EA039344B1 - Heterocyclic compound as jak inhibitor and salts and therapeutic use thereof - Google Patents

Abstract

Disclosed are heterocyclic derivatives as a JAK inhibitor and salts thereof. In addition, also disclosed are a medicine comprising the compound and salts thereof as an active ingredient, and the use thereof in the preparation of a medicine for treating JAK kinase-associated diseases, such as immune system diseases, rheumatoid arthritis and tumours.

Description

Technical field

This invention relates to a class of heterocyclic compounds as JAK inhibitors, salts thereof and medicaments containing said compounds or salts thereof as active ingredients, and relates to their use in the preparation of medicaments for the treatment of JAK-associated target diseases such as diseases of the immune systems, rheumatoid arthritis and tumors.

State of the art

The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signal transduction pathway where JAK plays an important role in cytokine signaling. Downstream substrates of the JAK family of kinases include signal transducers and transcription activators (STATs). The JAK protein is an important member of this pathway, and an abnormal increase in activity often leads to disease onset. Many diseases are associated with abnormal cellular responses of the JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancers, cardiovascular diseases, allergies and asthma, and Alzheimer's disease.

Rheumatoid arthritis (RA) is a chronic autoimmune disease commonly seen in the clinic, which is mainly characterized by joint swelling, pain, stiffness, deformity, and severe functional impairment. The incidence of RA among the population is 0.51.0%. Since the pathogenesis of RA is not clear, its pathological processes are difficult to control, and the incidence of disability is high, which seriously impairs the physical and mental health of patients and reduces the quality of life of patients. Current drugs used for the treatment of RA mainly include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and antibody-based drugs. For a long time, the first-line drugs for RA have been MBARLS. In 1988, the first MDR, methotrexate (MTX), was approved by the FDA for the treatment of RA, making MTX a milestone in the history of RA treatment. The drug is widely used due to its advantages such as efficacy, tolerability, safety, etc., but it has serious side effects including nausea, vomiting, stomach discomfort and hepatotoxicity. Conversely, newly developed antibody-based drugs have good efficacy and safety record for moderate to severe RA. However, since they target certain cytokines, the population for which they are beneficial is significantly limited, and in addition, the cost of treatment and injection also limits the promotion of such drugs.

In the last 20 years, the treatment of RA has improved significantly, and the condition of patients can be effectively controlled by the existing treatment regimen. However, RA patients still face problems such as disease recurrence, poor treatment response, poor long-term tolerance, and some side effects. More importantly, the quality of life of RA patients, including the functioning of organs such as joints, is not sufficiently improved by current treatments. Therefore, there is still an urgent clinical need in this area regarding the restoration of the normal functions of patients.

Studies have shown that the main treatment for RA is the production of large amounts of cytokines by the autocrine system of mononuclear cells/macrophages, lymphocytes, etc., infiltrated into RA synovial tissue and cells. These cytokines interact with and activate the JAK/STAT signaling pathway (Janus kinase/signal transducer and transcriptional signaling pathway activators) through various pathways. By specifically inhibiting the JAK/STAT signaling pathway, the cascade of these cytokines can be blocked, thereby improving the symptoms of damaged joints in RA patients. Therefore, the JAK/STAT signaling pathway is a potential target for RA treatment. In November 2012, the oral JAK inhibitor Tofacitinib was first approved by the FDA for the treatment of rheumatoid arthritis (RA) and became the first successful kinase inhibitor in the art.

The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signal transduction pathway where JAK plays an important role in cytokine signaling. JAK kinase (designated JAK, including the four known members JAK1, JAK2, JAK3, TYK2) is a small family of cytoplasmic non-receptor tyrosine protein kinase superfamilies. JAK3 is distributed in the bone marrow and lymphatic system, and JAK1, TYK2 and JAK2 are widely distributed in various tissue cells. When JAK binds to cytokine receptors on the cell surface, JAK receptor-bound JAKs are activated and, in turn, the receptors are phosphorylated. This provides a recruiting site for cytoplasmic signal transducers and transcription protein activators STAT (referred to as STAT, including STAT1-4, STAT5a, STAT5b, STAT6). JAKs phosphorylate the STAT protein, and the latter is transferred to the nucleus to regulate gene expression after dimerization. This pathway is the JAK/STAT signaling pathway (O'Shea J. J., et al., N. Engl. J. Med., 2013, 368:161-170).

The JAK/STAT signaling pathway is a signaling pathway stimulated by a variety of cytokines and growth factor receptors, including interleukins, interferons (IFN-α, IFN-β, IFN-γ), erythropoietin

- 1 039344 (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TRO), etc., which play a key role in the proliferation of immune cells and hematopoietic stem cells , and the biological process of immune regulation (Ghoreschi K., et al., Immunol. Rev., 2009, 228:273-287).

JAK1 can bind to IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 in the gp130 family, and other receptors containing γε, etc. (Rodig S. J., et al., Cell, 1998, 93:373-383). The JAK1 gene knockout method in mouse models shows that this enzyme plays a key role in regulating the biological action of various cytokine receptors described above (Kisseleva T., et al., Gene, 2002, 285:1-24). JAK1 is a new target in diseases such as immune diseases, inflammation and cancer. JAK1 inhibitors can be used to treat/prevent autoimmune diseases and inflammation (Hornakova T., et al., Blood, 2010, 115:3287-3295), such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunodeficiency syndrome (Hou S., et al., Hum. Genet., 2013, 132:1049-1058) and the like.

JAK2 plays an important role in the regulation of various receptor signals including IL-3, IFN-γ, EPO, GH and the like (Levy D. E., et al., Nat. Rev. Mol. Cell Biol., 2002, 3:651 -662). Knockout of JAK2 in a mouse model can lead to death in anemic animals (Schindler C., et al., J. Biol. Chem., 2007, 282:20059-20063); the basic mutation JAK2V617F on the JAK2 gene in humans is closely associated with the occurrence of polycythemia vera (PV) and essential thrombocythemia (ET) in myeloproliferative diseases, etc. (Ghoreschi K., et al., Immunol. Rev., 2009, 228:273-287).

JAK3 regulates cell signaling through binding to the gamma co-chain (γc) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. Mutations in JAK3 and γc can lead to severe combined immunodeficiency (SCID) (Villa A., et al., Blood, 1996, 88:817-823). Abnormal JAK3 activity is characterized by a significant increase in T cells and NK cells and loss of B cell function, which greatly affects the normal biological functions of the immune system. Based on its functional characteristics and specific tissue distribution, JAK3 becomes an attractive drug target for diseases associated with the immune system. Its inhibitors are of great clinical value in the treatment/prevention of rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases (Papageorgiou A.S., et al., 2004, Trends Pharm. Sci., 2004, 25:558-562).

TYK2 is the first member of the JAK family and can be activated by a variety of receptors such as interferons (IFN), IL-10, IL-12, IL-23, IL-27 and the like. In mice, loss of TYK2 function can cause defects in various cytokine receptor signaling pathways, resulting in viral infection, reduced antibacterial and immune function, and increased likelihood of lung infection (Kisseleva T., et al., 2002, Gene, 285:1-24). In addition, studies by Larner A.C group have shown that TYK2 can contribute to the inhibition of growth and metastasis of breast cancer (Zhang Q., et al., 2011, J. Interferon Cytokine Res., 31:671-677).

Since JAK kinase is involved in various physiological processes in the body, wide inhibition of various subtypes can have adverse consequences. Tofacitinib is used in patients with moderate to severe RA who do not respond well to or tolerate MTX. It has been observed to cause certain side effects in clinical studies, including infection, tuberculosis, tumor, anemia, liver damage, high cholesterol, and the like. Tofacitinib has a significant inhibitory effect on JAK1, JAK2 and JAK3 subtypes. Since JAK2 activity is associated with red blood cell differentiation and fat metabolism, it is believed that some of the above side effects are associated with a non-selective inhibition profile of the drug. Therefore, the search for selective inhibitors of JAK1 and/or JAK3 is becoming a new direction in drug research for RA.

At present, JAK inhibitors have been shown to be useful in drugs for the treatment of diseases of the circulatory system, tumors, rheumatoid arthritis, psoriasis and the like. Due to the significant medical use of JAK inhibitors in drugs for a variety of related diseases, the research and discovery of such compounds is extremely favorable.

The essence of the invention

The first object of this invention is to obtain a class of heterocyclic derivatives as JAK inhibitors.

In particular, the compounds disclosed in the present invention are selected from, but not limited to, the following structures:

- 2 039344

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetonitrile;

2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)

1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetonitrile

2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetonitrile

2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetonitrile;

2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)piperidin-4-yl)-N-(2 ,2,2trifluoroethyl)acetonitrile;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetamide;

2- (3- (4- (1H-pyrrolo[2,3-b] pyridin-3-yl) -1H-pyrazol-1-yl) -1 (ethylsulfonyl) azetidin-3-yl) -N- (2 ,2,2-trifluoroethyl)acetamide;

2-(3-(4-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1-(ethylsulfonyl)azetidin-3-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)-N-methylacetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetamide;

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1-(methylsulfonyl)azetidin-3-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1-(methylsulfonyl)azetidin-3-yl)-N-methylacetamide;

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1-(methylsulfonyl)azetidin-3-yl)acetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)azetidin-3-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)azetidin-3-yl)-N-methylacetamide;

2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)azetidin-3-yl)acetamide;

2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetamide;

2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)1,1-dioxotetrahydro-2H-thiopyran-4-yl)-N -(2,2,2-trifluoroethyl)acetamide;

2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1,1-dioxotetrahydro-2H-thiopyran-4-yl)-N -(2,2,2-trifluoroethyl)acetamide;

2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)1,1-dioxotetrahydro-2H-thiopyran-4-yl)-N -(2,2,2-trifluoroethyl)acetamide;

2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)piperidin-4-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(4-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl) 1-(methylsulfonyl)piperidin-4-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1(methylsulfonyl)piperidin-4-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

2-(1-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1yl)cyclopentyl)-N-(2,2,2-trifluoroethyl)acetamide;

2-(1-(4-(1H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1yl)cyclopentyl)-N-(2,2,2-trifluoroethyl)acetamide;

2-(1-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1yl)cyclopentyl)-N-(2,2,2-trifluoroethyl)acetamide;

3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3methyl-N-(2,2,2-trifluoroethyl)butanamide;

3-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3methyl-N-(2,2,2-trifluoroethyl)butanamide;

3-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-3methyl-N-(2,2,2-trifluoroethyl)butanamide;

- 3 039344 or their pharmaceutically acceptable salts.

Preferably, the compound described herein is selected from, but not limited to, the following structures:

3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(methylsulfonyl)-N-(2,2,2-trifluoroethyl)azetidine- 3-carboxamide;

3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl)azetidine- 3-carboxamide;

3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(cyclopropylsulfonyl)-N-(2,2,2-trifluoroethyl)azetidine- 3carboxamide;

3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(methylsulfonyl)-N-(2,2,2-trifluoroethyl) azetidine-3carboxamide;

3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl) azetidine-3carboxamide;

3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(cyclopropylsulfonyl)-N-(2,2,2trifluoroethyl)azetidine -3-carboxamide;

4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(methylsulfonyl)-N-(2,2,2-trifluoroethyl)piperidine- 4-carboxamide;

4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl)piperidine- 4-carboxamide;

4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(cyclopropylsulfonyl)-N-(2,2,2-trifluoroethyl)piperidine- 4carboxamide;

4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(methylsulfonyl)-N-(2,2,2-trifluoroethyl )piperidine-4carboxamide;

4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl )piperidine-4carboxamide;

4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-1-(cyclopropylsulfonyl)-N-(2,2,2trifluoroethyl) piperidine-4-carboxamide;

4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)N-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1 dioxide;

4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)-N-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran -4carboxamide 1,1-dioxide;

3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(ethylsulfonyl)azetidine-3-carbonitrile;

3-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino)-1-(ethylsulfonyl)azetidine-3-carbonitrile;

3-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)1-(ethylsulfonyl)azetidine-3-carbonitrile;

3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)1-(methylsulfonyl)azetidine-3-carbonitrile;

3-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino)-1-(methylsulfonyl)azetidine-3-carbonitrile;

3-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)1-(methylsulfonyl)azetidine-3-carbonitrile;

4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;

4-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;

4-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4yl)amino)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;

1-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)cyclobutane-3-carbonitrile;

1-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino)cyclobutane-3-carbonitrile;

1-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4yl)amino)cyclobutanecarbonitrile;

1-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4yl)amino)cyclopentanecarbonitrile;

1-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino)cyclopentanecarbonitrile;

1-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4yl)amino)cyclopentanecarbonitrile;

(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-4-4039344yl)amino-2-methylbutanenitrile;

(R)-2-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4yl)amino-2-methylbutanenitrile;

(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4yl)amino-2-methylbutanenitrile;

or their pharmaceutically acceptable salts.

Terminology

The term alkyl refers to a straight or branched alkyl group having 1-12 carbon atoms in the chain, and examples of the alkyl group include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and any group deemed equivalent to the above examples in the judgment of one skilled in the art and in accordance with the description provided.

The term alkoxy refers to an alkyl group, as defined above, which is bonded to an oxygen atom. The alkoxy group is attached to the parent molecule through an oxygen atom.

The term amino refers to a -NH ₂ group or a mono- or dialkylamino group.

The term cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro-polycyclic carbocyclic ring having 3-12 ring atoms. Illustrative examples of cycloalkyl groups include the following groups in their respective bound form:

The term aryl refers to a 5-6 membered carboaromatic ring such as benzene; bicyclic rings, where at least one of the rings is a carboaromatic ring, such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and tricyclic rings, where at least one of the rings is a carboaromatic ring, such as fluorene.

For example, an aryl group includes a 5-6 membered carboaromatic ring fused to a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that the point of attachment is on the carboaromatic ring . The divalent radical is derived from a substituted benzene derivative and a free valence atom on the ring, which is designated as a substituted phenylene radical. A divalent free radical is derived from a monovalent polycyclic hydrocarbon-free radical whose name ends in radical by reduction of the free valency of a hydrogen atom, where ene is added to the name after the corresponding monovalent free radical. For example, a naphthyl group having two attachment points is called a naphthylene group. However, the aryl group does not contain, and does not in any way intersect with, heterocyclic aryl groups as appropriately defined below. Thus, as defined herein, if one or more carboaromatic rings are attached to a heteroaromatic ring, the resulting ring system is an aromatic heterocyclic group and not an aryl group.

The term aromatic heterocyclic group refers to

A 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, for example 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, where the other ring atoms are carbon atoms;

8-12-membered bicyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, for example, 1-4 heteroatoms, and in some embodiments, 1-3 heteroatoms, where the other atoms of the ring are carbon atoms and, according to at least one ring is an aromatic ring; and

The term heterocycloalkyl refers to a saturated or partially unsaturated, monocyclic or polycyclic, cyclic hydrocarbon group containing 3-20 ring atoms, where

- 5 039344 one or more ring atoms are selected from heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer 0-2) and the remaining ring atoms are carbon. Preferably has 312 ring atoms, 1-4 of which are heteroatoms. More preferably, the heterocycloalkyl ring contains 3-10 ring atoms, and more preferably, the heterocycloalkyl ring contains 5-6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. The heterocyclic ring may or may not be substituted, and if substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylamino, halogen, hydroxyl, amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxy or carboxylate.

The term halogen means chlorine, fluorine, bromine or iodine. The term halo means chlorine, fluorine, bromine or iodine. The term haloalkyl refers to an alkyl group as defined above which is substituted with one or more halogen atoms.

The term haloalkoxy means an alkoxy group as defined above which is substituted by one or more halogen atoms.

The term acyl refers to an R-C(O)-group of a straight, branched or cyclic configuration, or a combination thereof, containing 1-10 carbon atoms, which are attached to the main structure via a hydroxyl functional group. Such a group may be saturated or unsaturated, and aliphatic or aromatic.

In the embodiment presented here, if the described compound contains a basic group, it can form a salt with an acid, and the salt of the pyrimidine derivative can be obtained by a method known to a person skilled in the art.

Common acid salts include organic acid salts, inorganic acid salts, and the like. In general, organic acid salts commonly used include citrate, fumarate, oxalate, malate, lactate, sulfonate (eg camphorsulfonate, p-toluenesulfonate, methanesulfonate and the like), etc.; inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates and the like.

For example, a lower alkyl sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or the like can form mesylate, triflate; and arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can form p-toluenesulfonate, benzenesulfonate; an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, citric acid or the like can form the corresponding salts; an amino acid such as glutamic acid or aspartic acid may form glutamate or aspartate. An inorganic acid such as hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carboxylic acid, sulfuric acid or phosphoric acid can also form the corresponding salts.

In the embodiment presented here, if the described compound contains an acidic group, it can form a salt with a base. The salt of the compound described here can be obtained by a method well known in the art. For example, it can form a salt with an alkali metal such as sodium, potassium or lithium; with an alkaline earth metal such as calcium or barium; with other metals such as magnesium or aluminium; and can also form a salt with an organic base such as dicyclohexylamine, guanidine or triethylamine.

In a second aspect, a medicament is provided which uses a JAK inhibitor compound or a pharmaceutically acceptable salt thereof as an active ingredient. The above medicinal product may contain one or more pharmaceutically acceptable carriers, including diluents, excipients, binders, wetting agents, disintegrants, absorption enhancers, surfactants, absorption carriers, lubricating agents, etc. common in the pharmaceutical field. If necessary, flavors, sweeteners, etc. may be added. The described drug can be prepared in various forms such as tablets, powders, granules, capsules, oral liquids and injectables, and drugs in the above various dosage forms can be prepared in a conventional manner in the pharmaceutical field.

In a third aspect, a heterocyclic compound is provided as a JAK inhibitor, and a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of autoimmune diseases, rheumatoid arthritis, skin conditions, multiple sclerosis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis in humans. or animal, especially for the treatment of diseases associated with JAK kinase.

The present inventors confirm by experiments that some of the compounds described herein have a good inhibitory effect on JAK kinase, especially JAK1, and have

- 6 039344 low inhibitory effect on JAK2, JAK3, which allows us to consider this product as a selective JAK inhibitor. The drug containing the compound or a pharmaceutically acceptable salt thereof has low toxicity in the treatment of autoimmune diseases, rheumatoid arthritis, skin conditions, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.

Detailed description of specific options

The practice of this description is described below by way of example, and the person skilled in the art will understand that modifications and substitutions of the relevant specifications fall within the scope of the claimed invention.

Example 1 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin3-yl)acetonitrile

Stage

one.

3-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-1-((2-trimethylsilyl)ethoxy)methyl)-1H pyrrolo[2,3-b]pyridine

2.7 g 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine, 3.2 g 1-(1ethoxyethyl)-4-(4.4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 3 g of potassium carbonate and 90 mg of Pd(dppf)Cl ₂ are dissolved in 21 ml of n-butanol and 7 ml of water, heated up to 100°C for 20 hours. The reaction is completed. The reaction solution was concentrated to dryness and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 1.2 g of an oil.

Step 2. 3-(1H-Pyrazol-4-yl)-1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

1.2 g of the product from step 1 is added to 9 ml of tetrahydrofuran and 22.5 ml of H2O. Then, 3 ml of 10% dilute hydrochloric acid was added to the mixture, and stirred at room temperature. The reaction is complete after 1 hour. Add 30% sodium hydroxide to adjust the pH to 7. The mixture is extracted with dichloromethane, dried (Na ₂ SO ₄ ) and concentrated to obtain 1.0 g of oil.

Step 3. 2-(1-(Ethylsulfonyl)-3-(4-(1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H- pyrazol-1-yl)-azetidin-3-yl)acetonitrile

0.5 g of the product from step 2 and 0.2 g of 2-(1-(ethylsulfonyl)azetidine-3-ylidene)acetonitrile are added to 20 ml of acetonitrile. 10 mg of DBU was added to the reaction mixture at room temperature and reacted for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with water. The organic layer is dried, filtered, concentrated and purified by column chromatography to obtain 0.6 g of the expected product.

Step 4 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin3-yl)acetonitrile.

5 ml of trifluoroacetic acid was added to 0.5 g of the product from step 3 and reacted at room temperature for 3 hours. After completion of the reaction (thin layer chromatography (ethyl acetate/petroleum ether 1:2)), the mixture was concentrated to dryness. 1 ml of ethylenediamine was added to the residue and reacted for 2 hours. The mixture was concentrated to dryness, filtered, concentrated and purified by column chromatography to give the desired product (0.3 g).

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 8.51 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.26 ( d, J=4.6 Hz,

1H), 8.09 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.15 (dd, J=7.9, 4.7 Hz, 1H), 4, 55 (d, J=8.8 Hz, 2H), 4.22 (d, J=8.8 Hz,

2H), 3.64 (s, 2H), 3.25 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H). MS (ESI): 367.14 (M+1).

Example 2 2-(4-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4-yl) acetonitrile

The synthesis is carried out according to the method of example 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 8.50 (s, 1H), 8.36-8.31 (m, 1H), 8.26 (dd, 1H ), 8.06 (s, 1H), 7.79 (d, 1H), 7.14 (dd, 1H), 3.29 (d, 4H), 3.13-2.96 (m, 4H) , 2.55 (d, 2H). MS (ESI): 356.11 (M+1).

Example 3 2-(4-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4-yl )acetonitrile

The synthesis is carried out according to the method of example 1.

Alternatively, the synthesis is carried out using the following steps.

Step 1. 2-(1,1-Dioxo-4-(4-(7-((2-(trimethylsilyl))ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)-1H -pyrazol-1 -yl)tetrahydro-2H-thiopyran-4-yl)acetonitrile

To a 250 ml round bottom flask, add 15 g of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and 100 ml of acetonitrile at room temperature under nitrogen protection and cooled to 0°C in an ice bath. Then 0.72 g of DBU and 9.0 g of 2-(1,1-dioxodihydro-2Hthiopyran-4(3H)-ylidene)acetonitrile are added, the reaction is continued at 0° C. for 5 hours, and then the mixture is reacted at room temperature 20°C overnight until the starting materials are practically used up. The reaction is monitored by thin layer chromatography. The solid is filtered and washed with ethyl acetate. The filtrate is concentrated to dryness. A solid is precipitated by adding ethyl acetate and then washed with ethyl acetate/n-hexane to give a solid. The solids are combined and dried to give 8 g of product.

Step 2. 2-(4-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4-yl )acetonitrile.

g of the product from step 1 was added to 30 ml of trifluoroacetic acid and reacted at room temperature for 3 hours. After completion of the reaction (thin layer chromatography (ethyl acetate/petroleum ether 1:2)), the mixture was concentrated to dryness. 1 ml of ethylenediamine is added and reacted for 2 hours. The mixture is concentrated to dryness, filtered, concentrated and purified by column chromatography to give 2.6 g of expected product.

1H NMR (400 MHz, DMSO-a ₆ ) δ 12.15 (s, 1H), 8.91 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7, 62 (m, 1H), 7.10 (m, 1H), 3.41 (s, 2H), 3.29 (m, 2H), 3.00-3.17 (m, 4H), 2.54 -2.60 (m, 2H). MS (ESI): 356.11 (M+1).

Example 4 acetonitrile

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The synthesis is carried out according to the method of example 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 8.78 (s, 1H), 8.33 (s, 1H), 8.20 (d, 1H), 7, 53 (d, 1H), 7.36 (d, 1H), 6.90 (d, 1H), 3.38 (s, 2H), 3.28-3.33 (m, 2H), 3.12 (m, 2H), 3.02 (m, 2H), 2.56 (m, 2H). MS (ESI): 356.11 (M+1).

Example 5 N-(2,2,2-trifluoroethyl)acetonitrile

The synthesis is carried out according to the method of example 1. MS (ESI): 385.14 (M+1).

Example 6 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin3-yl)acetamide

0.3 g of the product from example (1) and 10 ml of methanol are added to 2 ml of 1 M sodium hydroxide and reacted at 50°C for 2 hours. The pH is adjusted to 7 with hydrochloric acid, the methanol is removed and filtered to obtain the target product.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.33-8.23 (m, 3H), 7.99 (s, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.47 (s, 1H), 7.12 (dd, J=7.9, 4.7 Hz, 1H), 6.97 (s, 1H), 4, 46 (d, J=8.9 Hz, 2H), 4.35 (d, J=8.9 Hz, 2H), 3.20 (q, J=7.1 Hz, 2H), 3.08 ( s, 2H), 1.24 (t, J=7.3 Hz, 3H). MS (ESI): 389.14 (M+1).

Example 7 (2,2,2-trifluoroethyl)acetamide

Step 1. 2-(3-(4-H-Pyrrolo[2,3-b]pyridin-3-yl)-1 H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetic acid

4 ml of 1 M sodium hydroxide and 20 ml of methanol are added to 0.6 g of the product from example (1) and subjected to interaction at the boil under reflux for 10 hours. The pH is adjusted to 6 with hydrochloric acid and the methanol is removed. The mixture is extracted with dichloromethane, dried, concentrated and filtered to give 0.4 g of expected product.

Step 2. 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-n-nirazol-1-yl)-1-(ethylsulfonyl)azetidin3-yl)-N- (2,2,2-trifluoroethyl)acetamide.

0.4 g of the product from step 1 is dissolved in 5 ml of dry DMF and 0.18 g of N-(3

- 9 039344 dimethylaminopropyl)-N'-ethylcarbodiimide (EDC.HCl). After stirring for 1 hour, 0.1 g of trifluoroethylamine is added. After 2 hours of reaction, the mixture is diluted with water, extracted with dichloromethane, dried, concentrated and then purified by column chromatography to give 0.3 g of expected product.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 8.76 (m, 1H), 8.24-8.28 (m, 3H), 7.78 (s, 1H), 7.12 (m, 1H), 4.47 (d, 2H), 4.35 (d, 2H), 3.83 (m, 2H), 3.20 (m, 4H), 1, 24 (t, 3H). MS (ESI): 471.14 (M+1).

Example 8 N-(2,2,2-trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7.

¹ H NMR (400 MHz, DMSOCH) δ 11.12 (s, 1H), 8.73 (m, 1H), 8.71 (m, 1H), 8.68 (m, 1H), 8.39 ( s, 1H), 7.59 (d, 1H), 7.02 (d, 1H), 4.53 (d, 2H), 4.36 (d, 2H), 3.81 (m, 2H), 3.27 (s, 2H), 3.18-3.23 (m, 2H), 1.23 (t, 3H). MS (ESI): 472.13 (M+1).

Example 9 (2,2,2-trifluoroethyl)acetamide

Prepared as described in step 2 of Example 7. MS (ESI): 471.14 (M+1).

Example 10 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl )-N-methylacetamide

Prepared as described in step 2 of Example 7. MS (ESI): 403.15 (M+1).

Example 11 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin3-yl)acetamide

Obtained according to the method of example 6.

¹ H NMR (400 MHz, DMSOCH) δ 11.72 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.46 (dd, J=8.5, 5.4 Hz, 2H), 7.27 (d, J=5.0 Hz, 1H), 6.94 (s, 1H), 7, 79 (dd, J=3.5, 1.8 Hz, 1H), 3.64 (s, 2H), 4.47 (d, J=9.0 Hz, 2H), 4.32 (d, J =9.0 Hz, 2H), 3.17 (kv, J=7.3 Hz, 2H), 3.08 (s, 2H), 1.20 (t, J=7.3 Hz, 3H). MS (ESI): 389.14 (M+1).

Example 12 N-(2,2,2-trifluoroethyl)acetamide

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Prepared as described in Example 7, Step 2. MS (ESI): 458.12 (M+1).

Example 13 N-methylacetamide

Prepared as described in step 2 of Example 7. MS (ESI): 390.13 (M+1).

Example 14 2-(3-(4-(7H-pyrrolo[2,3-0]pyrimidin-4-yl)-III-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetamide

Prepared as described in Example 6. MS (ESI): 376.11 (M+1).

Example 15 N-(2,2,2-trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7. MS (ESI): 457.12 (M+1).

Example 16 N-methylacetamide

Prepared as described in Example 7, Step 2. MS (ESI): 389.14 (M+1).

Example 17 2-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetamide

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Prepared as described in Example 6. MS (ESI): 375.12 (M+1).

Example 18 2-(4-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4- yl)acetamide

Obtained according to the method of example 6.

¹ H NMR (400 MHz, DMSO-dQ δ 11.67 (s, 1H), 8.37-8.27 (m, 2H), 8.25 (dd, J=4.6 Hz, 1.4 Hz , 1H), 7.98 (s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.31 (s, 1H), 7.12 (dd, J=7.9, 4.7 Hz, 1H), 6.91 (s, 1H), 3.21 (d, J=13.2 Hz, 2H), 2.55 (d, J=11.9 Hz, 2H), 3 .08 (d, J=14.7 Hz, 2H), 3.08 (t, J=13.4 Hz, 2H), 2.95 (t, J=13.4 Hz, 2H), 2.69 (t, J=12.5 Hz, 2H), 2.61 (s, 2H) MS (ESI): 374.12 (M+1).

Example 19 2-(4-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4- yl)-N-(2,2,2-trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7.

1H NMR (400 MHz, DMSOCH) δ 11.68 (s, 1H), 8.61 (m, 1H), 8.28-8.32 (m, 2H), 8.24-8.25 (m, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.12 (m, 1H), 3.82 (m, 2H), 2.65-3.34 (m, 8H ), 2.50 (m, 2H). MS (ESI): 456.13 (M+1).

Example 20 2-(4-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro2H-thiopyran-4-yl) -N-(2,2,2-trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7.

1H NMR (400 MHz, DMSOL) δ 12.11 (s, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.59 (m, 1H), 8.39 (s , 1H), 7.59 (d, 1H), 7.05 (d, 1H), 3.81 (m, 2H), 3.24 (m, 2H), 3.12 (m, 2H), 2 .97 (m, 2H), 2.83 (s, 2H), 2.67 (m, 2H). MS (ESI): 457.12 (M+1).

Example 21 2-(4-(4-(7H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2Hthiopyran-4-yl) -N-(2,2,2-trifluoroethyl)acetamide

Prepared according to the procedure for step 2 of Example 7. MS (ESI): 456.12 (M+1).

Example 22 N-(2,2,2-trifluoroethyl)acetamide

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Prepared as described in Example 7, Step 2. MS (ESI): 485.15 (M+1).

Example 23 N-(2,2,2-trifluoroethyl)acetamide o _<z o

Prepared as described in Example 7, Step 2. MS (ESI): 486.15 (M+1).

Example 24 N-(2,2,2-trifluoroethyl)acetamide

Ch'r

Prepared as described in Example 7, Step 2. MS (ESI): 485.15 (M+1).

Example 25 2-(1-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclopentyl)-N-(2,2,2trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7.

¹ H NMR (400 MHz, DMSO-de) δ 11.60 (s, 1H), 8.42 (m, 1H), 8.22 (m, 2H), 8.10 (s, 1H), 7, 84 (s, 1H), 7.66 (d, 1H), 7.10 (m, 1H), 3.79 (m, 2H), 2.86 (s, 2H), 2.50 (m, 2H ), 2.07 (m, 2H), 1.71 (m, 2H), 1.58 (m, 2H). MS (ESI): 485.15 (M+1).

Example 26 2-(1-(4-(1H-Pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)-N-(2,2,2trifluoroethyl)acetamide

Prepared as described in Example 7, Step 2. MS (ESI): 485.15 (M+1).

Example 27 2-(1-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)-N-(2,2,2trifluoroethyl)acetamide

Prepared according to the method of step 2 of example 7. MS (ESI): 392.17 (M+1).

Example 28 3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2trifluoroethyl)butanamide

Prepared according to the method of step 2 of example 7. MS (ESI): 366.15 (M+1).

Example 29 3-(4-(7H-Pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2-13 039344 trifluoroethyl) butanamide

Prepared according to the procedure for step 2 of Example 7. MS (ESI): 367.14 (M+1).

Example 30 3-(4-(7H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2trifluoroethyl)butanamide

Prepared according to the procedure for step 2 of Example 7. MS (ESI): 367.14 (M+1).

Example 31 )azetidine-3-carboxamide

Stage 1. Methyl 3-((2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carboxylate \ o

3.3 g of 2,4-dichloropyrimidine and 5 g of methyl 3-amino-1-(methylsulfonyl)azetidine-3-carboxylate are dissolved in 50 ml of tetrahydrofuran. 5 ml of DIPEA are added and reacted at 40°C for 3 hours. The mixture is diluted with water, extracted with dichloromethane, dried, filtered, concentrated and purified by column chromatography to obtain 6 g of expected product.

Step 2. 3-((2-Chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carboxylic acid

g of the product from step 1 is dissolved in 10 ml. 4 ml of 2 M potassium hydroxide are added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed and hydrochloric acid is added to adjust the pH to 6. The mixture is filtered and dried to obtain 1.6 g of the expected product.

Step 3. 1-(Methylsulfonyl)-3-((2-(1-p-toluenesulfonyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)azetidin-3 -carboxylic acid

In 24 ml of dioxane/water (5:1) add 2 g of the product from step 2, 1.26 g of 3-(4,4,5,5-tetramethyl-1,3,2dioxolan-2-yl)-1-p -toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine, 1.0 g of potassium carbonate and 0.1 g of Pd(dppf)Cl ₂ and heated to 90°C and subjected to interaction for 3 h. The mixture is adjusted to pH 6 with hydrochloric acid and filtered. The filtrate is treated under reduced pressure to remove dioxane, diluted with water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain 1.8 g of the expected product.

Step 4. 3-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carboxylic acid

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To 0.8 g of the product from step 3 add 3 ml of 2 M potassium hydroxide and 10 ml of methanol and reflux for 2 hours. The solvent is removed and the pH is adjusted to 6 with hydrochloric acid and filtered to obtain 0.5 g target product.

Step 5. 3-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N(2,2,2-trifluoroethyl )azetidine-3-carboxamide.

0.3 g of the product from step 4 is dissolved in 5 ml of dry DMF. 0.16 g of N-(3dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was added and stirred for 2 hours. Then 0.098 g of 2,2,2-trifluoroethylamine was added and reacted for 1 hour. After completion of the reaction , the mixture is diluted with water, extracted with dichloromethane, dried, concentrated and purified by column chromatography to obtain 0.2 g of the expected product. MS (ESI): 470.12 (M+1).

Example 32 3-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N(2,2,2-trifluoroethyl )azetidine-3-carboxamide

Prepared as described in Example 31. MS (ESI): 484.13 (M+1).

Example 33 3-((2-( 1 H-Pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(cyclopropylsulfonyl)-N-(2,2,2 -trifluoroethyl)azetidine-3-carboxamide

Prepared as described in Example 31. MS (ESI): 496.13 (M+1).

Example 34 3-(5-Fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N-(2,2 ,2-trifluoroethyl)αzetidine-3-carboxamide

Prepared as described in Example 31. MS (ESI): 488.10 (M+1).

Example 35 3-(5-Fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N-(2,2 ,2-trifluoroethyl)azetidine-3-carboxamide

Prepared as described in Example 31. MS (ESI): 502.12 (M+1).

Example 36 3-(5-Fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)αmino)-1-(cyclopropylsulfonyl)-N-(2,2 ,2-trifluoroethyl)azetidine-3-carboxamide

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Prepared as described in Example 31. MS (ESI): 514.12 (M+1).

Example 37 )piperidine-4-carboxamide

Prepared as described in Example 31. MS (ESI): 498.15 (M+1).

Example 38 )piperidine-4-carboxamide

Prepared as described in Example 31. MS (ESI): 412.16 (M+1).

Example 39 -trifluoroethyl)piperidine-4-carboxamide

Prepared as described in Example 31. MS (ESI): 524.16 (M+1).

Example 40 2,2-trifluoroethyl)piperidine-4-carboxamide

Prepared as described in Example 31. MS (ESI): 516.16 (M+1).

Example 41 2,2-trifluoroethyl)piperidine-4-carboxamide

Prepared as described in Example 31. MS (ESI): 530.16 (M+1).

Example 42 2,2-trifluoroethyl)piperidine-4-carboxamide

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Prepared as described in Example 31. MS (ESI): 542.16 (M+1).

Example 43 4-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)tetrahydro-2H -thiopyran-4-carboxamide 1,1 -dioxide

Prepared as described in Example 31. MS (ESI): 469.12 (M+1).

Example 44 2H-thiopyran-4-carboxamide 1,1-dioxide

Prepared as described in Example 31. MS (ESI): 487.11 (M+1).

Example 45

Prepared as described in Example 31. MS (ESI): 384.12 (M+1).

Example 46 3-((2-(7H-Pyrrolo[2,3-b]pyrimidin-4-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)azetidine-3-carbonitrile

Prepared as described in Example 31. MS (ESI): 385.12 (M+1).

Example 47 3-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)azetidine-3-carbonitrile

Prepared as described in Example 31. MS (ESI): 385.12 (M+1).

Example 48 3-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carbonitrile

Prepared as described in Example 31. MS (ESI): 370.1 (M+1).

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Example 49 3-((2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carbonitrile

Prepared as described in Example 32. MS (ESI): 371.1 (M+1).

Example 50 3-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3-carbonitrile

Prepared as described in Example 31. MS (ESI): 370.1 (M+1).

Example 51 4-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)tetrahydro-2Hthiopyran-4-carbonitrile 1,1-dioxide

Prepared as described in Example 31. MS (ESI): 369.1 (M+1).

Example 52 4-((2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)tetrahydro-2Hthiopyran-4-carbonitrile 1,1-dioxide

Prepared as described in Example 31. MS (ESI): 370.1 (M+1).

Example 53 4-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide

Prepared as described in Example 31. MS (ESI): 369.1 (M+1).

Example 54 Carbonitrile

1-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclobutan-3-

Prepared as described in Example 31. MS (ESI): 291.13 (M+1).

Example 55 1-((2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)cyclobutan-3carbonitrile

Prepared as described in Example 31. MS (ESI): 292.13 (M+1).

Example 56 1-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)cyclobutanecarbonitrile

- 18 039344

Prepared as described in Example 31. MS (ESI): 291.13 (M+1).

Example 57 1-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentanecarbonitrile

Prepared as described in Example 31. MS (ESI): 305.15 (M+1).

Example 58 1-((2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)cyclopentanecarbonitrile

Prepared as described in Example 31. MS (ESI): 306.14 (M+1).

Example 59 1-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)cyclopentanecarbonitrile

Prepared as described in Example 31. MS (ESI): 305.14 (M+1).

Example 60 (R)-2-((2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile

Prepared as described in Example 31. MS (ESI): 293.14 (M+1).

Example 61 (R)-2-((2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile

Prepared as described in Example 31. MS (ESI): 294.15 (M+1).

Example 62 (R)-2-((2-(1H-Pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile

Prepared as described in Example 31. MS (ESI): 293.15 (M+1).

Example 63 JAK inhibition.

The study of the effect of compounds on the activity of purified recombinant JAK is carried out by studying the inhibitory effect of compounds on JAK at the enzymatic level. The principle of the experiment is to use a luminescent kinase assay to determine the content of ADP obtained by reacting JAK with a Poly (4:1 Glu, Tyr) peptide substrate: after ADP is converted to ATP, ATP can act as a substrate for the Ultra-Glo luciferase catalytic reaction, creating an optical signal. The luminescence signal positively correlates with the amount of ADP and kinase activity. Therefore, the inhibitory effect of compounds on recombinant JAK is determined by observing the luminescence signal generated by the reaction of JAK and substrate and is expressed as IC ₅₀ .

Experimental procedure: 10 different concentrations of compounds are incubated with JAK1, JAK2 and JAK3, respectively, for 60 min at 37°C. Substrate and ATP are then added, mixed and reacted at 37° C. for 50 minutes. Add 25 µl of ADP-Glo™ and mix for 2 min. The reaction is carried out for 50 min at room temperature. Then add 50 µl of defining reagent and mix for 2 min and incubate at room temperature for 50 min and determine with a chemiluminometer. The results are shown in table. one.

Table 1. Results of the JAK inhibition experiment with the compounds described here

Compound JAK1 inhibition 1C ₅₀ (nM) Inhibition of JAK2 1C ₅₀ (nM) Inhibited e JAK3 1C ₅₀ (nM) Compound Example 1 a b FROM Compound Example 2 a b ^With Compound Example 3 a b a Compound Example 4 a a With Compound Example 5 a b a Compound of Example 6 With With With Compound of example 7 With ^With With Compound Example 8 With With With Compound Example 9 With With With Compound of example 10 ^{With With With} Example compound 11 ^With With ^With Compound of Example 12 b b With Example compound 13 ^With With With Compound of example 14 b b With Compound of Example 15 a b a Example compound 18 a With a Example compound 19 b ^With Compound of example 20 b ^{With With} Example compound 21 b With With Compound of example 22 ^With With ^With Compound of Example 23 b ^With Compound Example 24 b ^{With With} Compound of example 25 b With b Compound of example 26 b ^{With With} Example compound 27 b ^{With With} Compound Example 28 With b With Compound Example 29 With b a Compound Example 31 With With b Compound Example 32 With With b Compound Example 33 With With b Compound Example 34 ^{With With} b Compound Example 36 b Compound of Example 37 ^{With With} b Compound Example 38 With ^With b Compound Example 39 With b Example compound 42 ^With b b Example compound 44 ^With b b Example compound 45 With b b Example compound 46 With With With Example compound 47 With ^With b Example compound 48 ^{With With With} Example compound 49 With FROM b Compound Example 50 With With FROM Example compound 51 ^{With With} b Example compound 52 With With Example compound 53 With With b Example compound 54 ^With With b Example compound 55 With With With Example compound 56 With With ^With

- 20 039344

Example compound 57 With With b Example compound 58 FROM FROM FROM Example compound 59 FROM FROM b Compound Example 60 FROM FROM b Compound Example 61 With With ^With Compound Example 62 FROM FROM FROM

Note: 1. (a) <20 nM;

2. (b) >20 nM - 50 nM;

3. (c) >50 nM.

As an example, Example 3 is compared with the results of an existing JAK inhibitor under the same experimental conditions, and the results are shown in Table 1. 2.

Table 2. Comparison of the inhibitory effect of the compound described here and existing JAK inhibitors on JAK

Compound JAK1 inhibition 1C ₅₀ (nM) Inhibition of JAK2 1C ₅₀ (nM) Inhibition of JAK3 1C ₅₀ (nM) Compound Example 3 10.5 22.0 19.0 Tofacitinib 20-50 20-50 <20 Ruxolitinib* 3.3 2, 8 390 Baricitinib* 5.9 5.5 >400

Note: Test results for Ruxolitinib and Baricitinib* are obtained from the FDA New Drug Application.

The results show that the compound of Example 3 has a strong inhibitory effect on JAK1 and a weak inhibitory effect on JAK2, suggesting a higher selectivity of the compound for JAK1 than Baricitinib and Ruxolitinib (compounds described in CN101448826A), and the latter two positive drug agents are not selective for JAK1 and JAK2.

Example 64 Effect of repeated administration of a compound described here on hematological parameters in rats.

Take 48 healthy Wistar rats, half 5 and half ^. According to their body weight, they are randomly assigned to a control group (Veh). The compound from example 3 is administered by probe at doses of 1.5 mg-kg ^-1 -s ^-1 and 4.5 mg-kg ^ -s' ¹ . Ruxolitinib is administered by gavage at a dose of 4.5 mg-kg^-c' ¹ . Each group included 12 rats, half 5 and half ^. The drug is administered by gavage once a day for 4 weeks and hematological parameters are examined 1 day and 2 days after the last injection.

Results: after cessation of administration for groups with oral administration of the compound from example 3 at doses of 1.5 mg-kg ^-1 -s ^-1 and 4.5 mg-kg ^ -s' ¹ compared with the control group (Veh) (P<0.05); for the Luxolitinib group (a compound described in CN101448826A) at a dose of 4.5 mg-kg ^-1 -s ^-1 , a significant decrease in the value of the hematological parameter of CCB animals was noted compared to the control group (Veh) (P<0.05), which allows suggest fewer side effects for the compounds described herein in the treatment of rheumatoid arthritis.

The results showed that the compound of Example 3 has a strong inhibitory effect on JAK1 and a weak inhibitory effect on JAK2, suggesting a higher selectivity of the compound for JAK1 compared to Baricitinib and Ruxolitinib (a compound described in CN 101448826 A), and the last two positive drugs are not selective for JAK1 and JAK2.

Claims (6)

1. Connection selected from the following structures: - 21 039344 - 22 039344 or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where the compound is selected from the following structures: 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile; 2-(4-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran4-yl)acetonitrile; 2-(4-(4-( 1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4yl)acetonitrile ; 2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4yl)acetonitrile ; 2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)piperidin-4-yl)acetonitrile; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)-N (2,2,2-trifluoroethyl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)-N (2,2,2-trifluoroethyl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)-N (2,2,2-trifluoroethyl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)-Nmethylacetamide ; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetamide; 2-(3-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)N-(2 ,2,2-trifluoroethyl)acetamide; 2-(3-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)N-methylacetamide; 2-(3-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)-N (2,2,2-trifluoroethyl)acetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)-N methylacetamide; 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetamide; 2-(4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4yl)acetamide ; 2- (4- (4- ( 1 H-pyrrolo [2,3-b] pyridin-3 -yl) -1 H-pyrazol-1 -yl) -1,1 -dioxotetrahydro-2H-thiopyran-4yl) - N-(2,2,2-trifluoroethyl)acetamide; 2-(4-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran4-yl)-N- (2,2,2-trifluoroethyl)acetamide; 2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1,1-dioxotetrahydro-2H-thiopyran-4yl)-N- (2,2,2-trifluoroethyl)acetamide; 2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)piperidin-4-yl)-N(2 ,2,2-trifluoroethyl)acetamide; 2-(4-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)piperidin-4yl)-N-(2, 2,2-trifluoroethyl)acetamide; - 23 039344 2-(4-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-III-pyrazol-1-yl)-1-(methylsulfonyl)piperidin-4-yl)-N(2 ,2,2-trifluoroethyl)acetamide; 2-(1-(4-(III-pyrrolo[2,3-b]pyridin-3-yl)-III-pyrazol-1-yl)cyclopentyl)-N-(2,2,2-trifluoroethyl)acetamide; 2-(1-(4-(1H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)-N-(2,2,2-trifluoroethyl) acetamide; 2-(1-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)cyclopentyl)-N-(2,2,2-trifluoroethyl)acetamide; 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide; 3-(4-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide; 3-(4-(7H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where the compound is selected from the following structures: 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N-(2,2,2trifluoroethyl)azetidine-3 -carboxamide; 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N-(2,2,2trifluoroethyl)azetidine-3 -carboxamide; 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(cyclopropylsulfonyl)-N(2,2,2-trifluoroethyl)azetidine- 3-carboxamide; 3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N(2,2,2-trifluoroethyl )azetidine-3-carboxamide; 3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N-(2,2,2trifluoroethyl) azetidine-3-carboxamide; 3-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(cyclopropylsulfonyl)N-(2,2,2-trifluoroethyl )azetidine-3-carboxamide; 4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N-(2,2,2trifluoroethyl)piperidine-4 -carboxamide; 4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N-(2,2,2trifluoroethyl)piperidine-4 -carboxamide; 4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(cyclopropylsulfonyl)-N(2,2,2-trifluoroethyl)piperidine- 4-carboxamide; 4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)-N(2,2,2- trifluoroethyl)piperidine-4-carboxamide; 4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)-N-(2,2,2trifluoroethyl )piperidine-4-carboxamide; 4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(cyclopropylsulfonyl)N-(2,2,2- trifluoroethyl)piperidine-4-carboxamide; 4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)tetrahydro2H-thiopyran-4-carboxamide 1,1-dioxide; 4-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)tetrahydro-2H -thiopyran-4-carboxamide 1,1-dioxide; 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)azetidine-3carbonitrile; 3-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)azetidine-3carbonitrile; 3-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)-1-(ethylsulfonyl)azetidine-3carbonitrile; 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3carbonitrile; 3-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3carbonitrile; 3-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)-1-(methylsulfonyl)azetidine-3carbonitrile; 4-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran-4carbonitrile 1,1-dioxide; 4-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran-4carbonitrile 1,1-dioxide; 4-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran-4carbonitrile 1,1-dioxide; 1-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclobutan-3-carbonitrile; 1-((2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-4-yl)amino)cyclobutan-3-carbonitrile; - 24 039344 1-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)cyclobutanecarbonitrile; 1-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclopentanecarbonitrile; 1-((2-(7H-pyrrolo[2,3-4]pyrimidin-4-yl)pyrimidin-4-yl)amino)cyclopentanecarboxynitrile; 1-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino)cyclopentanecarbonitrile; (K)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile; (K)-2-((2-(7H-pyrrolo[2,3-<1]pyrimidin-4-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile; (K)-2-((2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)amino-2-methylbutanenitrile; or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and pharmaceutically acceptable carriers. 5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the treatment of JAK kinase (Janus kinase) related diseases. 6. Use according to claim 5, wherein the disease is selected from autoimmune diseases, rheumatoid arthritis, skin conditions, multiple sclerosis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.