylamino, substituted C3-9Heteroaryl, substituted C3-9The substituent groups in the heteroaralmino are respectively and independently selected from halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-4Alkenyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstitutedSubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclylamino, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl groups.
5. (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] according to claim 1]Heptane derivatives, characterized in that R is5C substituted in (A)6-10Aryl, substituted C3-9The substituents in the heteroaryl group are independently selected from halogen, cyano, hydroxy, amino, -COOH, -COO (C)1-6Alkyl), -CONH2、-CONH(C1-6Alkyl), -CONH- (C)3-7Cycloalkyl), -CO- (C)3-7Cycloalkylamino), -CONH- (C)3-7Heterocycloalkyl), -CON (C)1-6Alkyl radical)2、-NHCO-(C1-6Alkyl), -NHCO- (C)3-7Cycloalkyl), -NHCO- (C)3-7Heterocycloalkyl), -NHCO- (C)6-10Aryl), -NHCO- (C)3-9Heteroaryl), substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C1-4Alkylamino, di [ substituted or unsubstituted C1-4Alkyl radical]Amino, substituted or unsubstituted C3-7Cycloalkylamino, substituted or unsubstituted C3-7Heterocyclylamino, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl or substituted or unsubstituted C3-7Any one or more of heterocycloalkyl groups.
6. The (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative of claim 1, wherein the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any one of the structures shown in formula a-3 or formula B-4:
Figure FDA0002501678860000031
wherein R is1Selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
R5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group;
R6selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group.
7. The (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative of claim 6, wherein the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any of the structures shown in formula IV:
Figure FDA0002501678860000041
8. the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative of claim 7, wherein the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative is selected from any of the structures shown in formula V:
Figure FDA0002501678860000042
9. a pharmaceutical composition comprising (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer, prodrug thereof.
10. A pharmaceutical formulation comprising a therapeutically effective amount of a (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative according to any one of claims 1-7, together with a pharmaceutically acceptable excipient.
11. Use of the (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative of any one of claims 1-8, the pharmaceutical composition of claim 9, or the pharmaceutical formulation of claim 10, in the manufacture of a medicament for the prevention or treatment of a disease caused by overactivation of Janus kinase.
12. The use according to claim 11, wherein the disease caused by Janus kinase comprises any one of autoimmune disease, inflammatory disease, allergic disease and cancer.
13. The use of claim 12, wherein said Janus kinase causes a disease selected from the group consisting of multiple sclerosis, lupus erythematosus, rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, psoriasis, asthma, vitiligo, psoriasis, alopecia, xerophthalmia, atopic dermatitis, autoimmune thyroid disorders, chronic or acute organ transplant rejection, ulcerative colitis, crohn's disease, leukemia, multiple myeloma, pancreatic cancer, brain tumors, alzheimer's disease, and type I diabetes.
14. A process for the preparation of (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative A-3 according to claim 6, which comprises the steps of: (S1) carrying out nucleophilic aromatic substitution reaction on the compound I-1 and the compound I-2 to obtain a compound A-1; (S2) treating the compound A-1 with hydrochloric acid or trifluoroacetic acid for deprotection to obtain a compound A-2; (S3) subjecting compound a-2 to a coupling reaction with an organic acid or an acid chloride, or with an amine and phosgene or with an amine and carbonyldiimidazole to give (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative a-3;
Figure FDA0002501678860000051
wherein R is1Selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4。
15. A process for the preparation of (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4 as claimed in claim 6, which comprises the steps of: (A1) carrying out nucleophilic aromatic substitution reaction on the compound I-3 and the compound I-1 to obtain a compound B-1; (A2) carrying out S nucleophilic aromatic substitution reaction on the compound B-1 and organic amine, or coupling the compound B-1 and the organic amine under the catalysis of Pd to obtain a compound B-2; (A3) deprotecting the compound B-2 with hydrochloric acid or trifluoroacetic acid to obtain a compound B-3; (A4) carrying out coupling reaction on the compound B-3 and organic acid or acyl chloride, or reacting with organic amine and solid phosgene, or reacting with amine and carbonyl diimidazole to obtain a compound B-4;
Figure FDA0002501678860000061
wherein R is1Selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
R5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group;
R6selected from hydrogen, deuterium,Halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group.
16. A process for producing (1R,4R,7R) -7-amino-2-azabicyclo [2,2,1] heptane derivative B-4 according to claim 1 to 6, which comprises the steps of: (B1) carrying out nucleophilic aromatic substitution reaction on the compound I-3 and the compound I-1 to obtain a compound B-1; (B2) compound B-1 is converted into compound B-5 after being treated and deprotected by hydrochloric acid or trifluoroacetic acid; (B3) carrying out coupling reaction on the compound B-5 and organic acid or acyl chloride, or reacting with organic amine and solid phosgene, or reacting with amine and carbonyl diimidazole to obtain a compound B-6; (B4) the compound B-6 and organic amine are subjected to coupling or nucleophilic aromatic substitution reaction under the catalysis of Pd to obtain a compound B-4;
Figure FDA0002501678860000062
wherein R is1Selected from hydrogen, deuterium, hydroxy, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Haloalkyl, substituted or unsubstituted C1-6Alkoxy, substituted or unsubstituted C1-6Haloalkoxy, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted C3-7Cycloalkoxy, substituted or unsubstituted C3-7Halocycloalkyl, substituted or unsubstituted C3-7Halogenocycloalkoxy, substituted or unsubstituted C3-7Heterocycloalkyl, substituted or unsubstituted C3-7Heterocycloalkoxy, substituted or unsubstituted C3-7Halogenated heterocycloalkyl, substituted or unsubstituted C3-7Halogenoheterocycloalkoxy, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9Heteroaryl, - (C ═ O) -R4、-(SO2)-R4Or- (SO) -R4；
R5Selected from substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C3-9A heteroaryl group;
R6selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl or C3-7A cycloalkoxy group.
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