CN107880038A

CN107880038A - [1,2,4] triazol [1,5 a] pyridine compounds and their and preparation method thereof and medical usage

Info

Publication number: CN107880038A
Application number: CN201710899860.7A
Authority: CN
Inventors: 殷惠军; 闫旭; 宗利斌; 董流昕; 韩亚超; 郗青川; 窦浩帅; 米桢; 杨琰
Original assignee: China Medicament Research & Development Center Co Ltd
Current assignee: China Medicament Research & Development Center Co Ltd
Priority date: 2016-09-30
Filing date: 2017-09-28
Publication date: 2018-04-06
Anticipated expiration: 2037-09-28
Also published as: CN107880038B

Abstract

The present invention relates to [1,2,4] triazol [1,5 a] pyridine compounds and their and preparation method thereof and medical usage.Especially, the present invention relates to the compound shown in formula I, its preparation method and pharmaceutical composition containing the compound, and its purposes as jak kinase inhibitor, the compound and its pharmaceutical composition containing the compound can be used for treatment and the active related disease of jak kinase, such as inflammation, autoimmune conditions, cancer etc..Each substituent in its formula of I it is defined as the description.

Description

[1,2,4] triazolo [1,5-a ] pyridine compound and preparation method and medical application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel [1,2,4] triazolo [1,5-a ] pyridine compound, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound in regulating the activity of Janus kinase (JAK) and treating and/or preventing diseases related to the activity of JAK.

Background

Intracellular signaling processes are an efficient way for cells to respond to external stimuli and ultimately elicit specific biological effects. Cytokines are capable of intracellular signaling through a variety of signal transduction pathways, thereby being involved in the regulation of hematopoietic functions and many important biological functions associated with immunity. The Janus kinase (JAK) family of protein tyrosine kinases and the activator of transcription (STAT) play important roles in cytokine signaling.

The Janus kinase (JAK) family plays a role in cytokine-dependent regulation of cellular proliferation and function involved in the immune response. Currently, there are four known mammalian JAK family members: jak1 (also known as Janus kinase-1), Jak2 (also known as Janus kinase-2), Jak3 (also known as Janus kinase, leukocyte; JAKL 1; L-JAK and Janus kinase-3), Tyk2 (also known as protein-tyrosine kinase 2). Jak1, Jak2, and Tyk2 are widely present in various tissues and cells, while Jak3 is only present in the bone marrow and lymphatic system.

Tyk2 was the first JAK kinase discovered and plays an important role in regulating the biological response of IL-12 and bacterial Lipopolysaccharide (LPS), and is also involved in IL-6, IL-10 and IL-12 mediated signal transduction pathways. Targeting Tyk2 could be a new strategy for treating IL-12-, IL-23-, or type I IFN-mediated diseases, including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis, inflammatory bowel disease, uveitis, sarcoidosis, and cancer.

Jak1 plays an important role in regulating the biological response functions of a variety of cytokine receptor families. Jak1 knockout mice have an early postnatal lethal factor phenotype and the nervous system is also compromised, resulting in congenital defects in young mice. The study shows that the mice with the Jak1 gene knockout can generate secretion defects of thymocytes and B cells, and the tissue with the Jak1 gene knockout has obviously weakened response to LIF, IL-6 and IL-10. Clinical trials have shown that selective Jak1 inhibitors also have RA-ameliorating effects in clinical studies, and the Jak1 inhibitor ABT-494 in phase III has positive results in two trials involving rheumatoid arthritis patients who do not respond adequately to methotrexate or one of the Tumor Necrosis Factor (TNF) blockers.

Jak2 plays an important role in Epo, IL-3, GM-CSF, IL-5, Tpo, and IFN γ -mediated signal transduction Jak2 knockout mice have an embryonic lethal factor phenotype leading to embryonic death at 12.5 days of gestation due to defective erythropoiesis.similar phenomena have been observed in Epo knockout mice, indicating that Epo is closely related to Jak2 kinase activity.Jak 2 kinase does not participate in IL-23 and IL-14 receptor family-mediated signal transduction.A study indicates that Jak2 kinase does not respond to IFN γ, but responds to IFN α and IL-6.A mutated Jak2 protein can activate downstream signals in the absence of cytokine stimulation, leading to spontaneous growth and/or play a cytokine-hypersensitivity response believed to promote the processes of these diseases.A Jak2 inhibitor has been described as having therapeutic effects on proliferative diseases.

Jak3 plays an important role in a variety of biological processes, such as lymphocyte proliferation processes, IgExtent receptor mediated mast cell degeneration, prevention of T cell activation, and involvement in signal transduction mediated by all γ C families, including IL-23, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 kinase function is not the same in humans and mice, e.g., Severe Combined Immunodeficiency Disease (SCID) patients have normal B cells but lack T cell function. This is because IL-7 plays an important role in B cell proliferation in mice but does not affect B cell proliferation in humans. The Jak3 gene knocks out SCID phenotype of mammals and the specific expression of JAK lymphocytes, making Jak3 an immunosuppressant target. Based on the role of Jak3 in regulating lymphocytes, targeting Jak3 and Jak3 mediated pathways can be useful in the treatment of autoimmune diseases.

After the cytokine binds to the receptor, the receptor forms a dimer, and JAKs coupled to the receptor approach each other and are activated by phosphorylation of tyrosine residues. And then catalyzes phosphorylation of tyrosine residues of the receptor itself to form a "docking site". Signal Transducers and Activators of Transcription (STATs) are a group of cytoplasmic proteins that regulate binding of DNA to target genes. STAT families include STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT 6. STAT recognizes the "docking site" through SH2 domain and is activated by phosphorylation of its C-terminal tyrosine residue by JAK kinases. The activated Stat factor is transferred into the nucleus and plays an important role in regulating innate and adaptive host immune responses.

Activation of the JAK/STAT signaling pathway contributes to the development of a variety of diseases, including, but not limited to, many aberrant immune responses, such as allergy, asthma, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis. It is also associated with cancers such as leukemia (acute myeloid leukemia and acute lymphocytic leukemia), solid tumors (uterine leiomyosarcoma, prostate cancer), and the like.

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by inflammation and destruction of joint structures. When the disease is not treated effectively, substantial disability and pain, and even premature death, result from loss of joint functionality. The aim of RA treatment is therefore not only to delay the progression of the disease but also to obtain a reduction in symptoms, thereby terminating joint destruction. The global prevalence of RA is about 0.8%, with women having a three-fold prevalence rate over men. RA is difficult to treat, there is currently no cure, and treatment focuses on relieving pain and preventing diseased joint degeneration. Clinical treatment strategies include nonsteroidal anti-inflammatory drugs (NSAIDs), hormones, disease-modifying antirheumatic drugs (DMARDS), and biologic drugs, mainly to relieve the symptoms of joint damage and swelling. Clinical application of DMARDS (such as methotrexate, hydroxychloroquine, leflunomide, sulfasalazine) and DMARDS has better effect when being combined with biological drugs. Despite the abundance of anti-RA drugs, pain still exists in more than 30% of patients. Recent studies have shown that intervention of the JAK/STAT signaling pathway is a new approach to RA treatment.

Tofacitinib is the first novel FDA-approved oral JAK inhibitor that acts on JAK1 and JAK3, and is a small molecule compound useful in the treatment of RA. Clinical trials indicate that tofacitinib exhibits a therapeutic effect that is not inferior to TNF inhibitors. The combined use of Methotrexate (MTX) and tofacitinib also has certain therapeutic effects on patients who are not responsive to TNF inhibitors. Therefore, tofacitinib is recommended for clinical first-line single drug administration, and has a therapeutic advantage compared with MTX. Increased phosphorylation of STAT1 and STAT3 was found in the synovial fluid of tofacitinib-treated patients, suggesting that it is primarily through intervention in the JAK/STAT signaling pathway. However, tofacitinib can bring some side effects while relieving the symptoms of RA, and cause certain infections, malignant tumors and lymphomas. Serious infections and malignancy-induced adverse reactions also have been reported during biopharmaceutical treatment of RA, and novel safety data suggest that the overall risk of infection and mortality for tofacitinib is similar to that of biological agents for treating RA. Given the pleiotropic nature of JAKs in many regulatory pathways and immune processes, non-selective JAK inhibitors carry risks of adverse effects, such as hypercholesterolemia and infection. Selective JAK inhibitors are an important direction of current research. Filgotinib, from Galapagos, Belgium, is a new generation of JAK1 selective inhibitor with reduced risk of anemia or infection with tofacitinib. In a recently completed clinical phase II trial on moderate to severe RA patients who do not respond adequately to methotrexate treatment, the primary endpoint reached after 12 weeks of Filgotinib treatment-80% for ACR20, with a 200mg dose showing statistical significance; at all dose levels ACR50 response and DAS28 reduction were statistically significant compared to controls; the safety level is similar to before, and the product has good toleranceAnd (4) sex. After 24 weeks, 64% of patients achieved DAS28 remission or low activity; all doses of ACR50 response, ACR70 response and DAS28 reduction showed statistically significant levels, reaching 39% ACR 70. However, Filgotinib was relatively weak against JAK1 IC₅₀Above 10nM, the clinical dose is also relatively high.

RA is a very heterogeneous disease and the therapeutic application of suitable drugs to RA patients is a major challenge. Although a range of JAK inhibitors have been disclosed, there is still a need to develop compounds with better selectivity and potency. Thus, there is a continuing need for new or improved agents that inhibit kinases such as Janus kinases for the development of new, more potent drugs for the treatment of RA or other JAK-associated diseases.

Disclosure of Invention

The inventor designs and synthesizes a series of compounds containing [1,2,4] triazolo [1,5-a ] pyridine skeleton, and screens JAK kinase activity, and research results show that the compounds have outstanding anti-JAK kinase activity and can be developed into medicines for treating diseases related to JAK kinase activity.

Therefore, the invention aims to provide a compound shown in the general formula I or a racemate, an enantiomer, a diastereoisomer, a mixture form, a prodrug or a pharmaceutically acceptable salt thereof,

R¹and R²Independently of each other, from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, heteroaryl, heterocyclyl, heteroaryl, alkoxy, heteroaryl, and mixtures thereof,-C(O)R^a、-O(O)C R^a、-C(O)OR^a、-C(O)NR^aR^b、-NH C(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^aSubstituted with one or more groups of (a);

or,

R¹and R²Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R^a、-O(O)C R^a、-C(O)OR^a、-C(O)NR^aR^b、-NH C(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^aSubstituted with one or more groups of (a);

cy is selected from aryl and heteroaryl;

each R³Independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^4aand R^4bEach independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R⁵selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; said cycloalkyl, heterocyclyl, aryl or heteroAryl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, imino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R^aand R^bEach independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

n1 is an integer from 1 to 4;

m1 is an integer of 1 to 4.

In a preferred embodiment of the present invention, the compounds of formula I according to the present invention or their racemates, enantiomers, diastereomers, or mixtures thereof, prodrugs thereof or pharmaceutically acceptable salts thereof, wherein Cy is selected from C₆～C₁₀Aryl or 6-to 10-membered heteroaryl, preferably phenyl or pyridyl.

In another preferred embodiment of the present invention, the compound of formula I according to the present invention, or its racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, is a compound of formula II, or its racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, as follows:

wherein R is¹、R²、R^4a、R^4bAnd R⁵As shown in the general formula IAs defined in (1).

In another preferred embodiment of the present invention, the compounds of formula I according to the present invention or their racemates, enantiomers, diastereomers, or their mixtures, prodrugs or pharmaceutically acceptable salts thereof, wherein R is^4bAnd R^4cEach independently selected from hydrogen, halogen, alkyl, said alkyl being optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In another preferred embodiment of the present invention, the compounds of formula I according to the present invention or their racemates, enantiomers, diastereomers, or their mixtures, prodrugs or pharmaceutically acceptable salts thereof, wherein R is⁵Selected from cycloalkyl, heterocyclyl, preferably C₃～C₆Cycloalkyl or 4-to 7-membered heterocycloalkyl; said cycloalkyl, heterocyclyl is optionally further substituted by one or more groups selected from halo, oxo, imino, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R⁵further preferred is

In another preferred embodiment of the present invention, the compound of formula I according to the present invention, or its racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, is a compound of formula III, or its racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug, or its pharmaceutically acceptable salt, as follows:

wherein R is¹、R²As defined in formula I.

In another preferred embodiment of the present invention, the compounds of formula I according to the present invention or their racemates, enantiomers, diastereomers, or their mixtures, prodrugs or pharmaceutically acceptable salts thereof, wherein R is¹And R²Independently of one another, from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably C_1-6Alkyl radical, C₃～C₆Cycloalkyl, 4-to 7-membered heterocyclic group, C₆～C₁₀Aryl, 6 to 10-membered heteroaryl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, indazolyl, indolyl, isoindolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiophenyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, pyrazolopyridinyl, triazolopyridinyl, imidazopyridinyl, pyrazolopiperazinyl, and the like;

wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, -C (O) R^aSubstituted with one or more groups of (a);

R^aselected from hydrogen, hydroxyl, alkyl, cycloalkyl.

In another preferred embodiment of the present invention, the compounds of formula I according to the present invention or their racemates, enantiomers, diastereomers, or their mixtures, prodrugs or pharmaceutically acceptable salts thereof, wherein R is¹And R²Nitrogen attached theretoThe atoms together form a 5 to 7 membered heterocyclic ring, preferably a 4 to 7 membered heterocyclic ring containing 1 to 2 nitrogen atoms, more preferably azetidinyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, piperazinyl, said heterocyclic ring being further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R^aSubstituted with one or more groups of (a); r^aSelected from hydrogen, hydroxyl, alkyl, cycloalkyl.

Typical compounds of the invention include, but are not limited to:

1-cyclopropyl-3- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (thiazol-2-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (oxazol-2-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-methyl-1H-pyrazol-4-yl) urea;

1-cyclopentyl-3- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) urea;

1-cyclohexyl-3- (5- (4- ((1, 1-dioxothiomorpholino) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-methyl-azetidin-3-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (2, 4-dimethyl-2H-pyrazol-3-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (pyridin-4-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-isopropyl-1H-pyrazol-4-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-acetyl-1H-pyrazol-4-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (2-fluoro-4, 5-dimethoxy-phenyl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- ((2-fluoro-4-methoxy-phenyl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-cyclopropyl-1H-pyrazol-4-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-methyl-1H-indazol-6-yl) urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) -urea;

1- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -3- (1-methyl-2, 2-dioxo-1, 3-dihydrobenzo [ C ] isothiazol-5-yl) urea;

n- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) piperidine-1-carboxamide,

or a racemate, enantiomer, diastereomer or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof.

The invention also provides a method for preparing the compound shown in the general formula I or the raceme, the enantiomer, the diastereoisomer, the mixture form, the prodrug or the pharmaceutically acceptable salt thereof, which comprises the following steps:

reacting the compound Ia with solid phosgene in a solvent to obtain a compound Ib, wherein the solvent is preferably ethyl acetate; then, reacting the compound Ib with a corresponding amine compound under an alkaline condition to obtain a compound I with a general formula, wherein triethylamine is preferably selected as the alkaline reagent;

wherein R is¹、R²、R³、R^4a、R^4b、R⁵Cy, m1, n1 are as defined in formula I.

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or its racemate, enantiomer, diastereomer, or mixture thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

The invention also relates to a method for preparing the composition, which comprises the step of mixing the compound shown in the general formula I or the raceme, the enantiomer, the diastereoisomer, the mixture form, the prodrug or the pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a compound shown in the general formula I, or a racemate, an enantiomer, a diastereoisomer, a mixture form, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound and application thereof in preparing Janus kinase inhibitors.

The invention further relates to a compound shown in the general formula I or a racemate, an enantiomer, a diastereoisomer, a mixture form, a prodrug or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound, and application of the compound in preparation of medicines for preventing and/or treating JAK activity-related diseases. The disease associated with JAK activity may be selected from inflammation, autoimmune diseases, or cancer, wherein the inflammation is for example arthritis, in particular rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, uveitis; such autoimmune diseases as multiple sclerosis, lupus, psoriasis, sarcoidosis; such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The invention also relates to a compound shown in the general formula I or a racemate, an enantiomer, a diastereoisomer, a mixture form, a prodrug or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and application thereof as a Janus kinase inhibitor.

The invention further relates to a compound shown in the general formula I or a racemate, an enantiomer, a diastereoisomer, a mixture form, a prodrug or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound, and application of the compound as a medicine for preventing and/or treating diseases related to JAK activity. The disease associated with JAK activity may be selected from inflammation, autoimmune diseases, or cancer, wherein the inflammation is for example arthritis, in particular rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, uveitis; such autoimmune diseases as multiple sclerosis, lupus, psoriasis, sarcoidosis; such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The present invention further relates to a method of inhibiting Janus kinase comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula I or its racemates, enantiomers, diastereomers, or mixture thereof, prodrug thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

The present invention further relates to a method for the prevention and/or treatment of a disease associated with JAK activity comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula I or its racemate, enantiomer, diastereomer or mixture thereof, prodrug thereof or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. The disease associated with JAK activity may be selected from inflammation, autoimmune diseases, or cancer, wherein the inflammation is for example arthritis, in particular rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, uveitis; such autoimmune diseases as multiple sclerosis, lupus, psoriasis, sarcoidosis; such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The compounds of formula I of the present invention may be used to form pharmaceutically acceptable acid addition salts with acids according to conventional methods in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.

In addition, the invention also comprises a prodrug of the compound shown in the general formula I. Prodrugs of the compounds of formula I are derivatives of the compounds of formula I which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the patient's integuments, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

The compound containing the [1,2,4] triazolo [1,5-a ] pyridine skeleton and pharmaceutically acceptable salts, hydrates or solvates thereof which are shown in the general formula I can be used as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into clinically acceptable dosage forms. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or may be used in combination with other drugs for the treatment of diseases associated with JAK activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

According to the invention, through Jak1, Jak2, Jak3 and Tyk2 activity tests, the compounds have remarkable Janus kinase regulating activity, so that the compounds can be used for treating and/or preventing diseases related to the JAK activity, such as inflammation, autoimmune diseases, cancer or other diseases. In particular for the preparation of a medicament for the treatment and/or prophylaxis of rheumatoid arthritis, psoriasis and/or diseases involving cartilage and bone joint degeneration.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims 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 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH₂-, "ethylene" means- (CH)₂)₂-, "propylene" means- (CH)₂)₃-, "butylene" means- (CH)₂)₄-and the like.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, 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 containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 to 6 ring atoms, of which 1-2 or 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1,2, 5-oxadiazolyl, pyranyl, or morpholinyl.Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which 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 bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to 5 to 14 membered polycyclic heterocyclic groups in which any two rings share two atoms which are not directly attached, which may contain one or moreDouble bonds, but not one ring having a completely conjugated pi-electron system, in which one or more ring atoms are selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an-OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to ═ O.

The term "carboxy" refers to-C (O) OH.

The term "mercapto" refers to-SH.

The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl is as defined above.

The term "acyl" refers to compounds containing the group-C (O) R, where R is alkyl, cycloalkyl, aryl, heteroaryl.

The term "sulfonic acid group" means-S (O)₂OH。

The term "sulfonate group" means-S (O)₂O (alkyl) or-S (O)₂O (cycloalkyl), wherein alkyl is as defined above.

The term "imino" refers to an ═ NR group where R can be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme.

The preparation method of the compound shown in the general formula I or the salt thereof is as follows.

Scheme 1

Synthesis of scheme 1:

under the high-temperature alkaline condition, the compounds Ia and R⁵H, reacting to obtain an intermediate Ib, wherein a base reagent of the reaction is preferably potassium carbonate; reacting the intermediate Ib with 5-bromine- [1,2,4] under the action of a catalyst at high temperature and under the alkaline condition]Triazolo [1,5-a]Suzuki reaction of pyridine-2-amine to obtain intermediate Ic, the alkali agent of the reaction is preferably potassium carbonate, and the catalyst is preferably Pd (dppf) Cl₂(ii) a Refluxing the obtained intermediate Ic with solid phosgene in a solvent to obtain an intermediate Id, wherein the solvent for the reaction is preferably ethyl acetate; under the high-temperature alkaline condition, the intermediate Id and R are reacted¹R²The NH reaction gives the compound of formula I, the base reagent of the reaction preferably being triethylamine.

The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, or cesium carbonate, sodium hydroxide, and lithium hydroxide.

Conditions that provide acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid.

Solvents used include, but are not limited to: ethyl acetate, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, water or N, N-dimethylformamide.

Catalysts used include, but are not limited to: pd(dppf)Cl₂、Pd₂(dba)₃、Pd(OAc)₂。

R¹、R²、R³、R^4a、R^4b、R⁵Cy, m1, n1 are as defined in formula (I).

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10^-6The units in (ppm) are given. NMR was measured using a Brukerdps model 300 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured using a 1100Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

Liquid phase preparation lc3000 HPLC and lc6000 HPLC (manufacturer: Innovation Consumer) were used.

HPLC was carried out by using Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18250X 4.6mm5vm column) and Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18250X 4.6mm5um column).

Average inhibition rate of kinase and IC₅₀The values were measured using a multifunctional staining 3 microplate reader (Biotech, USA).

The thin layer chromatography silica gel plate is Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses Qingdao marine silica gel 100-200 meshes and 200-300 meshes as a carrier.

Known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies such as the web-enabled mall, Beijing coupled, Sigma, Annage chemical, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.

The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying compounds comprise: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: the volume ratio of the solvent in the petroleum ether and ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1: preparation of 1-cyclopropyl-3- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) urea

Step 1: synthesis of 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -benzyl) thiomorpholine 1, 1-dioxide (Compound 1A)

50.00g (16.84mmol) of 4-bromomethylbenzeneboronic acid pinacol ester, 27.36g (20.24mmol) of 1, 1-dioxide thiomorpholine and 27.92g (20.20mmol) of potassium carbonate were put into a reaction flask, 250ml of N, N-dimethylformamide was added thereto, and the reaction was stirred at 80 ℃ for 4 hours. After cooling to room temperature, the reaction solution was poured into 1250ml of ice water, stirred for 30min, and filtered by suction to obtain the title product as a white solid, 47.2g, with a yield of 79.7%.

Step 2: synthesis of 4- (4- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine 1, 1-dioxide (Compound 1B)

Reacting 5-bromo- [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (from a commercial Buchner Co., Ltd.) 30.00g (0.14mol) was charged into a 1L three-necked flask, and to this were added sequentially 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -benzyl) thiomorpholine 1, 1-dioxide 58.50g (0.15mol), dioxane 400ml, potassium carbonate 58.60g (0.42mol), water 100ml, Pd (dppf) Cl₂5.78g (0.007 mol). The mixture was warmed to 90 ℃ under argon and the reaction was stirred for 16 h. After the reaction was completed, it was cooled to room temperature, 400ml of dichloromethane was added, followed by washing twice with 800ml of water, the organic layer was concentrated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 100:1) to give the title product as a pale yellow solid 27.2g, yield 54%, purity 96%.

And step 3: synthesis of 4- (4- (2-isocyanato- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) phenyl) thiomorpholine 1, 1-dioxide (Compound 1C)

2.00g (5.6mmol) of 4- (4- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine 1, 1-dioxide was charged into a 100ml reaction flask, 20ml of ethyl acetate and 4.98g (16.8mmol) of phosgene in solid form were added, and the reaction was stirred at elevated temperature under reflux for 6 hours. After the reaction, the reaction mixture was filtered while hot, and the filter cake was dried to give the title product as an off-white solid (2.01 g) in 94% yield.

And 4, step 4: synthesis of 1-cyclopropyl-3- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) urea (Compound 1)

0.29g (0.8mmol) of 4- (4- (2-isocyanato- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) phenyl) thiomorpholine 1, 1-dioxide was charged into a 50ml single-neck flask, and 5ml of THF, 0.23g (2.4mmol) of triethylamine and 0.28g (4.8mmol) of cyclopropylamine were successively added thereto. Under the protection of argon, the temperature is increased to reflux and the reaction is stirred for 16 hours. After the reaction was completed, 20ml of dichloromethane was added, and washed once with 20ml of water, 20ml of 10% aqueous hydrochloric acid solution, and 20ml of water, respectively, the organic phase was concentrated to dryness, and the residue was purified by preparative liquid chromatography (eluent: acetonitrile: water, gradient elution 1:9 to 7:3) to give the title product as a white solid (40 mg, yield 12%, purity 96%).

MS[M+H](m/z):441.1。

1H-NMR(300MHz)(DMSO)δ10.99(s,1H),8.23(m,J＝3Hz,1H),7.97(m,J＝6Hz,2H),7.22(m,2H),7.10(m,1H),6.97(m,1H),3.95(s,2H),3.24(m,4H),3.08(m,4H),2.65(m,1H),0.70(m,2H),0.43(m,2H).

Compounds 2-18 (see Table 2) of examples 2-18 were prepared, respectively, by the same procedure as in example 1, substituting cyclopropylamine with the corresponding amine (see Table 1) to react with intermediate compound 1C.

Table 1 corresponding list of amines used for the synthesis of the compounds of examples 2-18

TABLE 2 List of Compounds 2-18 of examples 2-18

Biological evaluation

Test example 1 in vitro kinase Activity

Experimental materials: jak1, Jak2, Jak3 and Tyk2 kinases, substrates for kinases GFP-STAT1, ATPLANTHASCREEN^TMTb-anti-pSTAT 1, EDTA, TR-FRET dilution buffer for kinase reaction, and Filgotinib, a control, were derived from the following Table 3.

TABLE 3

Preparing a medicine: the compound of the present invention was dissolved in DMSO solvent to prepare a 10mM stock solution. The final compound reaction maximum concentration is 10uM, 3 times of dilution, 10 concentration gradient, each concentration gradient is provided with 3 multiple holes.

The experimental method comprises the following steps: adding Jak 1500 ng/ml, Jak 215 ng/ml, Jak 3250 ng/ml and Tyk 2200 ng/ml kinase into 384 reaction plates containing the compounds respectively, and incubating for 15 minutes in a constant temperature incubator at 25 ℃; then, 4ul of the substrate mixture (20uM ATP and 0.1uM GFP-STAT1) was added to a 384 reaction plate containing JAK kinase and a compound, and the mixture was allowed to react in an incubator at 25 ℃ for 1 hour; 10ul of the antibody mixture (10mM EDTA and 2nM antibody) was added to the 384 reaction plate and reacted in a constant temperature incubator at 25 ℃ for 1 hour; the 384 reaction plates were taken out and read on an Envision multifunctional plate reader.

IC of the compound was obtained using the following non-linear fit equation₅₀(median inhibitory concentration):

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

x: log value of compound concentration

Y: emissivity (emision Ratio)

Bottom: minimum, Top: highest value, HillSlope: slope of

The inhibitory activity of the compounds of the present invention against Jak1, Jak2, Jak3 and Tyk2 is shown in Table 4 below.

TABLE 4 IC for in vitro JAK kinase inhibitory Activity of Compounds of the invention₅₀

Remarking: IC (integrated circuit)₅₀Values from 0 to 50nM are marked A, 50 to 500nM are marked B, values greater than 500 are marked C, NT represents not tested.

From the test results, it is clear that the compound of the invention has good in vitro anti-JAK kinase activity, and is equivalent to or superior to clinical II stage antirheumatic drug Filgotinib.

Test example 2: effect of Compounds of the invention on type II collagen-induced arthritis in DBA/1J mice

The type II collagen-induced DBA/1J mouse arthritis (CIA) model is an animal model widely used to study the activity of drugs for treating rheumatoid arthritis in humans.

Animals: DBA/1J mice, sex: male, number: 18, body weight: 14-16g, week age range: 6-7 weeks old, purchased from Witonglihua laboratory animal technology, Inc., Beijing, SPF grade, animal production license number: SCXK (Jing) 2012-0001, issuing unit: the scientific and technical committee of Beijing.

Grouping: model control group, group (30mg/Kg) was dosed (compound of example 1) with 9 animals per group.

An appropriate amount of the Bovine Type II Collage (from Chondrex. Inc.) was taken, dissolved in 0.05M acetic acid (4mg collagen/mL) and refrigerated overnight at4 ℃. The mixture was well emulsified with an equal amount of Freund's complete adjuvant in an ice bath, and each DBA/1J mouse was injected with 0.1mL (200. mu.g collagen) of the emulsion from the 2cm of the caudal root until the needle tip was inserted 0.5cm from the caudal root. Starting clinical symptom observation and arthritis scoring after 4 weeks of model building, sorting scores of all animals with symptoms, randomly grouping layer by layer, and dividing into 2 groups, namely a model control group (orally intragastrically administering a solvent with 0.5% CMC) and an administration group (orally intragastrically administering a 30mg/kg compound of the example 1); 2 times/day for 14 days; arthritis scores and weight changes were observed every 3 days after dosing.

Arthritis index score: the arthritis index was scored according to Wood's arthritis scoring criteria, as follows.

0 minute: is normal

1 minute: red swelling involving 1 finger joint

And 2, dividing: the mild red swelling of more than 2 finger joints or the entire paw

And 3, dividing: severe red and swollen foot and paw

And 4, dividing: severe redness and swelling of the paw, stiffness of the joints, and lack of elasticity.

Lesions were divided between 0 and 4 for each of the 4 paws and the total integral of the limb was calculated. The integrals (arthritis index) at different times were compared.

The effect of the compound of example 1 of the present invention on the arthritis score in CIA model animals is shown in table 5 below.

TABLE 5 Effect of the Compounds of example 1 of the invention on the arthritis score in CIA model animals

Remarking: p <0.05 compared to model control group.

And (4) conclusion: the compound provided by the invention can be used for remarkably reducing the arthritis score of a CIA model animal, and the compound is proved to have a remarkable improvement effect on the arthritis symptom of a CIA mouse.

While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

1. A compound shown in a general formula I or its raceme, enantiomer, diastereoisomer, or a mixture form, prodrug or medicinal salt,

wherein:

R¹and R²Independently of one another, from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroAryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R^a、-O(O)C R^a、-C(O)OR^a、-C(O)NR^aR^b、-NH C(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^aSubstituted with one or more groups of (a);

or,

R¹and R²Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclic ring further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NH C(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)NR^aR^b、-S(O)₂NR^aR^b、-NHS(O)R^a、-NHS(O)₂R^aSubstituted with one or more groups of (a);

cy is selected from aryl and heteroaryl;

R⁵selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, imino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

n1 is an integer from 1 to 4;

m1 is an integer of 1 to 4.

2. The compound of formula I according to claim 1, wherein Cy is selected from C, or a racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof₆～C₁₀Aryl or 6-to 10-membered heteroaryl, preferably phenyl or pyridyl.

3. The compound of the general formula I according to claim 1 or 2, which is a compound of the following general formula II, or a racemate, enantiomer, diastereomer, or mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof:

wherein R is¹、R²、R^4a、R^4bAnd R⁵As defined in claim 1.

4. A compound of formula I according to any one of claims 1 to 3, wherein R is R or a racemate, enantiomer, diastereomer or mixture thereof, prodrug thereof or pharmaceutically acceptable salt thereof^4aAnd R^4bEach independently selected from hydrogen, halogen, alkyl, said alkyl being optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

5. The compound of formula I according to any one of claims 1 to 4, wherein R is R or a racemate, enantiomer, diastereomer or mixture thereof, prodrug thereof or pharmaceutically acceptable salt thereof⁵Selected from cycloalkyl, heterocyclyl, preferably C₃～C₆Cycloalkyl group or 4-to 7-membered heterocycloalkyl group, more preferably

The cycloalkyl, heterocyclyl are optionally further substituted with one or more groups selected from halogen, oxo, imino, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

6. The compound of the general formula I according to any one of claims 1 to 5, which is a compound of the following general formula III, or a racemate, enantiomer, diastereomer, or mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following general formula III:

wherein R is¹、R²As defined in claim 1.

7. The compound of formula I according to any one of claims 1 to 6, wherein R is a racemate, enantiomer, diastereomer or mixture thereof, prodrug thereof or pharmaceutically acceptable salt thereof¹And R²Independently of one another, from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably C_1-6Alkyl radical, C₃～C₆Cycloalkyl, 4-to 7-membered heterocyclic group, C₆～C₁₀Aryl, 6-to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, -C (O) R^aSubstituted with one or more groups of (a);

R^aselected from hydrogen, hydroxyl, alkyl, cycloalkyl.

8. The compound of formula I according to any one of claims 1 to 7, wherein R is R or a racemate, enantiomer, diastereomer or mixture thereof, prodrug thereof or pharmaceutically acceptable salt thereof¹And R²Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclic ring further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R^aSubstituted with one or more groups of (a); r^aSelected from hydrogen, hydroxyl, alkyl, cycloalkyl.

9. A compound of formula I according to any one of claims 1 to 8, or a racemate, enantiomer, diastereomer or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

n- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) piperidine-1-carboxamide.

10. A process for the preparation of a compound of formula I according to any one of claims 1 to 9 or a racemate, enantiomer, diastereomer or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein R is¹、R²、R³、R^4a、R^4b、R⁵Cy, m1, n1 are as defined in claim 1.

11. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 9 or a racemate, enantiomer, diastereomer or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

12. Use of a compound of general formula I according to any one of claims 1 to 9 or a racemate, enantiomer, diastereomer or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a Janus kinase inhibitor.

13. Use of a compound of general formula I according to any one of claims 1 to 9 or a racemate, an enantiomer, a diastereomer or a mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the prevention and/or treatment of a disease associated with Janus kinase activity.

14. Use according to claim 13, wherein the disease is selected from inflammation, autoimmune diseases, or cancer, such as arthritis, in particular rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, uveitis, psoriasis; such autoimmune diseases as multiple sclerosis, lupus; such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.