CN109535132A

CN109535132A - 2- substituted pyrazolecarboxylic amino -4- substituted-amino -5- pyrimidinecarboxamides compound, composition and its application

Info

Publication number: CN109535132A
Application number: CN201811099717.0A
Authority: CN
Inventors: 张强; 刘彦生; 李兴福; 胡晨明
Original assignee: Beijing Saite Mingqiang Medicine Technology Co Ltd
Current assignee: Beijing Saite Mingqiang Medicine Technology Co Ltd
Priority date: 2017-09-21
Filing date: 2018-09-20
Publication date: 2019-03-29
Anticipated expiration: 2038-09-20
Also published as: CN113214230B; CN113214230A; CN109535132B

Abstract

The present invention relates to a kind of noval chemical compound, composition and its applications as JAK inhibitor.Specifically, the present invention provides a kind of compounds (as shown in formula (1)) or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, metabolite, isotope derivatives and solvate with strength JAK inhibitory, and it includes the pharmaceutical compositions of the compound.The invention also discloses the application of the compounds of this invention or pharmaceutical composition in medicine preparation, the drug is for treating autoimmune disease or cancer.

Description

2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to a compound with JAK kinase inhibitory activity or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in preparation of medicines.

Background

JAK kinases (Janus kinases) and their downstream effector, signal transduction and transcriptional activator proteins form an important cytokine signaling pathway, the JAK-STAT pathway. Researches show that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors and participate in the processes of cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like. The JAK kinase is a key kinase in the JAK-STAT signaling pathway, which was found to be two decades later, the first JAK kinase inhibitor (tofacitinib) was approved for rheumatoid arthritis treatment in 2012 [ Norman p., Selective JAK inhibitors in maintenance for rhematoid arthritis, Expert Opin investigdrug, 2014,23: 1067-.

JAK1, JAK2, JAK3 and TYK2 are three members in a JAK kinase family, the JAK kinase family consists of more than 1100 amino acids, the relative molecular mass can reach 120000-140000, the homology can reach 40% -70%, the JAK kinase family members can be sequentially divided into 7 homologous structural domains (JH) from the C end to the N end, the JH1 is a kinase region and is highly conserved in the JAK family; JH2 is a kinase-like region or "pseudo" kinase region, the pseudo kinase domain is a unique property of JAK protein which is different from other tyrosine proteins, the kinase region has no catalytic activity but has a regulating effect on the activity of JH1, and mutations in the domain can often lead to the enhancement or the reduction of the JAK kinase activity and further lead to the occurrence of certain diseases; JH3-JH4 is the SH 2domain (Src homology2domain) which contains about 100 amino acid residues that specifically recognize and bind phosphorylated tyrosine residues on ligands; JH5-JH7 are FERM domains that are conserved, primarily regulating JAK binding to receptors. JAK3, a member of the JAK kinase family, structurally contains the kinase domain described above, and changes in kinase activity are caused by mutations in specific amino acids in different domains.

The JAK-STAT signal pathway is an important intracellular signal transduction pathway in the processes of growth, activation, differentiation, apoptosis and function development of various cells. STATs are cytoplasmic proteins that bind to DNA in the regulatory region of target genes and are downstream substrates of JAK. The STAT family includes 7 members including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, and the like. The interaction between JAKs and STATs plays an important role in Cytokine receptor signaling pathways [ O' Sullivan LAet al, Cytokine receptor signaling through the JAK-Stat-Socs pathway indication, Mol Immunol,2007,44:2497-2506 ]. Cytokine receptors on cell surfaces, when bound to their respective cytokine ligands, cause dimerization of the receptor molecules, allowing JAK kinases coupled to the receptors to approach each other and become activated by interactive tyrosine phosphorylation. The JAK-STAT signaling pathway is a signaling pathway stimulated by multiple cytokine receptors, JAK kinases mediate signaling of most intracellular cytokines, such as Interleukins (ILs), Interferons (IFNs), Erythropoietins (EPO), Granulocyte and Macrophage Colony Stimulating Factor (GMCSF), somatotropin (GH), Prolactin (PRL), Thrombopoietin (TPO), platelet derived factor (PDGF), and Epidermal Growth Factor (EGF), and the like, and different receptors activate different subtypes of JAK kinases to exhibit differential biological functions [ Pesu m.et al, Therapeutic targeting of Janus kinases, Immunol Rev,2008,223: 132-.

JAK1 and JAK2 are expressed in each tissue cell of the human body, and JAK3 is mainly expressed in each hematopoietic tissue cell, and is mainly present in bone marrow cells, thymocytes, NK cells, activated B lymphocytes, and T lymphocytes. The deletion of JAK1 and JAK2 can cause lethal injury to human body, and the deletion of JAK3 can avoid toxic adverse reaction for damaging other tissue cells [ Yamaoka K., et al., JAK3 novel ligands-cell cytokinase and survival, Blood,2005,106: 3227-. Based on the functional characteristics and special tissue distribution of each subtype in the JAK kinase family, JAK3 has become a popular target for treating autoimmune diseases, and more clinical researches focus on blocking the JAK3 signal transduction path for treating rheumatoid arthritis. In 2012, the selective JAK3 inhibitor Tofacitinib passed clinical trials and was approved for the treatment of rheumatoid arthritis.

Tofacitinib (CP690550) is a pyrrolopyrimidine selective JAK3 kinase inhibitor developed by Pfizer, and has inhibitory activity (IC) on JAK3₅₀1nmol/L) is JAK2 (IC)₅₀20 times of 20nmol/L) and JAK1 (IC)₅₀112nmol/L) of the total. The study on the stereochemistry of Tofacitinib shows that the chiral structure of Tofacitinib determines that Tofacitinib can be specifically bound to JAK3 molecules, so that JAK3 phosphorylation is inhibited, STAT phosphorylation is further inhibited, and downstream inflammatory cytokine synthesis is inhibited. Tofacitinib shows good clinical curative effect in clinical research, and has good curative effect in rheumatoid arthritisIn the arthritis clinical trial study, the 5mg or 10mg Tofacitinib measuring group and the placebo group with the same amount show significant statistical difference, but the Tofacitinib is found to be related to the high risk of serious infection in the clinical trial study, and the long-term safety of the Tofacitinib is further studied.

The JAK-STAT signal pathway plays an important role in the cell differentiation and proliferation processes, and the change of the JAK activity also causes the change of the signal transmission of the pathway, thereby influencing the cell function. Based on the key role of JAK kinase in JAK-STAT signal transmission and the specific histiocyte distribution of JAK3 kinase, JAK3 becomes a good therapeutic target for diseases such as rheumatoid arthritis.

At present, JAK3 inhibitors are mainly used for treating patients with moderate and severe rheumatoid arthritis, and the drugs show good treatment effect and good safety in treatment, but the long-term safety of the drugs still needs to be further improved. During the clinical research process of Tofacitinib, certain adverse reactions including infection, tuberculosis, tumor and liver injury and the like can be caused after the medicament is used, so that the key problems to be solved urgently in the research field are to improve the drug effect of the JAK3 inhibitor and reduce toxic and side effects.

The JAK kinase has high ATP binding site homology of several subtypes and small structural difference, which is an important reason for low selectivity of JAK inhibitors. There is still room for improvement in therapeutic effect, selectivity and safety of a series of JAK kinase inhibitors disclosed so far, and there is still a need to develop JAK inhibitors having better drug efficacy and better safety. Although a high-selectivity JAK inhibitor is the focus of research in the field at present, in view of the fact that each member of a JAK kinase family is closely related to JAK-STAT signal transmission, the pan-JAK inhibitor can remarkably improve the drug effect and greatly reduce the drug dosage, thereby achieving the purpose of controlling toxic and side effects. In addition, the significant improvement of the drug efficacy will contribute to the development of anti-inflammatory drugs for transdermal administration. The research and development of the medicines provide a new way for treating autoimmune diseases such as psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease and the like, and cancers such as leukemia, lymphoma, multiple myeloma and the like. The compounds of the present invention exhibit excellent biological activity as JAK kinase inhibitors.

Disclosure of Invention

The invention provides a 2- (1-substituted pyrazole-4-) amino-4-substituted amino-5-pyrimidine carboxamide compound and application thereof in preparing a medicament for treating or preventing diseases caused by tyrosine kinases (such as JAK1, JAK2, JAK3 and TYK2) or variants thereof.

The present invention provides a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition in its effective polymorphic form, the compound having the structural formula (I):

wherein,

R¹is composed ofn₁Is 0-1, n₂Is 0-1, n₃Is a mixture of a water-soluble polymer and a water-soluble polymer, wherein the water-soluble polymer is 0-5%,

L₁is composed ofR⁴And/or R⁵Is H, C₁-C₃A linear alkyl group;

R²is composed ofn₄Is 0 to 3, n₅Is 0-1, n₆Is a mixture of a water-soluble polymer and a water-soluble polymer, wherein the water-soluble polymer is 0-5%,

L₂is composed ofR⁷And/or R⁸Is H, C₁-C₃A linear alkyl group.

The compound of formula (I) wherein R is a substituent³Comprises the following steps:

a) h, a hydroxyl group, a cyano group,

b)C₁-C₅a linear or branched alkyl group,

c)C₃-C₈cycloalkyl, more preferably C₃-C₇A cycloalkyl group,

d)C₁-C₅a straight-chain or branched alkoxy group, or a linear or branched alkoxy group,

e)C₁-C₅a straight-chain or branched alkylthio group,

f)5-7 membered heterocyclic ring, preferably said 5-7 membered heterocyclic ring contains 1-2 heteroatoms selected from O and/or N and/or S, and when the heteroatom is N, H or C is attached to N₁-C₄Alkyl radical, C₁-C₃Acyl, preferably acetyl, trifluoroacetyl, propionyl, N-diformyl, when the heteroatom is S, 0 to 2 oxygen atoms are attached to S,

g) substituted or unsubstituted five-membered aryl or heteroaryl, preferably, the structural formula of the substituted or unsubstituted five-membered aryl or heteroaryl isWherein: j. the design is a square₁And/or J₂And/or J₃And/or J₄C, N, S, O; r⁹Is C₁-C₃A linear or branched alkyl group,

or the structural formula of the substituted or unsubstituted five-membered aryl or heteroaryl is shown asWherein:

J₁、J₂、J₃、J₄each of which is independently C, N, S, O, is,

R²⁰、R²¹each independently is C₁-C₃A linear or branched alkyl group,

h) substituted or unsubstituted six-membered aryl or heteroaryl,

preferably, the substituted or unsubstituted six-membered aryl or heteroaryl has the structural formulaWherein:

Q₁、Q₂、Q₃、Q₄、Q₅is N or C;

R¹⁰and/or R¹¹And/or R¹²Comprises the following steps:

1)-F、-Cl、-Br、-CF₃、-OCF₃a cyano group;

2) -NR 'R ", R', R" being H, C₁-C₃Alkyl groups of (a);

3)C₁-C₃alkyl radical, C₂-C₅Alkynyl, C₃-C₅A cycloalkyl group;

4)SO₂R¹³wherein R is¹³Is H, C₁-C₃An alkyl group;

5)wherein q is 0-2, M is O, S, R¹⁴Is H, C₁-C₅Straight chain

Or a branched alkyl group;

6)wherein R is¹⁵、R¹⁶Is a straight-chain alkyl group,

or the structural formula of the substituted or unsubstituted six-membered aryl or heteroaryl is shown asWherein:

Q₁、Q₂、Q₃、Q₄、Q₅is N or C;

R¹⁷、R¹⁸each independently is:

a)-H，

b)-F、-Cl、-Br、-CF₃、-OCF₃a cyano group,

c) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

d)C₁-C₃alkyl radical, C₂-C₅Alkynyl, C₂-C₅Alkenyl radical, C₃-C₅A cycloalkyl group,

e)SO₂R¹³wherein R is¹³Is H, C₁-C₃An alkyl group, a carboxyl group,

f)wherein q is 0-2, M is O, S, R¹⁴Is H, C₁-C₅A linear or branched alkyl group,

g)wherein R is¹⁵、R¹⁶Is C₁-C₃The linear alkyl group of (a),

h)-(CH₂)_t-R¹⁹t is 1-2, R¹⁹Is C₃-C₅A cycloalkyl group;

i) containing 0-3 hetero atoms in six-membered aromatic rings and five-or six-membered rings or 1-3 hetero atomsA five-membered heteroaromatic ring and a five-or six-membered ring, preferably selected from:

the substituent R in the formula (I)⁶Comprises the following steps:

a) h and a hydroxyl group, wherein the hydroxyl group,

b) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

c)C₁-C₅a linear or branched alkyl group,

d)C₃-C₈a cycloalkyl group,

e)C₁-C₅a straight-chain or branched alkoxy group, or a linear or branched alkoxy group,

f)C₁-C₅a straight-chain or branched alkylthio group,

g) a heterocyclic group, preferably a five-or six-membered oxygen-and/or nitrogen-containing heterocyclic group, such as

The present invention provides a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, having the structural formula (I):

wherein,

R¹is composed ofn₁Is 0-2, n₂Is 0-1, n₃Is a mixture of a water-soluble polymer and a water-soluble polymer, wherein the water-soluble polymer is 0-5%,

L₁is composed ofR⁴And/or R⁵Is H, C₁-C₃A linear alkyl group;

L₂is composed ofR⁷And/or R⁸Is H, C₁-C₃A linear alkyl group;

R³is R²²Substituted C₁-C₃Alkoxy or R²²Substituted C₁-C₃Alkylthio radical, R²²Is hydroxy, C₁-C₃Alkoxy radical, C₁-C₃Alkylthio, -NR' R ", hydroxy-substituted C₁-C₃Alkoxy, amino substituted C₁-C₃Alkoxy, hydroxy-substituted C₁-C₃Alkylthio, amino substituted C₁-C₃Alkylthio, wherein R ', R' are H, C₁-C₃Alkyl groups of (a);

R⁶is a) H, a hydroxyl group,

b) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

c)C₁-C₅a linear or branched alkyl group,

d)C₃-C₈a cycloalkyl group,

f)C₁-C₅a straight-chain or branched alkylthio group, or

g)

It will be clear that the compounds of formula (I), isomers, crystals or prodrugs and pharmaceutically acceptable salts thereof may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.

One aspect of the present invention is a pharmaceutical composition comprising a compound of structural formula (I). The composition can be applied to autoimmune diseases such as psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease and cancers such as leukemia, lymphoma, multiple myeloma, including those with drug resistance by Tofacitinib, Pefinitinib, Decerntinib or other kinase inhibitors, cancers and the like.

It is a further object of the present invention to provide a method for treating autoimmune diseases and cancer comprising administering to a subject a therapeutically effective amount of a composition comprising a compound of the present invention. Autoimmune diseases, cancers that can be so treated are noted elsewhere herein, including autoimmune diseases, cancers, etc. that are resistant to treatment with Tofacitinib, Pefitinib, Roxolitinib, Decernotinib, or other kinase inhibitors.

One or more other therapies may also be used in combination in the treatment of cancer, including surgery, radiation therapy (e.g., gamma-rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, etc.), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and Tumor Necrosis Factor (TNF)), hyperthermia, cryotherapy, attenuating any adverse effects (e.g., antiemetics), and other therapeutic agents.

The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of diseases such as ocular fundus disease, dry eye, psoriasis, rheumatoid arthritis, skin rash, eczema, alopecia areata, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, inflammatory bowel disease and autoimmune diseases, as well as tumors, including those diseases which develop resistance to one or more other therapeutic agents, as noted elsewhere herein. The compounds of the invention are also useful in medicine for alleviating or preventing disease by inhibiting one or more kinases (e.g., JAK1, JAK2, JAK3, TYK 2).

The invention also provides a method for preparing the corresponding compound, which can be prepared by the following method. The synthetic route for the series (I) of compounds is shown below:

reagents and reaction conditions (a) DIEA, THF; (b) s-BuOH, TFA.

Detailed Description

The synthesis method of the intermediate is as follows:

preparation of intermediate 11- (2-methoxyethyl) -1H-pyrazol-4-amine:

step 1): preparation of 1- (2-methoxyethyl) -4-nitro-1H-pyrazole:

4-Nitro-1H-pyrazole (5g, 44.21mmol) was dissolved in DMF (20mL) and K was added₂CO₃(9.1g, 65.85mmol) and 1-bromo-2-methoxyethane (7.4g, 53.24mmol) were reacted at 50 ℃ for 16 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness for column chromatography (petroleum ether: ethyl acetate: 3: 1) to give 5g of a brown oil in yield66％。¹H NMR(400MHz,DMSO-d₆)δ8.85(s,1H),8.27(s,1H),4.35(t,J＝5.1Hz,2H),3.73(t,J＝5.2Hz,2H),3.24(s,3H).LCMS:m/z＝172.1(M+H)⁺.

Step 2): preparation of 1- (2-methoxyethyl) -1H-pyrazol-4-amine:

1- (2-methoxyethyl) -4-nitro-1H-pyrazole (5g, 29.21mmol) was dissolved in ethanol (25mL) and ethyl acetate (25mL), and Raney nickel (500mg) was added and reacted under a hydrogen atmosphere for 5 hours. The mixture was filtered through celite, and the filtrate was evaporated to dryness to give a brown solid (3.6 g, 87% yield).¹H NMR(400MHz,DMSO-d₆)δ7.01(s,1H),6.90(s,1H),4.04(t,J＝5.4Hz,2H),3.89–3.63(m,2H),3.58(t,J＝5.4Hz,2H),3.20(s,3H).LCMS:m/z＝142.1(M+H)⁺.

Preparation of intermediate 21- [2- (methylthio) ethyl ] -1H-pyrazol-4-amine:

step 1): preparation of 1- [2- (methylthio) ethyl ] -4-nitro-1H-pyrazole:

4-Nitro-1H-pyrazole (400mg, 3.54mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and 2- (methylthio) -1-ethanol (424mg, 4.60mmol), triphenylphosphine (1.4g, 5.32mmol) and DIAD (1.13g, 5.60mmol) were added dropwise under an argon atmosphere at 0 ℃ and reacted at 25 ℃ for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to column chromatography (petroleum ether: ethyl acetate 4: 1) to give 180mg of a yellow oil in 54% yield. LCMS M/z 188.0(M + H)⁺.

Step 2): preparation of 1- [2- (methylthio) ethyl ] -1H-pyrazol-4-amine:

1- [2- (methylthio) ethyl]-4-nitro-1H-pyrazole (300mg, 1.60mmol) was dissolved in a mixed solution of ethanol (2mL) and ethyl acetate (2mL), and Raney nickel (30mg) was added and reacted under a hydrogen atmosphere for 5 hours. The mixture was filtered through celite, and the filtrate was evaporated to dryness to give 210mg of a brown oil in 83% yield.¹H NMR(400MHz,DMSO-d₆)δ7.06(s,1H),6.91(s,1H),4.09(t,J＝6.9Hz,2H),3.81(s,2H),2.79(t,J＝6.9Hz,2H),1.99(s,3H).LCMS:m/z＝158.1(M+H)⁺.

TABLE 1 Synthesis of intermediates 3-22 (reference Process for Synthesis of intermediates 1 or 2)

Preparation of intermediate 231-cyclopropyl-1H-pyrazol-4-amine:

step 1): preparation of 1-cyclopropyl-4-nitro-1H-pyrazole:

4-Nitro-1H-pyrazole (200mg, 1.77mmol) was dissolved in anhydrous dichloromethane (15mL), and cyclopropylboronic acid (320mg, 3.72mmol), copper acetate (326mg, 1.79mmol), pyridine (144mg, 1.82mmol), sodium carbonate (432mg, 4.08mmol) were added and reacted for 4 hours under an argon atmosphere at 70 ℃. The reaction mixture was concentrated and column-chromatographed (petroleum ether: ethyl acetate 4: 1) to give 110mg of a yellow oil in 41% yield。LCMS:m/z＝154.1(M+H)⁺.

Step 2): preparation of 1-cyclopropyl-1H-pyrazol-4-amine: 1-cyclopropyl-4-nitro-1H-pyrazole (110mg, 0.72mmol) was dissolved in a mixed solution of ethanol (2mL) and ethyl acetate (2mL), and Raney nickel (15mg) was added and reacted under a hydrogen atmosphere for 3 hours. The mixture was filtered through celite, and the filtrate was evaporated to dryness to give 90mg of a brown oil with a yield of 90%.¹H NMR(400MHz,DMSO-d₆)δ7.02(s,1H),6.86(s,1H),3.89–3.61(m,2H),3.50–3.45(m,1H),0.91–0.73(m,4H).LCMS:m/z＝124.1(M+H)⁺.

Preparation of intermediate 241- (6-methoxyhexyl) -1H-pyrazol-4-amine:

step 1): preparation of 1- (6-bromohexane) -4-nitro-1H-pyrazole:

4-Nitro-1H-pyrazole (200mg, 1.77mmol) was dissolved in DMF (8mL) and K was added₂CO₃(732mg, 5.30mmol), 1, 6-dibromohexane (864mg, 3.54mmol), and reaction at 80 ℃ for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to dryness, and subjected to column chromatography (petroleum ether: ethyl acetate: 5: 1) to give 300mg of a colorless oil with a yield of 61%. LCMS M/z 276.0(M + H)⁺.

Step 2): preparation of 1- (6-methoxyhexyl) -4-nitro-1H-pyrazole:

1- (6-bromohexane) -4-nitro-1H-pyrazole (300mg, 1.09mmol) was dissolved in a methanol solution of sodium methoxide (33%, 7mL),the reaction was carried out at 25 ℃ for 16 hours. The reaction mixture was quenched with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to reverse phase column chromatography (petroleum ether: ethyl acetate: 5: 1) to give 230mg of colorless oil with a yield of 93%. LCMS M/z 228.1(M + H)⁺.

Step 3): preparation of 1- (6-methoxyhexyl) -1H-pyrazol-4-amine:

1- (6-Methoxyhexyl) -4-nitro-1H-pyrazole (230mg, 1.01mmol) was dissolved in a mixed solution of ethanol (2mL) and ethyl acetate (2mL), and Raney nickel (25mg) was added and reacted under a hydrogen atmosphere for 3 hours. The mixture was filtered through celite, and the filtrate was evaporated to dryness to give 190mg of a brown oil with a yield of 95%. LCMS M/z 198.2(M + H)⁺.

Preparation of intermediate 254-methyl-1-pentylamine:

3-Methylpentanenitrile (400mg, 4.11mmol) was dissolved in anhydrous tetrahydrofuran (5mL), lithium aluminum hydride (235mg, 6.18mmol) was added under argon protection at 0 deg.C, and the mixture was allowed to rise to 25 deg.C naturally and stirred for 16 hours. When the temperature is lowered to 0 ℃, 0.4mL of water, 0.4mL of 15% sodium hydroxide solution and 1.2mL of water are added in this order. After stirring for 15min, filtration and evaporation of the filtrate at low temperature gave 300mg of a yellow oil in a crude yield of 72%.¹H NMR(400MHz,CDCl₃)δ2.85(t,J＝7.6Hz,2H),1.60–1.46(m,3H),1.14–1.08(m,2H),0.95(d,6H).LCMS:m/z＝102.1(M+H)⁺.

TABLE 2 Synthesis of intermediates 26 to 28 (Synthesis of reference intermediate 29)

Preparation of intermediate 29[2- (methoxymethyl) phenyl ] methylamine:

step 1): preparation of 2- (methoxymethyl) benzonitrile:

dissolving 2- (chloromethyl) benzonitrile (500mg, 3.30mmol) in a methanol solution (33%, 5mL) of sodium methoxide, reacting at 25 ℃ for 4 hours, quenching with a saturated aqueous solution of ammonium chloride, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and evaporating to dryness to obtain a pale yellow oily substance, 450mg, and a crude yield of 93%. LCMS M/z 148.1(M + H)⁺.

Step 2): preparation of [2- (methoxymethyl) phenyl ] methylamine:

2- (methoxymethyl) benzonitrile (450mg, 3.06mmol) was dissolved in anhydrous tetrahydrofuran (15mL), lithium aluminum hydride (354mg, 9.32mmol) was added under argon protection at 0 ℃ and after 10 minutes, it was raised to 25 ℃ for reaction for 16 hours. 0.4mL of water, 0.4mL of 15% sodium hydroxide solution and 1.2mL of water were added in this order at 0 ℃ and after stirring for 10 minutes, the mixture was filtered and the filtrate was evaporated to dryness to give 360mg of a brown oil in 78% crude yield. LCMS M/z 152.1(M + H)⁺.

Preparation of intermediate 30 (2-methylpyridin-3-yl) methylamine:

2-Methylnicotinamide (200mg, 1.47mmol) was dissolved in anhydrous tetrahydrofuran (5mL), borane in tetrahydrofuran (1M, 7.4mL, 7.4mmol) was added dropwise under argon at 0 ℃ and after 30 minutes of reaction, the temperature was raised to 60 ℃ for 8 hours. Quenching with saturated ammonium chloride aqueous solution, and extracting with ethyl acetateDried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 200mg of colorless oil, and the crude product is directly used for the next reaction. LCMS M/z 123.1(M + H)⁺.

Preparation of intermediate 31[3- (dimethylcarbamoyl) benzyl ] amino hydrochloride:

3- (((tert-butoxycarbonyl) amino) methyl) benzoic acid (400mg, 1.59mmol) was dissolved in tetrahydrofuran (5mL), carbonyldiimidazole (337mg, 2.39mmol) was added thereto, and after stirring for 3 hours, a solution of dimethylamine in tetrahydrofuran (2M, 3.2mL, 6.4mmol) was added dropwise, followed by reaction at 60 ℃ for 16 hours with tube sealing. The reaction mixture was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate: 1). To the obtained white solid, hydrogen chloride in dioxane (4M, 4mL) was added, and after stirring at 25 ℃ for 2 hours, the reaction solution was evaporated to dryness to obtain 263mg of a white solid in 77% yield. LCMS M/z 179.1(M + H)⁺.

Examples

Example 14 preparation of benzylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- (benzylamino) pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (2g, 10.42mmol) was dissolved in tetrahydrofuran (20mL), and benzylamine (1.12g, 10.45mmol) and diisopropylethylamine (4g, 31.01mmol) were added, respectively, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (200mL) was added, the mixture was stirred for 15 minutes, then filtered, and the filter cake was washed with petroleum ether to give 2.1g of a white solid with a yield of 77%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.84(s,1H),7.48–7.33(m,5H),4.82(s,2H).LCMS:m/z＝263.1(M+H)⁺.

Step 2): preparation of 4-benzylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

2-chloro-4- (benzylamino) pyrimidine-5-carboxamide (100mg, 0.38mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (40mg, 0.41mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated, filtered and the solid was washed with acetonitrile to give 50mg of a white solid in 41% yield.¹H NMR(300MHz,DMSO-d₆+DCl/D₂O)δ8.75(s,1H),7.73(s,1H),7.55(s,1H),7.42–7.36(m,5H),4.79(s,2H),3.79(s,3H).LCMS:m/z＝324.1(M+H)⁺.

Example preparation of 24- [ (2-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (2-methoxybenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (80mg, 0.42mmol) was dissolved in tetrahydrofuran (3mL), and 2-methoxybenzylamine (57mg, 0.42mmol) and diisopropylethylamine (161mg, 1.25mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (30mL) was added, stirred for 15 minutes, filtered, and the filter cake was washed with petroleum ether to give 116mg of a white solid with a yield of 95%.¹HNMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.84(s,1H),7.42–7.35(m,2H),7.11(d,J＝8.2Hz,1H),7.04–6.96(m,1H),4.79(s,2H),3.86(s,3H).；¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.77,157.63,156.84,148.52,147.71,130.55,129.68,122.97,121.08,111.64,96.61,56.12,42.39.LCMS:m/z＝293.1(M+H)⁺.

Step 2): preparation of 4- [ (2-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2-methoxybenzyl) amino]Pyrimidine-5-carboxamide (116mg, 0.40mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (39mg, 0.40mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction solution was concentrated, column-chromatographed (dichloromethane: methanol ═ 95: 5), and the crude product was washed with acetonitrile to give 15mg of a white solid in 11% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.68(s,1H),7.68(s,1H),7.50(s,1H),7.32–7.22(m,1H),7.11(d,J＝7.4Hz,1H),7.05(d,J＝8.2Hz,1H),6.95–6.82(m,1H),4.66(s,2H),3.83(s,3H),3.75(s,3H).¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.86,161.02,157.36,149.69,144.70,131.25,129.45,128.42,124.82,123.12,120.85,119.52,111.38,100.76,56.01,40.98,39.31.LCMS:m/z＝354.2(M+H)⁺.

Example 34 preparation of- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (2-fluoro-6-methoxybenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (210mg, 1.09mmol) was dissolved in tetrahydrofuranTo pyran (8mL), respectively, (2-fluoro-6-methoxyphenyl) methylamine (170mg, 1.09mmol) and diisopropylethylamine (423mg, 3.27mmol) were added, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (60mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 75mg of a white solid in 66% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.82(s,1H),7.50–7.40(m,1H),7.03–6.96(m,1H),6.95–6.87(m,1H),4.77(s,2H),3.88(s,3H).LCMS:m/z＝311.1(M+H)⁺.

Step 2): preparation of 4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2-fluoro-6-methoxybenzyl) amino]Pyrimidine-5-carboxamide (75mg, 0.24mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (27mg, 0.28mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated and filtered, and the filter cake was washed with acetonitrile to give 65mg of a white solid in 73% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.72(s,1H),8.03(s,1H),7.75(s,1H),7.45–7.34(m,1H),7.03–6.93(m,1H),6.93–6.83(m,1H),4.83(s,2H),3.89(s,3H),3.88(s,3H).LCMS:m/z＝372.2(M+H)⁺.

Example preparation of 44- [ (2, 6-dimethylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (2, 6-dimethylbenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (70mg, 0.36mmol) was dissolved in tetra-ethyl acetateTo tetrahydrofuran (4mL), respectively, (2, 6-dimethylphenyl) methylamine (50mg, 0.37mmol) and diisopropylethylamine (141mg, 1.09mmol) were added, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (30mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 73mg of a white solid in 69% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.88(s,1H),7.31–7.18(m,1H),7.18–7.06(m,2H),4.73(s,2H),2.34(s,6H)；¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.98,157.34,148.46,147.77,137.93,131.33,129.36,129.10,96.61,41.68,19.77.LCMS:m/z＝291.1(M+H)⁺.

Step 2): preparation of 4- [ (2, 6-dimethylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2, 6-dimethylbenzyl) amino]Pyrimidine-5-carboxamide (73mg, 0.25mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (30mg, 0.31mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated and filtered, and the filter cake was washed with acetonitrile to give 50mg of a white solid in 57% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.76(s,1H),8.08(s,1H),7.75(s,1H),7.18(dd,J＝8.6,6.3Hz,1H),7.14–7.08(m,2H),4.74(s,2H),3.90(s,3H),2.32(s,6H).LCMS:m/z＝352.2(M+H)⁺.

Example preparation of 54- [ (2, 6-dichlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): 2-chloro-4- [ (2, 6-dichlorobenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (70mg, 0.36mmol) was dissolved in tetrahydrofuran (4mL), and (2, 6-dichlorophenyl) methylamine (64mg, 0.36mmol) and diisopropylethylamine (141mg, 1.09mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (40mL) was added, stirred for 15 minutes, filtered, and the filter cake was washed with petroleum ether to give 110mg of a white solid in 91% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.93(s,1H),7.67–7.60(m,2H),7.60–7.50(m,1H),5.03(s,2H).¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ167.05,157.86,149.16,147.94,135.98,132.68,130.34,129.74,96.46,42.77.LCMS:m/z＝331.0(M+H)⁺.

Step 2): preparation of 4- [ (2, 6-dichlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2, 6-dichlorobenzyl) amino]Pyrimidine-5-carboxamide (112mg, 0.34mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (40mg, 0.41mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated and filtered, and the filter cake was washed with acetonitrile to give 110mg of a white solid with a yield of 83%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.80(s,1H),8.07(s,1H),7.74(s,1H),7.66–7.55(m,2H),7.53–7.41(m,1H),5.03(s,2H),3.89(s,3H).LCMS:m/z＝392.1(M+H)⁺.

Example preparation of 64- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (2, 6-difluorobenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (210mg, 1.09mmol) was dissolved in tetrahydrofuran (8mL), and (2, 6-difluorophenyl) methylamine (156mg, 1.09mmol) and diisopropylethylamine (423mg, 3.27mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (80mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 285mg of a white solid in 87% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.90(s,1H),7.72–7.38(m,1H),7.38–7.08(m,2H),4.93(s,2H).LCMS:m/z＝299.0(M+H)⁺.

Step 2): preparation of 4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2, 6-difluorobenzyl) amino]Pyrimidine-5-carboxamide (94mg, 0.31mmol) was dissolved in sec-butanol (3mL), 1- (2-methoxyethyl) -1H-pyrazol-4-amine (53mg, 0.38mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated and filtered, and the filter cake was washed with acetonitrile to give 80mg of a white solid in 63% yield.¹HNMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.78(s,1H),8.09(s,1H),7.75(s,1H),7.58–7.39(m,1H),7.19–7.14(m,2H),4.90(s,2H),4.32(t,J＝5.1Hz,2H),3.70(t,J＝5.1Hz,2H),3.21(s,3H).LCMS:m/z＝404.2(M+H)⁺.

Example preparation of 74- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (210mg, 1.09mmol) was dissolved in tetrahydrofuran (8mL), and (2-fluoro-6-methoxyphenyl) methylamine (170mg, 1.09mmol) and diisopropylethylamine (423mg, 3.27mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (60mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 75mg of a white solid in 66% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.82(s,1H),7.50–7.40(m,1H),7.03–6.96(m,1H),6.95–6.87(m,1H),4.77(s,2H),3.88(s,3H).LCMS:m/z＝311.1(M+H)⁺.

Step 2): preparation of 4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2-fluoro-6-methoxybenzyl) amino]Pyrimidine-5-carboxamide (118mg, 0.38mmol) was dissolved in sec-butanol (3mL), 1- (2-methoxyethyl) -1H-pyrazol-4-amine (64mg, 0.45mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction solution was concentrated, filtered and washed with acetonitrile to obtain 100mg of a white solid in a yield of 63%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.75(s,1H),8.12(s,1H),7.82(s,1H),7.53–7.33(m,1H),6.98(d,J＝8.4Hz,1H),6.95–6.73(m,1H),4.83(s,2H),4.32(t,J＝5.1Hz,2H),3.89(s,3H),3.70(t,J＝5.1Hz,2H),3.21(s,3H).LCMS:m/z＝416.2(M+H)⁺.

Example 84 preparation of- [ (5-hydroxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (5-hydroxypentyl) amino ] pyrimidine-5-carboxamide

2, 4-dichloropyrimidine-5-carboxamide (100mg, 0.52mmol) was dissolved in tetrahydrofuran (4mL), and 5-amino-1-pentanol (54mg, 0.52mmol) and diisopropylethylamine (202mg, 1.56mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (40mL) was added, and after stirring for 15 minutes, the solid was filtered and the filter cake was washed with petroleum ether to give 80mg of a white solid with a yield of 59%. LCMS M/z 259.1(M + H)⁺.

Step 2): preparation of 4- [ (5-hydroxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (5-hydroxypentyl) amino]Pyrimidine-5-carboxamide (80mg, 0.31mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (37mg, 0.38mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated and filtered, and the filter cake was washed with acetonitrile to give 70mg of a white solid with a yield of 71%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.68(s,1H),7.96(s,1H),7.68(s,1H),3.87(s,3H),3.60–3.47(m,2H),3.39(t,J＝6.3Hz,2H),1.69–1.54(m,2H),1.51–1.40(m,2H),1.40–1.29(m,2H).LCMS:m/z＝320.2(M+H)⁺.

Example 94 preparation of- [ (5-methoxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1), step 2) in the same manner as in example 8

Step 3): preparation of 4- [ (5-bromopentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 4- [ (5-hydroxypentyl) amino group]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Pyrimidine-5-carboxamide (60mg, 0.19mmol) was dissolved in anhydrous dichloromethane (4mL), carbon tetrabromide (187mg, 0.56mmol) and triphenylphosphine (148mg, 0.56mmol) were added sequentially under argon protection at 0 deg.C, and the reaction was allowed to warm to 25 deg.C for 2 hours. The methanol was quenched and column chromatography was evaporated to dryness (dichloromethane: methanol ═ 10:1) to give a pale yellow solid 70mg, yield 95%. LCMS M/z 382.1(M + H)⁺.

Step 4): preparation of 4- [ (5-methoxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 4- [ (5-bromopentyl) amino group]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Pyrimidine-5-carboxamide (70mg, 0.18mmol) was dissolved in a methanol solution of sodium methoxide (33%, 7mL) and reacted at 25 ℃ for 16 hours. The reaction solution was quenched with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to reverse phase column chromatography (water: methanol: 7: 3), and the crude product was washed with acetonitrile to obtain 35mg of a white solid, with a yield of 57%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.69(s,1H),8.02(s,1H),7.76(s,1H),3.90(s,3H),3.53(t,J＝6.7Hz,2H),3.31(t,J＝6.1Hz,2H),3.20(s,3H),1.69–1.57(m,2H),1.57–1.44(m,2H),1.44–1.30(m,2H).LCMS:m/z＝334.2(M+H)⁺.

Example 104- [ (3-hydroxy-3-methylbutyl) amino]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Preparation of pyrimidine-5-carboxamide:

step 1): preparation of methyl 3- [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino ] propionate

2, 4-dichloropyrimidine-5-carboxamide (100mg, 0.52mmol) was dissolved in tetrahydrofuran (4mL), and methyl aminopropionate hydrochloride (73mg, 0.52mmol) and diisopropylethylamine (202mg, 1.56mmol) were added, respectively, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (40mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 90mg of a white solid in 67% yield. LCMS M/z 259.1(M + H)⁺.

Step 2): preparation of methyl 3- [ (5-carbamoyl-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl) amino ] propionate:

reacting 3- [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino]Methyl propionate (90mg, 0.35mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (41mg, 0.42mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated, the solid filtered and washed with acetonitrile to give 80mg of a white solid in 72% yield. LCMS M/z 320.1(M + H)⁺.

Step 3): preparation of 4- [ (3-hydroxy-3-methylbutyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 3- [ (5-carbamoyl-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Pyrimidin-4-yl) amino]Methyl propionate (80mg, 0.25mmol) was dissolved in anhydrous tetrahydrofuran (2mL), and under the protection of argon at 0 deg.C, methyl Grignard reagent (1M, 0.75mL, 0.75mmol) was added dropwise and reacted at 25 deg.C for 16 hours. Quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to thin layer chromatography (dichloromethane: methanol 10:1), and the crude product was washed with acetonitrile to give 15mg of a white solid with a yield of 19%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.57(s,1H),8.01(s,1H),7.62(s,1H),3.78(s,3H),3.63–3.47(m,2H),1.71–1.56(m,2H),1.08(s,6H).LCMS:m/z＝320.2(M+H)⁺.

Example 114 preparation of- [ [ (1-acetylpiperidin-4-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of tert-butyl 4- [ [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino ] methyl ] piperidine-1-carboxylate:

2, 4-dichloropyrimidine-5-carboxamide (100mg, 0.52mmol) was dissolved in tetrahydrofuran (4mL), and tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (112mg, 0.52mmol) and diisopropylethylamine (202mg, 1.57mmol) were added, respectively, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (40mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 150mg of a white solid in 79% yield. LCMS M/z 370.2(M + H)⁺.

Step 2): preparation of tert-butyl 4- [ [ (5-carbamoyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino ] methyl ] piperidine-1-carboxylate:

reacting 4- [ [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino group]Methyl radical]Tert-butyl piperidine-1-carboxylate (150mg, 0.41mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (48mg, 0.49mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction solution was concentrated and filtered, and the filter cake was washed with petroleum ether to give 115mg of a white solid in 66% yield. LCMS M/z 431.2(M + H)⁺.

Step 3): preparation of 4- [ [ (1-acetylpiperidin-4-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 4- [ [ (5-carbamoyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino]Methyl radical]Tert-butyl piperidine-1-carboxylate (115mg, 0.27mmol) was dissolved in dichloromethane (3mL), and trifluoroacetic acid (1mL) was slowly added dropwise thereto, followed by stirring at 25 ℃ for 2 hours. The reaction mixture was evaporated to dryness. The crude product was dissolved in dichloromethane (4mL), triethylamine (160mg, 1.58mmol) was added under argon protection at 0 ℃ and after stirring for 2 minutes, acetyl chloride (63mg, 0.80mmol) was added dropwise and the reaction was carried out at 25 ℃ for 2 hours. The reaction solution was concentrated and subjected to thin layer chromatography (dichloromethane: methanol ═ 10:1) to give 30mg of a white solid in a yield of 30% in two steps.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.72(s,1H),8.02(s,1H),7.75(s,1H),4.47–4.25(m,1H),3.90(s,3H),3.48(d,J＝6.7Hz,2H),3.17–3.02(m,1H),2.54(s,3H),2.13–2.07(m,2H),2.04–1.89(m,1H),1.80–1.63(m,2H),1.32–1.05(m,2H).LCMS:m/z＝373.2(M+H)⁺.

Example 124 preparation of- [ [2- (1-acetylpiperidin-4-yl) ethyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

step 1): preparation of tert-butyl 4- [2- [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino ] ethyl ] piperidine-1-carboxylate:

2, 4-dichloropyrimidine-5-carboxamide (200mg, 1.04mmol) was dissolved in tetrahydrofuran (5mL), and tert-butyl 4- (2-aminoethyl) piperidine-1-carboxylate (238mg, 1.04mmol) and diisopropylethylamine (404mg, 3.13mmol) were added, respectively, and the reaction was carried out at 25 ℃ for 2 hours. Saturated brine (50mL) was added, stirred for 15min, filtered, and the filter cake was washed with petroleum ether to give 270mg of a white solid in 68% yield. LCMS m/z 384.2(M+H)⁺.

Step 2): preparation of tert-butyl 4- [2- [ (5-carbamoyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino ] ethyl ] piperidine-1-carboxylate:

4- [2- [ (5-carbamoyl-2-chloropyrimidin-4-yl) amino group]Ethyl radical]Tert-butyl piperidine-1-carboxylate (270mg, 0.70mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (83mg, 0.85mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated, the solid filtered and washed with acetonitrile to give 170mg of a white solid in 54% yield. LCMS M/z 445.3(M + H)⁺.

Step 3): preparation of 4- [ [2- (1-acetylpiperidin-4-yl) ethyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 4- [2- [ (5-carbamoyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino]Ethyl radical]Tert-butyl piperidine-1-carboxylate (170mg, 0.38mmol) was dissolved in dichloromethane (6mL), and trifluoroacetic acid (2mL) was slowly added dropwise thereto, followed by stirring at 25 ℃ for 2 hours. The reaction mixture was evaporated to dryness. The crude product was dissolved in dichloromethane (6mL), triethylamine (176mg, 1.36mmol) was added under argon protection at 0 ℃ and after stirring for 2 minutes, acetyl chloride (69mg, 0.88mmol) was added dropwise and the reaction was allowed to proceed at 25 ℃ for 2 hours. The reaction solution was concentrated and subjected to thin layer chromatography (dichloromethane: methanol ═ 10:1) to give 10mg of a pale yellow solid in 7% yield in two steps.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.58(s,1H),7.90(s,1H),7.63(s,1H),4.34–4.08(m,1H),3.79(s,3H),3.77–3.64(m,1H),3.53–3.37(m,2H),3.04–2.83(m,1H),2.45–2.38(m,1H),1.98(s,3H),1.69–1.55(m,2H),1.52–1.37(m,3H),1.11–0.79(m,2H).LCMS:m/z＝387.2(M+H)⁺.

Example 134- [ [ 4-amino-2-fluorobenzyl]Amino group]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Preparation of pyrimidine-5-carboxamide:

step 1): preparation of 2-chloro-4- [ (2-fluoro-4-nitrobenzyl) amino ] pyrimidine-5-carboxamide:

2, 4-dichloropyrimidine-5-carboxamide (100mg, 0.52mmol) was dissolved in tetrahydrofuran (4mL), and (2-fluoro-4-nitrophenyl) methylamine hydrochloride (108mg, 0.52mmol) and diisopropylethylamine (202mg, 1.57mmol) were added, respectively, to react at 25 ℃ for 2 hours. Saturated brine (40mL) was added, and after stirring for 15 minutes, the solid was filtered and the filter cake was washed with petroleum ether to give 120mg of a yellow solid with a yield of 71%. LCMS M/z 326.0(M + H)⁺.

Step 2): preparation of 4- [ [ 2-fluoro-4-nitrobenzyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

reacting 2-chloro-4- [ (2-fluoro-4-nitrobenzyl) amino]Pyrimidine-5-carboxamide (120mg, 0.37mmol) was dissolved in sec-butanol (3mL), 1-methyl-1H-pyrazol-4-amine (43mg, 0.44mmol) and trifluoroacetic acid (0.1mL) were added, and the reaction was sealed at 100 ℃ for 2 hours. The reaction was concentrated, the solid filtered and washed with acetonitrile to give 80mg of a brown solid in 56% yield. LCMS M/z 387.1(M + H)⁺.

Step 3): preparation of 4- [ [ 4-amino-2-fluorobenzyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:

2- [, [ ]2-fluoro-4-nitrobenzyl]Amino group]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]Pyrimidine-5-carboxamide (80mg, 0.21mmol) was dissolved in a mixed solution of ethanol (3mL) and water (1mL), and then ammonium chloride solid (112mg, 2.10mmol) and iron powder (117mg, 2.10mmol) were added, and the mixture was heated to 70 ℃ for reaction for hours. The reaction solution was cooled, filtered through celite, and subjected to thin layer chromatography (dichloromethane: methanol 10:1) to give 52mg of a yellow solid in 70% yield.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.76(s,1H),7.70(s,1H),7.60–7.47(m,1H),7.47–7.34(m,2H),7.32–7.19(m,1H),4.83(s,2H),3.81(s,3H).LCMS:m/z＝357.2(M+H)⁺.

Synthesis of the remaining examples

Synthesis of subsequent specific examples the synthesis of the corresponding intermediate a and the target compound B was carried out according to the synthetic route shown below in a similar manner to example 1 using starting materials with different substituents, as shown in tables 3 and 4 below.

Reaction conditions are as follows: 1) r¹CH₂NH₂,DIEA,THF,25℃,2～16h；2)TFA,s-BuOH,60～100℃,2～16h.

TABLE 3 structures and characterizations of intermediate Compound A and target Compound B of examples 14-180

TABLE 4 structures and characterization of intermediate Compound A and target Compound B of example 181-227

Experimental example 1 test for inhibition of kinase Activity of JAK1, JAK2, JAK3 and TYK2 by the Compound of the present invention

In the in vitro assembled enzymatic reaction, compounds with different concentrations are added to detect the inhibition of the specific enzymatic reaction by the compounds, and the specific test method is as follows:

TABLE 5 instruments, materials and reagents for testing

Second, testing method

The following will be exemplified by JAK3, and specific experimental conditions for JAK1, JAK2, JAK3, TYK2 are shown in the appendix.

1. Preparing a reagent:

preparation of EDTA (0.5M pH8.0) solution by accurately weighing 14.612g of EDTA powder, adding ultrapure water, and adjusting the volume to 100mL (if insoluble, heating to 37 deg.C, adjusting pH to 8.0 with 1N NaOH solution)

1 × Kinase Assay Buffer: into a reagent bottle were added 25mL of HEPES solution (1M), 190.175mgEGTA, 5mL of MgCl₂The solution (1M), 1mL DTT, 50. mu.L Tween-20, and ultrapure water were added to make a volume of 500mL (pH adjusted to 7.5).

1 × Detection Buffer 1mL of 10 × Detection Buffer was added to 9mL of water and mixed.

4 × stop solution: 0.8mL of the above EDTA (0.5M, pH8.0) solution, 1mL of 10 XDetection Buffer, and 8.2mL of ultrapure water were mixed together.

4 XJAK 3 Kinase solution A Kinase stock solution was diluted with 1 XKinase Assay Buffer to a concentration of 0.36nM, mixed well and stored on ice.

4 × substrate solution: substrate ULight was diluted with 1 × Kinase Assay Buffer^TM-Labeled JAK-1(Tyr1023) Peptide stock solution to 200nM and mixed well.

4 × ATP solution: the ATP stock was diluted with 1 XKinase Assay Buffer to a concentration of 40. mu.M and mixed well.

4 × detection solution: the Detection antibody Europium-anti-phosphorus-tyrosine antibody (PT66) was diluted with 1 XDeprotection Buffer to a concentration of 8nM and mixed well.

2 × substrate/ATP mixture: the 4 Xsubstrate solution and 600. mu.l of 4 XATP solution were mixed in equal amounts (prepared before use).

2. Experimental procedure

1) The dilution of the compound is carried out,

in a 96-well plate, compounds were diluted with DMSO solutions at 3-fold ratios to form 11 gradients, and another pure DMSO solution served as a positive control; a new 96-well plate was prepared, and the solution was diluted 25-fold with ultrapure water (DMSO concentration: 4%)

2) Rotating Compounds to 384 well plates

The compound solution diluted with ultrapure water in the above 96-well plate was transferred to the corresponding well of a 384-well plate according to a standard 2-well carousel.

3) Add 4 × kinase solution: mu.l of the 4 Xkinase solution was added to the corresponding reaction well of the 384-well plate using a line gun, and pre-reacted at room temperature for 5 minutes.

4) Add 2 Xsubstrate/ATP mix 5. mu.l of the above 2 Xsubstrate/ATP mix to the corresponding reaction well of a 384 well plate using a discharge gun.

5) Negative control: a negative control well was set in a 384-well plate, and 2.5. mu.l/well of 4 Xsubstrate, 2.5. mu.l of 4 Xenzyme solution, 2.5. mu.l of 1 XKinase Assay Buffer, and 2.5. mu.l of ultrapure water containing 4% DMSO were added to the well.

6) And (4) centrifuging, mixing uniformly, and reacting for 60min at room temperature in the dark.

7) Termination of the enzymatic reaction:

5. mu.l of the 4 Xstop solution was pipetted into the corresponding well of 384-well plate, centrifuged and mixed, and reacted at room temperature for 5 minutes.

8) And (3) color development reaction:

5. mu.l of the 4 × detection solution was pipetted into the mesopores of 384-well plate, centrifuged and mixed, and reacted at room temperature for 60 min.

9) The 384 well plate is placed in a plate reader, and a corresponding program detection signal is called.

10) Inhibition rate and IC₅₀And (3) calculating:

pore reading 10000 × EU 665/EU 615 values

Inhibition rate [1- (experimental well reading-negative control well reading)/(positive control well reading-negative control well reading) ]. 100%

Inputting the drug concentration and the corresponding inhibition rate into GraphPad Prism5 for processing and calculating the corresponding IC₅₀The value is obtained.

Test conditions:

JAK1 kinase activity assay:

JAK1 (final concentration 10 nM); ATP (final concentration 10 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 100 nM); the enzymatic reaction time was 2 hours. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

JAK2 kinase activity assay:

JAK2 (final concentration 0.25 nM); ATP (final concentration 5 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50 nM); the enzymatic reaction time was 1 hour. The maximum final concentration of the compound was 2.5. mu.M, with a 3-fold gradientAfter dilution, the total concentration was 11, with a minimum final concentration of 0.042 nM. The final concentration of DMSO is 1%.

JAK3 kinase activity assay:

JAK3 (final concentration 0.36 nM); ATP (final concentration 10 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50 nM); the enzymatic reaction time was 1 hour. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

TYK2 kinase activity assay:

TYK2 (final concentration 8 nM); ATP (final concentration 20 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 100 nM); the enzymatic reaction time was 2 hours. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

Table 6 shows the results of measurement of inhibitory activity of some of the compounds of the present invention against tyrosine kinases JAK1, JAK2, JAK3 and TYK 2. IC in the following Table₅₀The values represent the concentration of compound at which the enzyme inhibits maximally 50%, and NT means that the corresponding enzyme was not tested.

TABLE 6 results of determination of inhibitory Activity of partial Compounds of the present invention against JAK1, JAK2, JAK3 and TYK2 tyrosine kinases

Experimental example 2 quantitative AlphaLISA detection of STAT5 phosphorylation in HEL cells by Compounds of the invention

HEL cells are treated by Tofacitinib and S1 partial compounds with different concentrations, and then are stimulated by IL-4 with 100ng/mL, and then the signal of pSTAT5 is quantitatively detected by AlphaLISA, wherein the specific test method is as follows:

table 7. test reagents:

dilution and preparation of related solutions

1. Acceptor Mix: the Reaction Buffer1, Reaction Buffer2, Activation Buffer and Acceptor Beads are mixed according to the ratio of 47: 47: 4:2, and placing on an ice box (for use within 30 min)

Donor Mix, now prepared, the Dilution Buffer and Donor Beads were mixed according to 49: 1, and placing on an ice box (operating under low light, using within 30 min).

2. The Positive control lysate is prepared by packaging lyophilized powder +250 μ L water (10.5 μ L per tube) and storing at-20 deg.C. (used up within one month)

Second, the experimental procedure

1. Collecting HEL cells, washing with PBS for three times (1000rpm,4min), inoculating the cells in a 96-well plate according to 10 ten thousand cells/well/45 μ L DMEM (phenol red free), making two multiple wells for each concentration, and culturing for 1 h;

2. adding 15 mu L of Tofacitinib with different concentrations into each hole, uniformly mixing by using a rifle, and culturing for 1 h;

3. adding 20 μ L of 400ng/mL IL-4 into each well, mixing, and culturing for 15 min;

4. then adding 20 μ L of 5 × Lysis buffer into each well, and mixing on the mixing sprite at 350rpm for 10 min; after cracking, centrifuging at low speed, 800rpm for 1 min;

5. pipetting 10. mu.L of the lysate and adding to 384 plates respectively;

6. adding 5 μ L Acceptor Mix into each well, sealing, wrapping with tinfoil paper in dark place, mixing for 1-2min, and incubating at room temperature for 2 h; (Low speed shaking on mixing elfin during incubation)

7. Adding 5 μ L Donor Mix into each well, sealing, wrapping with tinfoil paper, mixing for 1-2min, and incubating at room temperature for 2 hr; (Low light operation, low speed shaking on mixing sprite during incubation)

8. And opening a corresponding program in the Envision of the multifunctional plate reader to read the reading value of the pore plate.

9. Inhibition rate and IC₅₀And (3) calculating:

Table 8 shows the results of the quantitative AlphaLISA assay for STAT5 phosphorylation in HEL cells with a portion of the compounds of the invention.

TABLE 8 results of quantitative determination of STAT5 phosphorylation in HEL cells by partial compounds of the present invention

Experimental example 3 test of inhibitory Activity of Compound of the present invention on mouse spleen cell proliferation

The specific experimental steps are as follows:

1) compound dilution: a total of 9 concentrations were obtained starting from the highest concentration of 5000nM after 3-fold gradient dilution (5000 nM for the maximum final concentration of drug and 0.76nM for the minimum final concentration in this experiment).

2) Taking a culture dish with the diameter of 6 cm, placing a cell filter sieve with the aperture of 70 mu m in the culture dish, and then adding 2mL of HBSS solution into the sieve to infiltrate the bottom of the culture dish;

3) euthanasia adult Balb/c mice with carbon dioxide, soaking in 75% alcohol for 1 minute, placing into a safety cabinet, cutting a small opening in the middle of the left ventral side of the mice, exposing the abdominal wall, and finding out the spleen;

4) taking spleen, removing surrounding adipose tissues, putting the spleen on a cell filtering sieve in a culture dish, and properly shearing;

5) gently grinding the spleen with the flat part at the top end of the syringe piston to obtain a cell suspension;

6) collecting cell suspension from a culture dish, and slowly adding the cell suspension into a 15ml centrifuge tube containing 5ml of Ficoll-Paque PLUS;

7) centrifugation was carried out at 400g for 30 minutes at room temperature;

8) after the centrifugation is finished, the upper layer is slowly removed by a suction pipe, and then the middle layer, namely spleen cells, is slowly sucked out;

9) placing the collected spleen cell suspension into another 15ml centrifuge tube, adding 10ml RPMI1640 complete culture medium, centrifuging at 300g and 4 ℃ for 4 minutes;

10) the supernatant was discarded, and the cells were resuspended by adding complete medium, and then subjected to cell counting. The cell suspension is washed repeatedly according to the ninth step;

11) transferring the cells to a culture dish (containing 2.5 mu g/mL of concanavalin A) at a cell density of 200-500 ten thousand/mL for overnight culture;

12) the next day, the cells were transferred to a 15mL centrifuge tube and centrifuged at 300g for 5 min;

13) discarding the supernatant, adding 5mL of RPMI1640 complete culture solution, blowing and beating uniformly, mixing 10 μ L of cell suspension and 10 μ L of trypan blue uniformly, counting by using a cell counter, and recording the number of cells and the survival rate.

14) Inoculating the cell suspension into a 96-well plate, and inoculating 80 mu l of cell suspension into each well, wherein the density of the cell suspension is 100000 cells/well;

15) adding 20 μ L of the 5 × compound solution diluted with the culture solution into each well, and mixing well;

16) after 72 hours of culture, 10. mu.L of CCK-8 reagent is added into each well, and the mixture is incubated for 2 hours (the reaction time can be adjusted according to the color depth);

17) the OD value was read at 450nm on a multifunction plate reader.

18) Data processing:

cell survival (%) - (As-Ab)/(Ac-Ab) ]. 100%

As: OD value of the experimental well (cell-containing medium, CCK-8, compound),

ac: OD value of control well (cell-containing medium, CCK-8),

ab: OD of blank wells (medium without cells and compounds, CCK-8),

the values were then introduced into Graphpad Prism5 software for curve fitting and IC50 was calculated.

Table 9 shows the results of the test for the inhibitory activity of the compounds of the present invention on mouse splenocyte proliferation, wherein A represents IC₅₀Less than or equal to 100nM, B represents IC₅₀Greater than 100nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but smallAt or equal to 1000nM, D denotes IC₅₀Greater than 1000 nM.

TABLE 9 test results of the inhibitory Activity of the Compounds of the present invention on mouse splenocyte proliferation

Use, formulation, administration

Medical use and indications

The biological data provided by the invention indicate that the compound of the invention is beneficial for treating or preventing diseases caused by tyrosine kinase (JAK1, JAK2, JAK3 and TYK2) abnormality. Over one fifth of the compounds of the present invention have been shown to strongly inhibit JAK tyrosine kinase activity, whereas the JAK kinase family is closely related to the development and metastasis of autoimmune diseases and cancer. Thus, the compounds of the present invention are useful in the treatment of autoimmune diseases, including but not limited to: psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, and Crohn's disease. The compounds of the invention are also useful in the treatment of cancer, including primary and metastatic cancers, including solid tumors. Such cancers include, but are not limited to, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, biliary tract cancer. The compounds of the invention also include the treatment of cancer resistant to one or more other therapeutic methods. The compounds of the present invention may also be used in diseases other than autoimmune diseases and cancer, including but not limited to ocular fundus disease, pulmonary fibrosis, liver fibrosis, etc., associated with JAK1 kinase and/or JAK2 and/or JAK3 kinase. The compounds of the present invention may be administered as monotherapy or in combination therapy, in combination with a plurality of the compounds of the present invention or in combination with other drugs other than those of the present invention.

Pharmaceutical process

The pharmaceutical methods of the invention comprise determining a therapeutically effective amount of a compound of the invention to a subject in need thereof. The "therapeutically effective dose" will vary depending on the stage, progression or severity of the disease. The daily dosage of the compounds and compositions of the present invention will depend upon a variety of factors including the condition being treated, the severity of the condition, the pharmaceutical efficacy of the particular compound employed, the particular composition, the age, body weight, general health, sex and diet, the route and schedule of administration, the rate of metabolism and/or excretion of the compound, the duration of treatment, and the like. In addition, the compounds of the invention can be administered to humans and other animals in dosages and in dosages with a pharmaceutically acceptable carrier. Modes of administration include oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (e.g., via transdermal patches, powders, ointments, or drops), sublingual, buccal, or nasal spray, and the like. The effective dose of the compounds of the present invention is generally measured in terms of the amount administered per kg of body weight of the patient, preferably 0.1 to 125 mg/kg of body weight, and generally 0.01 to 500 mg/kg of body weight. Administration may be one or more times, daily, weekly, every other day or every other day, or on an intermittent schedule. For example, the compound may be administered daily, weekly (e.g., monday), indefinitely or over a period of weeks (e.g., 4-10 weeks). The effective dosage of the compounds of the present invention will vary depending upon the compound employed, the mode of administration, the severity of the disease, the condition being treated and the various physical factors of the patient involved. In most cases, satisfactory therapeutic results are achieved when the preferred compounds of the invention are administered at a daily dosage of about 0.01 to about 500 mg/kg. The dosage is preferably 0.1-125 mg/kg, and the dosage is more preferably 1-25 mg/kg. Parenteral dosages are generally at an oral dosage level of about 10% to 20%. When the compounds of the present invention are used as part of a combination treatment regimen, the components of each composition will be administered during a desired treatment period. Whether comprising the two components as separate dosage units or as a single dosage form, the components of the composition may be administered simultaneously during the treatment period, may be administered at different times during the treatment period, or may be administered as a pre-treatment of the other.

As to compounds

The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts can be formed by reacting the isolated and purified compounds of the present invention with a suitable free base or acid.

Pharmaceutically non-toxic acid salts include, but are not limited to, amino salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, for example, ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanes, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanes, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, salts of citric acid, salts of lactic acid, salts of 2-naphthalenesulfonates, nicotinates, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is by hydrolysis of the prodrug in the blood or by enzymatic action in the blood or tissue to the parent compound.

Composition comprising a metal oxide and a metal oxide

The compositions described herein consist of any of the compounds (or prodrugs, or pharmaceutically acceptable salts, or other pharmaceutically acceptable derivatives thereof) described herein, and one or more pharmaceutically acceptable carriers or excipients. These compositions may optionally further comprise one or more additional therapeutic agents. The compounds of the invention may be co-administered to a patient in need thereof with one or more other treatment regimens (e.g., administration of Tofacitinib or other kinase inhibitors, interferons, bone marrow transplantation, farnesyl transferase inhibitors, bisphosphonates, thalidomide, cancer vaccines, hormonal therapy, antibodies, radiation, etc.). The pharmaceutical composition of the compound may be another anti-inflammatory or anti-cancer agent or agents.

As described herein, the compositions of the present invention comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier, including any and all solvents, diluents or other carriers, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Some examples of pharmaceutically acceptable carrier materials include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; ethylene glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, may also be present in the composition. Formulation of

The invention also encompasses a class of compositions (collectively referred to herein as "carrier" materials) in which the active compounds of the invention are used in combination with one or more pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and also includes other active ingredients, if desired. The active compounds of the present invention may be administered by any suitable route, preferably in the form of pharmaceutical compositions adapted to such route of administration for the effective dosage required for the intended treatment. The compounds and compositions of the present invention may be administered orally, mucosally, topically, rectally, pulmonarily, e.g., by inhalation spray, or parenterally, including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, intrasternal, and infusion techniques. The administration is in the form of a dosage unit-based formulation and contains pharmaceutically acceptable carriers, adjuvants, and excipients. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. Examples of such dosage units are tablets or capsules. For example, they may contain the active ingredient in an amount of from 1 to 2000 mg, preferably from 1 to 500mg, more usually from 5 to 200 mg. The appropriate daily dosage for a person or other mammal may vary depending on the patient and other factors, but may be determined again using conventional methods. As previously mentioned, the amount of compound in the administration and dosage regimen of the compounds and/or compositions contemplated by the present invention will depend upon a variety of factors including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, dosage regimens can vary widely, but can be determined using standard methods. Typical daily dosage is 0.01-500 mg/kg body weight, preferably 0.1-125 mg/kg body weight, more preferably 1-25 mg/kg body weight.

The active compounds of the present invention are generally combined with one or more adjuvants, excipients or carriers to make up the route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose alkanoates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation provided by dispersing the active compound in hydroxypropylmethyl cellulose. Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin (e.g. liniments, lotions, ointments, creams or pastes) and drops suitable for administration to the eye, ear or nose. Suitable topical dosages of the compounds of the invention are 0.1-150 mg, one to four times daily, preferably 1 to 2 times daily. For topical administration, where an ointment is used, the active ingredient may be combined with any paraffin or water-miscible ointment as the base. Alternatively, the active ingredient may be formulated as a water-in-oil emulsion base cream. If desired, the aqueous phase of the cream base may include, for example, at least 30% by weight of a polyhydric alcohol such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerin, polyethylene glycol, and mixtures thereof. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The compounds may also be administered by transdermal means. Preferably transdermal administration will be accomplished using a patch containing a reservoir and a porous membrane or solid matrix. The oily phase of the emulsion of the invention may be constituted in a known manner by known ingredients, comprising a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, the hydrophilic emulsifier is used simultaneously with the lipophilic emulsifier as stabilizer, and it is also preferred that it is used in combination with oils and fats. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include tween 60, span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with an emulsifying wax, or other materials well known in the art. The cream should preferably be a non-greasy, non-staining and washable product, and have a suitable consistency to avoid leakage from the tube or other container. Straight or branched chain, mono-or dibasic alkyl esters such as diisoadipate, isohexadecyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or mixed branched chain esters may also be used. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in these formulations in a concentration of 0.5% to 20% by weight, more advantageously 0.5 to 10% by weight, most preferably about 1.5% by weight. The formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from one or more sterile powders or granules using the formulations for oral administration mentioned herein or carriers or diluents using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art.

The active ingredient may also be administered by injection, in combination with a suitable carrier including saline, dextrose or water, or with cyclodextrin (Captisol), co-solvent solubilization (i.e., propylene glycol), or micelle solubilization (i.e., tween 80). The formulations may also be presented as sterile injectable solutions or suspensions in a non-toxic parenterally-acceptable diluent or solvent, for example as 1, 3-butanediol. Solvents which may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides.

For pulmonary administration, the pharmaceutical compositions may be administered in the form of an aerosol or with an inhaler, including a dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. The pharmaceutical compositions may be formulated with conventional pharmaceutical procedures such as sterilization and/or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like in tablets and pills or may be formulated with enteric coatings. Such compositions may also contain adjuvants such as wetting agents, sweetening, flavoring and perfuming agents.

The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternative compositions of the invention include a compound having formula (I) as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise one or more additional therapeutic agents, including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressive agents, anti-cancer agents, antiviral agents, anti-inflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproliferative compounds.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant which may be administered to a patient with the compounds of the present invention and which does not destroy pharmaceutical activity and which is non-toxic at dosages sufficient to deliver a therapeutic amount for administration.pharmaceutically acceptable carriers, adjuvants and excipients may be used in the pharmaceutical compositions of the present invention, including but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Self Emulsifying Drug Delivery Systems (SEDDS), such as d-atopHerol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids using surfactants, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, trisilicon, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and polyethylene glycol, and cyclodextrin, such as polyethylene glycol, and other solubilizing agents useful for enhancing the oral administration of pharmaceutical compositions when such as the aqueous suspension of the pharmaceutical active ingredient in aqueous, or aqueous suspension formulations, including but not limited to the aqueous, such as the aqueous, colloidal silica, or saline-modified, and/or saline-soluble, and/or other suspending agents, such as are used in the art known, and/or other pharmaceutical suspensions of the art for oral suspension, including, the pharmaceutical excipients used in the art of the pharmaceutical formulations described herein, the art of the use of the pharmaceutical formulations of the pharmaceutical excipients, including, the pharmaceutical excipients, the use of the pharmaceutical excipients, including, the pharmaceutical suspensions of which are used for the pharmaceutical excipients, the art of the pharmaceutical excipients, the pharmaceutical suspensions of which may be used in the pharmaceutical excipients, including, the pharmaceutical excipients, the pharmaceutical suspensions may be used in the aqueous, the pharmaceutical suspensions of which are used in the present invention, and the pharmaceutical suspensions may be used.

Combination drug

The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.

The foregoing is a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various improvements and modifications can be made to the embodiment of the present invention without departing from the principle of the present invention, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims

1. A compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, of the formula (I):

wherein,

L₁is composed ofR⁴And/or R⁵Is H, C₁-C₃A linear alkyl group;

L₂is composed ofR⁷And/or R⁸Is H, C₁-C₃A linear alkyl group;

R³is a) a hydrogen, hydroxy, cyano,

b)C₁-C₅a linear or branched alkyl group,

c)C₃-C₇a cycloalkyl group,

e)C₁-C₅a straight-chain or branched alkylthio group,

f) a 5-to 7-membered heterocyclic ring,

g) substituted or unsubstituted five-membered aryl or heteroaryl,

h) substituted or unsubstituted six-membered aryl or heteroaryl,

i) a six-membered aromatic ring or a five-membered or six-membered ring containing 0 to 3 heteroatoms, or a five-membered aromatic heterocyclic ring and a five-membered or six-membered ring containing 1 to 3 heteroatoms, such as:

R⁶is a) H, a hydroxyl group,

b) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

c)C₁-C₅a linear or branched alkyl group,

d)C₃-C₈a cycloalkyl group,

f)C₁-C₅a straight-chain or branched alkylthio group,

g) a heterocyclic group.

2. The compound according to claim 1, wherein the 5-7 membered heterocyclic ring contains 1-2 heteroatoms selected from O and/or N and/or S, and when the heteroatom is N, H or C is attached to N₁-C₄Alkyl radical, C₁-C₃Acyl, preferably acetyl, trifluoroacetyl, propionyl, N-diformyl; when the heteroatom is S, 0-2 oxygen atoms are attached to S.

3. The compound of claim 1, or an isomer, solvate or pharmaceutically acceptable salt thereof, wherein the substituted five-membered aryl or heteroaryl has the structural formulaWherein:

J₁and/or J₂And/or J₃And/or J₄In the order of C, N, S, O, is,

R⁹is C₁-C₃Straight or branched chain alkyl.

4. The compound according to claim 1, wherein the substituted or unsubstituted five-membered aryl or heteroaryl has the structural formulaWherein:

J₁、J₂、J₃、J₄each independently C, N,S、O，

R²⁰、R²¹Each independently is C₁-C₃Straight or branched chain alkyl.

5. The compound of claim 1, wherein the substituted or unsubstituted six-membered aryl or heteroaryl has the structural formulaWherein:

Q₁、Q₂、Q₃、Q₄、Q₅is N or C;

R¹⁰and/or R¹¹And/or R¹²Comprises the following steps:

a)-F、-Cl、-Br、-CF₃、-OCF₃a cyano group,

b) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

c)C₁-C₃alkyl radical, C₂-C₅Alkynyl, C₃-C₅A cycloalkyl group,

d)SO₂R¹³wherein R is¹³Is H, C₁-C₃An alkyl group, a carboxyl group,

e)wherein q is 0-2, M is O, S, R¹⁴Is H, C₁-C₅A linear or branched alkyl group,

f)wherein R is¹⁵、R¹⁶Is straight chain alkyl.

6. A compound according to claim 1, or an isomer, solvate or pharmaceutically acceptable salt thereof, wherein the structure of the substituted or unsubstituted six-membered aryl or heteroaryl groupIs of the formulaWherein:

Q₁、Q₂、Q₃、Q₄、Q₅is N or C;

R¹⁷、R¹⁸each independently is:

a)-H，

b)-F、-Cl、-Br、-CF₃、-OCF₃a cyano group,

c) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

e)SO₂R¹³wherein R is¹³Is H, C₁-C₃An alkyl group, a carboxyl group,

g)wherein R is¹⁵、R¹⁶Is C₁-C₃The linear alkyl group of (a),

h)-(CH₂)_t-R¹⁹t is 1-2, R¹⁹Is C₃-C₅A cycloalkyl group.

7. The compound according to claim 1, wherein the heterocyclic group is a five-or six-membered oxygen-and/or nitrogen-containing heterocyclic group such as:

8. a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, of the formula (I):

wherein,

L₁is composed ofR⁴And/or R⁵Is H, C₁-C₃A linear alkyl group;

L₂is composed ofR⁷And/or R⁸Is H, C₁-C₃A linear alkyl group;

R⁶is a) H, a hydroxyl group,

b) -NR 'R ", R', R" being H, C₁-C₃The alkyl group of (a) is,

c)C₁-C₅a linear or branched alkyl group,

d)C₃-C₈a cycloalkyl group,

f)C₁-C₅a straight-chain or branched alkylthio group, or

9. A compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, selected from the group consisting of:

4-benzylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-dimethylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-dichlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ [ 4-amino-2-fluorobenzyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4-n-butylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- (n-pentylamino) pyrimidine-5-carboxamide;

4-isobutylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4-neopentylaminopyrimidine-5-carboxamide;

4- (isopentylamino) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3, 3-dimethylbutyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (4-methylpentyl) amino) pyrimidine-5-carboxamide;

4- [ (cyclopropylmethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (cyclobutylmethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (cyclopentylmethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (cyclohexylmethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-cyclopropylethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-cyclopentylethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (4-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (4-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3-methylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-methylbenzyl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-ethylbenzyl) amino ] pyrimidine-5-carboxamide;

4- [ (2-cyclopropylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-trifluoromethylbenzyl) amino ] pyrimidine-5-carboxamide;

4- [ (2-cyanobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-ethoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-isopropoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-trifluoromethoxybenzyl) amino ] pyrimidine-5-carboxamide;

4- [ [2- (methoxymethyl) benzyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 3-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-3-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 3-dichlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-3-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-3-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 3-dimethylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 4-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-4-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-4-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-4-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-4-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxy-4-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 5-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-5-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-5-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-5-fluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-5-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ [2- (trifluoromethyl) -5-fluorobenzyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxy-5-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 5-dimethoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6- (trifluoromethyl) benzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methyl-6-chlorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-dimethoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3, 5-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (3, 5-dimethoxybenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2,3, 6-trifluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2,3, 5-trifluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluoro-3-methylbenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-3, 6-difluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2,4, 6-trifluorobenzyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- (phenethylamino) pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (3-methylphenylethyl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (3-methoxyphenethyl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluorophenethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methylphenylethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxyphenylethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-chlorophenethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (pyridin-4-ylmethyl) amino ] pyrimidine-5-carboxamide;

4- [ [ (2-fluoropyridin-3-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ [ (2-methoxypyridin-3-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ [ (2-ethoxypyridin-3-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ [ (2-tert-butoxypyridin-3-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ [2- (pyridin-3-yl) ethyl ] amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ [ (2, 3-dihydrobenzo [ b ] [1,4] dioxan-5-yl) methyl ] amino ] pyrimidine-5-carboxamide;

2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ [ (1H-indol-3-yl) methyl ] amino ] pyrimidine-5-carboxamide;

(S) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-phenylpropyl) amino ] pyrimidine-5-carboxamide;

(R) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ (2-phenylpropyl) amino ] pyrimidine-5-carboxamide;

4-benzylamino-2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

2- [ (1H-pyrazol-4-yl) amino ] -4- [ (2, 6-difluorobenzyl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ (1-ethyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ (1-isopropyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ (1-cyclopropyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ (1-cyclobutyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- ((tetrahydrofuran-2-yl) methyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- ((tetrahydrofuran-3-yl) methyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-methylthioethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2- (morpholin-1-yl) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluorobenzyl) amino ] -2- [ [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-chlorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-chlorobenzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-chlorobenzyl) amino ] -2- [ [1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

2- [ (1H-pyrazol-4-yl) amino ] -4- [ (2-fluoro-6-methoxybenzyl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-ethyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-isopropyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-cyclopropyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-cyclobutyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-cyclopentyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-cyclohexyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ (1-cycloheptyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-methylthioethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- { [1- (1-methylpiperazin-4-yl) -1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2- (pyrrol-1-yl) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2- (piperidin-1-yl) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2- (morpholin-1-yl) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (6-methoxyhexyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6-methoxybenzyl) amino ] -2- [ [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ [ 2-fluoro-6- (trifluoromethyl) benzyl ] amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6- (trifluoromethyl) benzyl) amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-fluoro-6- (trifluoromethyl) benzyl) amino ] -2- [ [1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxybenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-methoxy-5-chlorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-dimethylbenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-6-methylbenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-dichlorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2,3, 6-trifluorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2, 6-difluoro-3-methylbenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ (2-chloro-3, 6-difluorobenzyl) amino ] -2- [ [1- (2-hydroxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide;

4- [ [ 2-fluoro-3-methoxybenzyl ] amino ] -2- [ [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] amino ] pyrimidine-5-carboxamide.

10. A compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, selected from the group consisting of:

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- (isopentylamino) pyrimidine-5-carboxamide;

4- (isopentylamino) -2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2- (2-hydroxyethoxy) ethyl) amino) pyrimidine-5-carboxamide;

4- ((2- (2-hydroxyethoxy) ethyl) amino) -2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-ethyl-1H-pyrazol-4-yl) amino) -4- ((2-ethylbenzyl) amino) pyrimidine-5-carboxamide;

4- ((2-ethylbenzyl) amino) -2- ((1-propyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-ethylbenzyl) amino) -2- ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-cyclopropyl-1H-pyrazol-4-yl) amino) -4- ((2-ethylbenzyl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-ethylbenzyl) amino) pyrimidine-5-carboxamide;

4- ((2-ethylbenzyl) amino) -2- ((1- (tetrahydro-2H-pyran-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-methyl-1H-pyrazol-4-yl) amino) -4- ((2-propylbenzyl) amino) pyrimidine-5-carboxamide;

4- ((2-isopropylbenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2- (cyclopropylmethyl) benzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-methoxybenzyl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2, 6-difluorobenzyl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-propyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-cyclopropyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-fluorobenzyl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-cyclobutyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-cyclopentyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1-cyclohexyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-chloro-6-fluorobenzyl) amino) -2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-bromo-6-fluorobenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-bromo-6-fluorobenzyl) amino) -2- ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-fluoro-6-methylbenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-fluoro-6-methylbenzyl) amino) -2- ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-ethyl-1H-pyrazol-4-yl) amino) -4- ((2-fluoro-6- (trifluoromethyl) benzyl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-fluoro-6- (trifluoromethyl) benzyl) amino) pyrimidine-5-carboxamide;

4- ((2-ethyl-6-fluorobenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-ethyl-1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-fluorobenzyl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-fluorobenzyl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2-fluoro-6-methoxybenzyl) amino) pyrimidine-5-carboxamide;

4- ((2, 6-dimethylbenzyl) amino) -2- ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2, 6-dimethylbenzyl) amino) -2- ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethylbenzyl) amino) pyrimidine-5-carboxamide;

4- ((2, 6-dimethylbenzyl) amino) -2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

4- ((2-ethynylbenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide;

2- ((1-methyl-1H-pyrazol-4-yl) amino) -4- ((2-vinylbenzyl) amino) pyrimidine-5-carboxamide;

2- ((1-methyl-1H-pyrazol-4-yl) amino) -4- ((2- (propyl-1-en-1-yl) benzyl) amino) pyrimidine-5-carboxamide;

4- ((2-allylbenzyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide.

11. The compound according to any one of claims 1 to 10, or an isomer, solvate or pharmaceutically acceptable salt thereof, wherein the salt comprises: malate, hydrochloride, sulfate, methanesulfonate, formate, acetate, citrate, tartrate, fumarate, gluconate, oxalate.

12. A pharmaceutical composition for the treatment of diseases associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2 consisting of a compound of formula (I) as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof or a prodrug thereof and a pharmaceutically acceptable carrier or excipient.

13. A pharmaceutical composition comprising: comprising as active ingredient a compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, one or more further therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.

14. The use of a compound of formula (I) according to any one of claims 1-10 or a pharmaceutically acceptable salt or prodrug thereof in a medicament for the treatment of autoimmune diseases and cancer associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2, wherein the diseases include: fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.